Immunoglobulin Fusion Proteins And Compositions Thereof

Abstract

Disclosed herein are immunoglobulin fusion proteins that have a first antibody region attached to an extender fusion region. The extender fusion region contains a therapeutic agent and a beta strand secondary structure. The extender fusion region may contain 7 or fewer consecutive amino acids based on or derived from an ultralong CDR3. Alternatively, the extender fusion region contains a rigid stalk protein structure, but does not contain an amino acid sequence based on or derived from an ultralong CDR3. The extender fusion region may also have one or more linkers or proteolytic cleavage sites. The immunoglobulin fusion proteins may have additional therapeutic agents and extender fusion regions. Also disclosed herein are pharmaceutical compositions of immunoglobulin fusion proteins and methods for using the immunoglobulin fusion proteins for the treatment or prevention of a disease or condition in a subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a U.S. National Stage entry of International Application No. PCT/US2014/046429, filed Jul. 11, 2014; which claims the benefit of U.S. Provisional Application No. 61/845,287 filed Jul. 11, 2013; U.S. Provisional Application No. 61/845,280 filed Jul. 11, 2013; U.S. Provisional Application No. 61/925,904 filed Jan. 10, 2014; and U.S. Provisional Application No. 62/017,713 filed Jun. 26, 2014, all of which are incorporated by reference herein in their entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 6, 2016, is named 41135-707-831-SEQUENCE.txt and is 587,784 bytes in size.

BACKGROUND OF THE INVENTION

[0003] Antibodies are natural proteins that the vertebrate immune system forms in response to foreign substances (antigens), primarily for defense against infection. For over a century, antibodies have been induced in animals under artificial conditions and harvested for use in therapy or diagnosis of disease conditions, or for biological research. Each individual antibody producing cell produces a single type of antibody with a chemically defined composition. However, antibodies obtained directly from animal serum in response to antigen inoculation actually comprise an ensemble of non-identical molecules (e.g., polyclonal antibodies) made from an ensemble of individual antibody producing cells.

[0004] Antibody fusion constructs can be used to improve the delivery of drugs or other agents to target cells, tissues and tumors. Antibody fusion constructs may comprise a chemical linker to attach a drug or other agent to an antibody. Exemplary antibody fusion constructs and methods of producing antibody fusion constructs are disclosed in US patent application numbers 20060182751, 20070160617 and U.S. Pat. No. 7,736,652.

[0005] Disclosed herein are novel immunoglobulin fusion proteins and methods of producing such immunoglobulin fusion proteins. Further disclosed herein are uses of the immunoglobulin fusion proteins for the treatment of various diseases and conditions. Methods of extending the half-life of a therapeutic agent are also disclosed herein.

SUMMARY OF THE INVENTION

[0006] Disclosed herein are immunoglobulin fusion proteins comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a first beta strand secondary structure region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248. The first extender fusion region may not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain selected from a BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and an F18 ultralong complementary determining region 3 heavy chain. The first extender fusion region may not contain more than 7 consecutive amino acids that are based on or derived from a bovine ultralong CDR3. The first extender fusion region may not comprise an amino acid sequence that is based on or derived from a bovine ultralong CDR3. The first antibody region may be a human antibody or human antibody fragment and wherein the first beta strand secondary structure is based on or derived from a human beta strand secondary structure. The first antibody region may be based on or derived from a monoclonal antibody. The first antibody region may be based on or derived from an antibody designed to selectively interact with a target selected from a cancer cell and a virus. The first antibody region may be based on or derived from an anti-Her2 antibody, trastuzumab, an anti-CD47 antibody and palivizumab. The first extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The first extender fusion region may further comprise a second extender peptide, wherein the second extender peptide comprises a second beta strand secondary structure and wherein the first beta strand secondary structure and the second beta strand secondary structure form a beta sheet. The first extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-114 and 305. The second extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 115-128 and 308. The first extender peptide may comprise an amino acid sequence of ETKKYQXnS (SEQ ID NO: 110). The first extender peptide may comprise an amino acid sequence of ETKKYQXnS (SEQ ID NO: 305), wherein n is equal to a number selected from 1-8. The immunoglobulin fusion proteins disclosed herein may further comprise a second extender peptide, wherein the second extender peptide comprises an amino acid sequence of SX.sub.1TX.sub.2NX.sub.3 (SEQ ID NO: 306). X.sub.1, X.sub.2 and X.sub.3 may be independently selected from a polar amino acid. The polar amino acid may be Y. The immunoglobulin fusion proteins may further comprise a second extender peptide, wherein the second extender peptide comprises an amino acid sequence of YX.sub.1YX.sub.2Y (SEQ ID NO: 128). The first extender fusion region may comprise one or more linkers selected from SEQ ID NOs:161-166 and 309. The immunoglobulin fusion proteins may have the Formula II: A.sup.1-E.sup.1-T.sup.1-E.sup.2 or Formula IIA:

##STR00001##

wherein A1 is the first antibody region; E1 is the first extender peptide, E2 is a second extender peptide; and T1 is the first therapeutic agent. The fusion protein may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion proteins may comprise an amino acid sequence that is at least about 50% identical to an amino acid sequence of any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion proteins may further comprise a second antibody region based on or derived from an antibody or fragment thereof. The immunoglobulin fusion proteins may further comprise a second extender fusion region. The immunoglobulin fusion protein may further comprise a second therapeutic agent. The immunoglobulin fusion proteins may have the Formula III: (A.sup.1-E.sup.1-T.sup.1-E.sup.2)-(A.sup.2-E.sup.3-T.sup.2-E.sup.4) or Formula IIIA

##STR00002##

wherein: A.sup.1 is the first antibody region; E.sup.1 is the first extender peptide; T.sup.1 is the first therapeutic agent; A.sup.2 is a second antibody region; E.sup.2, E.sup.3, E.sup.4 are extender peptides; and T.sup.2 is a second therapeutic agent. The first therapeutic agent may be based on or derived from a biomolecule selected from a peptide and a protein. The protein or peptide may be selected from a growth factor, a cytokine, a chemokine, a hormone and a toxin. The peptide or protein may not be naturally occurring. The first therapeutic agent may be based on or derived from a cyclic peptide. The first therapeutic agent may be a conformationally constrained peptide. The first therapeutic agent may be selected from an agonist, an antagonist, a ligand and a substrate. The first therapeutic agent may be selected from bGCSF, hGCSF, bGMCSF, hGMCSF, GDF11, interferon-beta or interferon-alpha, interleukin 11 (IL-11), exendin-4, GLP-1, relaxin, oxyntomodulin, leptin, betatrophin, bovine growth hormone (bGH), human growth hormone (hGH), parathyroid hormone, erythropoietin, Moka1, VM-24, Mamba1, angiopoeitin-like 3 (ANGPTL3), a homolog thereof and a derivative thereof. The first therapeutic agent may interact with a target selected from CXCR4 and a neutrophil elastase inhibitor. The first therapeutic agent may be based on or derived from an amino acid sequence selected from any one of SEQ ID NOs: 263-298 or encoded by a nucleic acid sequence based on or derived from any one of SEQ ID NOs: 227-262. The first therapeutic agent may be based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 263-298 or encoded by a nucleic acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 227-262. The extender fusion region may further comprise one or more proteolytic cleavage sites. The one or more proteolytic cleavage sites may be at the N-terminus, C-terminus, or N- and C-termini of a therapeutic agent. The one or more proteolytic cleavage sites may be within a therapeutic agent. The one or more proteolytic cleavage sites may comprise a Factor Xa cleavage site. The one or more proteolytic cleavage sites may be in one or more extender peptides. The one or more proteolytic cleavage sites may be in the antibody region.

[0007] Further disclosed herein are polynucleotides comprising a nucleic acid sequence encoding an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248.

[0008] Disclosed herein are vectors comprising a polynucleotide comprising a nucleic acid sequence encoding an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248.

[0009] Further disclosed herein are host cells comprising a polynucleotide comprising a nucleic acid sequence encoding an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248.

[0010] Disclosed herein are methods of producing an immunoglobulin fusion protein, the method comprising culturing a host cell comprising a polynucleotide comprising a nucleic acid sequence encoding an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248 under conditions wherein the polynucleotide sequence is expressed, thereby producing an immunoglobulin fusion protein.

[0011] Further disclosed herein are pharmaceutical compositions comprising an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248. The pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.

[0012] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended figures. For the purpose of illustrating the disclosure, shown in the figures are embodiments which are presently preferred. It should be understood, however, that the disclosure is not limited to the precise arrangements, examples and instrumentalities shown. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures.

[0014] In some figures, trastuzumab is referred to as Herceptin. It is to be understood that trastuzumab and Herceptin may be used interchangeably throughout this disclosure. In some figures, an immunoglobulin fusion protein is described in the following order: antibody, secondary structure (e.g. beta strand), therapeutic agent, and antibody region to which the therapeutic agent is attached; for example, trastuzumab-beta hEPO (CDRH3). Wherein the secondary structure is a beta sheet or a coiled coil, the secondary structure may simply be referred to as beta or coil, respectively. The immunoglobulin fusion protein comprising a secondary structure may additionally comprise a linker, although the presence of the linker may not be indicated in the description or name of the immunoglobulin fusion protein. The immunoglobulin fusion protein may be described in any other manner, for example, trastuzumab-CDRH3-direct-hEPO is the same fusion as trastuzumab-direct hEPO (CDRH3), wherein direct may be indicative of the absence of a secondary structure and/or the presence of a linker. In some instances, an antibody is abbreviated in the figures, for example, bAb or BLVH12 are abbreviations for bovine antibody. PBS is an abbreviation of phosphate buffered saline. In some instances, hAb is an abbreviation for Herceptin or trastuzumab antibody. In some instances, H2 is an abbreviation of CDRH2, H3 is an abbreviation of CDRH3, and L3 is an abbreviation of CDRL3. In some instances, CDRH3 and CDR3H indicate a complementary determining region 3 of a heavy chain, CDRH2 and CDR2H indicate a complementary determining region 3 of a heavy chain, and CDRL3 and CDR3L indicate a complementary determining region 3 of a light chain.

[0015] FIG. 1 depicts an exemplary schematic of various immunoglobulin fusion proteins with an extender peptide comprising a beta strand structure.

[0016] FIG. 2 depicts an exemplary schematic of various immunoglobulin fusion proteins with extender peptides.

[0017] FIGS. 3A-3G depict exemplary schematics of various non-antibody regions.

[0018] FIG. 4 depicts an exemplary schematic of various extender peptides. FIG. 4 discloses SEQ ID NOS 119, 111, 120, 111, 121, 111, 122, 111, 123, 111, 124, 111, 119, 111, 125, 112, 126, 113, 127 and 114, respectively, in order of appearance.

[0019] FIG. 5 depicts an SDS-PAGE of an immunoglobulin-beta-strand bovine granulocyte colony-stimulating factor (bGCSF) based fusion protein.

[0020] FIG. 6 depicts a graph of the in vitro proliferative activity of immunoglobulin-beta-strand bovine granulocyte colony-stimulating factor (bGCSF) based fusion proteins in mouse NFS-60 cells.

[0021] FIG. 7 depicts a graph of the binding affinity of a trastuzumab-beta-strand bovine granulocyte colony-stimulating factor (bGCSF) based fusion protein to a Her2 receptor.

[0022] FIG. 8 depicts an SDS-PAGE of an trastuzumab-beta-strand-Exendin-4 based fusion protein.

[0023] FIG. 9 depicts in vitro activities of trastuzumab-beta strand-Exendin-4 L1 IgGs.

[0024] FIG. 10 depicts an SDS-PAGE gel of trastuzumab-beta strand-Mokatoxin-1 (Moka1) L1 IgG (1) and trastuzumab-beta strand-Vm24 L1 IgG (2).

[0025] FIG. 11 depicts in vitro activity of trastuzumab-beta-Moka1 and trastuzumab-beta-Vm24 IgGs, specifically in vitro inhibition of T-cell activation.

[0026] FIG. 12 depicts an SDS-PAGE gel of trastuzumab-CDR3H-beta strand-human erythropoietin (hEPO) IgG.

[0027] FIG. 13 depicts ESI-MS of the heavy chain of trastuzumab-CDR3H-beta-hEPO fusion protein treated with Peptide-N-Glycosidase and DTT (Exp: 68789 Da; Obs: 68669 Da (matching the mass of the heavy chain of trastuzumab-CDR3H-beta-hEPO without Glu1) and 69614 Da (due to O-glycosylation on hEPO)).

[0028] FIG. 14 depicts in vitro activity of trastuzumab-CDR3H-beta-hEPO IgG on proliferation of TF-1 cells.

[0029] FIG. 15 depicts an SDS-PAGE gel of trastuzumab (CDRH3)-beta human growth hormone fusion protein.

[0030] FIG. 16 depicts an SDS-PAGE gel of trastuzumab (CDRH2)-beta human growth hormone fusion protein.

[0031] FIG. 17 depicts an exemplary schematic representation of engineering Moka1 toxin or Vm24 toxin into an ultralong CDR3H.

[0032] FIG. 18 depicts an SDS-PAGE gel of a BLV1H12-CDR3H-beta Moka1 IgG with (L1) or without (L0) a GGGGS linker (SEQ ID NO: 164).

[0033] FIG. 19 depicts BLV1H12-CDR3H-beta Moka1 IgG inhibits human peripheral blood mononuclear cells (PBMCs) activation.

[0034] FIG. 20 depicts BLV1H12-CDR3H-beta Moka1 IgG inhibits human T-cell activation.

[0035] FIG. 21 depicts an SDS-PAGE gel of a BLV1H12-CDR3H-beta VM24 IgG with one linker (L1) or two (L2) GGGGS linkers (SEQ ID NO: 164). FIG. 21 discloses `GGGSGGGGS` as SEQ ID NO: 165.

[0036] FIG. 22 depicts BLV1H12-CDR3H-beta VM24 IgG inhibits human T-cell activation.

[0037] FIG. 23 depicts an exemplary schematic representation of engineering human erythropoietin (hEPO) into an ultralong CDR3H.

[0038] FIG. 24 depicts an SDS-PAGE gel of BLV1H12-CDRH3-beta hEPO fusion protein.

[0039] FIG. 25 depicts in vitro activities of BLV1H12-CDRH3-beta hEPO fusion protein.

[0040] FIG. 26 depicts pharmacokinetics of BLV1H12-CDRH3-beta hEPO and trastuzumab-CDRH3-beta hEPO fusion proteins in mice.

[0041] FIG. 27 depicts pharmacodynamics of BLV1H12-CDRH3-beta hEPO and trastuzumab-CDRH3-beta hEPO fusion proteins in mice.

[0042] FIG. 28 depicts an exemplary schematic representation of engineering glucagon-like peptide 1 (GLP-1) or Exendin-4 (Ex-4) into an ultralong CDR3H.

[0043] FIG. 29 depicts an SDS-PAGE gel of BLV1H12-CDRH3-beta GLP-1 and BLV1H12-CDRH3-beta Ex-4 with and without protease treatment.

[0044] FIG. 30 depicts in vitro activities of BLV1H12-CDRH3-beta GLP1/Ex-4 Clip fusion proteins on activating GLP1 receptor (GLP1R).

[0045] FIGS. 31 A-B depict plasma stabilities of BLV1H12-CDRH3-beta Ex-4 RN fusion proteins. Percentages of Ab-Ex-4 RN were determined on the basis of activities measured at time 0 through in vitro assay using HEK293 cells with GLP-1 receptor-CRE (cAMP response element)-Luc.

[0046] FIG. 32 depicts pharmacokinetics of BLV1H12-CDRH3-beta Ex-4 RN fusion protein in mice. Amount of Ex-4 and Ab-Ex-4 RN in mice plasma were determined through in vitro activity assay using HEK293 cells with GLP-1 receptor-CRE (cAMP response element)-Luc. Plasma concentrations at first time point (30 min) were taken as the maxima.

[0047] FIGS. 33A-B depict BLV1H12-CDRH3-beta Ex-4 RN fusion protein reduces blood glucose levels (30 min) in mice by oral glucose tolerance test in CD1 mice (3 g/kg), I.V. injection (200 ul/injection); N=5; Ex-4: 0.5 ug; Ab-Ex-4 RN: 100 ug.

[0048] FIGS. 34 A-B depict BLV1H12-CDRH3-beta Ex-4 RN fusion protein provides extended control of blood glucose levels in mice by oral glucose tolerance test (OGTT) in CD1 mice 24 h post treatment of fusion protein. OGTT in CD1 mice (3 g/kg). S.C. injection (200 ul/injection); N=5; Ab: 100 & 200 ug; Ex-4: 0.5 ug; Ab-Ex-4 RN: 100 & 200 ug. ** p<0.01.

[0049] FIGS. 35 A-B depict BLV1H12-CDRH3-beta Ex-4 RN fusion protein provides extended control of blood glucose levels in mice by oral glucose tolerance test (OGTT) in CD1 mice 48 h post treatment of fusion protein. OGTT in CD1 mice (3 g/kg). S.C. injection (200 ul/injection); N=5; Ab: 100 & 200 ug; Ex-4: 0.5 ug; Ab-Ex-4 RN: 100 & 200 ug.* p<0.05, ** p<0.01.

[0050] FIG. 36 depicts an exemplary scheme for grafting bovine granulocyte colony-stimulating factor (GCSF) onto the `knob` domain of bovine BLV1H12 antibody with ultralong CDR3H region. FIG. 36 discloses `(GGGGS)n` as SEQ ID NO: 164.

[0051] FIGS. 37 A-E depicts proliferative activities of BLV1H12 (Ab)-bovine granulocyte colony-stimulating factor (GCSF) fusion proteins on mouse NFS-60 cells. Ln=(GGGGS)n, n=0 or 1 (SEQ ID NO: 164).

[0052] FIGS. 38 A-E depicts proliferative activities of BLV1H12 (Ab)-bovine granulocyte colony-stimulating factor (GCSF) fusion proteins on human granulocyte progenitors. Ln=(GGGGS)n, n=0 or 1 (SEQ ID NO: 164).

[0053] FIGS. 39 A-B depict pharmacokinetics of BLV1H12-beta-bovine granulocyte colony-stimulating factor (GCSF) fusion proteins in mice. Ln=(GGGGS)n, n=0 or 1 (SEQ ID NO: 164).

[0054] FIGS. 40 A-B depict proliferative activities of BLV1H12 (Ab)-bovine granulocyte colony-stimulating factor (GCSF) fusion proteins on mice neutrophils, blood stained and counted at the 10th day post-injection. N.C.: negative control. Ln=(GGGGS)n, n=0 or 1 (SEQ ID NO: 164).

[0055] FIG. 41A depicts an SDS-PAGE gel of BLV1H12 Fab-CDR3H-beta human growth hormone fusion protein.

[0056] FIG. 41B depicts an SDS-PAGE gel of BLV1H12 hFc(IgG)-CDR3H-beta human growth hormone fusion protein.

[0057] FIGS. 42 A-C depict proliferation of NB2 cells (A), Ba/F3 cells (B) and IM9 STATS (C) by BLV1H12 Fab-CDR3H-beta human growth hormone fusion protein and BLV1H12 hFc(IgG)-CDR3H-beta human growth hormone fusion protein.

[0058] FIG. 43A depicts an SDS-PAGE gel of BLV1H12-CDR3H-beta human leptin fusion protein.

[0059] FIG. 43B depicts leptin receptor activity with the addition of human Leptin or BLV1H12-CDR3H-beta human leptin fusion protein.

[0060] FIGS. 44 A-C depict SDS-PAGE gels of expressed and purified (A) BLV1H12-CDR3H-beta human relaxin clip fusion protein (SEQ ID NOs: 274 and 40), (B) BLV1H12-CDR3H-beta human relaxin clip fusion protein with engineered connector peptide (SEQ ID NOs: 276 and 40), (C) BLV1H12-CDR3H-beta human relaxin clip fusion protein with GGSIEGR linker (SEQ ID NO: 307) (SEQ ID NOs: 275 and 40).

[0061] FIG. 45 depicts (A) crystal structure of CXCR4 (green) in complex with a .beta.-hairpin peptide antagonist CVX15 (yellow) (PDB code 3OE0), (B) crystal structure of bovine antibody BLV1H12 (PDB code 4K3D) depicts a disulfide cross-linked "knob" domain (red) grafted onto a solvent-exposed .beta.-strand "stalk" (yellow), (C) a cartoon representation of the anti-CXCR4 antibody design. The loop region of the .beta.-hairpin that resides outside the binding pocket of CXCR4 (blue) is removed and the anti-parallel .beta.-strand region (green) is reconnected by selected .beta.-turns to generate an inverted .beta.-hairpin that is fused to the knob domain truncated bovine antibody scaffold. (D) A schematic representation of CVX15 and the engineered CDRs with .beta.-turn promoting residues highlighted in bold. Potential interactions of bAb-AC1 with the CXCR4 ligand-binding pocket (blue box) are depicted on the basis of an analysis of the CXCR4-CVX15 complex. FIG. 45 discloses `Tyr-Arg-Lys-Cys-Arg-Gly-Gly-Arg-Arg-Trp-Cys-Tyr-Gln-Lys` as SEQ ID NO: 231.

[0062] FIG. 46 depicts SDS-PAGE gel of purified BLV1H12-beta BCCX2 HC 1 (bAb-AC1) (SEQ ID NOs: 92 and 40) and BLV1H12-beta BCCX2 HC 4 (bAb-AC4) (SEQ ID NOs: 95 and 40) with or without the addition of reducing reagent DTT.

[0063] FIG. 47 depicts SDS-PAGE gel of purified trastuzumab-beta BCCX2 HC long (HLCX) (SEQ ID NOs: 96 and 40), trastuzumab-beta BCCX2 HC medium HMCX (SEQ ID NOs: 97 and 40), trastuzumab-beta BCCX2 HC short (HSCX) (SEQ ID NOs: 98 and 40), with or without reducing reagent DTT.

[0064] FIG. 48 depicts flow cytometry analysis of interactions between CXCR4 and engineered antibodies.

[0065] FIG. 49 depicts SDF-1 binds to CXCR4 with a K.sub.d value of 14.2.+-.1.2 nM determined by Tag-lite HTRF binding assay. Tag-lite labeled CXCR4 cells were incubated with increasing concentrations of the fluorescent SDF-1 for 3 h at room temperature. The signal was recorded by an EnVision multi-label plate reader (PerkinElmer) at 620 nm and 665 nm with 340 nm excitation.

[0066] FIG. 50A depicts specific binding between BLV1H12-beta BCCX2 HC 1, BLV1H12-beta BCCX2 HC 2, BLV1H12-beta BCCX2 HC3 and CXCR4 determined by a Tag-lite HTRF binding assay.

[0067] FIG. 51 depicts competition between BLV1H12-beta BCCX2 IgG fusions and 12G5 (66.6 nM) for binding to Jurkat cells in a dose dependent manner with an IC.sub.50 value of 39.3 nM.

[0068] FIG. 52 depicts flow cytometry analysis of bAb-AC4 (1 .mu.g/mL) binding to (A) Jurkat cells and (B) CHO cells. Cells were first blocked with blocking buffer (PBS supplemented with 3% BSA) at 4.degree. C. for 10 min and then incubated with various concentrations of antibodies in blocking buffer for 1 h. Cells were then washed with PBS and incubated with Alexa Fluor 647 conjugated goat anti-human IgG (0.5 .mu.g/ml) in blocking buffer. After incubation, cells were washed and analyzed by flow cytometry. (C) bAb-AC4 (200 nM) completely blocks the binding between 12G5 (66 nM) and Jurkat cells. Jurkat cells were pre-incubated with 200 nM bAb-AC4 in blocking buffer at 4.degree. C. for 30 min. Fluorescein conjugated 12G5 was added in blocking buffer to a final concentration of 10 .mu.g/mL for an additional 30 min Cells were then washed with PBS and analyzed by a flow cytometer.

[0069] FIG. 53 depicts specific bindings between bAb-AC4 and CXCR4 receptor determined by Tag-lite HTRF binding assay with a K.sub.i value of 0.9 nM. Tag-lite labeled CXCR4 cells were incubated with increasing concentrations of bAb-AC4 in the presence of 50 nM fluorescent ligand for 3 h at room temperature. The signal was recorded by an EnVision multi-label plate reader (PerkinElmer) at 620 nm and 665 nm with 340 nm excitation.

[0070] FIG. 54 depicts a cartoon representation of the migration assay. CXCR4 expressing cells migrate from top well of the transwell plate through a fibronectin layer to the bottom chamber filled with 10 ng/ml SDF-1.

[0071] FIGS. 55 A-C depict (A) 300 nM of bAb-AC4 efficiently blocks SDF-1 induced CXCR4 activation measured by intracellular calcium flux. (B) The antibodies bAb-AC1 and bAb-AC4 potently inhibit SDF-1 induced migration of Ramos cells in a dose dependent manner with EC50 values of 8.5 nM and 3.2 nM, respectively. At saturating concentration, they are able to completely inhibit SDF-1 induced chemotaxis. (C) Bottom chamber images of SDF-1 induced Ramos cell migration after treatment with no antibody, 12G5, or bAb-AC4 at 300 nM, respectively.

[0072] FIG. 56 depicts pretreatment with 300 nM antibodies significantly reduced (bAb-AC1) or completely blocked (bAb-AC4) SDF-1 induced calcium flux in Ramos cells. Fluo-4 loaded Ramos cells were washed with HBSS/HEPES twice and re-suspended in assay buffer (HBSS with 30 mM HEPES and 2.5 mM probenecid) at a density of 10.sup.6 cells/ml. Antibodies were added and incubated with loaded cells for 1 h and calcium flux signals were recorded on a fluorescence laser-imaging plate reader immediately upon addition of SDF-1 at a final concentration of 50 nM.

[0073] FIG. 57 depicts flow cytometry analysis of Jurkat cell binding by trastuzumab-beta BCCX2 HC long (HLCX) (SEQ ID NOs: 96 and 40), trastuzumab-beta BCCX2 HC medium HMCX (SEQ ID NOs: 97 and 40), trastuzumab-beta BCCX2 HC short (HSCX) (SEQ ID NOs: 98 and 40), at 0.1 ug/ml.

[0074] FIG. 58 depicts inhibition of SDF-1 induced Ramos cell migration by HLCX, HMCX, HSCX.

[0075] FIG. 59 A depicts CXCR4 receptor binding with anti-CXCR4 bAb fusion proteins.

[0076] FIG. 59 B depicts CXCR4 receptor binding with anti-CXCR4 hAb fusion proteins.

[0077] FIG. 60 A depicts an SDS-PAGE gel of BLV1H12 Fab-CDRH3-beta-bovine trypsin inhibitor (BTI) fusion protein after purification.

[0078] FIG. 60 B depicts BLV1H12 Fab-CDRH3-beta-bovine trypsin inhibitor (BTI) fusion protein potently inhibits trypsin enzymatic activity.

[0079] FIG. 60 C depicts kinetic characterization of BTI fusion protein-trypsin interaction by biolayer interferometry experiment, blue curves represent experimental data and red curves represent the statistical fitting of curves.

[0080] FIG. 61 depicts an SDS-PAGE gel of human BVK antibody Fab-CDRH3-beta-elastase (BEI) fusion protein.

[0081] FIG. 62 depicts rationally designed anti-Neutrophil Elastase (NE) antibody fusion proteins BEI1 and BEI2 potently inhibit human neutrophil elastase activity with low nanomolar inhibition constants (18.7 nM and 18.2 nM respectively)

[0082] FIG. 63 depicts SDS-PAGE gels of human BVK CDRH3 beta neutrophil elastase inhibitor (HEI) fusion proteins.

[0083] FIG. 64 depicts HEI fusion proteins inhibit elastase proteolytic activity in vitro. HEI fusion proteins include, Human BVK-beta HEI HC 4 (SEQ ID NOs: 103 and 102), Human BVK-beta HEI HC 5 (SEQ ID NOs: 104 and 102), Human BVK-beta HEI HC 6 (SEQ ID NOs: 105 and 102), Human BVK-beta HEI HC 7 (SEQ ID NOs: 106 and 102), Human BVK-beta HEI HC 8 (SEQ ID NOs: 107 and 102), and Human BVK-beta HEI HC 9 (SEQ ID NOs: 108 and 102).

[0084] FIGS. 65 A-B depict selectivity of HEI fusion proteins. None of the HEI fusion proteins have any effect on the activity of trypsin (A) or chymotryspin (B).

[0085] FIGS. 66 A-B depict in vitro proliferative activities of trastuzumab fusion antibody containing a CDR3H beta sheet human erythropoietin (H3-beta/hEPO) extender fusion region and a CDR3L coiled coil human granulocyte colony stimulating factor (L3-coil/hGCSF) extender fusion region.

DETAILED DESCRIPTION OF THE INVENTION

[0086] Disclosed herein are immunoglobulin fusion proteins comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a first beta strand secondary structure region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248. The first extender fusion region may not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain selected from a BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and an F18 ultralong complementary determining region 3 heavy chain. The first extender fusion region may not contain more than 7 consecutive amino acids that are based on or derived from a bovine ultralong CDR3.

[0087] Disclosed herein are immunoglobulin fusion proteins and methods of producing such immunoglobulin fusion proteins. The immunoglobulin fusion protein may comprise (a) a non-antibody region; and (b) a first antibody region comprising 6 or fewer consecutive amino acids of a complementarity determining region 3 (CDR3).

[0088] Further disclosed herein are immunoglobulin fusion proteins comprising (a) a non-antibody region; and (b) an antibody region, wherein the antibody region comprises an antibody sequence comprising 6 or fewer consecutive amino acids of a complementarity determining region (CDR). The CDR may be a CDR1. The CDR may be a CDR2. The CDR may be a CDR3.

[0089] Further disclosed herein are immunoglobulin fusion proteins comprising (a) a non-antibody region; and (b) an antibody region, wherein the non-antibody region replaces at least a portion of an antibody from which the antibody region is based on or derived from. The non-antibody region may replace at least a portion of a complementarity determining region. The non-antibody region may replace at least a portion of a variable domain. The non-antibody region may replace at least a portion of a constant domain. The non-antibody region may replace at least a portion of a heavy chain. The non-antibody region may replace at least a portion of a light chain.

[0090] Further disclosed herein are immunoglobulin fusion proteins comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises: (a) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure, and wherein the first extender peptide comprises (i) 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that is not based on or derived from an ultralong CDR3; and (b) a therapeutic agent.

[0091] Further disclosed herein are immunoglobulin fusion proteins comprising an antibody region attached to a non-antibody region, wherein the non-antibody region comprises: (a) a first extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The secondary structure may be a beta strand.

[0092] Further disclosed herein are dual fusion proteins comprising two or more therapeutic agents attached to an antibody or fragment thereof. At least one therapeutic agent may be inserted into the antibody or fragment thereof. Two or more therapeutic agents may be inserted into the antibody or fragment thereof. The therapeutic agents may replace at least a portion of the antibody or fragment thereof.

[0093] Exemplary immunoglobulin fusion proteins with an extender peptide comprising a beta strand are depicted in FIG. 1. As shown in FIG. 1, an antibody region (1110) comprising two immunoglobulin heavy chains (1115, 1120) and two immunoglobulin light chains (1125, 1130) is attached to an extender fusion region (1135) comprising two extender peptides (1140, 1145) and a therapeutic agent (1150) to produce immunoglobulin fusion proteins (1160, 1170, 1180). As shown in FIG. 1, the immunoglobulin fusion protein (1160) comprises an extender fusion region attached to one of the immunoglobulin heavy chains of the antibody region. As shown in FIG. 1, the immunoglobulin fusion protein (1170) comprises an extender fusion region attached to one of the immunoglobulin light chains of the antibody region. Also shown in FIG. 1, the immunoglobulin fusion protein (1180) comprises two extender fusion regions attached two immunoglobulin chains of the antibody region. The two extender peptides may form a beta sheet. The two extender peptides may form anti-parallel beta strands.

[0094] Additional exemplary immunoglobulin fusion proteins are depicted in FIG. 2. Formula IA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising an extender peptide (E.sup.1) attached to a therapeutic agent (T.sup.1).

[0095] Formula IIA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising two extender peptides (E.sup.1 and E.sup.2) attached to a therapeutic agent (T.sup.1). Formula IIIA of FIG. 2 depicts an immunoglobulin dual fusion protein comprising two antibody regions (A.sup.1 and A.sup.2) attached to each other. The immunoglobulin dual fusion protein may comprise (a) a first antibody region (A.sup.1) attached to a first extender fusion region comprising two extender peptides (E.sup.1 and E.sup.2) attached to a first therapeutic agent (T.sup.1); and (b) a second antibody region (A.sup.2) attached to a second extender fusion region comprising two extender peptides (E.sup.3 and E.sup.4) attached to a second therapeutic agent (T.sup.2).

[0096] Formula IVA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising a linker (L.sup.1) attached to a therapeutic agent (T.sup.1), with the linker and therapeutic agent located between two extender peptides (E.sup.1 and E.sup.2).

[0097] Formula VA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising a proteolytic cleavage site (P.sup.1) attached to a therapeutic agent (T.sup.1), with the proteolytic cleavage site and therapeutic agent located between two extender peptides (E.sup.1 and E.sup.2). Formula VB of FIG. 2 shows the clipped version of Formula VA, wherein the proteolytic cleavage site is cleaved by a protease, which results in release of one end of the therapeutic agent.

[0098] Formula VIA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising a therapeutic agent (T.sup.1) attached to a linker (L.sup.1) and a proteolytic cleavage site (P.sup.1), which the therapeutic agent, linker and proteolytic cleavage site located between two extender peptides (E.sup.1 and E.sup.2). Formula VIB of FIG. 2 shows the clipped version of Formula VIA, wherein the proteolytic cleavage site is cleaved by a protease, which results in release of one end of the therapeutic agent.

[0099] Formula VIIA of FIG. 2 depicts an immunoglobulin dual fusion protein comprising two antibody regions (A.sup.1 and A.sup.2). The first antibody region (A.sup.1) is attached to a first extender fusion region comprising a therapeutic agent (T.sup.1) with two linkers (L.sup.1 and L.sup.2) on each end, with the therapeutic agent and linkers located between two extender peptides (E.sup.1 and E.sup.2). The second antibody region (A.sup.2) is attached to a second extender fusion region comprising a therapeutic agent (T.sup.2) attached to a proteolytic cleavage site (P.sup.1). The therapeutic agent and proteolytic cleavage site in the second extender fusion region are flanked by two linkers (L.sup.3 and L.sup.4). The therapeutic agent, proteolytic cleavage site and the two linkers of the second extender region are flanked by two extender peptides (E.sup.1 and E.sup.2).

[0100] Formula VIIIA of FIG. 2 depicts an immunoglobulin fusion protein comprising an antibody region (A.sup.1) attached to an extender fusion region comprising two extender peptides (E.sup.1 and E.sup.2), two linkers (L.sup.1 and L.sup.2), two proteolytic cleavage sites (P.sup.1 and P.sup.2) and a therapeutic agent (T.sup.1). Formula VIIIB of FIG. 2 shows the clipped version of Formula VIIIA, wherein the proteolytic cleavage sites located on the N- and C-termini of the therapeutic agent are cleaved by a protease, which results in release of the therapeutic agent from the immunoglobulin fusion protein.

[0101] Further disclosed herein are methods of treating a disease or condition in a subject in need thereof. The method may comprise administering to the subject an immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide; and (b) a therapeutic agent. The extender peptide may be based on or derived from an ultralong CDR3. The extender peptide may comprise 7 or fewer amino acids from an ultralong CDR3 sequence. Alternatively, or additionally, the extender peptide does not comprise an amino acid sequence based on or derived from an ultralong CDR3. The extender peptide may comprise one or more secondary structures. The one or more secondary structures may be a beta strand. The method may comprise administering to the subject an immunoglobulin fusion protein comprising a first antibody region; and a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a region containing a first beta strand secondary structure; and wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248. The first extender fusion region may not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain selected from a BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and an F18 ultralong complementary determining region 3 heavy chain. The first extender fusion region may not contain more than 7 consecutive amino acids that are based on or derived from a bovine ultralong CDR3. The first extender fusion region may not comprise an amino acid sequence that is based on or derived from a bovine ultralong CDR3.

[0102] Further disclosed herein are methods of extending the half-life of a therapeutic agent. The method may comprise attaching an extender peptide to a therapeutic agent to produce an extender fusion peptide. The method may further comprise attaching an antibody region to the extender peptide, therapeutic agent, or extender fusion peptide. The method may comprise incorporating a therapeutic agent into an antibody region. The method may comprise incorporating an antibody region into a therapeutic agent. The method may comprise grafting a therapeutic agent into an antibody region. The method may comprise grafting an antibody region into a therapeutic agent.

[0103] Further disclosed herein are methods of extending the half-life of a therapeutic agent. The method may comprise attaching an antibody region to the therapeutic agent to produce an immunoglobulin fusion protein. The method may further comprise attaching one or more linkers or proteolytic cleavage sites to the immunoglobulin fusion protein. The one or more linkers may be attached to an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be attached to an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be inserted into the therapeutic agent.

[0104] Further disclosed herein are methods of improving the delivery of a therapeutic agent. The method may comprise attaching an extender peptide to a therapeutic agent. The method may further comprise attaching an antibody region to the extender peptide, therapeutic agent, or extender fusion peptide.

[0105] Further disclosed herein are methods of improving the delivery of a therapeutic agent. The method may comprise attaching an antibody region to a therapeutic agent to produce an immunoglobulin fusion protein. The method may further comprise attaching one or more linkers or proteolytic cleavage sites to the immunoglobulin fusion protein. The one or more linkers may be incorporated at an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be incorporated at an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be incorporated within the therapeutic agent. The one or more proteolytic cleavage sites may be incorporated within antibody region. The one or more proteolytic cleavage sites may be incorporated within the extender fusion region. The one or more proteolytic cleavage sites may be incorporated within the extender peptide. The one or more linkers may be attached to an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be attached to an N- and/or C-terminus of the therapeutic agent. The one or more proteolytic cleavage sites may be inserted into the therapeutic agent.

[0106] Before the present methods and compositions are described, it is to be understood that this invention is not limited to a particular method or composition described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

[0107] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0108] The terms "homologous," "homology," or "percent homology" when used herein to describe to an amino acid sequence or a nucleic acid sequence, relative to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87: 2264-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated into the basic local alignment search tool (BLAST) programs of Altschul et al. (J. Mol. Biol. 215: 403-410, 1990). Percent homology of sequences can be determined using the most recent version of BLAST, as of the filing date of this application.

[0109] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0110] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0111] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the peptide" includes reference to one or more peptides and equivalents thereof, e.g. polypeptides, known to those skilled in the art, and so forth.

[0112] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0113] Immunoglobulin Fusion Proteins

[0114] The immunoglobulin fusion proteins disclosed herein may comprise one or more antibody regions. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody. The immunoglobulin domain may be from a recombinant antibody. The immunoglobulin domain may be from a mammalian antibody. The mammalian antibody may be a human antibody. The human antibody may be a human engineered or fully human antibody. The mammalian antibody may be a murine antibody. The mammalian antibody may be a non-human primate antibody. The mammalian antibody may be a bovine antibody.

[0115] The immunoglobulin domain may be a human antibody, wherein a portion of the human antibody is replaced with a non-human peptide. The immunoglobulin domain may be a human antibody, wherein a non-human peptide is added to the human antibody. The non-human peptide may be a portion of a non-human antibody or non-human antibody fragment. The portion of the non-human antibody or non-human antibody fragment may be a portion of a bovine antibody or a fragment thereof. The portion of the non-human antibody or non-human antibody fragment may be a CDR. The CDR may be a CDR3. The CDR may be a CDR2. The CDR may be a CDR1. The CDR may be an ultralong CDR. The CDR may be an ultralong CDR3. The CDR may be a bovine ultralong CDR. The CDR may be a bovine ultralong CDR3. The human antibody may have a sequence that is about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% homologous to a fully human antibody. The human antibody may have a sequence that is less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 11%, less than about 12%, less than about 13%, less than about 14% or less than about 15% homologous to a non-human peptide, a non-human protein or a non-human antibody. The portion of the human antibody that may be replaced may be a CDR or a portion thereof. The portion of the human antibody that may be replaced may be at least a portion of a variable fragment of the human antibody. The portion of the human antibody replaced may be at least a portion of a Fab of the human antibody. The portion of the human antibody replaced may be a portion a light chain or heavy chain of the human antibody. The non-human peptide may be less than about 4, less than about 5, less than about 6, less than about 7, less than about 8, less than about 9, less than about 10, less than about 11, less than about 12, less than about 13, less than about 14, less than about 15, less than about 16, less than about 17, less than about 18, less than about 19, less than about 20, less than about 22, less than about 23, less than about 24, less than about 25, less than about 26, less than about 27, less than about 28, less than about 29 or less than about 30 amino acids. The non-human peptide may be less than about 35 amino acids. The non-human peptide may be less than about 8 amino acids. The non-human peptide may be less than about 7 amino acids. The non-human peptide may be less than about 6 amino acids.

[0116] The immunoglobulin domain may be from a humanized antibody. The humanized antibody may comprise a portion that is less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9% or less than about 10% homologous to a non-human antibody. The humanized antibody may be at least about 90%, at least about 92%, at least about 94%, at least about 96%, at least about 98%, or at least about 99% homologous to a human antibody. By non-limiting example, the non-human antibody may be a non-human primate antibody. By non-limiting example, the non-human antibody may be a bovine antibody. The non-human antibody may be a murine antibody. The humanized antibody may be a monoclonal antibody.

[0117] The immunoglobulin fusion protein may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304.

[0118] The immunoglobulin fusion protein may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The immunoglobulin fusion protein may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The amino acids may be consecutive. Alternatively, or additionally, the amino acids are nonconsecutive.

[0119] The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is based on or derived from any one of SEQ ID NOs: 41-75, 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 41-75, 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303.

[0120] The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin fusion protein may be encoded by a nucleotide sequence comprising 1300 or more nucleotides based on or derived from any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The nucleotides may be consecutive. Alternatively, or additionally, the nucleotides are nonconsecutive.

[0121] The immunoglobulin fusion protein may further comprise one or more immunoglobulin light chains. The immunoglobulin fusion protein may comprise at least two immunoglobulin light chains. The immunoglobulin light chain may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 257-259. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250.

[0122] The immunoglobulin light chain may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The immunoglobulin light chain may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The amino acids may be consecutive. Alternatively, or additionally, the amino acids are nonconsecutive.

[0123] The immunoglobulin light chain may be encoded by a nucleotide sequence that is based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259.

[0124] The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence comprising 1300 or more nucleotides based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The nucleotides may be consecutive. Alternatively, or additionally, the nucleotides are nonconsecutive.

[0125] The immunoglobulin fusion protein may further comprise one or more immunoglobulin heavy chains. The immunoglobulin fusion protein may comprise at least two immunoglobulin heavy chains. The immunoglobulin heavy chain may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may not comprise an amino acid sequence selected from SEQ ID NOs: 248-250. The immunoglobulin heavy chain may not comprise an amino acid sequence based on or derived from SEQ ID NOs: 248-250. The immunoglobulin heavy chain may not comprise more than about 6, about 7, about 8, about 15, about 20 or about 35 consecutive amino acids from SEQ ID NOs: 248-250.

[0126] The immunoglobulin heavy chain may comprise an amino acid sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence comprising 50 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence comprising 100 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The immunoglobulin heavy chain may comprise an amino acid sequence comprising 200 or more amino acids based on or derived from any one of SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The amino acids may be consecutive. Alternatively, or additionally, the amino acids are nonconsecutive.

[0127] The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% homologous to any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may not be encoded by a nucleotide sequence selected from SEQ ID NOs: 254-256. The immunoglobulin heavy chain may not be encoded by a nucleotide sequence based on or derived from SEQ ID NOs: 254-256.

[0128] The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 450, 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 1100, 1200, 1300, 1400, 1500 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 100 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 500 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 1000 or more nucleotides based on or derived from any one of SEQ ID NOs: 5-13, 16-19 and 254-256. The immunoglobulin heavy chain may be encoded by a nucleotide sequence comprising 1300 or more nucleotides based on or derived from any one of SEQ ID NOs: 4-6 and 8-11. The nucleotides may be consecutive. Alternatively, or additionally, the nucleotides are nonconsecutive.

[0129] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 24-27, 29-33 and 36-39; and (b) a first immunoglobulin light chain comprising an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin fusion heavy chain comprising an amino acid sequence that is at least about 50% identical to SEQ ID NOs: 24-27, 29-33 and 36-39; and (b) a first immunoglobulin light chain comprising an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278. The first immunoglobulin fusion heavy chain may comprise an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to any one of SEQ ID NOs24-27, 29-33 and 36-39. The first immunoglobulin light chain comprising an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278.

[0130] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin fusion heavy chain encoded by a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19; and (b) a first immunoglobulin light chain encoded by a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin fusion heavy chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19; and (b) a first immunoglobulin light chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The first immunoglobulin fusion heavy chain encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19. The first immunoglobulin light chain encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297.

[0131] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain comprising an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 24-27, 29-33, and 36-39; and (b) a first immunoglobulin fusion light chain comprising an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain comprising an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 24-27, 29-33, and 36-39; and (b) a first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278. The first immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278.

[0132] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain encoded by a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19; and (b) a first immunoglobulin fusion light chain encoded by a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19; and (b) a first immunoglobulin fusion light chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The first immunoglobulin heavy chain encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 5-13 and 16-19. The first immunoglobulin fusion light chain encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259.

[0133] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain comprising an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 260-277; and (b) a first immunoglobulin fusion light chain comprising an amino acid sequence that is based on or derived from SEQ ID NO: 278. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain comprising an amino acid sequence that is at least about 50% identical to any one of SEQ ID NOs: 260-277; and (b) a first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 50% identical to SEQ ID NO: 278. The first immunoglobulin heavy chain may comprise an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to any one of SEQ ID NOs: 260-277. The first immunoglobulin fusion light chain comprising an amino acid sequence that is at least about 60%, 70%, 75%, 80%, 90%, 95%, or 97% identical to SEQ ID NO: 278.

[0134] The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain encoded by a nucleotide sequence of any one of SEQ ID NOs: 279-296; and (b) a first immunoglobulin fusion light chain encoded by a nucleotide sequence of SEQ ID NOs: 297. The immunoglobulin fusion protein may comprise (a) a first immunoglobulin heavy chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 279-296; and (b) a first immunoglobulin fusion light chain encoded by a nucleotide sequence that is at least 50% or more homologous to a nucleotide sequence of SEQ ID NO: 297. The first immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 279-296. The first immunoglobulin fusion light chain may be encoded by a nucleotide sequence that is at least 60%, 70%, 75%, 80%, 90%, 95%, or 97% or more homologous to a nucleotide sequence of SEQ ID NO: 297.

[0135] The immunoglobulin fusion proteins disclosed herein may comprise a therapeutic agent, wherein the therapeutic agent is a functional peptide. The immunoglobulin fusion protein may comprise a functional peptide grafted into an antibody scaffold. The functional peptide may be a linear peptide. The functional peptide may be a modified cyclic peptide. The functional peptide may comprise a peptide modified to comprise a .beta.-hairpin structure. The .beta.-hairpin structure may be locked into a .beta.-hairpin conformation by one or more bonds between two or more amino acid residues of the .beta.-hairpin structure. The N terminus and/or the C terminus of the functional peptide may be grafted to the extender fusion region of the immunoglobulin fusion protein. The N terminus of the functional peptide may be grafted to a first extender peptide of the extender fusion region and the C terminus of the functional peptide may be grafted to a second extender peptide of the extender fusion region. The functional peptide may comprise a peptide modified to comprise a conformationally constrained peptide. A conformationally constrained peptide may have a greatly improved binding affinity and/or specificity to a target relative to an endogenous or naturally-occurring binding partner of the target. An endogenous or naturally-occurring binding partner of the target may be a ligand or substrate of the target. By non-limiting example, the conformationally constrained peptide may be a peptide comprising a .beta.-hairpin structure. The conformationally constrained peptide may comprise a region that binds to a binding site of a target. The target may be a receptor. By non-limiting example, the receptor may be a G protein coupled receptor (GPCR). By non-limiting example, the GPCR may be CXCR4. The target may be an enzyme. By non-limiting example, the enzyme may be a neutrophil elastase. The binding site of the target may be a deep pocket of a ligand binding domain or substrate binding domain. The functional peptide or portion thereof may bind the deep pocket of a ligand binding domain or substrate binding domain such that it blocks a target ligand and/or substrate from binding. The functional peptide or portion thereof may bind the deep pocket of a ligand binding domain or substrate binding domain such that it partially blocks the target ligand and/or substrate from binding. The functional peptide or portion thereof may bind the deep pocket of a ligand binding domain or substrate binding domain such that it completely blocks the target ligand or substrate from binding. The functional peptide or portion thereof may bind the surface of the ligand binding domain or substrate binding domain. The functional peptide may be an agonist. The functional peptide may be an antagonist. The functional peptide may be an inhibitor. The functional peptide may be a ligand. The functional peptide may be a substrate.

[0136] Dual Fusions

[0137] Disclosed herein are immunoglobulin dual fusion proteins comprising one or more antibody regions attached to a first extender fusion region and a second extender fusion region, wherein the first extender fusion region comprises a first therapeutic agent and a first extender peptide comprising a beta strand and the second extender fusion region comprises a second therapeutic agent and a second extender peptide selected from a beta strand and/or a linker peptide. The first extender fusion region may not comprise more than 7 consecutive amino acid from SEQ ID NO. 248.

[0138] Further disclosed herein are immunoglobulin dual fusion proteins comprising one or more antibody regions attached to a first extender fusion region and a second extender fusion region, wherein the first extender fusion region comprises a first therapeutic agent and a first extender peptide comprising a beta strand and the second extender fusion region comprises a second therapeutic agent and a second extender peptide selected from an alpha helix and/or a linker peptide. The first extender fusion region may not comprise more than 7 consecutive amino acid from SEQ ID NO. 248.

[0139] Disclosed herein are immunoglobulin dual fusion proteins comprising one or more antibody regions attached to a first extender fusion region and a second extender fusion region, wherein the first extender fusion region comprises a first therapeutic agent and a first extender peptide comprising a beta strand and the second extender fusion region comprises a second therapeutic agent and no extender peptide. The first extender fusion region may not comprise more than 7 consecutive amino acid from SEQ ID NO. 248.

[0140] Further disclosed herein are immunoglobulin dual fusion proteins comprising (a) an antibody region attached to a non-antibody region, wherein the non-antibody region comprises (i) an extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the first extender peptide does not comprise an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second therapeutic agent. Attachment of the antibody region to the non-antibody region may comprise insertion of the non-antibody region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different.

[0141] Alternatively, the immunoglobulin dual fusion protein comprises (a) an antibody region attached to a non-antibody region, wherein the non-antibody region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the first extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second therapeutic agent. Attachment of the antibody region to the non-antibody region may comprise insertion of the non-antibody region into the antibody region. The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different.

[0142] The immunoglobulin dual fusion protein may comprise an antibody region attached to (a) a first extender fusion region comprising a first extender peptide, wherein the first extender peptide comprises (i) an amino acid sequence comprising a beta strand secondary structure and wherein the first extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second extender fusion region comprising (i) a second extender peptide, wherein the second extender peptide is selected from (1) a beta strand, an alpha helix and a linker or (2) no extender peptide; and (ii) a second therapeutic agent. The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The first extender fusion region may comprise one or more additional extender peptides. The one or more additional extender peptides may comprise a beta strand secondary structure. The second extender fusion region may comprise one or more additional extender peptides, wherein the one or more additional extender peptides are selected from a beta strand, an alpha helix and a linker peptide. The second extender fusion region may not comprise an extender peptide.

[0143] The dual fusion antibody may comprise (a) a first immunoglobulin fusion protein comprising a first antibody region attached to a first extender fusion region, wherein the first extender fusion region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second immunoglobulin fusion protein comprising a second antibody region attached to a second extender fusion region, wherein the second extender fusion region comprises (i) a second extender peptide and (ii) a second therapeutic agent. The second extender peptide may be a linker peptide. The linker may be flexible. The linker may be rigid.

[0144] The dual fusion antibody may comprise (a) a first immunoglobulin fusion protein comprising a first antibody region attached to a first extender fusion region, wherein the first extender fusion region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second immunoglobulin fusion protein comprising a second antibody region attached to a second extender fusion region, wherein the second extender fusion region consists essentially of a second therapeutic agent.

[0145] The dual fusion antibody may comprise (a) a first immunoglobulin fusion protein comprising a first antibody region attached to a first extender fusion region, wherein the first extender fusion region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the first extender peptide does not comprise an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second immunoglobulin fusion protein comprising a second antibody region attached to a second extender fusion region, wherein the second extender fusion region comprises (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent.

[0146] The dual fusion antibody may comprise (a) a first immunoglobulin fusion protein comprising a first antibody region attached to a first extender fusion region, wherein the first extender fusion region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second immunoglobulin fusion protein comprising a second antibody region attached to a second extender fusion region, wherein the second extender fusion region comprises (i) a second extender peptide comprising at least one secondary structure and (ii) a second therapeutic agent.

[0147] The dual fusion antibody may comprise (a) a first immunoglobulin fusion protein comprising a first antibody region attached to a first extender fusion region, wherein the first extender fusion region comprises (i) a first extender peptide, wherein the first extender peptide comprises an amino acid sequence comprising a beta strand secondary structure and wherein the extender peptide comprises 7 or fewer amino acids based on or derived from an ultralong CDR3; and (ii) a first therapeutic agent; and (b) a second immunoglobulin fusion protein comprising a second antibody region attached to a second extender fusion region, wherein the second extender fusion region comprises (i) a second extender peptide comprises at least one alpha helix and (ii) a second therapeutic agent. The second extender fusion region may comprise one or more additional extender peptides, wherein the one or more additional extender peptides include an alpha helix. The second extender fusion region may comprise a coiled coil secondary structure.

[0148] The first therapeutic agent and the second therapeutic agent may be the same. The first therapeutic agent and the second therapeutic agent may be different. The immunoglobulin dual fusion protein may further comprise one or more additional therapeutic agents. The two or more therapeutic agents may be the same. Alternatively, or additionally, the two or more therapeutic agents may be different.

[0149] The first antibody region and the second antibody region may be the same. For example, the first antibody region and the second antibody region comprise an immunoglobulin heavy chain. Alternatively, the first antibody region and the second antibody region may comprise an immunoglobulin light chain. The first antibody region and the second antibody region may be different. For example, the first antibody region comprises an immunoglobulin heavy chain and the second antibody region comprises an immunoglobulin light chain or vice versa. The immunoglobulin dual fusion protein may further comprise one or more additional antibody regions. The two or more antibody regions may be the same. Alternatively, or additionally, the two or more antibody regions may be different.

[0150] The immunoglobulin dual fusion protein may further comprise one or more additional extender peptides. The two or more extender peptides may be the same. Alternatively, or additionally, the two or more extender peptides are different.

[0151] The immunoglobulin dual fusion protein may further comprise one or more additional antibody regions. The two or more antibody regions may be the same. Alternatively, or additionally, the two or more antibody regions are different.

[0152] The immunoglobulin dual fusion protein may further comprise one or more linkers. The immunoglobulin dual fusion protein may further comprise two or more linkers. The two or more linkers may be the same. Alternatively, or additionally, the two or more linkers are different.

[0153] The immunoglobulin dual fusion protein may further comprise one or more proteolytic cleavage sites. The immunoglobulin dual fusion protein may further comprise two or more proteolytic cleavage sites. The two or more proteolytic cleavage sites may be the same. Alternatively, or additionally, the two or more proteolytic cleavage sites are different.

[0154] Antibody Region

[0155] The immunoglobulin fusion proteins disclosed herein comprise one or more antibody regions. The antibody region may comprise an antibody or fragment thereof. The antibody region may comprise at least a portion of an immunoglobulin heavy chain, immunoglobulin light chain, or a combination thereof. The antibody region may comprise two or more immunoglobulin chains or portions thereof. The antibody region may comprise three or more immunoglobulin chains or portions thereof. The antibody region may comprise four or more immunoglobulin chains or portions thereof. The antibody region may comprise two immunoglobulin heavy chains and two immunoglobulin light chains.

[0156] The immunoglobulin fusion proteins disclosed herein may comprise one or more immunoglobulin regions. The immunoglobulin region may comprise an immunoglobulin or a fragment thereof. The immunoglobulin region may comprise at least a portion of an immunoglobulin heavy chain, immunoglobulin light chain, or a combination thereof. The immunoglobulin region may comprise two or more immunoglobulin chains or portions thereof. The immunoglobulin region may comprise three or more immunoglobulin chains or portions thereof. The immunoglobulin region may comprise four or more immunoglobulin chains or portions thereof. The immunoglobulin region may comprise five or more immunoglobulin chains or portions thereof. The immunoglobulin region may comprise two immunoglobulin heavy chains and two immunoglobulin light chains.

[0157] The immunoglobulin region may comprise an entire immunoglobulin molecule or any polypeptide comprising fragment of an immunoglobulin including, but not limited to, heavy chain, light chain, variable domain, constant domain, complementarity determining region (CDR), framework region, fragment antigen binding (Fab) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallizable (Fc) region, single chain variable fragment (scFV), di-scFv, single domain immunoglobulin, trifunctional immunoglobulin, chemically linked F(ab')2, and any combination thereof. The immunoglobulin region may comprise one or more mutations. The Fc region may be a mutated Fc region. The mutated Fc region may comprise one or more mutations that eliminate an antibody-dependent cellular cytotoxicity (ADCC) effect of an Fc region. The mutated Fc region may comprise one or more mutations. The mutated Fc region may comprise about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 mutations. The mutated Fc region may comprise about 6 mutations. The mutated Fc region may comprise about 1 deletion. The mutated Fc region may comprise about 6 mutations and 1 deletion.

[0158] In some embodiments, an immunoglobulin heavy chain may comprise an entire heavy chain or a portion of a heavy chain. For example, a variable domain or region thereof derived from a heavy chain may be referred to as a heavy chain or a region of a heavy chain. In some embodiments, an immunoglobulin light chain may comprise an entire light chain or a portion of a light chain. For example, a variable domain or region thereof derived from a light chain may be referred to as a light chain or a region of a light chain. A single domain immunoglobulin includes, but is not limited to, a single monomeric variable immunoglobulin domain, for example, a shark variable new antigen receptor immunoglobulin fragment (VNAR).

[0159] The immunoglobulin may be derived from any type known to one of skill in the art including, but not limited to, IgA, IgD, IgE, IgG, IgM, IgY, IgW. The immunoglobulin region may comprise one or more functional units, including but not limited to, 1, 2, 3, 4, and 5 functional units. Functional units may include, but are not limited to, non-immunoglobulin regions, heavy chain, light chain, variable domain, constant domain, complementarity determining region (CDR), framework region, fragment antigen binding (Fab) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallizable (Fc) region, single chain variable fragment (scFV), di-scFv, single domain immunoglobulin, trifunctional immunoglobulin, chemically linked F(ab')2, and any combination or fragments thereof. Non-immunoglobulin regions include, but are not limited to, carbohydrates, lipids, small molecules and therapeutic peptides. The immunoglobulin region may comprise one or more units connected by one or more disulfide bonds. The immunoglobulin region may comprise one or more units connected by a peptide linker, for example, an scFv immunoglobulin. The immunoglobulin may be a recombinant immunoglobulin including immunoglobulins with amino acid mutations, substitutions, and/or deletions. The immunoglobulin may be a recombinant immunoglobulin comprising chemical modifications. The immunoglobulin may comprise a whole or part of an immunoglobulin-drug conjugate.

[0160] The antibody region may comprise at least a portion of an immunoglobulin heavy chain. The antibody region may comprise one or more immunoglobulin heavy chains or a portion thereof. The antibody region may comprise two or more immunoglobulin heavy chains or a portion thereof. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence that is at least about 90% homologous to an immunoglobulin heavy chain. The immunoglobulin heavy chain may comprise an amino acid sequence selected from any one of SEQ ID NOs: 24-27, 29-33 and 36-39.

[0161] The antibody region may comprise an amino acid sequence comprising 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or more amino acids of an immunoglobulin heavy chain. The antibody region may comprise an amino acid sequence comprising 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or more amino acids of an immunoglobulin heavy chain. The amino acids may be consecutive. Alternatively, or additionally, the amino acids are non-consecutive.

[0162] The immunoglobulin heavy chain may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 5-13 and 16-19. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 5-13 and 16-19. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to any one of SEQ ID NOs: 5-13 and 16-19. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 75% homologous to any one of SEQ ID NOs: 5-13 and 16-19. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 85% homologous to any one of SEQ ID NOs: 5-13 and 16-19.

[0163] The antibody region may comprise at least a portion of an immunoglobulin light chain. The antibody region may comprise one or more immunoglobulin light chains or a portion thereof. The antibody region may comprise two or more immunoglobulin light chains or a portion thereof. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to an immunoglobulin light chain. The antibody region may comprise an amino acid sequence that is at least about 90% homologous to an immunoglobulin light chain. The immunoglobulin light chain may comprise an amino acid sequence selected from any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278.

[0164] The antibody region may comprise an amino acid sequence comprising 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or more amino acids of an immunoglobulin light chain. The antibody region may comprise an amino acid sequence comprising 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or more amino acids of an immunoglobulin light chain. The amino acids may be consecutive. Alternatively, or additionally, the amino acids are non-consecutive.

[0165] The immunoglobulin light chain may be encoded by a nucleotide sequence based on or derived from any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 75% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 85% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297 and 257-259.

[0166] The antibody region may comprise at least a portion of a complementarity-determining region (CDR). The antibody region may comprise one or more complementarity-determining regions (CDRs) or portions thereof. The antibody region may comprise 2, 3, 4, 5 or more complementarity-determining regions (CDRs) or portions thereof. The antibody region may comprise 6, 7, 8 or more complementarity-determining regions (CDRs) or portions thereof. The antibody region may comprise four or more complementarity-determining regions (CDRs) or portions thereof. The antibody region may comprise 9, 10, 11 or more complementarity-determining regions (CDRs) or portions thereof. The one or more CDRs may be CDR1, CDR2, CDR3 or a combination thereof. The one or more CDRs may be CDR1. The one or more CDRs may be CDR2. The one or more CDRs may be CDR3. The one or more CDRs may be a heavy chain CDR. The one or more CDRs may be a light chain CDR.

[0167] The antibody region may comprise an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids based on or derived from an amino acid sequence of a CDR. The antibody region may comprise an amino acid sequence comprising 3 or more amino acids based on or derived from an amino acid sequence of a CDR. The antibody region may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of a CDR. The antibody region may comprise an amino acid sequence comprising 10 or more amino acids based on or derived from an amino acid sequence of a CDR. The amino acids may be consecutive. The amino acids may be non-consecutive.

[0168] The antibody region may be based on or derived from at least a portion of an anti-T cell receptor antibody. The antibody region may be based on or derived from at least a portion of an anti-B cell receptor antibody.

[0169] The antibody region may be based on or derived from at least a portion of an anti-T cell co-receptor antibody. The antibody region may be based on or derived from at least a portion of an anti-CD3 antibody. The antibody region may be based on or derived from an anti-CD3 antibody. The anti-CD3 antibody may be UCHT1. The antibody region may be based on or derived from at least a portion of a Fab fragment of an anti-CD3 antibody. The antibody region may be based on or derived from an antibody fragment of an anti-CD3 antibody.

[0170] The antibody region may be based on or derived from an antibody or antibody fragment that binds to at least a portion of a receptor on a cell. The antibody region may be based on or derived from an antibody or antibody fragment that binds to at least a portion of a co-receptor on a cell. The antibody region may be based on or derived from an antibody or antibody fragment that binds to at least a portion of an antigen or cell surface marker on a cell. The cell may be a hematopoietic cell. The hematopoietic cell may be a myeloid cell. The myeloid cell may be an erythrocyte, thrombocyte, neutrophil, monocyte, macrophage, eosinophil, basophil, or mast cell. The hematopoietic cell may be a lymphoid cell. The lymphoid cell may be a B-cell, T-cell, or NK-cell. The hematopoietic cell may be a leukocyte. The hematopoietic cell may be a lymphocyte.

[0171] The antibody region may be based on or derived from an antibody or antibody fragment that binds to at least a portion of a receptor on a T-cell. The receptor may be a T-cell receptor (TCR). The TCR may comprise TCR alpha, TCR beta, TCR gamma and/or TCR delta. The receptor may be a T-cell receptor zeta.

[0172] The antibody region may be based on or derived from an antibody or antibody fragment that binds to at least a portion of a receptor on a lymphocyte, B-cell, macrophage, monocytes, neutrophils and/or NK cells. The receptor may be an Fc receptor. The Fc receptor may be an Fc-gamma receptor, Fc-alpha receptor and/or Fc-epsilon receptor. Fc-gamma receptors include, but are not limited to, Fc.gamma.RI (CD64), Fc.gamma.RIIA (CD32), Fc.gamma.RIIB (CD32), Fc.gamma.RIIIA (CD16a) and Fc.gamma.RIIIB (CD16b). Fc-alpha receptors include, but are not limited to, Fc.alpha.RI. Fc-epsilon receptors include, but are not limited to, Fc.epsilon.RI and Fc.epsilon.RII. The receptor may be CD89 (Fc fragment of IgA receptor or FCAR).

[0173] The antibody region may be based on or derived from an antibody or antibody fragment that binds at least a portion of a co-receptor on a T-cell. The co-receptor may be a CD3, CD4, and/or CD8. The antibody region may be based on or derived from an antibody fragment that binds to a CD3 co-receptor. The CD3 co-receptor may comprise CD3-gamma, CD3-delta and/or CD3-epsilon. CD8 may comprise CD8-alpha and/or CD8-beta chains.

[0174] The antibody region may be based on or derived from an anti-viral antibody. The anti-viral antibody may be directed against an epitope of a viral protein. The viral protein may be from a respiratory syncytial virus. The viral protein may be an F protein of the respiratory syncytial virus. The epitope may be in the A antigenic site of the F protein. The anti-viral antibody may be based on or derived from Palivizumab.

[0175] The antibody region may be based on or derived from an antiviral immunoglobulin G antibody. The antibody region may comprise at least a portion of an antiviral immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an antiviral immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to at least a portion of an antiviral immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an antiviral immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an antiviral immunoglobulin G antibody.

[0176] The antibody region may comprise an amino acid sequence that comprises 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an antiviral immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an antiviral immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 50 or more amino acids of an antiviral immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100 or more amino acids of an antiviral immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 200 or more amino acids of an antiviral immunoglobulin G antibody sequence.

[0177] The antibody region may be based on or derived from a palivizumab antibody. The antibody region may be a wild type palivizumab antibody. The antibody region may be a mutated palivizumab antibody. The antibody region may be a palivizumab wild type IgG1 heavy chain. The antibody may be a palivizumab antibody comprising a heptad mutation in an IgG1 heavy chain. The antibody region may be a palivizumab antibody comprising a triple mutation in an hIgG4 heavy chain. The antibody region may be a light chain paired with a palivizumab antibody. The antibody region may comprise at least a portion of a palivizumab antibody. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of a palivizumab antibody. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to at least a portion of a palivizumab antibody. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of a palivizumab antibody. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of a palivizumab antibody.

[0178] The antibody region may comprise an amino acid sequence that comprises 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of a palivizumab antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of a palivizumab antibody sequence. The antibody region may comprise an amino acid sequence that comprises 50 or more amino acids of a palivizumab antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100 or more amino acids of a palivizumab antibody sequence. The antibody region may comprise an amino acid sequence that comprises 200 or more amino acids of a Palivizumab antibody sequence.

[0179] The antibody region may be a trastuzumab antibody or fragment thereof. The antibody region may be a trastuzumab wild type antibody. The antibody region may be a mutated trastuzumab antibody. The antibody region may be a trastuzumab antibody that comprises a heptad mutation in the IgG1 heavy chain. The antibody region may be a trastuzumab antibody that comprises a triple mutation in the IgG4 heavy chain. The antibody region may be a light chain paired with the trastuzumab antibody. The antibody region may be based on or derived from a trastuzumab immunoglobulin G antibody. The antibody region may comprise at least a portion of a trastuzumab immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of a trastuzumab immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to at least a portion of a trastuzumab immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of a trastuzumab immunoglobulin G antibody. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of a trastuzumab immunoglobulin G antibody.

[0180] The antibody region may comprise an amino acid sequence that comprises 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of a trastuzumab immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of a trastuzumab immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 50 or more amino acids of a trastuzumab immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100 or more amino acids of a trastuzumab immunoglobulin G antibody sequence. The antibody region may comprise an amino acid sequence that comprises 200 or more amino acids of a trastuzumab immunoglobulin G antibody sequence.

[0181] The antibody region may be based on or derived from an anti-Her2 antibody. The antibody region may comprise at least a portion of an anti-Her2 antibody. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an anti-Her2 antibody. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to at least a portion of an anti-Her2 antibody. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an anti-Her2 antibody. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an anti-Her2 antibody.

[0182] The antibody region may comprise an amino acid sequence that comprises 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an anti-Her2 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an anti-Her2 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 50 or more amino acids of an anti-Her2 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100 or more amino acids of an anti-Her2 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 200 or more amino acids of an anti-Her2 antibody sequence.

[0183] The antibody region may be based on or derived from an anti-CD47 antibody. The antibody region may comprise at least a portion of an anti-CD47 antibody. The antibody region may comprise an amino acid sequence that is at least about 50% homologous to at least a portion of an anti-CD47 antibody. The antibody region may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more homologous to at least a portion of an anti-CD47 antibody. The antibody region may comprise an amino acid sequence that is at least about 70% homologous to at least a portion of an anti-CD47 antibody. The antibody region may comprise an amino acid sequence that is at least about 80% homologous to at least a portion of an anti-CD47 antibody.

[0184] The antibody region may comprise an amino acid sequence that comprises 10, 20, 30, 40, 50, 60, 70, 80, 90 or more amino acids of an anti-CD47 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900 or more amino acids of an anti-CD47 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 50 or more amino acids of an anti-CD47 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 100 or more amino acids of an anti-CD47 antibody sequence. The antibody region may comprise an amino acid sequence that comprises 200 or more amino acids of an anti-CD47 antibody sequence.

[0185] The antibody region may be based on or derived from an anti-cancer antibody. Examples of anti-cancer antibody include, but are not limited to, abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, certolizumab, cetuximab, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, muromonab-cd3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab, trastuzumab.

[0186] The antibody region may comprise at least a portion of a human antibody. The antibody region may comprise at least a portion of a humanized antibody. The antibody region may comprise at least a portion of a chimeric antibody. The antibody region may be based on or derived from a human antibody. The antibody region may be based on or derived from a humanized antibody. The antibody region may be based on or derived from a chimeric antibody. The antibody region may be based on or derived from a monoclonal antibody. The antibody region may be based on or derived from a polyclonal antibody. The antibody region may comprise at least a portion of an antibody from a mammal, avian, reptile, amphibian, or a combination thereof. The mammal may be a human. The mammal may be a non-human primate. The mammal may be a dog, cat, sheep, goat, cow, rabbit, or mouse. The antibody region may comprise an antibody to a non-naturally occurring peptide or non-naturally-occurring protein.

[0187] The antibody region may be a human antibody, wherein a portion of the human antibody is replaced with a non-human peptide. The antibody region may be a human antibody, wherein a non-human peptide is added to the human antibody. The non-human peptide may be a portion of a non-human antibody or non-human antibody fragment. The portion of the non-human antibody or non-human antibody fragment may be a portion of a bovine antibody or a fragment thereof. The portion of the non-human antibody or non-human antibody fragment may be a non-human CDR. The non-human CDR may be a non-human CDR3. The CDR may be a CDR2. The CDR may be an ultralong CDR. The CDR may be an ultralong bovine CDR. The CDR may be a bovine ultralong CDR3. The CDR may be an ultralong bovine CDR of an antibody heavy chain. The CDR may be a bovine ultralong CDR3 of an antibody heavy chain. The CDR may be an ultralong bovine CDR of an antibody light chain. The CDR may be a bovine ultralong CDR3 of an antibody light chain. The CDR may be a portion of an ultralong bovine CDR. The CDR may be a portion of a bovine ultralong CDR3. For example, some bovine antibodies have unusually long CDR3 sequences compared to other vertebrates. A typical CDR3 is about 8 to about 16 amino acids in length. An ultralong CDR3 sequence may be greater than about 35 amino acids in length. An ultralong CDR3 sequence may be greater than about 40 amino acids in length. An ultralong CDR3 sequence may be greater than about 50 amino acids in length. An ultralong CDR3 sequence may be greater than 60 amino acids in length. An ultralong CDR3 may be between about 50 and 61 amino acids in length. The ultralong CDR3 may comprise multiple cysteines. An ultralong CDR3 may comprise disulfide-bonded mini-domains as a result of the multiple cysteines. A significant proportion of the ultralong CDR3 may be encoded by a D-region of a VH gene formed through a process called V(D)J recombination. The ultralong CDR3 may comprise a stalk domain. The ultralong CDR3 may comprise a .beta.-strand stalk domain and a knob domain. The ultralong CDR3 may comprise a .beta.-strand stalk that supports a structurally diverse, disulfide-bonded, knob domain. The .beta.-strand stalk may comprise a .beta.-sheet. The immunoglobulin fusion proteins disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is not based on or derived from an ultralong CDR3. The immunoglobulin fusion proteins disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 35 or fewer consecutive amino acids of an ultralong CDR3. The immunoglobulin fusion proteins disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 15 or fewer consecutive amino acids of an ultralong CDR3. The immunoglobulin fusion proteins disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 7 or fewer consecutive amino acids of an ultralong CDR3. The portion of the bovine ultralong CDR3 may have a length of less than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 about 12, about 13, about 14, about 15, about 16, about 18, about 19 or about 20 amino acids. The immunoglobulin fusion protein may contain less than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 about 12, about 13, about 14, about 15, about 16, about 18, about 19 or about 20 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The immunoglobulin fusion protein may contain 7 or fewer amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The immunoglobulin fusion protein may contain 15 or fewer amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The immunoglobulin fusion protein may contain less than about 20 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The immunoglobulin fusion protein may contain less than about 35 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3.

[0188] The bovine ultralong CDR3 may be selected from BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and F18. The bovine ultralong CDR3 may be selected from BF4E9, B-L1 and B-L2. The bovine ultralong CDR3 may be BLV1H12. The bovine ultralong CDR3 may not be selected from BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and F18. The bovine ultralong CDR3 not be selected from BF4E9, B-L1 and B-L2. The bovine ultralong CDR3 may not be BLV1H12. The bovine ultralong CDR3 may comprise a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be based on or derived from a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be about 50% homologous to a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be about 50%, about 60%, about 70%, about 80% or about 90% homologous to a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence based on or derived from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence based on or derived from a portion of any one of SEQ ID NOs: 248-250.

[0189] The human antibody may have a sequence that is about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% homologous to a fully human antibody. The human antibody may have a sequence that is less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 11%, less than about 12%, less than about 13%, less than about 14% or less than about 15% homologous to a non-human peptide or non-human protein. The portion of the human antibody that may be replaced may be a CDR or a portion thereof. The portion of the human antibody that may be replaced may be at least a portion of a variable fragment of the human antibody. The portion of the human antibody replaced may be at least a portion of a Fab of the human antibody. The portion of the human antibody replaced may be a portion a light chain or heavy chain of the human antibody. The non-human peptide may be less than about 4, less than about 5, less than about 6, less than about 7, less than about 8, less than about 9, less than about 10, less than about 11, less than about 12, less than about 13, less than about 14, less than about 15, less than about 16, less than about 17, less than about 18, less than about 19, less than about 20, less than about 22, less than about 23, less than about 24, less than about 25, less than about 26, less than about 27, less than about 28, less than about 29 or less than about 30 amino acids.

[0190] The antibody region may comprise a sequence based on or derived from one or more antibodies and/or antibody fragment sequences. The antibody region may comprise a sequence that is at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more homologous to a sequence based on or derived from one or more antibodies and/or antibody fragments. The antibody region may comprise a sequence that is at least about 70% homologous to a sequence based on or derived from one or more antibodies and/or antibody fragments. The antibody region may comprise a sequence that is at least about 80% homologous to a sequence based on or derived from one or more antibodies and/or antibody fragments. The antibody region may comprise a sequence that is at least about 90% homologous to a sequence based on or derived from one or more antibodies and/or antibody fragments. The antibody region may comprise a sequence that is at least about 95% homologous to a sequence based on or derived from one or more antibodies and/or antibody fragments. The sequence may be a peptide sequence. Alternatively, the sequence is a nucleotide sequence.

[0191] The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 20, 17, 15, 12, 10, 8, 6, 5, 4 or fewer amino acids. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 4 or fewer amino acids. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 3 or fewer amino acids. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 2 or fewer amino acids. The antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 1 or fewer amino acids. The amino acids may be consecutive, nonconsecutive, or a combination thereof. For example, the antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 3 consecutive amino acids. Alternatively, or additionally, the antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 2 non-consecutive amino acids. In another example, the antibody region may comprise a peptide sequence that differs from a peptide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 5 amino acids, wherein 2 of the amino acids are consecutive and 2 of the amino acids are non-consecutive.

[0192] The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 15 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 12 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 9 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 6 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 4 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 3 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 2 or fewer nucleotides or base pairs. The antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than or equal to about 1 or fewer nucleotides or base pairs. The nucleotides or base pairs may be consecutive, nonconsecutive, or a combination thereof. For example, the antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 3 consecutive nucleotides or base pairs. Alternatively, or additionally, the antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 2 non-consecutive nucleotides or base pairs. In another example, the antibody region may comprise a nucleotide sequence that differs from a nucleotide sequence based on or derived from one or more antibodies and/or antibody fragments by less than about 5 nucleotides or base pairs, wherein 2 of the nucleotides or base pairs are consecutive and 2 of the nucleotides or base pairs are non-consecutive.

[0193] The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by one or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by two or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by three or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by four or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by five or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by six or more amino acid substitutions. The peptide sequence of the antibody region may differ from the peptide sequence of the antibody or antibody fragment that it is based on and/or derived from by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 17, 20, 25 or more amino acid substitutions.

[0194] The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by one or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by two or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by three or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by four or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by five or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by six or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by nine or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by twelve or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by fifteen or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by eighteen or more nucleotide and/or base pair substitutions. The nucleotide sequence of the antibody region may differ from the nucleotide sequence of the antibody or antibody fragment that it is based on and/or derived from by 20, 22, 24, 25, 27, 30 or more nucleotide and/or base pair substitutions.

[0195] The antibody region may comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids. The antibody region may comprise at least about 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700 or more amino acids. The antibody region may comprise at least about 100 amino acids. The antibody region may comprise at least about 200 amino acids. The antibody region may comprise at least about 400 amino acids. The antibody region may comprise at least about 500 amino acids. The antibody region may comprise at least about 600 amino acids.

[0196] The antibody region may comprise less than about 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200 or 1100 amino acids. The antibody region may comprise less than about 1000, 950, 900, 850, 800, 750, or 700 amino acids. The antibody region may comprise less than about 1500 amino acids. The antibody region may comprise less than about 1000 amino acids. The antibody region may comprise less than about 800 amino acids. The antibody region may comprise less than about 700 amino acids.

[0197] The IFP may further comprise an antibody region comprising 30 or fewer consecutive amino acids of a complementarity determining region 3 (CDR3). The antibody region may comprise 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 15 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 14 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 13 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 12 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 11 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 10 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 9 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 8 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 7 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 6 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 5 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 4 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 3 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 2 or fewer consecutive amino acids of a CDR3. The antibody region may comprise 1 or fewer consecutive amino acids of a CDR3. In some instances, the antibody region does not contain a CDR3.

[0198] The IFP may comprise a first antibody region comprising 6 or fewer consecutive amino acids of a complementarity determining region 3 (CDR3). The first antibody region may comprise 5 or fewer consecutive amino acids of a CDR3. The first antibody region may comprise 4 or fewer consecutive amino acids of a CDR3. The first antibody region may comprise 3 or fewer consecutive amino acids of a CDR3. The first antibody region may comprise 2 or fewer consecutive amino acids of a CDR3. The first antibody region may comprise 1 or fewer consecutive amino acids of a CDR3. In some instances, the first antibody region does not contain a CDR3.

[0199] The IFP may further comprise a second antibody region comprising 30 or fewer consecutive amino acids of a complementarity determining region 3 (CDR3). The second antibody region may comprise 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 15 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 14 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 13 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 12 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 11 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 10 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 9 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 8 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 7 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 6 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 5 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 4 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 3 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 2 or fewer consecutive amino acids of a CDR3. The second antibody region may comprise 1 or fewer consecutive amino acids of a CDR3. In some instances, the second antibody region does not contain a CDR3.

[0200] Non-Antibody Region

[0201] The immunoglobulin fusion proteins disclosed herein may comprise one or more non-antibody regions. The immunoglobulin fusion proteins disclosed herein may comprise two or more non-antibody regions. The immunoglobulin fusion proteins disclosed herein may comprise 3, 4, 5, 6, 7, 8, 9, 10 or more non-antibody regions.

[0202] The two or more non-antibody regions may be attached to one or more antibody regions. The two or more non-antibody regions may be attached to two or more antibody regions. The two or more non-antibody regions may be attached to one or more immunoglobulin chains. The two or more non-antibody regions may be attached to two or more immunoglobulin chains. The two or more non-antibody regions may be attached to one or more subunits within the one or more antibody regions. The two or more non-antibody regions may be attached to two or more subunits within the one or more antibody regions.

[0203] The non-antibody regions may comprise one or more therapeutic agents. The non-antibody regions may comprise two or more therapeutic agents. The non-antibody regions may comprise 3, 4, 5, 6, 7 or more therapeutic agents. The therapeutic agents may be different. The therapeutic agents may be the same.

[0204] The non-antibody regions may comprise one or more extender peptides. The non-antibody regions may comprise two or more extender peptides. The non-antibody regions may comprise 3, 4, 5, 6, 7 or more extender peptides. The extender peptides may be different. The extender peptides may be the same. The non-antibody region comprising one or more extender peptides may be referred to as an extender fusion region.

[0205] The non-antibody regions may comprise one or more linkers. The non-antibody regions may comprise two or more linkers. The non-antibody regions may comprise 3, 4, 5, 6, 7 or more linkers. The linkers may be different. The linkers may be the same. The linker may directly connect the therapeutic agent to the antibody region. In some instances, the non-antibody region does not comprise a linker.

[0206] The non-antibody region may be inserted into the antibody region. Insertion of the non-antibody region into the antibody region may comprise removal or deletion of a portion of the antibody from which the antibody region is based on or derived from. The non-antibody region may replace at least a portion of a heavy chain. The non-antibody region may replace at least a portion of a light chain. The non-antibody region may replace at least a portion of a V region. The non-antibody region may replace at least a portion of a D region. The non-antibody region may replace at least a portion of a J region. The non-antibody region may replace at least a portion of a variable region. The non-antibody region may replace at least a portion of a constant region. The non-antibody region may replace at least a portion of a complementarity determining region (CDR). The non-antibody region may replace at least a portion of a CDR1. The non-antibody region may replace at least a portion of a CDR2. The non-antibody region may replace at least a portion of a CDR3. The non-antibody region may replace at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of the antibody or portion thereof. For example, the non-antibody region may replace at least about 50% of a CDR. The non-antibody region may replace at least about 70% of a CDR. The non-antibody region may replace at least about 80% of a CDR. The non-antibody region may replace at least about 90% of a CDR. The non-antibody region may replace at least about 95% of a CDR.

[0207] Extender Fusion Region

[0208] The immunoglobulin fusion proteins disclosed herein may comprise one or more extender fusion regions. The extender fusion region may be a non-antibody region disclosed herein. The immunoglobulin fusion proteins may comprise two or more extender fusion regions. The immunoglobulin fusion proteins may comprise 3, 4, 5, 6, 7, 8, 9, 10 or more extender fusion regions.

[0209] The two or more extender fusion regions may be attached to one or more antibody regions. The two or more extender fusion regions may be attached to two or more antibody regions. The two or more extender fusion regions may be attached to one or more immunoglobulin chains. The two or more extender fusion regions may be attached to two or more immunoglobulin chains. The two or more extender fusion regions may be attached to one or more subunits within the one or more antibody regions. The two or more extender fusion regions may be attached to two or more subunits within the one or more antibody regions.

[0210] The extender fusion regions may comprise one or more extender peptides. The extender fusion regions may comprise two or more extender peptides. The extender fusion regions may comprise 3, 4, 5, 6 or more extender peptides.

[0211] The extender fusion regions may comprise one or more therapeutic agents. The extender fusion regions may comprise two or more therapeutic agents. The extender fusion regions may comprise 3, 4, 5, 6, 7 or more therapeutic agents. The therapeutic agents may be different. The therapeutic agents may be the same.

[0212] The immunoglobulin fusion proteins disclosed herein may comprise an antibody region attached to an extender fusion region. The extender fusion region may be attached to the N-terminus, C-terminus, or N- and C-terminus of the antibody region. The antibody region may be directly attached to the extender fusion region. Alternatively, or additionally, the antibody region may be indirectly attached to the non-antibody sequence. Attachment of the extender fusion region to the antibody region may comprise covalent attachment. Attachment may comprise fusion of the extender fusion region to the antibody region. Attachment may comprise chemical conjugation.

[0213] Alternatively, or additionally, attachment comprises insertion of the extender fusion region into the antibody region. The extender fusion region may be inserted into a heavy chain of the antibody region. The extender fusion region may be inserted into a light chain of the antibody region. The extender fusion region may be inserted into a variable domain of the antibody region. The extender fusion region may be inserted into a constant domain of the antibody region. The extender fusion region may be inserted into a complementarity-determining region (CDR) of the antibody region.

[0214] The extender fusion region may replace at least a portion of an antibody from which the antibody region is based on or derived. The extender fusion region may replace at least a portion of a heavy chain of an antibody from which the antibody region may be based on or derived. The extender fusion region may replace at least a portion a light chain of an antibody from which the antibody region may be based on or derived. The extender fusion region may replace at least a portion of a variable domain of an antibody from which the antibody region may be based on or derived. The extender fusion region may replace at least a portion of a variable domain of an antibody from which the antibody region may be based on or derived. The extender fusion region may replace at least a portion of a complementarity-determining region (CDR) of an antibody from which the antibody region may be based on or derived. The extender fusion region may replace at least a portion of a CDR1, CDR2, CDR3, or a combination thereof of an antibody from which the antibody or fragment thereof may be based on or derived. The extender fusion region may replace at least a portion of a CDR3 of an antibody from which the antibody region may be based on or derived.

[0215] The extender fusion region may comprise a CDR or portion thereof. The extender fusion region may comprise a human CDR or portion thereof. The extender fusion region may comprise a non-human CDR or portion thereof. The CDR or portion thereof may be a CDR3 or portion thereof. The CDR or portion thereof may be a CDR2 or portion thereof. The CDR or portion thereof may be an ultralong CDR or portion thereof. The CDR or portion thereof may be an ultralong bovine CDR or portion thereof. The CDR or portion thereof may be a bovine ultralong CDR3 or portion thereof. The CDR or portion thereof may be an ultralong bovine CDR of an antibody heavy chain or portion thereof. The CDR or portion thereof may be a bovine ultralong CDR3 of an antibody heavy chain or portion thereof. The CDR or portion thereof may be an ultralong bovine CDR of an antibody light chain or portion thereof. The CDR or portion thereof may be a bovine ultralong CDR3 of an antibody light chain or portion thereof. The CDR or portion thereof may be a portion of an ultralong bovine CDR. The CDR or portion thereof may be a portion of a bovine ultralong CDR3. For example, some bovine antibodies have unusually long CDR3 sequences compared to other vertebrates. A typical CDR3 is about 8 to about 16 amino acids in length. An ultralong CDR3 sequence may be greater than about 35 amino acids in length. An ultralong CDR3 sequence may be greater than about 40 amino acids in length. An ultralong CDR3 sequence may be greater than about 50 amino acids in length. An ultralong CDR3 sequence may be greater than 60 amino acids in length. An ultralong CDR3 may be between about 50 and 61 amino acids in length. The ultralong CDR3 may comprise multiple cysteines. An ultralong CDR3 may comprise disulfide-bonded mini-domains as a result of the multiple cysteines. A significant proportion of the ultralong CDR3 may be encoded by a D-region of a VH gene formed through a process called V(D)J recombination. The ultralong CDR3 may comprise a stalk domain. The ultralong CDR3 may comprise a .beta.-strand stalk domain and a knob domain. The ultralong CDR3 may comprise a .beta.-strand stalk that supports a structurally diverse, disulfide-bonded, knob domain. The .beta.-strand stalk may comprise a .beta.-sheet. The immunoglobulin fusion proteins disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is not based on or derived from an ultralong CDR3. The extender fusion regions disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 35 or fewer consecutive amino acids of an ultralong CDR3. The extender fusion regions disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 15 or fewer consecutive amino acids of an ultralong CDR3. The extender fusion regions disclosed herein may comprise a .beta.-strand stalk, wherein the .beta.-strand stalk is encoded by a sequence that is based on or derived from a sequence of 7 or fewer consecutive amino acids of an ultralong CDR3. The portion of the bovine ultralong CDR3 may have a length of less than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 about 12, about 13, about 14, about 15, about 16, about 18, about 19 or about 20 amino acids. The immunoglobulin fusion protein may contain less than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 about 12, about 13, about 14, about 15, about 16, about 18, about 19 or about 20 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The extender fusion regions may contain 7 or fewer amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The immunoglobulin fusion protein may contain 15 or fewer amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The extender fusion regions may contain less than about 20 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The extender fusion regions may contain less than about 35 amino acids based on, derived from, identical to or homologous to a bovine ultralong CDR3. The bovine ultralong CDR3 may be selected from BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and F18. The bovine ultralong CDR3 may be selected from BF4E9, B-L1 and B-L2. The bovine ultralong CDR3 may be BLV1H12. The bovine ultralong CDR3 may not be selected from BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, and F18. The bovine ultralong CDR3 not be selected from BF4E9, B-L1 and B-L2. The bovine ultralong CDR3 may not be BLV1H12. The bovine ultralong CDR3 may comprise a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be based on or derived from a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be about 50% homologous to a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may be about 50%, about 60%, about 70%, about 80% or about 90% homologous to a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence selected from any one of SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence based on or derived from SEQ ID NOs: 248-250. The bovine ultralong CDR3 may not comprise a sequence based on or derived from a portion of any one of SEQ ID NOs: 248-250.

[0216] The extender fusion region may replace at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amino acids of an antibody from which the antibody region is based on or derived. The extender fusion region may replace at least about 1 or more amino acids of an antibody from which the antibody region is based on or derived. The extender fusion region may replace at least about 3 or more amino acids of an antibody from which the antibody region is based on or derived. The extender fusion region may replace at least about 5 or more amino acids of an antibody from which the antibody region is based on or derived.

[0217] The extender fusion region may comprise at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids. The extender fusion region may comprise at least about 150, 200, 250, 300, 350, 400, 450, 500 or more amino acids. The extender fusion region may comprise at least about 10 or more amino acids. The extender fusion region may comprise at least about 25 or more amino acids. The extender fusion region may comprise at least about 50 or more amino acids. The extender fusion region may comprise at least about 75 or more amino acids. The extender fusion region may comprise at least about 100 or more amino acids.

[0218] The extender fusion region may comprise less than about 1000, 900, 800, 700, 600, or 500 amino acids. The extender fusion region may comprise less than about 450, 400, 350, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 70, 60, 50 amino acids. The extender fusion region may comprise less than about 400 amino acids. The extender fusion region may comprise less than about 300 amino acids. The extender fusion region may comprise less than about 250 amino acids.

[0219] The extender fusion region may comprise between about 10 to about 500 amino acids. The extender fusion region may comprise between about 10 to about 400 amino acids. The extender fusion region may comprise between about 10 to about 300 amino acids. The extender fusion region may comprise between about 10 to about 250 amino acids. The extender fusion region may comprise between about 20 to about 500 amino acids. The extender fusion region may comprise between about 20 to about 400 amino acids. The extender fusion region may comprise between about 20 to about 300 amino acids.

[0220] Extender fusion regions may comprise (a) one or more extender peptides; (b) one or more therapeutic agents; (c) optionally, one or more linkers; and (d) optionally, one or more proteolytic cleavage sites. Exemplary extender fusion regions are depicted in FIG. 3A-G. For example, as shown in FIG. 3A, an extender fusion region comprises an extender peptide (210) and a therapeutic agent (220). As shown in FIG. 3B, an extender fusion region comprises two extender peptides (210, 230) and a therapeutic agent (220). As shown in FIG. 3C, an extender fusion region comprises an extender peptide (210) and a therapeutic agent (220) connected by a linker (240). As shown in FIG. 3D, an extender fusion region comprises an extender peptide (210), and therapeutic agent (220) flanked by two linkers (240, 250). As shown in FIG. 3E, an extender fusion region comprises an extender peptide (210), a therapeutic agent (220) and a proteolytic cleavage site (260), wherein the proteolytic cleavage site (260) is inserted between the extender peptide and therapeutic agent. As shown on FIG. 3F, an extender fusion region comprises two extender peptides (210, 230), two linkers (240, 250) and a therapeutic agent (220). As shown on FIG. 3G, an extender fusion region comprises two extender peptides (210, 230), two linkers (240, 250), a proteolytic cleavage site (260) and a therapeutic agent (220).

[0221] The extender fusion regions may comprise (a) a first extender peptide, wherein the first extender peptide comprises (i) an amino acid sequence comprising a beta strand secondary structure; and (ii) 7 or fewer amino acids based on or derived from an ultralong CDR3; and (b) a therapeutic agent. The extender fusion regions may further comprise one or more additional extender peptides comprising a beta strand secondary structure. The extender fusion regions may further comprise one or more linkers. The extender fusion regions may further comprise one or more proteolytic cleavage sites.

[0222] The extender fusion regions may comprise (a) a first extender peptide, wherein the first extender peptide comprises (i) an amino acid sequence comprising a beta strand secondary structure; and (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a first therapeutic agent. The extender fusion regions may further comprise one or more additional extender peptides comprising a beta strand secondary structure. The extender fusion regions may further comprise one or more linkers. The extender fusion regions may further comprise one or more proteolytic cleavage sites.

[0223] Extender Peptide

[0224] The immunoglobulin fusion proteins disclosed herein may comprise two or more extender peptides. The two or more extender peptides may be attached to the N-terminus, C-terminus, or N- and C-terminus of a therapeutic agent. The two or more extender peptides may be attached to each end of a therapeutic agent. The two or more extender peptides may be attached to different ends of a therapeutic agent.

[0225] The extender fusion region of the immunoglobulin fusion proteins disclosed herein may comprise one or more extender peptides. The extender fusion region may comprise 2 or more extender peptides. The extender fusion region may comprise 3 or more extender peptides. The extender fusion region may comprise 4 or more extender peptides. The extender fusion region may comprise 5 or more extender peptides. The extender fusion region may comprise a first extender peptide and a second extender peptide.

[0226] The extender peptide may comprise a secondary structure region, wherein the secondary structure region comprises a secondary structure and one or more additional amino acids. The secondary structure region may comprise a secondary structure and about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 16 about 18 about 20, about 22, about 24, about 26, about 28, about 30, about 32, about 34, about 36, about 38 or about 40 additional amino acids. The secondary structure region may comprise a secondary structure and about 1 to about 100 additional amino acids. The secondary structure region may be a beta strand secondary structure region. The secondary structure region may comprise a secondary structure and a peptide. The extender peptide may comprise one or more secondary structures. The extender peptide may comprise two or more secondary structures. The extender peptide may comprise 3, 4, 5, 6, 7 or more secondary structures. The two or more extender peptide may comprise one or more secondary structures. The two or more extender peptides may comprise two or more secondary structures. The two or more extender peptides may comprise 3, 4, 5, 6, 7 or more secondary structures. Each extender peptide may comprise at least one secondary structure. The secondary structures of the two or more extender peptides may be the same. Alternatively, the secondary structures of the two or more extender peptides may be different.

[0227] The one or more secondary structures may comprise one or more beta strands. The extender peptides may comprise two or more beta strands. For example, the first extender peptide comprises a first beta strand and the second extender peptide comprises a second beta strand. The extender peptides may comprise 3, 4, 5, 6, 7 or more beta strands. The two or more beta strands may be anti-parallel. The two or more beta strands may be parallel. The two or more beta strands may form a beta sheet.

[0228] The one or more extender peptides may comprise at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids. The one or more extender peptides may comprise at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more amino acids. The one or more extender peptides may comprise at least about 35, 40, 45, 50 or more amino acids.

[0229] The one or more extender peptides may comprise less than about 100 amino acids. The one or more extender peptides may comprise less than about 95, 90, 85, 80, 75, 70, 65, 60, 55, or 50 amino acids. The one or more extender peptides may comprise less than about 90 amino acids. The one or more extender peptides may comprise less than about 80 amino acids. The one or more extender peptides may comprise less than about 70 amino acids.

[0230] The two or more extender peptides may be the same length. For example, the first extender peptide and the second extender peptide are the same length. Alternatively, the two or more extender peptides are different lengths. In another example, the first extender peptide and the second extender peptide are different lengths. The two or more extender peptides may differ in length by at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids. The two or more extender peptides may differ in length by at least about 1 or more amino acids. The two or more extender peptides may differ in length by at least about 3 or more amino acids. The two or more extender peptides may differ in length by at least about 5 or more amino acids.

[0231] The extender peptide may be adjacent to an antibody region. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the antibody region. The extender peptide may be adjacent to a non-antibody region. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the non-antibody region. The extender peptide may be adjacent to a therapeutic agent. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the therapeutic agent. The extender peptide may be adjacent to a linker. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the linker. The extender peptide may be adjacent to a proteolytic cleavage site. The extender peptide may be attached to the N-terminus, C-terminus, or N- and C-terminus of the proteolytic cleavage site.

[0232] The extender peptide may connect the therapeutic agent to the antibody region. The extender peptide may be between the antibody region and the therapeutic agent, linker, and/or proteolytic cleavage site. The extender peptide may be between two or more antibody regions, therapeutic agents, linkers, proteolytic cleavage sites or a combination thereof. The extender peptide may be N-terminal to the antibody region, therapeutic agent, the linker, the proteolytic cleavage site, or a combination thereof. The extender peptide may be C-terminal to the antibody region, therapeutic agent, the linker, the proteolytic cleavage site, or a combination thereof. The extender peptide may comprise a linker. The linker may be rigid. The linker may be flexible. The linker may comprise one or more amino acids.

[0233] The extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308. The extender peptide may comprise an amino acid sequence that is at least about 85% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-128, 305 and 308.

[0234] The first extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 109-114 and 305. The first extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-114 and 305. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-114 and 305. The first extender peptide may comprise an amino acid sequence that is at least about 75% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-114 and 305. The first extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 109-114 and 305.

[0235] The second extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 115-128 and 308. The second extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 115-128 and 308. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 115-128 and 308. The second extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 115-128 and 308. The second extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 115-128 and 308.

[0236] The immunoglobulin fusion protein may comprise a first extender peptide. The first extender peptide may comprise a first beta strand. The therapeutic agent may comprise a second extender peptide. The second extender peptide may comprise a second beta strand. The first beta strand and the second beta strand may form a beta sheet.

[0237] The extender peptide may comprise an amino acid sequence of X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7 (SEQ ID NO: 109), wherein X.sup.1 is a negatively charged amino acid; X.sup.2 is a polar, uncharged amino acid; X.sup.3 is a positively charged amino acid; X.sup.4 is a positively charged amino acid; X.sup.5 is a hydrophobic amino acid; X.sup.6 is a polar, uncharged amino acid; and X.sup.7 is a polar, uncharged amino acid. A negatively charged amino acid may be D or E. A polar, uncharged amino acid may be S, T, C, Y, N, or Q. A positively charged amino acid may be K, R, or H. A hydrophobic amino acid may be G, A, V, L, I, M, W, F or P. X.sup.1 may be E or D. X.sup.2 may be T. X.sup.3 may be K. X.sup.4 may be K. X.sup.5 may be Y. X.sup.6 may be Q. X.sup.7 may be S. One or more additional amino acids may be inserted into SEQ ID NO: 109. One to ten amino acids may be inserted into SEQ ID NO: 109. The two or more additional amino acids may be inserted into one or more sites within SEQ ID NO: 109. The two or more additional amino acids may be inserted into two or more sites within SEQ ID NO: 109. The one or more additional amino acids may be inserted between X.sup.6 and X.sup.7 of SEQ ID NO: 109. The two or more additional amino acids may be contiguous. Alternatively, or additionally, the two or more amino acids are not contiguous. Alternatively, or additionally, one or more amino acids are added to one or more ends of SEQ ID NO: 109.

[0238] The extender peptide may comprise an amino acid sequence of ETKKYQX.sub.nS (SEQ ID NO: 305). N may be between 1 and 8. X.sub.n may be independently selected from a charged amino acid. X.sub.n may be independently selected from a basic amino acid. X.sub.n may be independently selected from an acidic amino acid. X.sub.n may be independently selected from a polar amino acid. X.sub.n may be independently selected from K, R, H, T and E.

[0239] The extender peptide may comprise an amino acid sequence of X.sup.1TX.sup.2NX.sup.3 (SEQ ID NO: 115). X.sup.1, X.sup.2 or X.sup.3 may be a polar amino acid. The polar amino acid may be S, T, C, Y, N, or Q. The polar amino acid may be Y. X.sup.1, X.sup.2 or X.sup.3 may be Y. X.sup.1, X.sup.2 or X.sup.3 may be the same amino acid. X.sup.1, X.sup.2 or X.sup.3 may be different amino acids. One or more additional amino acids may be inserted into SEQ ID NO: 115. One to ten amino acids may be inserted into SEQ ID NO: 115. The two or more additional amino acids may be inserted into one or more sites within SEQ ID NO: 115. The two or more additional amino acids may be inserted into two or more sites within SEQ ID NO: 115. The two or more additional amino acids may be contiguous. Alternatively, or additionally, the two or more amino acids are not contiguous. Alternatively, or additionally, one or more amino acids are added to one or more ends of SEQ ID NO: 115. The one or more additional amino acids may be N-terminal to X.sup.1 of SEQ ID NO: 115. The one or more additional amino acids N-terminal to X.sup.1 may be S. The one or more additional amino acids may be C-terminal to X.sup.3 of SEQ ID NO: 115. The one or more additional amino acids C-terminal to X.sup.3 may be E.

[0240] The extender peptide may comprise an amino acid sequence of YX.sup.1YX.sup.2Y (SEQ ID NO: 128). X.sup.1 or X.sup.1 may be a polar amino acid. The polar amino acid may be S, T, C, Y, N, or Q. The polar amino acid may be T or N. X.sup.1 or X.sup.1 may be independently selected from T or N. X.sup.1 or X.sup.1 may be the same amino acid. X.sup.1 or X.sup.1 may be different amino acids. One or more additional amino acids may be inserted into SEQ ID NO: 128. One to ten amino acids may be inserted into SEQ ID NO: 128. The two or more additional amino acids may be inserted into one or more sites within SEQ ID NO: 128. The two or more additional amino acids may be inserted into two or more sites within SEQ ID NO: 128. The two or more additional amino acids may be contiguous. Alternatively, or additionally, the two or more amino acids are not contiguous. Alternatively, or additionally, one or more amino acids are added to one or more ends of SEQ ID NO: 128. The N-terminus of SEQ ID NO: 128 may further comprise a S residue. The C-terminus of SEQ ID NO: 128 may further comprise an E residue.

[0241] The extender peptide may comprise an amino acid sequence of SX.sub.nX.sup.1TX.sup.2NX.sup.3X.sup.4 (SEQ ID NO: 308). N may be between 1 and 8. X.sub.n may be one or more polar amino acids. X.sub.n may 2, 3, 4, 5, 6, 7 or more polar amino acids. X.sub.n may comprise one or more non-polar amino acids.

[0242] The extender peptide may comprise 5 or more polar amino acids. The extender peptide may comprise 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more polar amino acids. The polar amino acids may be consecutive. Alternatively, or additionally, the polar amino acids may be non-consecutive.

[0243] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 111; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 119. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 111; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 119. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 111. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 119. The first extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 111. The first extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 119. The second extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 119. The second extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 119.

[0244] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 111; and (b) a second extender peptide comprising an amino acid sequence based on or derived from any one of SEQ ID NOs: 120-124. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 111; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of any one of SEQ ID NOs: 120-124. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 111. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of any one of SEQ ID NOs: 120-124. The first extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 111. The first extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 111. The second extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of any one of SEQ ID NOs: 120-124. The second extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of any one of SEQ ID NOs: 120-124.

[0245] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from any one of SEQ ID NOS: 118-119 and 308; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 126. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of any one of SEQ ID NOS: 118-119 and 308; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 126. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NOS: 118-119 and 308. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 126. The first extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of any one of SEQ ID NOS: 118-119 and 308. The first extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of any one of SEQ ID NOS: 118-119 and 308. The second extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 126. The second extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 126.

[0246] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 114; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 127. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 114; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 127. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 172. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 127. The first extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 114. The first extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 114. The second extender peptide may comprise an amino acid sequence comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 127. The second extender peptide may comprise an amino acid sequence comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 127.

[0247] The extender peptides disclosed herein may be based on or derived from a CDR. The extender peptides disclosed herein may be based on or derived from a CDR3. The extender peptide may be based on or derived from a human CDR. The extender peptide may not be based on or derived from any CDR. The extender peptide may be synthetic. The extender peptide may comprise a beta strand secondary structure. The extender fusion region may comprise a first extender peptide comprising a beta strand and a second extender peptide comprising a second beta strand, wherein the first beta strand and the second beta strand form a beta sheet. The extender peptide may not comprise a beta strand. The extender peptide may form a rigid structure. The rigid structure may not comprise a beta strand. The rigid structure may not comprise an alpha helix. The CDR3 may be an ultralong CDR3. An "ultralong CDR3" or an "ultralong CDR3 sequence", used interchangeably herein, may comprise a CDR3 that is not derived from a human antibody sequence. An ultralong CDR3 may be 35 amino acids in length or longer, for example, 40 amino acids in length or longer, 45 amino acids in length or longer, 50 amino acids in length or longer, 55 amino acids in length or longer, or 60 amino acids in length or longer. The ultralong CDR3 may be a heavy chain CDR3 (CDR-H3 or CDRH3). The ultralong CDR3 may comprise a sequence derived from or based on a ruminant (e.g., bovine) sequence. An ultralong CDR3 may comprise one or more cysteine motifs. An ultralong CDR3 may comprise at least 3 or more cysteine residues, for example, 4 or more cysteine residues, 6 or more cysteine residues, or 8 or more cysteine residues. Additional details on ultralong CDR3 sequences can be found in Saini S S, et al. (Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies, European Journal of Immunology, 1999), Zhang Y, et al. (Functional antibody CDR3 fusion proteins with enhanced pharmacological properties, Angew Chem Int Ed Engl, 2013), Wang F, et al. (Reshaping antibody diversity, Cell, 2013) and U.S. Pat. No. 6,740,747.

[0248] The extender peptides may comprise 7 or fewer amino acids based on or derived from a CDR. The extender peptides may comprise 6, 5, 4, 3, 2, 1 or fewer amino acids based on or derived from a CDR. The amino acids may be consecutive. The amino acids may be non-consecutive. The CDR may be CDR1. The CDR may be CDR2. The CDR may be CDR3. The CDR may be an ultralong CDR. The CDR may be bovine. The CDR may be human. The CDR may be non-human.

[0249] The extender peptides may be based on or derived from a CDR, wherein the CDR is not an ultralong CDR3. The extender peptides may comprise 10 or fewer amino acids based on or derived from a CDR3. The extender peptides may comprise 9, 8, 7, 6, 5, 4, 3, 2, 1 or fewer amino acids based on or derived from a CDR3. The extender peptides may comprise 8 or fewer amino acids based on or derived from a CDR3. The extender peptides may comprise 7 or fewer amino acids based on or derived from a CDR3. The extender peptides may comprise 5 or fewer amino acids based on or derived from a CDR3. The extender peptide may be based on or derived from a human sequence. The extender peptide may be based on or derived from a non-human sequence. The extender peptide may be a synthetic sequence. The extender peptide may be based on or derived from a human sequence encoding a protein secondary structure. The extender peptide may be based on or derived from a human sequence encoding a beta strand. The first extender peptide may be based on or derived from a human sequence encoding a beta strand and the second extender peptide may be based on or derived from a human sequence encoding a beta strand, wherein the first beta strand and the second beta strand form a beta sheet.

[0250] The extender peptides may comprise an amino acid sequence that is less than about 50% identical to an amino acid sequence comprising an ultralong CDR3. The extender peptides may comprise an amino acid sequence that is less than about 45%, 40%, 35%, 30%, 25%, 20%, 25%, or 10% identical to an amino acid sequence comprising an ultralong CDR3. The extender peptides may comprise an amino acid sequence that is less than about 30% identical to an amino acid sequence comprising an ultralong CDR3. The extender peptides may comprise an amino acid sequence that is less than about 25% identical to an amino acid sequence comprising an ultralong CDR3. The extender peptides may comprise an amino acid sequence that is less than about 20% identical to an amino acid sequence comprising an ultralong CDR3.

[0251] The extender peptide may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 1 or more amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 3 or more amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 5 or more amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The two or more amino acids attached to or inserted into the ultralong CDR3 may be contiguous. Alternatively, or additionally, the two or more amino acids attached to or inserted into the ultralong CDR3 are not contiguous.

[0252] The extender peptide may comprise 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or fewer amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 20 or fewer amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 15 or fewer amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The extender peptide may comprise 10 or fewer amino acids attached to or inserted into an ultralong CDR3-based portion of the extender peptide. The amino acids attached to or inserted into the ultralong CDR3 may be contiguous. Alternatively, or additionally, the amino acids attached to or inserted into the ultralong CDR3 are not contiguous.

[0253] Various extender peptides comprising anti-parallel beta strands and their thermostability are depicted in FIG. 4.

[0254] Therapeutic Agent

[0255] The immunoglobulin fusion proteins disclosed herein may comprise one or more therapeutic agents. The therapeutic agent may be a protein. The therapeutic agent may be a polypeptide. The therapeutic agent may be a peptide. The therapeutic agent may be a functional peptide. The therapeutic agent may be a synthetic and/or non-naturally occurring peptide. The therapeutic agent may be an agonist and/or an activator. The therapeutic agent may be an antagonist and/or an inhibitor. The therapeutic agent may be a substrate. The therapeutic agent may be a binding partner. The therapeutic agent may be a small molecule. The therapeutic agent may be a co-factor and/or co-regulator. The immunoglobulin fusion proteins disclosed herein may comprise two or more therapeutic agents. The immunoglobulin fusion proteins disclosed herein may comprise 3, 4, 5, 6 or more therapeutic agents. The two or more therapeutic agents may be the same. The two or more therapeutic agents may be different.

[0256] The one or more therapeutic agents may be based on or derived from a protein. The protein may be a growth factor, cytokine, hormone or toxin. The growth factor, by non-limiting example, may be GCSF, GMCSF or GDF11. The GCSF may be a bovine GCSF (bGCSF). The GCSF may be a human GCSF. The GMCSF may be a bovine GMCSF or a human GMCSF. The therapeutic agent may be grafted into an ultralong CDR3H of an antibody region, as shown in FIG. 36. FIG. 36 shows an exemplary scheme for grafting bGCSF onto the `knob` domain of a bovine antibody with an ultralong CDR3H region.

[0257] The cytokine may be an interferon or interleukin. The cytokine, by non-limiting example, may be stromal cell-derived factor 1 (SDF-1). The interferon may be interferon-beta. The interferon may be interferon-alpha. The interleukin may be interleukin 11 (IL-11). The interleukin may be interleukin 8 (IL-8) or interleukin 21 (IL-21).

[0258] The hormone, by non-limiting example, may be exendin-4, GLP-1, relaxin, oxyntomodulin, leptin, betatrophin, bovine growth hormone (bGH), human growth hormone (hGH), erythropoietin (EPO), or parathyroid hormone. The hormone may be somatostatin. The parathyroid hormone may be a human parathyroid hormone. The erythropoietin may be a human erythropoietin. The therapeutic agent may be grafted into an ultra-long CDR3H of an antibody region, as shown in FIG. 23. In some embodiments, the therapeutic agent replaces a portion of an ultralong CDR3H. In some embodiments, the therapeutic agent replaces a knob domain of an ultralong CDR3H. FIG. 28 depicts an exemplary schematic representation of engineering glucagon-like peptide 1 (GLP-1) or Exendin-4 (Ex-4) into an ultralong CDR3H. The resulting GLP-1 and/or Ex-4 fusion proteins comprise an N-terminal proteolytic cleavage site. The fusion proteins may be cleaved to release the N-terminus of GLP-1 and/or Ex-4.

[0259] The toxin, by non-limiting example, may be Moka1, or Vm-24. The toxin may be ziconotide or chlorotoxin. The therapeutic agent may be grafted into an ultra-long CDR3H of an antibody region, as shown in FIG. 17. In some embodiments, the therapeutic agent replaces a knob domain of an ultralong CDR3H. FIG. 17 depicts the replacement of a knob domain of an ultralong CDR3H on a bovine antibody (PDB ID: 4K3D) with a toxin.

[0260] The protein may be angiogenic. The protein may be anti-angiogenic. The protein, by non-limiting example, may be angiopoeitin-like 3 (ANGPTL3). The angiopoeitin-like 3 may be a human angiopoeitin-like 3.

[0261] The one or more therapeutic agents may be based on or derived from a peptide. The peptide, by non-limiting example, may be a neutrophil elastase inhibitor (EI).

[0262] The therapeutic agent may be based on or derived from an amino acid sequence selected from any one of SEQ ID NOs: 263-298. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 263-298. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 263-298.

[0263] The therapeutic agent may comprise an amino acid sequence comprising at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or more amino acids of any one of SEQ ID NOs: 200-235. The therapeutic agent may comprise an amino acid sequence comprising at least about 10 or more amino acids of any one of SEQ ID NOs: 200-235. The therapeutic agent may comprise an amino acid sequence comprising at least about 15 or more amino acids of any one of SEQ ID NOs: 200-235. The therapeutic agent may comprise an amino acid sequence comprising at least about 20 or more amino acids of any one of SEQ ID NOs: 200-235. The therapeutic agent may comprise an amino acid sequence comprising at least about 30 or more amino acids of any one of SEQ ID NOs: 200-235. The amino acids may be consecutive. The amino acids may be non-consecutive.

[0264] The therapeutic agent may be based on or derived from an amino acid sequence selected from any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 200-235.

[0265] The therapeutic agent may be encoded by a nucleic acid sequence based on or derived from any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 50% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 167-199.

[0266] The therapeutic agent may be encoded by a nucleic acid sequence based on or derived from any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 50% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 70% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleic acid sequence that may be at least about 80% homologous to any one of SEQ ID NOs: 167-199.

[0267] The therapeutic agents may be inserted into the antibody region. Insertion of the therapeutic agent into the antibody region may comprise removal or deletion of one or more amino acids from the antibody region.

[0268] The one or more extender peptides may be attached to the N-terminus, C-terminus or both the N- and C-termini of a therapeutic agent. The one or more linkers may be attached to the N-terminus, C-terminus or both the N- and C-termini of a therapeutic agent. The one or more proteolytic cleavage sites may be attached to the N-terminus, C-terminus or both the N- and C-termini of a therapeutic agent. Alternatively, the therapeutic agent may be connected to the antibody region without the aid of an extender peptide. The therapeutic agent may be connected to the antibody via one or more linkers.

[0269] The therapeutic agent may be an agonist. The therapeutic agent may be an antagonist. The therapeutic agent may be a peptide. The therapeutic agent may be a cyclic peptide. The cyclic peptide may comprise a polypeptide chain wherein the amino termini and carboxyl termini, amino termini and side chain, carboxyl termini and side chain, or side chain and side chain are linked with a covalent bond that generates a ring. The cyclic peptide may comprise a 2 or more amino acids. The cyclic peptide may be selected from a cyclic isopeptide, a cyclic depsipeptide, a bicyclic peptide and a homodetic cyclic peptide. The cyclic peptide may comprise a naturally occurring cyclic peptide. The cyclic peptide may comprise a synthetic cyclic peptide. The cyclic peptide may comprise a modified naturally occurring peptide. The peptide may comprise a conformationally constrained peptide. The peptide may comprise a peptide modified to comprise a conformationally constrained peptide. The conformationally constrained peptide may have a reduced conformational entropy relative to a respective peptide that is not conformationally constrained. The conformationally constrained peptide may comprise a rigid feature and/or a rigid region and/or a rigid domain. The conformationally constrained peptide may be locked into a conformation by one or more bonds between non-consecutive amino acids. The one or more bonds may be a disulfide bond. A conformationally constrained peptide may have a greatly improved binding affinity and/or specificity to a target relative to endogenous or naturally-occurring binding partners of the target. By non-limiting example, the conformationally constrained peptide may be a peptide comprising a .beta.-hairpin structure. The conformationally constrained peptide may comprise a region that is U-shaped, rigid, stalk-like, knob-like, pointed, angular or shaped to fit into a specific region of a target or binding partner. The therapeutic agent may further comprise one or more turn sequences. The turn sequence may comprise one or more amino acids. The turn sequence comprise about 1, about 2, about 3, about 4 or about 5 amino acids. The turn sequence may comprise one or more amino acids selected from glycine, asparagine and proline. The turn sequence may provide the therapeutic agent with a target binding conformation. The therapeutic agent may be a non-cyclic peptide. The therapeutic agent may be less than about 30 peptides, less than about 25 peptides, less than 20 peptides, less than about 15 peptides or less than about 10 peptides. The peptide may be synthesized. The peptide may be genetically encoded. The therapeutic agent may be naturally occurring. The therapeutic agent may be synthetic. The therapeutic agent may be a naturally occurring peptide comprising a modification. The modification can be an addition of one or more amino acids. The modification can be a deletion of one or more amino acids. The modification may be a re-arrangement of two or more amino acids.

[0270] The therapeutic agent may bind a target. The target may be a cell surface molecule. The target may be a circulating molecule. The cell surface molecule may be a receptor. By non-limiting example, the receptor may be a G protein coupled receptor. The receptor may be CXCR4. The target may be an enzyme. By non-limiting example, the enzyme may be a neutrophil elastase. The therapeutic agent may be about 80%, about 85%, about 90%, about 95% or about 100% effective at blocking a competing target-binding molecule as measured by a competitive binding assay. The therapeutic agent may be about 80%, about 85%, about 90%, about 95% or about 100% effective at blocking a competing target-binding molecule as measured by a target activity assay. The therapeutic agent may have a greater binding affinity for a target than a competing target-binding molecule. The competing target-binding molecule may be ligand. The competing target-binding molecule may be a substrate. The competing target-binding molecule may be endogenous. The competing target-binding molecule may be exogenous. The competing target-binding molecule may be naturally occurring. The competing target-binding molecule may be synthetic. The competing target-binding molecule may be organic. The competing target-binding molecule may be inorganic. The competing target-binding molecule may be a toxin. The competing target-binding molecule may be molecule on another cell. By way of non-limiting examples, the competing target-binding molecule may be selected from a chemokine, a cytokine, a growth factor, an integrin, a cell adhesion molecule, a biomolecule and a hormone. The therapeutic agent may bind a deep pocket, a cavity, an active site or a fold of a ligand binding domain or a catalytic domain of a target and block endogenous or exogenous ligands or substrates from binding to the target. The therapeutic agent may bind the surface of a ligand binding domain or catalytic domain of a target to effectively block endogenous or exogenous ligand or substrate binding to the target.

[0271] Linkers

[0272] The immunoglobulin fusion proteins, antibody regions, and/or extender fusion regions may further comprise one or more linkers. The immunoglobulin fusion proteins, antibody regions, and/or extender fusion region may further comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more linkers. The extender fusion region may further comprise one or more linkers. The extender fusion region may further comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more linkers. The one or more linkers may be rigid. The one or more linkers may be flexible. The linker may comprise about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 amino acids. The linker may comprise about 10, about 15, about 20, about 25, about 30, about 35 or about 40 amino acids.

[0273] The one or more linkers are attached to the N terminus, C terminus or both N and C termini of a therapeutic agent. The one or more linkers are attached to the N terminus, C terminus or both N and C termini of the extender peptide. The one or more linkers are attached to the N-terminus, C-terminus or both N and C termini of a proteolytic cleavage site. The one or more linkers may be attached to a therapeutic agent, extender peptide, proteolytic cleavage site, extender fusion region, antibody region, or a combination thereof.

[0274] The one or more linkers may comprise the sequence (X.sup.eX.sup.fX.sup.gX.sup.h).sub.n(SEQ ID NO: 309). N may be 1 to 5. X.sup.e, X.sup.f and X.sup.g are independently selected from a hydrophobic amino acid. X.sup.h may be a polar, uncharged amino acid. The linker sequence may further comprise one or more cysteine (C) residues. The one or more cysteine residues are at the N-terminus, C-terminus, or a combination thereof.

[0275] The one or more linkers may comprise an amino acid sequence selected from any one of SEQ ID NOs: 161-166 and 309. The one or more linkers may comprise an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 161-166 and 309. The one or more linkers may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to any one of SEQ ID NOs: 161-166 and 309. The one or more linkers may comprise an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 161-166 and 309. The one or more linkers may comprise an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 161-166 and 309.

[0276] Proteolytic Cleavage Site

[0277] The immunoglobulin fusion proteins disclosed herein may further comprise one or more proteolytic cleavage sites. The immunoglobulin fusion protein comprising one or more proteolytic cleavage sites may be referred to herein as a clip fusion protein and/or a clipped version (of the fusion protein). The immunoglobulin fusion protein may comprise a connecting peptide, wherein the connecting peptide comprises a proteolytic cleavage site. The connecting peptide comprising the proteolytic cleavage site may be located between the therapeutic agent and the antibody region. The connecting peptide comprising the proteolytic cleavage site may be located between the extender fusion region and the antibody region. The connecting peptide comprising the proteolytic cleavage site may be located between the extender peptide and the therapeutic agent. The connecting peptide comprising the proteolytic cleavage site may be located within the extender peptide. The connecting peptide comprising the proteolytic cleavage site may be located within the antibody region. The connecting peptide comprising the proteolytic cleavage site may be located within the extender fusion region. The connecting peptide comprising the proteolytic cleavage site may be located within the therapeutic agent. The proteolytic cleavage site may be selected from any one of SEQ ID NOs: 236-239. The immunoglobulin fusion proteins disclosed herein may further comprise 2 or more proteolytic cleavage sites. The immunoglobulin fusion proteins disclosed herein may further comprise 3 or more proteolytic cleavage sites. The immunoglobulin fusion proteins disclosed herein may further comprise 4, 5, 6, 7 or more proteolytic cleavage sites.

[0278] The immunoglobulin fusion proteins disclosed herein may comprise a sequence with one or more cleavage sites between (a) the antibody region and the extender fusion region; (b) the antibody region and the extender peptide; (c) the extender peptide and therapeutic agent; or (d) a combination of a-c. The extender fusion region may comprise one or more proteolytic cleavage sites. The one or more cleavage sites may be on the C-terminus, N-terminus, and/or N- and C-terminus of a therapeutic agent. The one or more cleavage sites may be on the C-terminus, N-terminus, and/or N- and C-terminus of the extender peptide. The one or more cleavage sites may be on the C-terminus, N-terminus, and/or N- and C-terminus of the antibody region. The proteolytic cleavage site may be on the N- or C-terminus of the therapeutic agent. Digestion of the proteolytic cleavage site may result in release of the N- or C-terminus of the therapeutic agent from the immunoglobulin fusion protein. For example, an immunoglobulin fusion protein which may be cleaved to release the amino-terminus of a therapeutic agent is referred to as RN, for released N-terminus. The proteolytic cleavage site may be on the N- and C-termini of the therapeutic agent. Digestion of the proteolytic cleavage site may result in release of the therapeutic agent from the immunoglobulin fusion protein.

[0279] Alternatively, or additionally, the proteolytic cleavage site is located within the amino acid sequence of the therapeutic agent, extender peptide, antibody region, or a combination thereof. The therapeutic agent may comprise one or more proteolytic cleavage sites within its amino acid sequence. For example, a clip fusion protein may be SEQ ID NO: 78, which discloses an exendin-4 fusion protein comprising two internal proteolytic cleavage sites. Digestion of the proteolytic cleavage sites within the relaxin protein may result in release of an internal fragment of the relaxin protein.

[0280] Two or more proteolytic cleavage sites may surround a therapeutic agent, extender peptide, linker, antibody region, or combination thereof. Digestion of the proteolytic cleavage site may result in release of a peptide fragment located between the two or more proteolytic cleavage sites. For example, the proteolytic cleavage sites may flank a therapeutic agent-linker peptide. Digestion of the proteolytic cleavage sites may result in release of the therapeutic agent-linker.

[0281] The proteolytic cleavage site may be recognized by one or more proteases. The one or more proteases may be a serine protease, threonine protease, cysteine protease, aspartate protease, glutamic protease, metalloprotease, exopeptidases, endopeptidases, or a combination thereof. The proteases may be selected from the group comprising Factor VII or Factor Xa. Additional examples of proteases include, but are not limited to, aminopeptidases, carboxypeptidases, trypsin, chymotrypsin, pepsin, papain, and elastase.

[0282] Dual Fusion Proteins

[0283] Further disclosed herein are dual fusion proteins. As used herein, dual fusion proteins may also be referred to as immunoglobulin dual fusion proteins and immunoglobulin fusion proteins. Dual fusion proteins disclosed herein may comprise one or more immunoglobulin fusion proteins disclosed herein or one or more portions thereof. The dual fusion protein may comprise two or more therapeutic agents and one or more antibody regions. The dual fusion protein may comprise one or more immunoglobulin fusion proteins disclosed herein. The antibody region may comprise a heavy chain and a light chain. At least one therapeutic agent may be inserted into the heavy chain. At least one therapeutic agent may be inserted into the light chain. The two or more therapeutic agents may be inserted the heavy chain. The two or more therapeutic agents may be inserted into the light chain. By non-limiting example, the dual fusion protein may comprise GCSF and EPO as the therapeutic agents. Also by non-limiting example, the dual fusion protein may comprise leptin and exendin-4 as the therapeutic agents.

[0284] The dual fusion protein may comprise one antibody region and two or more extender fusion regions. The dual fusion protein may comprise a first extender fusion region and a second extender fusion region. The first extender fusion region may comprise a beta strand. The first extender fusion region may comprise at least two beta strands, wherein the two beta strands form a beta sheet. The two beta strands may be parallel. The two beta strands may be anti-parallel. The second extender fusion region may comprise a beta strand. The second antibody region may comprise at least two beta strands, wherein the two beta strands form a beta sheet. The two beta strands may be parallel. The two beta strands may be anti-parallel. The second extender fusion region may comprise an alpha helix. The second extender fusion may comprise two alpha helices, wherein the alpha helices form a coiled coil. The alpha helices may be parallel. The alpha helices may be anti-parallel. The second extender fusion region may comprise a linker. The linker may be less than about 20 amino acids. The linker may be less than about 10 amino acids. The second extender fusion region may comprise two or more linkers. The linker may be less than about 7 amino acids. The first extender fusion region and/or the second extender fusion region may be a non-antibody region.

[0285] The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 24-27, 29-33, and 36-39. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 248-250.

[0286] The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 76, 240 and 244. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 76, 240 and 244. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to SEQ ID NOs: 76, 240 and 244. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 76, 240 and 244. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to SEQ ID NOs: 76, 240 and 244.

[0287] The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 77, 241 and 245. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 77, 241 and 245. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 77, 241 and 245. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 77, 241 and 245. The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 77, 241 and 245.

[0288] The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 81, 242 and 246. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 81, 242 and 246.

[0289] The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 83, 243 and 247. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 83, 243 and 247. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 83, 243 and 247. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 83, 243 and 247. The dual fusion protein may comprise a heavy chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 83, 243 and 247.

[0290] The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 50% homologous to SEQ ID NO: 201. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NO: 201. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 70% homologous to SEQ ID NO: 201. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 80% homologous to SEQ ID NO: 201. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 90% homologous to SEQ ID NO: 201.

[0291] The dual fusion protein may comprise a light chain fusion based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 80% homologous to SEQ ID NOs: 1-4, 14, 15, 20 and 297. The dual fusion protein may a light chain fusion based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 1-4, 14, 15, 20 and 297. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NO: 210. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to SEQ ID NO: 210. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 70% homologous to SEQ ID NO: 210. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 80% homologous to SEQ ID NO: 210. The light chain fusion may further comprise a therapeutic agent based on or derived from an amino acid sequence that is at least about 90% homologous to SEQ ID NO: 210.

[0292] At least a portion of the dual fusion protein may be encoded by one or more nucleic acid sequences that are at least about 50% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304, and 240-247. At least a portion of the dual fusion protein may be encoded by one or more nucleic acid sequences that are at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304, and 240-247. At least a portion of the dual fusion protein may be encoded by one or more nucleic acid sequences that are at least about 70% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304, and 240-247. At least a portion of the dual fusion protein may be encoded by one or more nucleic acid sequences that are at least about 80% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304, and 240-247. At least a portion of the dual fusion protein may be encoded by one or more nucleic acid sequences that are at least about 90% homologous to any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304, and 240-247.

[0293] The dual fusion protein may be comprise an antibody region that is encoded by one or more nucleotide sequences that are at least about 50% homologous to any one of SEQ ID NOs: 1-20 and 254-259. The dual fusion protein may be comprise an antibody region that is encoded by one or more nucleotide sequences that are at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 1-20 and 254-259. The dual fusion protein may be comprise an antibody region that is encoded by one or more nucleotide sequences that are at least about 70% homologous to any one of SEQ ID NOs: 1-20 and 254-259. The dual fusion protein may be comprise an antibody region that is encoded by one or more nucleotide sequences that are at least about 80% homologous to any one of SEQ ID NOs: 1-20 and 254-259. The dual fusion protein may be comprise an antibody region that is encoded by one or more nucleotide sequences that are at least about 90% homologous to any one of SEQ ID NOs: 1-20 and 254-259.

[0294] The dual fusion protein may comprise two or more therapeutic agents, wherein at least one of the therapeutic agents are encoded by a nucleotide sequence that is at least about 50% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleotide sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleotide sequence that is at least about 70% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleotide sequence that is at least about 80% homologous to any one of SEQ ID NOs: 167-199. The therapeutic agent may be encoded by a nucleotide sequence that is at least about 90% homologous to any one of SEQ ID NOs: 167-199.

[0295] The dual fusion protein may be comprise an antibody region that is based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 21-40 and 248-253. The dual fusion protein may be comprise an antibody region that is based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 21-40 and 248-253. The dual fusion protein may be comprise an antibody region that is based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 21-40 and 248-253. The dual fusion protein may be comprise an antibody region that is based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 21-40 and 248-253. The dual fusion protein may be comprise an antibody region that is based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 21-40 and 248-253. The dual fusion protein may comprise two or more therapeutic agents, wherein at least one of the therapeutic agents are based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 97% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 70% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 80% homologous to any one of SEQ ID NOs: 200-235. The therapeutic agent may be based on or derived from an amino acid sequence that is at least about 90% homologous to any one of SEQ ID NOs: 200-235.

[0296] Exemplary immunoglobulin dual fusion proteins are depicted in FIG. 2, Formula IIIA and Formula VIIA. As shown in Formula IIIA of FIG. 2, the immunoglobulin dual fusion protein may comprise (a) a first antibody region (A.sup.1) attached to a first extender fusion region comprising a first therapeutic agent (T.sup.1) attached to two extender peptides (E.sup.1, E.sup.2); and (b) a second antibody region (A.sup.2) attached to a second extender fusion region comprising a second therapeutic agent (T.sup.2) attached to two extender peptides (E.sup.3, E.sup.4). The immunoglobulin dual fusion proteins may further comprise one or more linkers and one or more proteolytic cleavage sites. The one or more proteolytic cleavage sites may be attached to the N- and/or C-terminus of a therapeutic agent. Proteolytic cleavage of the proteolytic cleavage site may release the N- and/or C-terminus of the therapeutic agent from the immunoglobulin fusion protein. Formula VIIA of FIG. 2 depicts an exemplary immunoglobulin dual fusion protein in which the N-terminus of the second therapeutic agent (T.sup.2) has been released. E.sub.3 may comprise a peptide selected from a beta strand, an alpha helix and a linker E.sub.4 may comprise a peptide selected from a beta strand, an alpha helix and a linker. An immunoglobulin dual fusion protein may comprise (a) a first antibody region (A.sup.1) attached to a first extender fusion region comprising a first therapeutic agent (T.sup.1) attached to two extender peptides (E.sup.1, E.sup.2); and (b) a second antibody region (A.sup.2) attached directly to a second therapeutic agent (T.sup.2). The therapeutic agent may comprise one or more secondary structures. The therapeutic agent may comprise a beta strand. The therapeutic agent may comprise an alpha helix. The therapeutic agent may comprise a linker. The therapeutic agent may comprise a rigid domain and/or region. The therapeutic agent may comprise a stalk-like feature. The therapeutic agent may comprise a knob-like feature. The therapeutic agent may comprise a beta sheet. The therapeutic agent may comprise a coiled coil. The therapeutic agent may comprise a hairpin structure. The therapeutic agent may comprise a beta hairpin structure.

[0297] The second extender fusion region may comprise one or more secondary structures, wherein the secondary structure comprises one or more alpha helices. The one or more alpha helices may form a coiled coil secondary structure. The extender peptides may comprise two or more alpha helices. By non-limiting example, the second extender fusion region may comprise a first extender peptide, wherein the first extender peptide comprises a first alpha helix and the second extender peptide comprises a second alpha helix. The extender peptides may comprise 3, 4, 5, 6, 7 or more alpha helices. The two or more alpha helices may be anti-parallel. The two or more alpha helices may be parallel. The two or more alpha helices may form one or more coiled-coil domains. The one or more alpha helices may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 135-138 and 145-160. The extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138 and 145-160. The extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138 and 145-160. The extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138 and 145-160. The extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138 and 145-160. The extender peptide may comprise an amino acid sequence that is at least about 85% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138 and 145-160.

[0298] The first extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 135-138, 149, 151, 153, 155, 157 and 159. The first extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138, 149, 151, 153, 155, 157 and 159. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138, 149, 151, 153, 155, 157 and 159. The first extender peptide may comprise an amino acid sequence that is at least about 75% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138, 149, 151, 153, 155, 157 and 159. The first extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 135-138, 149, 151, 153, 155, 157 and 159.

[0299] The second extender peptide may comprise an amino acid sequence that is based on or derived from any one of SEQ ID NOs: 145-148, 150, 152, 154, 156, 158, and 160. The second extender peptide may comprise an amino acid sequence that is at least about 50% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 145-148, 150, 152, 154, 156, 158, and 160. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 145-148, 150, 152, 154, 156, 158, and 160. The second extender peptide may comprise an amino acid sequence that is at least about 70% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 145-148, 150, 152, 154, 156, 158, and 160. The second extender peptide may comprise an amino acid sequence that is at least about 80% homologous to an amino acid sequence based on or derived from any one of SEQ ID NOs: 145-148, 150, 152, 154, 156, 158, and 160.

[0300] The extender peptide may comprise the sequence X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7X.sup.8X.sup.9X.sup.10X.- sup.11X.sup.12X.sup.13X.sup.14 (SEQ ID NO: 129). X.sup.1-X.sup.14 may be independently selected from a positively charged amino acid or a hydrophobic amino acid. X.sup.1-X.sup.14 may be independently selected from the group comprising alanine (A), asparagine (N), isoleucine (I) leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K). X.sup.1-X.sup.14 may be independently selected from the group comprising alanine (A), leucine (L) and lysine (K). Alanine may comprise at least about 30% of the total amino acid composition Alanine may comprise less than about 70% of the total amino acid composition. Leucine may comprise at least about 20% of the total amino acid composition. Leucine may comprise less than about 50% of the total amino acid composition. Lysine may comprise at least about 20% of the total amino acid composition. Lysine may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 70% of the total amino acid composition. The hydrophobic amino acids may comprise less than about 90% of the total amino acid composition.

[0301] The extender peptide may comprises the sequence (X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7).sub.n (SEQ ID NO. 310). N may be 1-5. N may be 1-3. X.sup.1-X.sup.7 may be independently selected from a positively charged amino acid or a hydrophobic amino acid. X.sup.1-X.sup.7 may be independently selected from the group comprising alanine (A), asparagine (N), isoleucine, (I), leucine (L), valine (V), glutamine (Q), glutamic acid (E) and lysine (K). Alanine (A) may comprise at least about 30% of the total amino acid composition Alanine (A) may comprise less than about 70% of the total amino acid composition. Leucine may comprise at least about 20% of the total amino acid composition. Leucine may comprise less than about 50% of the total amino acid composition. Lysine may comprise at least about 20% of the total amino acid composition. Lysine may comprise less than about 50% of the total amino acid composition. Asparagine may comprise about 50% of the total amino acid composition. Isoleucine may comprise about 50% of the total amino acid composition. Valine may comprise about 50% of the total amino acid composition. Glutamine may comprise about 50% of the total amino acid composition. Glutamic acid may comprise about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 70% of the total amino acid composition. The hydrophobic amino acids may comprise less than about 90% of the total amino acid composition.

[0302] The first extender peptide may comprise the sequence X.sup.aX.sup.bX.sup.cX.sup.d(X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.- sup.7).sub.n (SEQ ID NO: 311). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid. X.sup.c may be a polar, uncharged amino acid. X.sup.a, X.sup.b and X.sup.d may be the same amino acid. X.sup.a, X.sup.b and X.sup.d may be different amino acids.

[0303] The first extender peptide may comprise the sequence X.sup.aX.sup.bX.sup.cX.sup.d(AKLAALK).sub.n (SEQ ID NO. 312). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. X.sup.1-X.sup.7 may be independently selected from a positively charged amino acid or a hydrophobic amino acid. X.sup.1-X.sup.7 may be independently selected from the group comprising A, L and K. A may comprise at least about 30% of the total amino acid composition. A may comprise less than about 70% of the total amino acid composition. L may comprise at least about 20% of the total amino acid composition. L may comprise less than about 50% of the total amino acid composition. K may comprise at least about 20% of the total amino acid composition. K may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 70% of the total amino acid composition. The hydrophobic amino acids may comprise less than about 90% of the total amino acid composition. X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid. X.sup.c may be a polar, uncharged amino acid. X.sup.a, X.sup.b and X.sup.d may be the same amino acid. X.sup.a, X.sup.b and X.sup.d may different amino acids. X.sup.a, X.sup.b and X.sup.d may be Glycine (G). X.sup.c may be Serine (S).

[0304] The first extender peptide may comprise the sequence (AKLAALK).sub.n (SEQ ID NO. 313). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. The first extender peptide may comprise the sequence GGSG(AKLAALK).sub.n (SEQ ID NO: 314). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. The second extender peptide may comprise the sequence X.sup.aX.sup.bX.sup.cX.sup.d (X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7).sub.n (SEQ ID NO: 311). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. X.sup.1-X.sup.7 may be independently selected from a positively charged amino acid or a hydrophobic amino acid. X.sup.1-X.sup.7 may be independently selected from the group comprising alanine (A), leucine (L) and lysine (K). A may comprise at least about 30% of the total amino acid composition. A may comprise less than about 70% of the total amino acid composition. L may comprise at least about 20% of the total amino acid composition. L may comprise less than about 50% of the total amino acid composition. K may comprise at least about 20% of the total amino acid composition. K may comprise less than about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 50% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 60% of the total amino acid composition. The hydrophobic amino acids may comprise at least about 70% of the total amino acid composition. The hydrophobic amino acids may comprise less than about 90% of the total amino acid composition. X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid. X.sup.c may be a polar, uncharged amino acid. X.sup.a, X.sup.b and X.sup.d may be the same amino acid. X.sup.a, X.sup.b and X.sup.d may different amino acids. X.sup.a, X.sup.b and X.sup.d may be Glycine (G). X.sup.c may be Serine (S).

[0305] The second extender peptide may comprise the sequence (ELAALEA).sub.n X.sup.aX.sup.bX.sup.cX.sup.d (SEQ ID NO: 315). n may be equal to a number selected from any one of the numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be equal to 1. n may be equal to 2. n may be equal to 3. X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid. X.sup.c may be a polar, uncharged amino acid. X.sup.a, X.sup.b and X.sup.d may be the same amino acid. X.sup.a, X.sup.b and X.sup.d may be different amino acids. X.sup.a, X.sup.b and X.sup.d may be Glycine (G). X.sup.c may be Serine (S).

[0306] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 31; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 39. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 31; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 39. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 31. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 39. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 31. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 31. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 39. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 39.

[0307] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 136; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 146. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 136; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 146. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 136. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 146. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 136. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 136. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 146. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 146.

[0308] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 149; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 150. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 149; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 150. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 149. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 150. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 149. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 149. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 150. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 150.

[0309] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 151; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 152. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 151; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 152. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 151. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 152. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 151. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 151. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 152. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 152.

[0310] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 153; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 154. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 153; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 154. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 153. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 154. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 153. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 153. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 154. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 154.

[0311] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 155; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 156. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 155; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 156. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 155. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 156. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 155. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 155. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 156. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 156.

[0312] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 157; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 158. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 157; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 158. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 157. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 158. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 157. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 215. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 158. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 158.

[0313] The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 159; and (b) a second extender peptide comprising an amino acid sequence based on or derived from SEQ ID NO: 160. The immunoglobulin fusion protein may comprise (a) a first extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 159; and (b) a second extender peptide comprising an amino acid sequence that is at least about 50% homologous to an amino acid sequence of SEQ ID NO: 160. The first extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 159. The second extender peptide may comprise an amino acid sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to an amino acid sequence of SEQ ID NO: 160. The first extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 159. The first extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 159. The second extender peptide may comprise an amino acid sequencing comprising 3, 4, 5, 6, 7 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 160. The second extender peptide may comprise an amino acid sequencing comprising 5 or more amino acids based on or derived from an amino acid sequence of SEQ ID NO: 160.

[0314] The aliphatic amino acids may comprise at least about 20% of the total amino acids of the extender peptides. The aliphatic amino acids may comprise at least about 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 42%, 45% or more of the total amino acids of the extender peptides. The aliphatic amino acids may comprise at least about 22% of the total amino acids of the extender peptides. The aliphatic amino acids may comprise at least about 27% of the total amino acids of the extender peptides.

[0315] The aliphatic amino acids may comprise less than about 50% of the total amino acids of the extender peptides. The aliphatic amino acids may comprise less than about 47%, 45%, 43%, 40%, 38%, 35%, 33% or 30% of the total amino acids of the extender peptides.

[0316] The aliphatic amino acids may comprise between about 20% to about 45% of the total amino acids of the extender peptides. The aliphatic amino acids may comprise between about 23% to about 45% of the total amino acids of the extender peptides. The aliphatic amino acids may comprise between about 23% to about 40% of the total amino acids of the extender peptides.

[0317] The aromatic amino acids may comprise less than about 20% of the total amino acids of the extender peptides. The aromatic amino acids may comprise less than about 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% or 10% of the total amino acids of the extender peptides. The aromatic amino acids may comprise between 0% to about 20% of the total amino acids of the extender peptides.

[0318] The non-polar amino acids may comprise at least about 30% of the total amino acids of the extender peptides. The non-polar amino acids may comprise at least about 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% of the total amino acids of the extender peptides. The non-polar amino acids may comprise at least about 32% of the total amino acids of the extender peptides.

[0319] The non-polar amino acids may comprise less than about 80% of the total amino acids of the extender peptides. The non-polar amino acids may comprise less than about 77%, 75%, 72%, 70%, 69%, or 68% of the total amino acids of the extender peptides.

[0320] The non-polar amino acids may comprise between about 35% to about 80% of the total amino acids of the extender peptides. The non-polar amino acids may comprise between about 38% to about 80% of the total amino acids of the extender peptides. The non-polar amino acids may comprise between about 38% to about 75% of the total amino acids of the extender peptides. The non-polar amino acids may comprise between about 35% to about 70% of the total amino acids of the extender peptides.

[0321] The polar amino acids may comprise at least about 20% of the total amino acids of the extender peptides. The polar amino acids may comprise at least about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35% or more of the total amino acids of the extender peptides. The polar amino acids may comprise at least about 23% of the total amino acids of the extender peptides.

[0322] The polar amino acids may comprise less than about 80% of the total amino acids of the extender peptides. The polar amino acids may comprise less than about 77%, 75%, 72%, 70%, 69%, or 68% of the total amino acids of the extender peptides. The polar amino acids may comprise less than about 77% of the total amino acids of the extender peptides. The polar amino acids may comprise less than about 75% of the total amino acids of the extender peptides. The polar amino acids may comprise less than about 72% of the total amino acids of the extender peptides.

[0323] The polar amino acids may comprise between about 25% to about 70% of the total amino acids of the extender peptides. The polar amino acids may comprise between about 27% to about 70% of the total amino acids of the extender peptides. The polar amino acids may comprise between about 30% to about 70% of the total amino acids of the extender peptides.

[0324] Alternatively, the immunoglobulin fusion proteins disclosed herein do not comprise an extender peptide.

[0325] Vectors, Host Cells and Recombinant Methods

[0326] Immunoglobulin fusion proteins, as disclosed herein, may be expressed by recombinant methods. Generally, a nucleic acid encoding an immunoglobulin fusion protein may be isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or for expression. DNA encoding the immunoglobulin fusion protein may be prepared by PCR amplification and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to nucleotides encoding immunoglobulin fusion proteins). In an exemplary embodiment, nucleic acid encoding an immunoglobulin fusion protein is PCR amplified, restriction enzyme digested and gel purified. The digested nucleic acid may be inserted into a replicable vector. The replicable vector containing the digested immunoglobulin fusion protein insertion may be transformed or transduced into a host cell for further cloning (amplification of the DNA) or for expression. Host cells may be prokaryotic or eukaryotic cells.

[0327] Polynucleotide sequences encoding polypeptide components (e.g., antibody region, extender peptide, therapeutic agent) of the immunoglobulin fusion proteins may be obtained by PCR amplification. Polynucleotide sequences may be isolated and sequenced from cells containing nucleic acids encoding the polypeptide components. Alternatively, or additionally, polynucleotides may be synthesized using nucleotide synthesizer or PCR techniques. Once obtained, sequences encoding the polypeptide components may be inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in prokaryotic and/or eukaryotic hosts.

[0328] In addition, phage vectors containing replicon and control sequences that are compatible with the host microorganism may be used as transforming vectors in connection with these hosts. For example, bacteriophage such as .lamda.GEM.TM.-11 may be utilized in making a recombinant vector which may be used to transform susceptible host cells such as E. coli LE392.

[0329] Immunoglobulin fusion proteins may be expressed intracellularly (e.g., cytoplasm) or extracellularly (e.g., secretion). For extracellular expression, the vector may comprise a secretion signal which enables translocation of the immunoglobulin fusion proteins to the outside of the cell.

[0330] Suitable host cells for cloning or expression of immunoglobulin fusion proteins-encoding vectors include prokaryotic or eukaryotic cells. The host cell may be a eukaryotic. Examples of eukaryotic cells include, but are not limited to, Human Embryonic Kidney (HEK) cell, Chinese Hamster Ovary (CHO) cell, fungi, yeasts, invertebrate cells (e.g., plant cells and insect cells), lymphoid cell (e.g., YO, NSO, Sp20 cell). Other examples of suitable mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); baby hamster kidney cells (BHK); mouse sertoli cells; monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TR1 cells; MRC 5 cells; and FS4 cells. The host cell may be a prokaryotic cell (e.g., E. coli).

[0331] Host cells may be transformed with vectors containing nucleotides encoding an immunoglobulin fusion proteins. Transformed host cells may be cultured in media. The media may be supplemented with one or more agents for inducing promoters, selecting transformants, or amplifying or expressing the genes encoding the desired sequences. Methods for transforming host cells are known in the art and may include electroporation, calcium chloride, or polyethylene glycol/DMSO.

[0332] Alternatively, host cells may be transfected or transduced with vectors containing nucleotides encoding an immunoglobulin fusion proteins. Transfected or transduced host cells may be cultured in media. The media may be supplemented with one or more agents for inducing promoters, selecting transfected or transduced cells, or expressing genes encoding the desired sequences.

[0333] Additionally, host cells may express a protease that cleaves the proteolytic site of the immunoglobulin fusion protein. The host cells may be transfected or transduced with a polynucleotide, wherein the polynucleotide or portion thereof encodes the protease. The protease may be Factor Xa.

[0334] The expressed immunoglobulin fusion proteins may be secreted into and recovered from the periplasm of the host cells or transported into the culture media. Protein recovery from the periplasm may involve disrupting the host cell. Disruption of the host cell may comprise osmotic shock, sonication or lysis. Centrifugation or filtration may be used to remove cell debris or whole cells. The immunoglobulin fusion proteins may be further purified, for example, by affinity resin chromatography.

[0335] Alternatively, immunoglobulin fusion proteins that are secreted into the culture media may be isolated therein. Cells may be removed from the culture and the culture supernatant being filtered and concentrated for further purification of the proteins produced. The expressed polypeptides may be further isolated and identified using commonly known methods such as polyacrylamide gel electrophoresis (PAGE) and Western blot assay.

[0336] Immunoglobulin fusion proteins production may be conducted in large quantity by a fermentation process. Various large-scale fed-batch fermentation procedures are available for production of recombinant proteins. Large-scale fermentations have at least 1000 liters of capacity, preferably about 1,000 to 100,000 liters of capacity. These fermentors use agitator impellers to distribute oxygen and nutrients, especially glucose (a preferred carbon/energy source). Small scale fermentation refers generally to fermentation in a fermentor that is no more than approximately 100 liters in volumetric capacity, and can range from about 1 liter to about 100 liters.

[0337] In a fermentation process, induction of protein expression is typically initiated after the cells have been grown under suitable conditions to a desired density, e.g., an OD550 of about 180-220, at which stage the cells are in the early stationary phase. A variety of inducers may be used, according to the vector construct employed, as is known in the art and described herein. Cells may be grown for shorter periods prior to induction. Cells are usually induced for about 12-50 hours, although longer or shorter induction time may be used.

[0338] To improve the production yield and quality of the immunoglobulin fusion proteins disclosed herein, various fermentation conditions may be modified. For example, to improve the proper assembly and folding of the secreted immunoglobulin fusion proteins polypeptides, additional vectors overexpressing chaperone proteins, such as Dsb proteins (DsbA, DsbB, DsbC, DsbD and or DsbG) or FkpA (a peptidylprolyl cis,trans-isomerase with chaperone activity) may be used to co-transform the host prokaryotic cells. The chaperone proteins have been demonstrated to facilitate the proper folding and solubility of heterologous proteins produced in bacterial host cells.

[0339] To minimize proteolysis of expressed heterologous proteins (especially those that are proteolytically sensitive), certain host strains deficient for proteolytic enzymes may be used for the present disclosure. For example, host cell strains may be modified to effect genetic mutation(s) in the genes encoding known bacterial proteases such as Protease III, OmpT, DegP, Tsp, Protease I, Protease Mi, Protease V, Protease VI and combinations thereof. Some E. coli protease-deficient strains are available.

[0340] Standard protein purification methods known in the art may be employed. The following procedures are exemplary of suitable purification procedures: fractionation on immunoaffinity or ion-exchange columns, ethanol precipitation, reverse phase HPLC, chromatography on silica or on a cation-exchange resin such as DEAE, chromatofocusing, SDS-PAGE, ammonium sulfate precipitation, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography and gel filtration using, for example, Sephadex G-75.

[0341] Immunoglobulin fusion proteins may be concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon.RTM. ultrafiltration unit.

[0342] Protease inhibitors or protease inhibitor cocktails may be included in any of the foregoing steps to inhibit proteolysis of the immunoglobulin fusion proteins.

[0343] In some cases, an immunoglobulin fusion protein may not be biologically active upon isolation. Various methods for "refolding" or converting a polypeptide to its tertiary structure and generating disulfide linkages, may be used to restore biological activity. Such methods include exposing the solubilized polypeptide to a pH usually above 7 and in the presence of a particular concentration of a chaotrope. The selection of chaotrope is very similar to the choices used for inclusion body solubilization, but usually the chaotrope is used at a lower concentration and is not necessarily the same as chaotropes used for the solubilization. In most cases the refolding/oxidation solution will also contain a reducing agent or the reducing agent plus its oxidized form in a specific ratio to generate a particular redox potential allowing for disulfide shuffling to occur in the formation of the protein's cysteine bridge(s). Some of the commonly used redox couples include cysteine/cystamine, glutathione (GSH)/dithiobis GSH, cupric chloride, dithiothreitol(DTT)/dithiane DTT, and 2-mercaptoethanol(bME)/di-thio-b(ME). In many instances, a cosolvent may be used to increase the efficiency of the refolding, and common reagents used for this purpose include glycerol, polyethylene glycol of various molecular weights, arginine and the like.

[0344] Compositions

[0345] Disclosed herein are compositions comprising an immunoglobulin fusion protein and/or component of an immunoglobulin fusion protein disclosed herein. The compositions may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more immunoglobulin fusion proteins. The immunoglobulin fusion proteins may be different. Alternatively, the immunoglobulin fusion proteins may be the same or similar. The immunoglobulin fusion proteins may comprise different antibody regions, extender fusion regions, extender peptides, therapeutic agents or a combination thereof.

[0346] The compositions may further comprise one or more pharmaceutically acceptable salts, excipients or vehicles. Pharmaceutically acceptable salts, excipients, or vehicles for use in the present pharmaceutical compositions include carriers, excipients, diluents, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffering agents, antimicrobials, and surfactants.

[0347] Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers. The pharmaceutical compositions may include antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counter ions such as sodium; and/or nonionic surfactants such as Tween, pluronics, or polyethylene glycol (PEG). Also by way of example, suitable tonicity enhancing agents include alkali metal halides (preferably sodium or potassium chloride), mannitol, sorbitol, and the like. Suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like. Hydrogen peroxide also may be used as preservative. Suitable cosolvents include glycerin, propylene glycol, and PEG. Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin. Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like. The buffers may be conventional buffers such as acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl. Acetate buffer may be about pH 4-5.5, and Tris buffer may be about pH 7-8.5. Additional pharmaceutical agents are set forth in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.

[0348] The composition may be in liquid form or in a lyophilized or freeze-dried form and may include one or more lyoprotectants, excipients, surfactants, high molecular weight structural additives and/or bulking agents (see, for example, U.S. Pat. Nos. 6,685,940, 6,566,329, and 6,372,716). In one embodiment, a lyoprotectant is included, which is a non-reducing sugar such as sucrose, lactose or trehalose. The amount of lyoprotectant generally included is such that, upon reconstitution, the resulting formulation will be isotonic, although hypertonic or slightly hypotonic formulations also may be suitable. In addition, the amount of lyoprotectant should be sufficient to prevent an unacceptable amount of degradation and/or aggregation of the protein upon lyophilization. Exemplary lyoprotectant concentrations for sugars (e.g., sucrose, lactose, trehalose) in the pre-lyophilized formulation are from about 10 mM to about 400 mM. In another embodiment, a surfactant is included, such as for example, nonionic surfactants and ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80); poloxamers (e.g., poloxamer 188); poly(ethylene glycol) phenyl ethers (e.g., Triton); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl ofeyl-taurate; the MONAQUAT.TM. series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68 etc). Exemplary amounts of surfactant that may be present in the pre-lyophilized formulation are from about 0.001-0.5%. High molecular weight structural additives (e.g., fillers, binders) may include for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch, and zein. Exemplary concentrations of high molecular weight structural additives are from 0.1% to 10% by weight. In other embodiments, a bulking agent (e.g., mannitol, glycine) may be included.

[0349] Compositions may be suitable for parenteral administration. Exemplary compositions are suitable for injection or infusion into an animal by any route available to the skilled worker, such as intraarticular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, or intralesional routes. A parenteral formulation typically will be a sterile, pyrogen-free, isotonic aqueous solution, optionally containing pharmaceutically acceptable preservatives.

[0350] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringers' dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, anti-microbials, anti-oxidants, chelating agents, inert gases and the like. See generally, Remington's Pharmaceutical Science, 16th Ed., Mack Eds., 1980.

[0351] Compositions described herein may be formulated for controlled or sustained delivery in a manner that provides local concentration of the product (e.g., bolus, depot effect) and/or increased stability or half-life in a particular local environment. The compositions may comprise the formulation of immunoglobulin fusion proteins, polypeptides, nucleic acids, or vectors disclosed herein with particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., as well as agents such as a biodegradable matrix, injectable microspheres, microcapsular particles, microcapsules, bioerodible particles beads, liposomes, and implantable delivery devices that provide for the controlled or sustained release of the active agent which then may be delivered as a depot injection. Techniques for formulating such sustained- or controlled-delivery means are known and a variety of polymers have been developed and used for the controlled release and delivery of drugs. Such polymers are typically biodegradable and biocompatible. Polymer hydrogels, including those formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature or pH sensitive properties, may be desirable for providing drug depot effect because of the mild and aqueous conditions involved in trapping bioactive protein agents. See, for example, the description of controlled release porous polymeric microparticles for the delivery of pharmaceutical compositions in WO 93/15722.

[0352] Suitable materials for this purpose include polylactides (see, e.g., U.S. Pat. No. 3,773,919), polymers of poly-(a-hydroxycarboxylic acids), such as poly-D-(-)-3-hydroxybutyric acid (EP 133,988A), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., Biopolymers, 22: 547-556 (1983)), poly(2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15: 167-277 (1981), and Langer, Chem. Tech., 12: 98-105 (1982)), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Other biodegradable polymers include poly(lactones), poly(acetals), poly(orthoesters), and poly(orthocarbonates). Sustained-release compositions also may include liposomes, which may be prepared by any of several methods known in the art (see, e.g., Eppstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688-92 (1985)). The carrier itself, or its degradation products, should be nontoxic in the target tissue and should not further aggravate the condition. This may be determined by routine screening in animal models of the target disorder or, if such models are unavailable, in normal animals.

[0353] The immunoglobulin fusion proteins disclosed herein may be microencapsulated.

[0354] A pharmaceutical composition disclosed herein can be administered to a subject by any suitable administration route, including but not limited to, parenteral (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or local), topical, oral, or nasal administration.

[0355] Formulations suitable for intramuscular, subcutaneous, peritumoral, or intravenous injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.

[0356] For intravenous injections, an active agent can be optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0357] Parenteral injections optionally involve bolus injection or continuous infusion. Formulations for injection are optionally presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative. The pharmaceutical composition described herein can be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of an active agent in water soluble form. Additionally, suspensions are optionally prepared as appropriate oily injection suspensions.

[0358] Alternatively or additionally, the compositions may be administered locally via implantation into the affected area of a membrane, sponge, or other appropriate material on to which an immunoglobulin fusion protein disclosed herein has been absorbed or encapsulated. Where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of an immunoglobulin fusion protein, nucleic acid, or vector disclosed herein may be directly through the device via bolus, or via continuous administration, or via catheter using continuous infusion.

[0359] A pharmaceutical composition comprising an immunoglobulin fusion protein disclosed herein may be formulated for inhalation, such as for example, as a dry powder. Inhalation solutions also may be formulated in a liquefied propellant for aerosol delivery. In yet another formulation, solutions may be nebulized. Additional pharmaceutical composition for pulmonary administration include, those described, for example, in WO 94/20069, which discloses pulmonary delivery of chemically modified proteins. For pulmonary delivery, the particle size should be suitable for delivery to the distal lung. For example, the particle size may be from 1 .mu.m to 5 .mu.m; however, larger particles may be used, for example, if each particle is fairly porous.

[0360] Certain formulations comprising an immunoglobulin fusion protein disclosed herein may be administered orally. Formulations administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents may be included to facilitate absorption of a selective binding agent. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders also may be employed.

[0361] Another preparation may involve an effective quantity of an immunoglobulin fusion protein in a mixture with non-toxic excipients which are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions may be prepared in unit dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0362] Suitable and/or preferred pharmaceutical formulations may be determined in view of the present disclosure and general knowledge of formulation technology, depending upon the intended route of administration, delivery format, and desired dosage. Regardless of the manner of administration, an effective dose may be calculated according to patient body weight, body surface area, or organ size.

[0363] Further refinement of the calculations for determining the appropriate dosage for treatment involving each of the formulations described herein are routinely made in the art and is within the ambit of tasks routinely performed in the art. Appropriate dosages may be ascertained through use of appropriate dose-response data.

[0364] The compositions disclosed herein may be useful for providing prognostic or providing diagnostic information.

[0365] "Pharmaceutically acceptable" may refer to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.

[0366] "Pharmaceutically acceptable salt" may refer to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

[0367] "Pharmaceutically acceptable excipient, carrier or adjuvant" may refer to an excipient, carrier or adjuvant that may be administered to a subject, together with at least one antibody of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0368] "Pharmaceutically acceptable vehicle" may refer to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.

[0369] Kits

[0370] Further disclosed herein are kits which comprise one or more immunoglobulin fusion proteins or components thereof. The immunoglobulin fusion proteins may be packaged in a manner which facilitates their use to practice methods of the present disclosure. For example, a kit comprises an immunoglobulin fusion protein described herein packaged in a container with a label affixed to the container or a package insert that describes use of the immunoglobulin fusion protein in practicing the method. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The container may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The kit may comprise a container with an immunoglobulin fusion protein contained therein. The kit may comprise a container with (a) an antibody region of an immunoglobulin fusion protein; (b) an extender fusion region of an immunoglobulin fusion protein; (c) an extender peptide of the extender fusion region; (d) a therapeutic agent of the extender fusion region; or (e) a combination of a-d. The kit may further comprise a package insert indicating that the first and second compositions may be used to treat a particular condition. Alternatively, or additionally, the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer (e.g., bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution). It may further comprise other materials desirable from a commercial and user standpoint, including, but not limited to, other buffers, diluents, filters, needles, and syringes. The immunoglobulin fusion protein may be packaged in a unit dosage form. The kit may further comprise a device suitable for administering the immunoglobulin fusion protein according to a specific route of administration or for practicing a screening assay. The kit may contain a label that describes use of the immunoglobulin fusion protein composition.

[0371] The composition comprising the immunoglobulin fusion protein may be formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to mammals, such as humans, bovines, felines, canines, and murines. Typically, compositions for intravenous administration comprise solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and/or a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients may be supplied either separately or mixed together in unit dosage form. For example, the immunoglobulin fusion protein may be supplied as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the immunoglobulin fusion protein. Where the composition is to be administered by infusion, it may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

[0372] The amount of the composition described herein which will be effective in the treatment, inhibition and/or prevention of a disease or disorder associated with aberrant expression and/or activity of a therapeutic agent may be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation may also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro, animal model test systems or clinical trials.

[0373] Therapeutic Use

[0374] Further disclosed herein are immunoglobulin fusion proteins for and methods of treating, alleviating, inhibiting and/or preventing one or more diseases and/or conditions. The method may comprise administering to a subject in need thereof a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal is a bovine. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The therapeutic agent may be GCSF, bovine GCSF, human GCSF, Moka1, Vm24, Mamba1, neutrophil elastase inhibitor, human GLP-1, Exendin-4, human EPO, human GMCSF, human interferon-beta, human interferon-alpha, relaxin, oxyntomodulin, leptin, betatrophin, growth differentiation factor 11 (GDF11), parathyroid hormone, angiopoietin-like 3 (ANGPTL3), IL-11, human growth hormone (hGH), BCCX2, CVX15, elafin or derivative or variant thereof. Alternatively, or additionally, therapeutic agent is interleukin 8 (IL-8), IL-21, ziconotide, somatostatin, chlorotoxin, SDF1 alpha or derivative or variation thereof. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease, heteroimmune disease or condition, inflammatory disease, pathogenic infection, thromboembolic disorder, respiratory disease or condition, metabolic disease, central nervous system (CNS) disorder, bone disease or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The therapeutic agent may be hGCSF or a derivative thereof and the disease or condition may be neutropenia. The therapeutic agent may be leptin or a derivative thereof and the disease or condition may be diabetes. The therapeutic agent may be hGH or a derivative thereof and the disease or condition may be a growth disorder. The therapeutic agent may be IFN-alpha or a derivative thereof and the disease or condition may be a viral infection. The therapeutic agent may be Mamba1 or a derivative thereof and the disease or condition may be pain. The therapeutic agent may be BCCX2 and the disease or condition may be cancer. The therapeutic agent may be CVX15 or a derivative thereof and the disease or condition may be cancer. The therapeutic agent may be elafin and the disease or condition may be inflammation. The therapeutic agent may be a neutrophil elastase inhibitor and the condition may be pain.

[0375] The disease and/or condition may be a chronic disease or condition. Alternatively, the disease and/or condition is an acute disease or condition. The disease or condition may be recurrent, refractory, accelerated, or in remission. The disease or condition may affect one or more cell types. The one or more diseases and/or conditions may be an autoimmune disease, inflammatory disease, cardiovascular disease, metabolic disorder, pregnancy, and cell proliferative disorder.

[0376] The disease or condition may be an autoimmune disease. In some cases, the autoimmune disease may be scleroderma, diffuse scleroderma or systemic scleroderma.

[0377] The disease or condition may be an inflammatory disease. In some cases, the inflammatory disease may be hepatitis, fibromyalgia or psoriasis.

[0378] The disease or condition may be a rheumatic disease. In some cases, the rheumatic disease may be Ankylosing spondylitis, back pain, bursitis, tendinitis, shoulder pain, wrist pain, bicep pain, leg pain, knee pain, ankle pain, hip pain, Achilles pain, Capsulitis, neck pain, osteoarthritis, systemic lupus, erythematosus, rheumatoid arthritis, juvenile arthritis, Sjogren syndrome, Polymyositis, Behcet's disease, Reiter's syndrome, or Psoriatic arthritis. The rheumatic disease may be chronic. Alternatively, the rheumatic disease is acute.

[0379] The disease or condition may be a cardiovascular disease. In some cases, the cardiovascular disease may be acute heart failure, congestive heart failure, compensated heart failure, decompensated heart failure, hypercholesterolemia, atherosclerosis, coronary heart disease or ischemic stroke. The cardiovascular disease may be cardiac hypertrophy.

[0380] The disease or condition may be a metabolic disorder. In some cases, the metabolic disorder may be hypercholesterolemia, hypobetalipoproteinemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia, ketosis, hypolipidemia, refractory anemia, appetite control, gastric emptying, non-alcoholic fatty liver disease, obesity, type I diabetes mellitus, type II diabetes mellitus, gestational diabetes mellitus, metabolic syndrome. The metabolic disorder may be type I diabetes. The metabolic disorder may be type II diabetes.

[0381] The disease or condition may be pregnancy. The immunoglobulin fusion proteins may be used to treat preeclampsia or induce labor.

[0382] The disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be a leukemia, lymphoma, carcinoma, sarcoma, or a combination thereof. The cell proliferative disorder may be a myelogenous leukemia, lymphoblastic leukemia, myeloid leukemia, myelomonocytic leukemia, neutrophilic leukemia, myelodysplastic syndrome, B-cell lymphoma, burkitt lymphoma, large cell lymphoma, mixed cell lymphoma, follicular lymphoma, mantle cell lymphoma, hodgkin lymphoma, recurrent small lymphocytic lymphoma, hairy cell leukemia, multiple myeloma, basophilic leukemia, eosinophilic leukemia, megakaryoblastic leukemia, monoblastic leukemia, monocytic leukemia, erythroleukemia, erythroid leukemia, hepatocellular carcinoma, solid tumors, lymphoma, leukemias, liposarcoma (advanced/metastatic), myeloid malignancy, breast cancer, lung cancer, ovarian cancer, uterine cancer, kidney cancer, pancreatic cancer, and malignant glioma of brain.

[0383] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is oxyntomodulin. The disease or condition may be a metabolic disorder. The metabolic disorder may be diabetes. Diabetes may be type II diabetes mellitus. Diabetes may be type I diabetes. The metabolic disorder may be obesity. Additional metabolic disorders include, but are not limited to, metabolic syndrome, appetite control or gastric emptying.

[0384] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein, wherein the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is relaxin. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be acute heart failure. Additional cardiovascular diseases include, but are not limited to, congestive heart failure, compensated heart failure or decompensated heart failure. The disease or condition may be an autoimmune disorder. The autoimmune disorder may be scleroderma, diffuse scleroderma or systemic scleroderma. The disease or condition may be an inflammatory disease. The inflammatory disease may be fibromyalgia. The disease or condition may be fibrosis. Alternatively, the disease or condition is pregnancy. The immunoglobulin fusion protein may be used to treat preeclampsia or induce labor.

[0385] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is betatrophin. The disease or condition may be a metabolic disorder. The metabolic disorder may be obesity. Alternatively, the metabolic disorder is diabetes. Diabetes may be type I diabetes mellitus or type II diabetes mellitus.

[0386] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise GDF11. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is GDF11. The disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be acute, chronic, recurrent, refractory, accelerated, in remission, stage I, stage II, stage III, stage IV, juvenile or adult. The cell proliferative disorder may be a myelogenous leukemia, lymphoblastic leukemia, myeloid leukemia, myelomonocytic leukemia, neutrophilic leukemia, myelodysplastic syndrome, B-cell lymphoma, burkitt lymphoma, large cell lymphoma, mixed cell lymphoma, follicular lymphoma, mantle cell lymphoma, hodgkin lymphoma, recurrent small lymphocytic lymphoma, hairy cell leukemia, multiple myeloma, basophilic leukemia, eosinophilic leukemia, megakaryoblastic leukemia, monoblastic leukemia, monocytic leukemia, erythroleukemia, erythroid leukemia, hepatocellular carcinoma, solid tumors, lymphoma, leukemias, liposarcoma (advanced/metastatic), myeloid malignancy, breast cancer, lung cancer, ovarian cancer, uterine cancer, kidney cancer, pancreatic cancer, and malignant glioma of brain. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be age-related cardiac disease. The disease or condition may be cardiac hypertrophy.

[0387] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is angiopoietin-like 3. The metabolic disorder may be hypercholesterolemia, hypobetalipoproteinemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia, hypolipidemia or ketosis. The disease or condition may be a cardiovascular disease. The cardiovascular disease may be atherosclerosis, coronary heart disease or ischemic stroke. The disease or condition may be a rheumatic disease. The rheumatic disease may be ankylosing spondylitis, back pain, bursitis, tendinitis, shoulder pain, wrist pain, bicep pain, leg pain, knee (patellar) pain, ankle pain, hip pain, Achilles pain, Capsulitis, Neck pain, osteoarthritis, systemic lupus, erythematosus, rheumatoid arthritis, juvenile arthritis, Sjogren syndrome, scleroderma, Polymyositis, Behcet's disease, Reiter's syndrome, Psoriatic arthritis. In some cases, the disease or condition may be a cell proliferative disorder. The cell proliferative disorder may be hepatocellular carcinoma or ovarian cancer. The disease or condition may be an inflammatory disease. The inflammatory disease may be hepatitis.

[0388] Disclosed herein may be a method of preventing or treating a disease or condition in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The immunoglobulin fusion protein may comprise one or more immunoglobulin heavy chains, light chains, or a combination thereof. The immunoglobulin fusion protein sequence may share 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99%, or more amino acid sequence identity to a heavy chain sequence provided by SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304. The antibody region may comprise an immunoglobulin heavy chain. The immunoglobulin heavy chain polypeptide sequence may share 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99%, or more amino acid sequence identity to a heavy chain sequence provided by SEQ ID NOs: 24-27, 29-33, 36-39 and 251-253. The antibody region may comprise an immunoglobulin light chain. The immunoglobulin light chain polypeptide sequence may share 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99%, or more amino acid sequence identity to a light chain sequence provided by SEQ ID NOs: 21-23, 28, 34, 35 or 40. The immunoglobulin fusion protein may be encoded by a nucleotide sequence that is at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more homologous to a nucleotide sequence of any one of SEQ ID NOs: 41-75 279-296, 299, 301, and 303. The immunoglobulin heavy chain may be encoded by a nucleotide sequence that is at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99%, or more homologous to SEQ ID NOs: 5-13 or 16-19. The immunoglobulin light chain may be encoded by a nucleotide sequence that is at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99%, or more homologous to SEQ ID NOs: 1-4, 14, 15 or 20. The immunoglobulin fusion protein may further comprise one or more linkers. The immunoglobulin fusion protein may further comprise one or more proteolytic cleavage sites. The disease or condition may be an autoimmune disease, heteroimmune disease or condition, inflammatory disease, pathogenic infection, thromboembolic disorder, respiratory disease or condition, metabolic disease, central nervous system (CNS) disorder, bone disease or cancer. The disease or condition may be a blood disorder. In some instances, the disease or condition may be obesity, diabetes, osteoporosis, anemia, or pain.

[0389] Disclosed herein is a method of preventing or treating an autoimmune disease in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Moka1 or a derivative or variant thereof. The therapeutic agent may be VM-24 or a derivative or variant thereof. The therapeutic agent may be beta-interferon or a derivative or variant thereof. The immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. The mammalian antibody may be a murine antibody. The antibody, antibody region or extender fusion region may further comprise a linker. The linker may attach Moka1, VM-24, beta-interferon, or a derivative or variant thereof to the extender peptide. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The autoimmune disease may be a T-cell mediated autoimmune disease. T-cell mediated autoimmune diseases include, but are not limited to, multiple sclerosis, type-1 diabetes, and psoriasis. In other instances, the autoimmune disease lupus, Sjogren's syndrome, scleroderma, rheumatoid arthritis, dermatomyositis, Hasmimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, pemphigus vulgaris, vitiligo, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, Ord's thyroiditis, Graves' disease, Guillain-Barre syndrome, acute disseminated encephalomyelitis, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, Goodpasture's syndrome, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, Wegener's granulomatosis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia. Lupus can include, but may be not limited to, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus, childhood discoid lupus erythematosus, generalized discoid lupus erythematosus, localized discoid lupus erythematosus, chilblain lupus erythematosus (hutchinson), lupus erythematosus-lichen planus overlap syndrome, lupus erythematosus panniculitis (lupus erythematosus profundus), tumid lupus erythematosus, verrucous lupus erythematosus (hypertrophic lupus erythematosus), complement deficiency syndromes, drug-induced lupus erythematosus, neonatal lupus erythematosus, and systemic lupus erythematosus. The disease or condition may be multiple sclerosis. The disease or condition may be diabetes.

[0390] Further disclosed herein is a method of preventing or treating a disease or condition which would benefit from the modulation of a potassium voltage-gated channel in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The potassium voltage-gated channel may be a KCNA3 or K.sub.v1.3 channel. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Moka1 or a derivative or variant thereof. The therapeutic agent may be VM24 or a derivative or variant thereof. The immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach Moka1, VM-24, or a derivative or variant thereof to the extender peptide. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease. The autoimmune disease may be a T-cell mediated autoimmune disease. The disease or condition may be episodic ataxia, seizure, or neuromyotonia. Modulating a potassium voltage-gated channel may comprise inhibiting or blocking a potassium voltage-gated channel. Modulating a potassium voltage-gated channel may comprise activating a potassium voltage-gated channel.

[0391] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is an antagonist of CXCR4. The antagonist of CXCR4 may be a 16 residue cyclic peptide analogue e of a horseshoe crab peptide polyphemusin (CVX.sub.15). The antagonist of CXCR4 may be a modified C VX15 (BCCX2). The CXCR4 antagonist may be encoded by an amino acid sequence selected from SEQ ID NOs: 231-234. The disease or condition may be an immunodeficiency. The disease or condition may be a viral infection and/or due to a viral infection. The disease or condition may be HIV and/or AIDS. The disease or condition may be whim syndrome. The disease or condition may be hypogammaglobulinemia. The disease or condition may be a tumor. The disease or condition may be a cancer. The disease or condition may be a metastatic cancer. The disease or condition may be hematopoietic stem cell mobilization. The disease or condition may be a cardiovascular disease.

[0392] Further disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an immunoglobulin fusion protein disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises an extender peptide and a therapeutic agent, wherein the therapeutic agent is a neutrophil elastase inhibitor. The neutrophil elastase inhibitor may be encoded by an amino acid of SEQ ID NO. 235. The disease or condition may be selected from a neutropenia, a severe congenital neutropenia, pulmonary emphysema, cystic fibrosis, inflammation, postperfusion syndrome. The disease or condition may be a respiratory disorder. The disease or condition may be bronchoalveolar lavage fluid. The disease or condition may be an alpha 1-antitrypsin deficiency. The disease or condition may be asthma. The disease or condition may be chronic obstructive pulmonary disorder.

[0393] Provided herein is a method of preventing or treating a metabolic disease or condition in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, Exendin-4, or a derivative or variant thereof. The GLP-1 may be a human GLP-1. The antibody or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, Exendin-4, or a derivative or variant thereof to the extender peptide. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. Metabolic diseases and/or conditions may include disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism (organic acidurias), fatty acid oxidation and mitochondrial metabolism, porphyrin metabolism, purine or pyrimidine metabolism, steroid metabolism, mitochondrial function, peroxisomal function, urea cycle disorder, urea cycle defects or lysosomal storage disorders. The metabolic disease or condition may be diabetes. In other instances, the metabolic disease or condition may be glycogen storage disease, phenylketonuria, maple syrup urine disease, glutaric acidemia type 1, Carbamoyl phosphate synthetase I deficiency, alcaptonuria, Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), acute intermittent porphyria, Lesch-Nyhan syndrome, lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia, Kearns-Sayre syndrome, Zellweger syndrome, Gaucher's disease, or Niemann Pick disease.

[0394] Provided herein is a method of preventing or treating a central nervous system (CNS) disorder in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, Exendin-4 or a derivative or variant thereof. The GLP-1 may be a human GLP-1. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, Exendin-4, or a derivative or variant thereof to the immunoglobulin domain or fragment thereof. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The CNS disorder may be Alzheimer's disease (AD). Additional CNS disorders include, but are not limited to, encephalitis, meningitis, tropical spastic paraparesis, arachnoid cysts, Huntington's disease, locked-in syndrome, Parkinson's disease, Tourette's, and multiple sclerosis.

[0395] Provided herein is a method of preventing or treating a disease or condition which benefits from a GLP-1R and/or glucagon receptor (GCGR) agonist in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1, Exendin-4 or a derivative or variant thereof. The GLP-1 may be a human GLP-1. The immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, Exendin-4, or a derivative or variant thereof to the extender peptide. In other instances, the linker attaches the extender fusion region to the antibody region. The disease or condition may be a metabolic disease or disorder. The disease or condition may be diabetes. In other instances, the disease or condition may be obesity. Additional diseases and/or conditions which benefit from a GLP-1R and/or GCGR agonist include, but are not limited to, dyslipidemia, cardiovascular and fatty liver diseases.

[0396] Provided herein is a method of preventing or treating a blood disorder in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be erythropoietin, GMCSF or a derivative or variant thereof. The erythropoietin may be a human erythropoietin. The GMCSF may be a human GMCSF. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach erythropoietin, GMCSF, or a derivative or variant thereof to the extender peptide. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The blood disorder may be anemia. Examples of anemia include, but are not limited to, hereditary xerocytosis, congenital dyserythropoietic anemia, Rh null disease, infectious mononucleosis related anemia, drugs-related anemia, aplastic anemia, microcytic anemia, macrocytic anemia, normocytic anemia, hemolytic anemia, poikilocytic anemia, spherocytic anemia, drepanocytic anemia, normochromic anemia, hyperchromic anemia, hypochromic anemia, macrocytic-normochromic anemia, microcytic-hypochromic anemia, normocytic-normochromic anemia, iron-deficiency anemia, pernicious anemia, folate-deficiency anemia, thalassemia, sideroblastic anemia, posthemorrhagic anemia, sickle cell anemia, chronic anemia, achrestic anemia, autoimmune haemolytic anemia, Cooley's anemia, drug-induced immune haemolytic anemia, erythroblastic anemia, hypoplastic anemia, Diamond-Blackfan anemia, Pearson's anemia, transient anemia, Fanconi's anemia, Lederer's anemia, myelpathic anemia, nutritional anemia, spur-cell anemia, Von Jaksh's anemia, sideroblatic anemia, sideropenic anemia, alpha thalassemia, beta thalassemia, hemoglobin h disease, acute acquired hemolytic anemia, warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, primary cold autoimmune hemolytic anemia, secondary cold autoimmune hemolytic anemia, secondary autoimmune hemolytic anemia, primary autoimmune hemolytic anemia, x-linked sideroblastic anemia, pyridoxine-responsive anemia, nutritional sideroblastic anemia, pyridoxine deficiency-induced sideroblastic anemia, copper deficiency-induced sideroblastic anemia, cycloserine-induced sideroblastic anemia, chloramphenicol-induced sideroblastic anemia, ethanol-induced sideroblastic anemia, isoniazid-induced sideroblastic anemia, drug-induced sideroblastic anemia, toxin-induced sideroblastic anemia, microcytic hyperchromic anemia, macrocytic hyperchromic anemia, megalocytic-normochromic anemia, drug-induced immune hemolytic anemia, non-hereditary spherocytic anemia, inherited spherocytic anemia, and congenital spherocytic anemia. In other instances, the blood disorder may be malaria. Alternatively, the blood disorder may be lymphoma, leukemia, multiple myeloma, or myelodysplastic syndrome. The blood disorder may be neutropenia, Shwachmann-Daimond syndrome, Kostmann syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, meyloperoxidase deficiency, or Chediak Higashi syndrome.

[0397] Provided herein is a method of preventing or treating a disease or disorder which benefits from stimulating or increasing white blood cell production in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GMCSF or a derivative or variant thereof. The GMCSF may be a human GMCSF. The immunoglobulin fusion protein or antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or disorder may be neutropenia, Shwachmann-Daimond syndrome, Kostmann syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, meyloperoxidase deficiency, or Chediak Higashi syndrome.

[0398] Provided herein is a method of preventing or treating a disease or disorder which benefits from stimulating or increasing red blood cell production in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be erythropoietin or a derivative or variant thereof. The erythropoietin may be a human erythropoietin. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach erythropoietin, or a derivative or variant thereof to the extender peptide. The linker may attach the antibody region to the extender fusion region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or disorder may be anemia.

[0399] Provided herein is a method of preventing or treating obesity in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be GLP-1 or a derivative or variant thereof. The GLP-1 may be a human GLP-1. The therapeutic agent may be Exendin-4 or a derivative or variant thereof. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach GLP-1, Exendin-4, or a derivative or variant thereof to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

[0400] Provided herein is a method of preventing or treating a pain in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The subject may be a mammal. In certain instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be a Mamba1 or a derivative or variant thereof. The immunoglobulin fusion proteins, antibody regions, and/or extender fusion regions may further comprise one or more linkers. The linker may attach the Mamba1 or a derivative or variant thereof to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

[0401] Provided herein is a method of preventing or treating a disease or condition which benefits from modulating a sodium ion channel in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The subject may be a mammal. In certain instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. Modulating a sodium ion channel may comprise inhibiting or blocking a sodium ion channel. Modulating a sodium ion channel may comprise activating a sodium ion channel. The disease or condition may be Dravet Syndrome, generalized epilepsy with febrile seizures plus (GEFS+), paramyotonia congenital or erythromelalgia. The disease or condition may be pain.

[0402] Provided herein is a method of preventing or treating a disease or condition which benefits from modulating an acid sensing ion channel (ASIC) in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The subject may be a mammal. In certain instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be Mamba 1 or a derivative or variant thereof. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. Modulating an ASIC may comprise inhibiting or blocking the ASIC. Modulating an ASIC may comprise activating the ASIC. The disease or condition may be a central nervous system disorder. In other instances, the disease or condition is pain.

[0403] Provided herein is a method of preventing or treating a pathogenic infection in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be alpha-interferon or a derivative or variant thereof. The therapeutic agent may be beta-interferon or a derivative or variant thereof. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach alpha-interferon, beta-interferon, or a derivative or variant thereof to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The pathogenic infection may be a bacterial infection. The pathogenic infection may be a fungal infection. The pathogenic infection may be a parasitic infection. The pathogenic infection may be a viral infection. The viral infection may be a herpes virus.

[0404] Provided herein is a method of preventing or treating a cancer in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The composition may further comprise a pharmaceutically acceptable carrier. The subject may be a mammal. The mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be beta-interferon or a derivative or variant thereof. The therapeutic agent may be CVX15 or a derivative or variant thereof. The therapeutic agent may be BCCX2 or a derivative or variant thereof. The antibody may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. The immunoglobulin domain may be from a mammalian antibody. Alternatively, the immunoglobulin domain may be from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody may be a murine antibody. The immunoglobulin fusion protein, antibody region, and/or extender fusion region may further comprise one or more linkers. The linker may attach beta-interferon, CVX15, BCCX2 or a derivative or variant thereof to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The cancer may be a hematological malignancy. The hematological malignancy may be a leukemia or lymphoma. The hematological malignancy may be a B-cell lymphoma, T-cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, chronic myeloid leukemia, mantle cell lymphoma, nodular lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, or small lymphocytic leukemia.

[0405] Provided herein is a method of preventing or treating pain in a subject in need thereof comprising administering to the subject a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising an alpha helix and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The subject may be a mammal. In certain instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be a neutrophil elastase inhibitor or a derivative or variant thereof. The immunoglobulin fusion proteins, antibody regions, and/or extender fusion regions may further comprise one or more linkers. The linker may attach the neutrophil elastase inhibitor or a derivative or variant thereof to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent.

[0406] Provided herein is a method of preventing or treating a disease or condition which would benefit from modulation of a receptor in a subject in need thereof comprising administering to the subject a composition disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises one or more immunoglobulin fusion proteins comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The subject may be a mammal. In certain instances, the mammal may be a human. Alternatively, the mammal may be a bovine. The therapeutic agent may be hGCSF or a derivative or variant thereof and the receptor may be GCSFR. The therapeutic agent may be erythropoeitin or a derivative or variant thereof and the receptor may be EPOR. The therapeutic agent may be Exendin-4 or a derivative or variant thereof and the receptor may be GLP1R. The therapeutic agent may be GLP-1 or a derivative or variant thereof and the receptor may be GLP1R. The therapeutic agent may be leptin or a derivative or variant thereof and the receptor may be LepR. The therapeutic agent may be hGH or a derivative or variant thereof and the receptor may be GHR. The therapeutic agent may be interferon-alpha or a derivative or variant thereof and the receptor may be IFNR. The therapeutic agent may be interferon-beta or a derivative or variant thereof and the receptor may be IFNR. The therapeutic agent may be relaxin or a derivative or variant thereof and the receptor may be LGR7. The therapeutic agent may be CVX15 or a derivative or variant thereof and the receptor may be CXCR4. The therapeutic agent may be BCCX2 or a derivative or variant thereof and the receptor may be CXCR4. The therapeutic agent may be a neutrophil elastase inhibitor or a derivative or variant thereof. The therapeutic agent may be GMCSF or a derivative or variant thereof and the receptor may be GMCSFR. The one or more antibodies, antibody fragments, or immunoglobulin constructs further comprise a linker. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The disease or condition may be an autoimmune disease. The autoimmune disease may be a T-cell mediated autoimmune disease. The disease or condition may be a metabolic disorder. The metabolic disorder may be diabetes. The disease or condition may be an inflammatory disorder. The inflammatory disorder may be multiple sclerosis. The disease or condition may be a cell proliferative disorder. The disease or condition may be a blood disorder. The blood disorder may be neutropenia. The blood disorder may be anemia. The disease or condition may be a pathogenic infection. The pathogenic infection may be a viral infection. The disease or condition may be a growth disorder. The disease or condition may be a cardiovascular condition. The cardiovascular condition may be acute heart failure. Modulating the receptor may comprise inhibiting or blocking the receptor. Modulating the receptor may comprise activating the receptor. The therapeutic agent may act as a receptor agonist. The therapeutic agent may act as a receptor antagonist.

[0407] Provided herein is a method of preventing or treating a disease in a mammal in need thereof comprising administering a pharmaceutical composition described herein to said mammal. In some embodiments, the disease may be an infectious disease. In certain embodiments, the infectious disease may be mastitis. In some embodiments, the infectious disease may be a respiratory disease. In certain embodiments, the respiratory disease may be bovine respiratory disease of shipping fever. In certain embodiments, the mammal in need may be a dairy animal selected from a list comprising cow, camel, donkey, goat, horse, reindeer, sheep, water buffalo, moose and yak. In some embodiments, the mammal in need may be bovine.

[0408] Provided may be a method of preventing or treating mastitis in a dairy animal, comprising providing to said dairy animal an effective amount of a composition comprising one or more immunoglobulin fusion proteins disclosed herein. The immunoglobulin fusion protein may comprise an antibody region attached to a non-antibody region. The non-antibody region may comprise a therapeutic agent. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising an amino acid sequence comprising a beta strand and (i) an amino acid sequence comprising 7 or fewer amino acids based on or derived from an ultralong CDR3 or (ii) an amino acid sequence that does not comprise an ultralong CDR3; and (b) a therapeutic agent. The antibody region may comprise a heavy chain polypeptide based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 77 and 81. The antibody region may further comprise a light chain polypeptide based on or derived from an amino acid sequence that is at least about 50% homologous to any one of SEQ ID NOs: 21-23, 28, 34, 35, 40 and 278. The therapeutic agent may be GCSF. The GCSF may be a bovine GCSF. The GCSF may be a human GCSF. In some embodiments, the dairy animal may be a cow or a water buffalo.

[0409] Provided are methods of treatment, inhibition and prevention of a disease or condition in a subject in need thereof by administration to the subject of an effective amount of an immunoglobulin fusion protein or pharmaceutical composition described herein. The immunoglobulin fusion protein may be substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject may be an animal, including but not limited to animals such as cows, pigs, sheep, goats, rabbits, horses, chickens, cats, dogs, mice, etc. The subject may be a mammal. The subject may be a human. The subject may be a non-human primate. Alternatively, the subject may be a bovine. The subject may be an avian, reptile or amphibian.

[0410] Additional Uses

[0411] Further disclosed herein are uses of an immunoglobulin fusion protein (IFP) in the manufacture of a medicament for the treatment of a disease or condition. The IFP may be any of the IFPs disclosed herein. Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a disease or condition, the immunoglobulin fusion protein comprising an antibody region attached to a non-antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. Further disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a disease or condition, the IFP comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may comprise GCSF. The GCSF may be a human GCSF. The therapeutic agent may be Moka1. The therapeutic agent may be VM24. The therapeutic agent may be Exendin-4. The therapeutic agent may be erythropoietin. The erythropoietin may be a human erythropoeitin. The therapeutic agent may be leptin. The therapeutic agent may be a growth hormone (GH). The growth hormone may be a human growth hormone (hGH). The therapeutic agent may be inteferon-alpha. The therapeutic agent may be interferon-beta. The therapeutic agent may be GLP-1. The therapeutic agent may be relaxin. The therapeutic agent may be Mamba1. The therapeutic agent may be CVX15. The therapeutic agent may be BCCX2. The therapeutic agent may be a neutrophil elastase inhibitor. The therapeutic agent may be elafin. The therapeutic agent may be betatrophin. The therapeutic agent may be GDF11. The therapeutic agent may be GMCSF. The disease or condition may be an autoimmune disease, heteroimmune disease or condition, inflammatory disease, pathogenic infection, thromboembolic disorder, respiratory disease or condition, metabolic disease, central nervous system (CNS) disorder, bone disease or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The disease or condition may be a growth disorder.

[0412] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a cell proliferative disorder. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The cell proliferative disorder may be cancer. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule.

[0413] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a metabolic disorder. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The metabolic disorder may be diabetes. Diabetes may be type I diabetes. Diabetes may be type II diabetes. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Exendin-4. The therapeutic agent may be GLP-1. The therapeutic agent may be leptin. The therapeutic agent may be betatrophin.

[0414] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of an autoimmune disease or condition. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Moka1. The therapeutic agent may be VM24.

[0415] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of an inflammatory disease or condition. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The inflammatory disease or condition may be multiple sclerosis. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be elafin. The therapeutic agent may be interferon-beta.

[0416] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a disease or condition of the central nervous system. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The disease or condition of the central nervous system may be pain. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Mamba1.

[0417] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a cardiovascular disease or condition. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The cardiovascular disease or condition may be acute heart failure. The cardiovascular disease or condition may be cardiac hypertrophy. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be relaxin. The therapeutic agent may be GDF11.

[0418] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a hematological disease or condition. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The hematological disease or condition may be anemia. The hematological disease or condition may be neutropenia. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be GCSF. The GCSF may be a human GCSF. The therapeutic agent may be erythropoietin. The erythropoietin may be a human erythropoietin. The therapeutic agent may be GMCSF.

[0419] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a pathogenic infection. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The pathogenic infection may be a viral infection. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be interferon-alpha.

[0420] Disclosed herein is the use of an immunoglobulin fusion protein in the manufacture of a medicament for the treatment of a growth disorder. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprising an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. Examples of growth disorders included, but are not limited to, achondroplasia, achondroplasia in children, acromegaly, adiposogenital dystrophy, dwarfism, gigantism, Brooke Greenberg, hemihypertrophy, hypochondroplasia, Jansen's metaphy seal chondrodysplasia, Kowarski syndrome, Leri-Weill dyschondrosteosis, local gigantism, macrodystrophia lipomatosa, Majewski's polydactyly syndrome, microcephalic osteodysplastic primordial dwarfism type II, midget, overgrowth syndrome, parastremmatic dwarfism, primordial dwarfism, pseudoachondroplasia, psychosocial short stature, Seckel syndrome, short rib-polydactyly syndrome and Silver-Russell syndrome. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be a growth hormone. The growth hormone may be a human growth hormone (hGH).

[0421] Further disclosed herein are uses of an immunoglobulin fusion protein for the treatment of a disease or condition. Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a disease or condition in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one secondary structure; and (b) a therapeutic agent. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may comprise GCSF. The GCSF may be a human GCSF. The therapeutic agent may be Moka1. The therapeutic agent may be VM24. The therapeutic agent may be Exendin-4. The therapeutic agent may be erythropoietin. The erythropoietin may be a human erythropoietin. The therapeutic agent may be leptin. The therapeutic agent may be a growth hormone (GH). The growth hormone may be a human growth hormone (hGH). The therapeutic agent may be interferon-alpha. The therapeutic agent may be interferon-beta. The therapeutic agent may be GLP-1. The therapeutic agent may be relaxin. The therapeutic agent may be Mamba1. The therapeutic agent may be CVX15. The therapeutic agent may be BCCX2. The therapeutic agent may be a neutrophil elastase inhibitor. The therapeutic agent may be elafin. The therapeutic agent may be betatrophin. The therapeutic agent may be GDF11. The therapeutic agent may be GMCSF. The disease or condition may be an autoimmune disease, heteroimmune disease or condition, inflammatory disease, pathogenic infection, thromboembolic disorder, respiratory disease or condition, metabolic disease, central nervous system (CNS) disorder, bone disease or cancer. In other instances, the disease or condition is a blood disorder. In some instances, the disease or condition is obesity, diabetes, osteoporosis, anemia, or pain. The disease or condition may be a growth disorder.

[0422] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a cell proliferative disorder in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The cell proliferative disorder may be cancer. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be CVX15. The therapeutic agent may be BCCX2.

[0423] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a respiratory disorder in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The respiratory disorder may be selected from asthma, bronchitis, emphysema, pneumonia, pulmonary hypertension, pulmonary edema, pleural mesothelioma, a respiratory tract infection, tuberculosis, pulmonary hyperplasia and a common cold. The respiratory disorder may be chronic obstructive pulmonary disorder. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof.

[0424] The therapeutic agent may be a neutrophil elastase inhibitor.

[0425] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a metabolic disorder in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The metabolic disorder may be diabetes. Diabetes may be type I diabetes. Diabetes may be type II diabetes. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Exendin-4. The therapeutic agent may be GLP-1. The therapeutic agent may be leptin. The therapeutic agent may be betatrophin.

[0426] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of an autoimmune disease or condition in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Moka1. The therapeutic agent may be VM24.

[0427] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of an inflammatory disease or condition in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The inflammatory disease or condition may be multiple sclerosis. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be elafin. The therapeutic agent may be interferon-beta.

[0428] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a disease or condition of the central nervous system in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The disease or condition of the central nervous system may be pain. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be Mamba1.

[0429] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a cardiovascular disease or condition in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The cardiovascular disease or condition may be acute heart failure. The cardiovascular disease or condition may be cardiac hypertrophy. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be relaxin. The therapeutic agent may be GDF11.

[0430] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a hematological disease or condition in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The hematological disease or condition may be anemia. The hematological disease or condition may be neutropenia. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be GCSF. The GCSF may be a human GCSF. The therapeutic agent may be erythropoietin. The erythropoietin may be a human erythropoietin. The therapeutic agent may be GMCSF.

[0431] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a pathogenic infection in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. The pathogenic infection may be a viral infection. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be interferon-alpha.

[0432] Disclosed herein is the use of an immunoglobulin fusion protein for the treatment of a growth disorder in a subject in need thereof. The IFP may be any of the IFPs disclosed herein. The IFP may comprise a non-antibody region attached to an antibody region, wherein the antibody region comprises 6 or fewer amino acids of an ultralong CDR3. The non-antibody region may comprise one or more therapeutic agents. In some instances, the immunoglobulin fusion protein comprises an antibody region attached to an extender fusion region, wherein the extender fusion region comprises (a) an extender peptide comprising at least one beta strand secondary structure; and (b) a therapeutic agent. The beta strand secondary structure may not comprise more than 7 consecutive amino acids from an ultralong CDR3 of SEQ ID NO. 248. Examples of growth disorders included, but are not limited to, achondroplasia, achondroplasia in children, acromegaly, adiposogenital dystrophy, dwarfism, gigantism, Brooke Greenberg, hemihypertrophy, hypochondroplasia, Jansen's metaphyseal chondrodysplasia, Kowarski syndrome, Leri-Weill dyschondrosteosis, local gigantism, macrodystrophia lipomatosa, Majewski's polydactyly syndrome, microcephalic osteodysplastic primordial dwarfism type II, midget, overgrowth syndrome, parastremmatic dwarfism, primordial dwarfism, pseudoachondroplasia, psychosocial short stature, Seckel syndrome, short rib-polydactyly syndrome and Silver-Russell syndrome. The extender fusion region may be inserted within the antibody region. The extender fusion region may be inserted within an immunoglobulin heavy chain of the antibody region. The extender fusion region may be inserted within an immunoglobulin light chain of the antibody region. The extender fusion region may be conjugated to the antibody region. The extender fusion region may be conjugated to a position within the antibody region. The antibody region may comprise one or more immunoglobulin domains. The immunoglobulin domain may be an immunoglobulin A, an immunoglobulin D, an immunoglobulin E, an immunoglobulin G, or an immunoglobulin M. The immunoglobulin domain may be an immunoglobulin heavy chain region or fragment thereof. In some instances, the immunoglobulin domain is from a mammalian antibody. Alternatively, the immunoglobulin domain is from a chimeric antibody. The immunoglobulin domain may be from an engineered antibody or recombinant antibody. The immunoglobulin domain may be from a humanized, human engineered or fully human antibody. The mammalian antibody may be a bovine antibody. The mammalian antibody may be a human antibody. In other instances, the mammalian antibody is a murine antibody. The immunoglobulin fusion protein, antibody region and/or extender fusion region may further comprise one or more linkers. The linker may attach therapeutic agent to the extender peptide. The linker may attach the extender fusion region to the antibody region. The linker may attach a proteolytic cleavage site to the antibody region, extender fusion region, extender peptide, or therapeutic agent. The therapeutic agent may be a peptide or derivative or variant thereof. Alternatively, therapeutic agent is a small molecule. The therapeutic agent may be a growth hormone. The growth hormone may be a human growth hormone (hGH).

[0433] Pharmacological Properties

[0434] Further disclosed herein are methods of improving one or more pharmacological properties of a therapeutic agent. The method may comprise producing an immunoglobulin fusion protein disclosed herein. Examples of pharmacological properties may include, but are not limited to, half-life, stability, solubility, immunogenicity, toxicity, bioavailability, absorption, liberation, distribution, metabolization, and excretion. Liberation may refer to the process of releasing of a therapeutic agent from the pharmaceutical formulation. Absorption may refer to the process of a substance entering the blood circulation. Distribution may refer to the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolization (or biotransformation, or inactivation) may refer to the recognition by an organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion may refer to the removal of the substances from the body.

[0435] The half-life of a therapeutic agent may greater than the half-life of the non-conjugated therapeutic agent. The half-life of the therapeutic agent may be greater than 4 hours, greater than 6 hours, greater than 12 hours, greater than 24 hours, greater than 36 hours, greater than 2 days, greater than 3 days, greater than 4 days, greater than 5 days, greater than 6 days, greater than 7 days, greater than 8 days, greater than 9 days, greater than 10 days, greater than 11 days, greater than 12 days, greater than 13 days, or greater than 14 days when administered to a subject. The half-life of the therapeutic agent may be greater than 4 hours when administered to a subject. The half-life of the therapeutic agent may be greater than 6 hours when administered to a subject.

[0436] The half-life of the therapeutic agent may increase by at least about 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 or more hours. The half-life of the therapeutic agent may increase by at least about 2 hours. The half-life of the therapeutic agent may increase by at least about 4 hours. The half-life of the therapeutic agent may increase by at least about 6 hours. The half-life of the therapeutic agent may increase by at least about 8 hours.

[0437] The half-life of a therapeutic agent may be at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10-fold greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 2-fold greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 5-fold greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 10-fold greater than the half-life of the non-conjugated therapeutic peptide.

[0438] The half-life of a therapeutic agent an antibody described herein may be at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 10% greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 20% greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 30% greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 40% greater than the half-life of the non-conjugated therapeutic peptide. The half-life of a therapeutic agent an antibody described herein may be at least about 50% greater than the half-life of the non-conjugated therapeutic peptide.

EXAMPLES

Example 1

Constructing Vectors of Trastuzumab-Beta-Strand Based Fusion Proteins for Expression in Mammalian Cells

[0439] Genes encoding bovine GCSF (bGCSF), Moka1, Vm24, Exendin-4 (Ex-4), human growth hormone (hGH), human GCSF (hGCSF) and human erythropoietin (hEPO) were synthesized by Genscript or IDT, and amplified by polymerase chain reaction (PCR). To optimize the folding and stability of fusion proteins, flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the bGCSF, Moka1 and Vm24 fragments. A cleavage site of Factor Xa was placed in front of the N-terminal of Ex-4. A flexible CGGGGS linker (SEQ ID NO: 316) was added immediately before the Factor Xa protease cleavage site and a GGGGSC linker (SEQ ID NO: 317) was added at the end of C-terminal of Ex-4 gene fragment to increase folding and stability of the fusion protein. Then, sequences encoding ETKKYQS (SEQ ID NO: 111) and SYTYNYE (SEQ ID NO: 119) from bovine antibody BLV1H12, which forms antiparallel beta-strands, were added at the ends of the N- and C-terminal of the above designed gene fragments, respectively. Subsequently, PCR fragments encoding genes of interest were grafted into the complementarity determining region 3 of the heavy chain (CDR3H) of trastuzumab IgG antibody by exploiting overlap extension PCR, to replace the Trp99-Met107 loop. The trastuzumab-beta-strand based hEPO fusion protein was further modified to replace the hIgG1 CH1-CH3 constant region of trastuzumab with hIgG4 CH1-CH3 constant region containing triple mutants (S228P, F234A and L235A) to generate trastuzumab-beta hEPO HC (SEQ ID NO: 303). To generate a trastuzumab-beta hGH (CDR2H) fusion protein (SEQ ID NO: 48), a fragment encoding hGH, linkers, and extender peptides was grafted into the complementarity determining region 2 of the heavy chain (CDR2H) of trastuzumab IgG. The expression vectors of trastuzumab-beta-strand based fusion proteins were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of trastuzumab IgG antibody was cloned into the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

Example 2

Expression and Purification of Trastuzumab-Beta-Strand Based Fusion Proteins

[0440] Trastuzumab-beta-strand based fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding trastuzumab-beta-strand fusion protein heavy chain and the trastuzumab light chain. Expressed fusion proteins were secreted into the culture medium and harvested every 48 hours for twice after transfection. The fusion proteins were purified by Protein A/G chromatography (Thermo Fisher Scientific, IL), and analyzed by SDS-PAGE gel. Trastuzumab-beta-strand based Ex-4 fusion protein was further treated with Factor Xa protease (GE Healthcare) following manufacture's protocol to release N-terminal of fused peptide. After treatment, fusion proteins were re-purified by Protein A/G affinity column to remove protease and analyzed by SDS-PAGE gel.

[0441] Purified trastuzumab-beta bGCSF IgG (SEQ ID NOs: 77 and 21) are shown in FIG. 5. Lane 1 is a protein molecular weight marker, lane 2 is purified trastuzumab-beta bGCSF IgG, lane 3 is purified trastuzumab-beta bGCSF IgG treated with DTT, lane 4 is purified trastuzumab IgG (SEQ ID NOs: 24 and 21), and lane 5 is purified trastuzumab IgG treated with DTT.

[0442] Purified trastuzumab-beta Moka1 IgG (SEQ ID NOs: 79 and 21) and trastuzumab-beta Vm24 (SEQ ID NOs: 80 and 21) are shown in FIG. 10. Lane 1 is a protein molecular weight marker, lane 2 is purified trastuzumab-beta Moka1 IgG, lane 3 is purified trastuzumab-beta Moka1 IgG treated with DTT, lane 4 is purified trastuzumab-beta Vm24 IgG, and lane 5 is purified trastuzumab-beta Vm24 IgG treated with DTT.

[0443] Purified trastuzumab-beta hEPO (CDR3H) IgG is shown in FIG. 12. Lane 1 is a protein molecular weight marker, lane 2 is purified trastuzumab-beta hEPO IgG (SEQ ID NOs: 304 and 21), and lane 3 is purified trastuzumab-beta hEPO IgG (SEQ ID NOs: 304 and 21) treated with DTT.

[0444] Purified trastuzumab-beta hGH (CDR3H) IgG (SEQ ID NOs: 82 and 21) is shown in FIG. 15. Lane 1 is a protein molecular weight marker, lane 2 is purified trastuzumab-beta hGH (CDR3H) IgG, and lane 3 is purified trastuzumab-beta hGH (CDR3H) IgG treated with DTT.

[0445] Purified trastuzumab-beta hGH (CDR2H) IgG (SEQ ID NOs: 298 and 21) is shown in FIG. 16. Lane 1 is a protein molecular weight marker, lane 2 is purified trastuzumab-beta hGH (CDR2H) IgG, and lane 3 is purified trastuzumab-beta hGH (CDR2H) IgG treated with DTT.

Example 3

In Vitro Study of Trastuzumab-Beta-Strand bGCSF Fusion Protein Proliferative Activity on Mouse NFS-60 Cells

[0446] Mouse NFS-60 cells were obtained from American Type Culture Collection (ATCC), VA, and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 0.05 mM 2-mercapoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). For proliferation assays, mouse NFS-60 cells were washed three times with RPMI-1640 medium and re-suspended in RPMI-1640 medium with 10% FBS and 0.05 mM 2-mercapoethanol at a density of 1.5.times.10.sup.5 cells/ml. In 96-well plates, 100 .mu.l of cell suspension was added into each well, followed by the addition of varied concentrations of bGCSF (SEQ ID NO: 200), bovine antibody BLV1H12-beta-strand (bAb-beta-strand IgG), bovine antibody BLV1H12-beta-strand-bGCSF fusion protein (bAb-beta-strand-bGCSF L1 IgG), trastuzumab IgG (SEQ ID NOs: 24 and 21) and trastuzumab-beta-strand-bGCSF L1 IgG (SEQ ID NOs: 77 and 21). The plates were incubated at 37.degree. C. in a 5% CO.sub.2 incubator for 72 hours. Cells were then treated with AlamarBlue (Invitrogen) ( 1/10 volume of cell suspension) for 4 hours at 37.degree. C. Fluorescence at 595 nm for each well was read to indicate the cell viability. Table 1 and FIG. 6 show the fluorescence of the NFS-60 cells treated with various concentrations of bGCSF, bovine antibody BLV1H12-beta-strand (bAb-beta-strand IgG), bovine antibody BLV1H12-beta-strand-bGCSF fusion protein (bAb-beta-strand-bGCSF L1 IgG), trastuzumab IgG and trastuzumab-beta-strand-bGCSF L1 IgG. As shown in FIG. 6, Line 1 represents bovine antibody BLV1H12-beta-strand (bAb-beta-strand IgG), Line 2 represents bovine antibody BLV1H12-beta-strand-bGCSF fusion protein (bAb-beta-strand-bGCSF L1 IgG), Line 3 represents trastuzumab IgG, Line 4 represents trastuzumab-beta-strand-bGCSF L1 IgG and Line 5 represents bGCSF. The EC.sub.50 of bAb-beta-strand-bGCSF L1 was 2.41.+-.0.20 ng/mL. The EC.sub.50 of trastuzumab-beta-strand-bGCSF L1 was 2.55.+-.0.19 ng/mL. The EC.sub.50 of bGCSF was 4.87.+-.0.29 ng/mL.

TABLE-US-00001 TABLE 1 bAb-beta- bAb-beta- strand bGCSF strand IgG Fluorescence L1 IgG Fluorescence Trastuzumab Fluorescence (ng/mL) Intensity (ng/mL) Intensity IgG (ng/mL) Intensity 1000 1536.3005 1000 7347.856 1000 1465.7345 333.33333 1531.6825 333.33333 7767.7615 333.33333 1464.256 111.11111 1603.698 111.11111 7854.0555 111.11111 1497.443 37.03704 1595.261 37.03704 7960.982 37.03704 1533.4505 12.34568 1566.7485 12.34568 7724.02 12.34568 1546.9655 4.11523 1734.544 4.11523 6141.9905 4.11523 1613.3125 1.37174 1629.575 1.37174 3506.5015 1.37174 1909.983 0.45725 1772.201 0.45725 2544.6685 0.45725 1751.1505 0.15242 1684.485 0.15242 2056.6535 0.15242 1596.733 0.05081 1661.1955 0.05081 1892.1955 0.05081 1674.4565 0.01694 1764.13 0.01694 2062.8835 0.01694 1729.6545 0.00565 1906.9825 0.00565 1977.5325 0.00565 1929.9635 Trastuzumab- beta-strand bGCSF L1 Fluorescence bGCSF Fluorescence IgG (ng/mL) Intensity (ng/mL) Intensity 1000 7667.935 1000 7432.54 333.33333 7880.162 333.33333 7270.466 111.11111 8011.944 111.11111 7464.5905 37.03704 7745.6735 37.03704 6922.3095 12.34568 7171.8625 12.34568 6116.986 4.11523 6003.3675 4.11523 4445.3315 1.37174 3451.5745 1.37174 2734.641 0.45725 2624.537 0.45725 2178.667 0.15242 1919.386 0.15242 1880.8455 0.05081 1853.41 0.05081 1864.7945 0.01694 1974.566 0.01694 2066.8105 0.00565 1855.4425 0.00565 2012.753

Example 4

Binding of Trastuzumab-Beta-Strand-bGCSF L1 to her2 Receptor

[0447] The binding affinity of trastuzumab-beta-strand-bGCSF L1 (SEQ ID NOs: 77 and 21) to Her2 receptor was examined by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) was coated on 96-well ELISA plate overnight at 4.degree. C., followed by blocking with 1% BSA in PBS (pH7.4) for 2 hours at 37.degree. C. After washing with 0.05% Tween-20 in PBS (pH7.4), varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-bGCSF L1 were added and incubated for 2 hours at 37.degree. C. Subsequently, goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) was added and incubated for 2 hours at 37.degree. C. Wells were subsequently washed and binding affinities were examined on the basis of fluorescence intensity at 425 nm by adding fluorogenic peroxidase substrate to each well. Table 2 displays the fluorescence intensity at 425 nm of the trastuzumab IgG and trastuzumab-beta-bGCSF IgG (SEQ ID NOs: 77 and 21). FIG. 7 shows a graphical representation of the data in Table 2. The EC.sub.50 of trastuzumab IgG was 110.+-.14 pM.

TABLE-US-00002 TABLE 2 Trastuzumab IgG Fluorescence Trastuzumab-beta-strand Fluorescence (pM) Intensity bGCSF L1 IgG (pM) Intensity 4074.07407 13113.5475 4074.07407 1913.388 1358.02469 11544.1275 1358.02469 599.727 452.6749 10776.7925 452.6749 336.4235 150.89163 7846.828 150.89163 253.0485 50.29721 4164.892 50.29721 211.2645 16.76574 1994.7745 16.76574 198.0155 5.58858 1023.4985 5.58858 196.9245 1.86286 566.8795 1.86286 188.7095

Example 5

In Vitro Study of Trastuzumab-Beta-Strand Moka1 Fusion Protein Inhibitory Activities on Human Peripheral Blood Mononuclear Cells (PBMCs)/T Cells Activation

[0448] Human PBMCs were isolated from fresh venous blood of healthy donors through ficoll gradient centrifugation, followed by re-suspension in RPMI1640 medium with 10% FBS and plating in 96-well plates at a density of 1.times.10.sup.6 cells/mL. Human T cells were purified from the isolated PBMCs using T cell enrichment kit. Purified PBMCs and T cells were pretreated for 1 h at 37.degree. C. and 5% CO.sub.2 with various concentrations of purified trastuzumab-beta-strand Moka1 fusion protein (SEQ ID NOs: 79 and 21), and then activated by anti-CD3 and CD28 antibodies. After 24 h treatment, supernatants were collected and the levels of secreted TNF-.alpha. measured using an ELISA kit. A graphical representation of the data is shown in FIG. 11.

Example 6

Binding of Trastuzumab-Beta-Strand-Moka1 to her2 Receptor

[0449] The binding affinity of trastuzumab-beta-strand-Moka1 fusion proteins to Her2 receptor is examined by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) is coated on 96-well ELISA plate overnight at 4.degree. C., followed by blocking with 1% BSA in PBS (pH7.4) for 2 hours at 37.degree. C. After washing with 0.05% Tween-20 in PBS (pH7.4), varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-Moka1 fusion proteins are added and incubated for 2 hours at 37.degree. C. Subsequently, goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added and incubated for 2 hours at 37.degree. C. Wells are subsequently washed and binding affinities are examined on the basis of fluorescence intensity at 425 nm by adding fluorogenic peroxidase substrate to each well.

Example 7

In Vitro Study of Trastuzumab-Beta-Strand-VM24 Fusion Protein Inhibitory Activities on Human Peripheral Blood Mononuclear Cells (PBMCs) T Cells Activation

[0450] Human T cells are purified from isolated PBMCs using a T cell enrichment kit. Purified T cells were pretreated for 1 h at 37.degree. C. and 5% CO.sub.2 with various concentrations of purified trastuzumab-beta-strand Vm24 fusion protein (SEQ ID NOs: 80 and 21), and then activated by anti-CD3 and CD28 antibodies. After 24 h treatment, supernatants were collected and the levels of secreted TNF-.alpha. were measured using an ELISA kit. A graphical representation of the data is shown in FIG. 11.

Example 8

Binding of Trastuzumab-Beta-Strand-VM24 to her2 Receptor

[0451] The binding affinity of trastuzumab-beta-strand-VM24 fusion proteins to Her2 receptor is examined by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) is coated on 96-well ELISA plate overnight at 4.degree. C., followed by blocking with 1% BSA in PBS (pH7.4) for 2 hours at 37.degree. C. After washing with 0.05% Tween-20 in PBS (pH7.4), varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-VM24 fusion proteins are added and incubated for 2 hours at 37.degree. C. Subsequently, goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added and incubated for 2 hours at 37.degree. C. Wells are subsequently washed and binding affinities are examined on the basis of fluorescence intensity at 425 nm by adding fluorogenic peroxidase substrate to each well.

Example 9

Expression and Purification of Trastuzumab-Beta-Strand Exendin-4 Based Fusion Proteins

[0452] Trastuzumab-beta-strand Exendin-4 based fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding trastuzumab-beta-strand Exendin-4 fusion protein heavy chain (SEQ ID NO: 78) and the trastuzumab light chain (SEQ ID NO: 21). Expressed fusion proteins were secreted into the culture medium and harvested at 48 and 96 hours after transfection. The fusion proteins were purified by Protein A/G chromatography (Thermo Fisher Scientific, IL), and analyzed by SDS-PAGE gel. Trastuzumab-beta-strand based Ex-4 fusion protein was further treated with Factor Xa protease (GE Healthcare) following manufacture's protocol to release N-terminal of fused peptide. After treatment, fusion proteins were re-purified by Protein A/G affinity column to remove protease and analyzed by SDS-PAGE gel. As shown in FIG. 8, Lane 1 and 4 contain the protein ladder, Lane 2 contains trastuzumab-beta strand-Exendin-4 fusion protein (SEQ ID NOs: 78 and 21), Lane 3 contains trastuzumab-beta strand-Exendin-4 fusion protein treated with DTT (SEQ ID NOs: 78 and 21), Lane 5 contains trastuzumab-beta strand-Exendin-4 fusion protein (SEQ ID NOs: 78 and 21) cleaved with Factor Xa, and Lane 6 contains trastuzumab-beta strand-Exendin-4 fusion protein (SEQ ID NOs: 78 and 21) cleaved with Factor Xa and treated with DTT.

Example 10

In Vitro Trastuzumab-Beta Exendin-4 Fusion Protein GLP-1 Receptor Activation Assay

[0453] HEK 293 cells overexpressing GLP-1 receptor (GLP-1R) and cAMP responsive element (CRE)-luciferase (Luc) reporter were grown in DMEM with 10% FBS at 37.degree. C. with 5% CO.sub.2. Cells were seeded in 384-well plates at a density of 5000 cells per well and treated with various concentrations of Ex-4 peptide (SEQ ID NO: 201), trastuzumab-CDR3H-beta-Ex-4 (SEQ ID NO: 78 and 21) and trastuzumab-CDR3H-beta-Ex-4 RN (SEQ ID NOs: 78 and 21, after cleavage with Factor Xa) fusion proteins for 24 hours at 37.degree. C. with 5% CO.sub.2. An immunoglobulin fusion protein which may be cleaved to release the amino-terminus of a therapeutic agent is referred to as RN, for released N-terminus Luminescence intensities were then measured using One-Glo (Promega, WI) luciferase reagent by following manufacturer's instruction. A graphical representation of the data is shown in FIG. 9.

Example 11

Binding of Trastuzumab-Beta-Strand-Exendin-4 to her2 Receptor

[0454] The binding affinity of trastuzumab-beta-strand-Exendin-4 fusion proteins to Her2 receptor is examined by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) is coated on 96-well ELISA plate overnight at 4.degree. C., followed by blocking with 1% BSA in PBS (pH7.4) for 2 hours at 37.degree. C. After washing with 0.05% Tween-20 in PBS (pH7.4), varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-Exendin-4 fusion proteins are added and incubated for 2 hours at 37.degree. C. Subsequently, goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added and incubated for 2 hours at 37.degree. C. Wells are subsequently washed and binding affinities are examined on the basis of fluorescence intensity at 425 nm by adding fluorogenic peroxidase substrate to each well.

Example 12

In Vitro Study of Trastuzumab-Beta-Strand hGCSF Fusion Protein Proliferative Activity on Mouse NFS-60 Cells

[0455] Mouse NFS-60 cells are obtained from American Type Culture Collection (ATCC), VA, and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 0.05 mM 2-mercapoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). For proliferation assays, mouse NFS-60 cells are washed three times with RPMI-1640 medium and re-suspended in RPMI-1640 medium with 10% FBS and 0.05 mM 2-mercapoethanol at a density of 1.5.times.10.sup.5 cells/ml. In 96-well plates, 100 .mu.l of cell suspension is added into each well, followed by the addition of varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-hGCSF fusion proteins. The plates are incubated at 37.degree. C. in a 5% CO.sub.2 incubator for 72 hours. Cells are then treated with AlamarBlue (Invitrogen) ( 1/10 volume of cell suspension) for 4 hours at 37.degree. C. Fluorescence at 595 nm for each well was read to indicate the cell viability.

Example 13

Binding of Trastuzumab-Beta-Strand-hGCSF to her2 Receptor

[0456] The binding affinity of trastuzumab-beta-strand-hGCSF fusion proteins to Her2 receptor is examined by ELISA. Human Her2-Fc chimera (5 ug/mL) (R&D Systems) is coated on 96-well ELISA plate overnight at 4.degree. C., followed by blocking with 1% BSA in PBS (pH7.4) for 2 hours at 37.degree. C. After washing with 0.05% Tween-20 in PBS (pH7.4), varied concentrations of trastuzumab IgG and trastuzumab-beta-strand-hGCSF fusion proteins are added and incubated for 2 hours at 37.degree. C. Subsequently, goat polyclonal anti-human kappa light chain antibody with HRP conjugate (Sigma) is added and incubated for 2 hours at 37.degree. C. Wells are subsequently washed and binding affinities are examined on the basis of fluorescence intensity at 425 nm by adding fluorogenic peroxidase substrate to each well.

Example 14

Trastuzumab-Beta-Strand-hGH hGHR-Ba/F3 Proliferation Assay

[0457] Murine Ba/F3 cells cell lines were stably transduced with hGHR under EF1.alpha. promoter. Clonal selected hGHR-Ba/F3 were maintained in 10% FBS in RPMI1640 with 50 ng/mL of hGH. Proliferation assay was performed in 96 well culture plate with 20,000 cells in 200 uL assay medium (10% FBS in RPMI1640) per well. Increasing concentrations of fusion-antibodies were incubated with cells for 72 hours. At the end of incubation period, 20 ul of Prestoblue was added to each well, and fluorescent signal was recorded on a Spectramax fluorescence plate reader at 590 nm with 550 nm excitation. See Table 3 for results of trastuzumab-beta-strand-hGH activity assays.

Example 15

Trastuzumab-Beta-Strand-hGH NB2 Proliferation Assay

[0458] Rat Nb2-11 cell lines (Sigma) were maintained in 10% FBS, 10% horse serum (HS) in RPMI with 55 uM .beta.-ME. A proliferation assay was performed in a 96 well culture plate with 50,000 cells in 200 uL assay medium (10% HS in RPMI with 55 uM .beta.-ME) per well. Increasing concentrations of fusion-antibodies were incubated with cells for 72 hours. At the end of incubation period, 20 ul of Prestoblue was added to each well, and fluorescent signal was recorded on a Spectramax fluorescence plate reader at 590 nm with 550 nm excitation.

Example 16

Trastuzumab-Beta-Strand-hGH Stat5 Phosphorylation Assay

[0459] Human IM9 cells from ATCC were maintained in 10% FBS in RPMI1640. The night before assay, 2.times.10e.sup.5 IM9 cells were seeded into V bottom 96 well plate in 200 uL assay medium (1% charcoal stripped FBS in RPMI) and starved overnight. On the day of experiment, starved cells were stimulated with hGH and fusion-antibody at various concentration for 10 min at 37.degree. C. After stimulation, cells were fixed by 4% formaldehyde at 37.degree. C. for 10 min, and permeabalized with 90% methanol. Cells were then blocked with 5% BSA at room temperature for 10 min and stained with Alexa Fluor.RTM. 488 conjugated anti-pStat5 (Tyr694) (C71E5) Rabbit mAb (Cell Signaling Technology, Inc.) following manufacture suggested protocol. Cells were then washed with PBS and analyzed by a flow cytometer. See Table 3 for results of trastuzumab-beta-strand-hGH activity assays.

TABLE-US-00003 TABLE 3 IM9 STAT5 NB2 Ba/F3-hGHR phos- EC50 (nM) proliferation proliferation phorylation hGH 0.084 .+-. 0.011 0.926 .+-. 0.059 0.3525 .+-. 0.090 hGH-hAb-.beta. (CDR3) 0.406 .+-. 0.059 2.851 .+-. 0.362 2.326 .+-. 0.441 hGH-hAb-.beta. (CDR2) 0.4667 .+-. 0.038

Example 17

In Vitro Proliferative Activity Assay of Trastuzumab-hEPO Fusion Protein on TF-1 Cells

[0460] Human TF-1 cells were cultured at 37.degree. C. with 5% CO.sub.2 in RPMI-1640 medium containing 10% fetal bovine serum (FBS), penicillin and streptomycin (50 U/mL), and 2 ng/ml human granulocyte macrophage colony stimulating factor (GM-CSF). To examine the proliferative activity of trastuzumab-hEPO fusion proteins, cells were washed three times with RPMI-1640 medium with 10% FBS, resuspended in RPMI-1640 medium with 10% FBS at a density of 1.5.times.10.sup.5 cells/ml, plated in 96-well plates (1.5.times.10.sup.4 cells per well) with various concentrations of hEPO (206), trastuzumab, and trastuzumab-beta hEPO fusion protein (SEQ ID NOs: 304 and 21), and then incubated for 72 hours at 37.degree. C. with 5% CO.sub.2. Cells were then treated with Alamar Blue (Life Technologies, CA) for 4 hours at 37.degree. C. Fluorescence intensity measured at 595 nm is proportional to cell viability. The EC.sub.50 values were determined by fitting data into a logistic sigmoidal function: y=A.sub.2+(A.sub.1-A.sub.2)/(1 (x/x.sub.0).sup.p), where A.sub.1 is the initial value, A.sub.2 is the final value, x.sub.0 is the inflection point of the curve, and p is the power. A graphical representation of the data is shown in FIG. 14.

Example 18

Rational Design, Expression and Purification of Beta Fusion Anti-CXCR4 Antibody

[0461] CVX15 is a 16 residue cyclic peptide which is an analogue of the horseshoe crab peptide polyphemusin and an antagonist of the chemokine receptor CXCR4. The x-ray crystal structure of a CVX15-CXCR4 complex reveals that the peptide is bound in a .beta.-hairpin conformation with its N- and C-termini inserted into the transmembrane cavity of CXCR4 and its hairpin loop exposed to solvent (FIG. 45A). Optimized variations of modified CVX15 peptides (may be referred to as BCCX2) were used to generate novel CXCR4 antagonist antibodies using antibody BLV1H12. This bovine antibody has an ultralong (61 residues) CDRH3 with an anti-parallel .beta.-sheet 20 .ANG. in length, terminating in a disulfide cross-linked knob domain (FIG. 45B). Replacement of this knob domain afforded an antibody with an extended CDR that can bind the ligand binding cavity of CXCR4. Schematic representations of three candidate antibody fusion proteins are shown in FIG. 45C. Briefly, the unnatural amino acids naphthylamine and citrulline of CVX15 were replaced by tryptophan and lysine based on sequence alignment with the peptide T22 from which CVX15 was derived. Next the N- and C-termini of the peptide were fused to sequences that promote .beta.-turns: Gly-Arg (YRKCRGGRRWCYQK in bAb-AC1 (SEQ ID NO: 231)), Pro-Arg (bAb-AC2, YRKCRGPRRWCYQK (SEQ ID NO: 232)), or Gly-Asn-Gly-Arg (SEQ ID NO: 318) (bAb-AC3, YRKCRGGNGRRWCYQK (SEQ ID NO: 233)). Based on the CVX15-CXCR4 complex structure, it was expected that such a .beta.-turn linker would not affect the interaction of the peptide with CXCR4 Finally, the loop region of CVX15 that resides outside the binding pocket of CXCR4 was removed and the resulting inverse hairpin sequence was substituted for the knob domain of BLV1H12. The final designs of the antibody-CVX fusion proteins are illustrated in FIG. 45D.

[0462] Genes containing engineered antibodies were assembled by overlapping PCR and inserted into the pFuse backbone vector (InvivoGen, CA). The antibodies were expressed by transient transfection of FreeStyle 293F cells (Life Technologies, CA). Briefly, 293-F cells at a density of 10.sup.6 cells/ml were transfected with heavy chain plasmid, light chain plasmid and 293fectin at a ratio of 2:1:6 as suggested by Life Technologies. Expression medium containing secreted proteins was harvested every 48 h twice after transfection. The three engineered antibodies were transiently expressed in FreeStyle 293 cells as a bovine-human chimera in which the Fc domain from human IgG1 was substituted for the bovine Fc. The antibodies were secreted into culture medium and purified by protein G column with yields of more than 5 mg/L (FIG. 46). The antibodies were purified by standard Protein A/G chromatography (Thermo Fisher Scientific, IL) and were analyzed by SDS-PAGE (FIGS. 46 and 47).

Example 19

Competition Assay of Beta Fusion Anti-CXCR4 Antibody by Flow Cytometry Analysis

[0463] Binding of the engineered antibodies to CXCR4 was measured by flow cytometry using human Jurkat cells, which highly express CXCR4. As shown in FIGS. 48A and 48B, all three antibodies (1 .mu.g/ml) bind Jurkat cells, while the control antibody (BLV1H12) showed no detectable binding. To confirm that the observed binding is indeed mediated by CXCR4, flow cytometry experiments were performed using Chinese hamster ovary (CHO) cells (which have no detectable CXCR4 expression based on flow cytometry staining with a FITC labeled anti-CXCR4 antibody (clone 12G5)), with and without CXCR4 transfection (FIG. 48C). Incubation of CXCR4 transfected CHO cells with 1 .mu.g/ml of the fusion antibodies resulted in a flow cytometry peak shift of 73.8%, 67.9% and 67.4% for bAb-AC1, bAb-AC2 and bAb-AC3, respectively. No peak shift was observed with non-transfected parental cells. In all cases, the control antibody showed no detectable binding. These results indicate that these engineered antibodies indeed bind specifically to CXCR4.

[0464] Cells were first blocked with blocking buffer (PBS supplemented with 3% BSA) at 4.degree. C. for 10 min and then incubated with various concentrations of antibodies in blocking buffer for 1 h. Cells were then washed with PBS and incubated with Alexa Fluor 647 conjugated goat anti-human IgG (Life Technologies, CA) in blocking buffer following manufacturer's instruction. After incubation, cells were washed and analyzed by LSR II flow cytometer (Becton Dickinson). In a competition experiment, cells were pre-incubated with various concentrations of antibodies in blocking buffer at 4.degree. C. for 30 min Fluorescein conjugated mouse anti-human CXCR4 monoclonal antibody (Clone 12G5, R&D system) was added in blocking buffer to a final concentration of 10 .mu.g/mL for an additional 30 min Cells were then washed with PBS and analyzed by a flow cytometer.

Example 20

Tag-Lite HTRF Binding Assay of Beta Fusion Anti-CXCR4 Antibody

[0465] To accurately determine the binding affinity between the engineered antibodies and CXCR4, we applied Tag-lite homogeneous time resolved fluorescence (HTRF) (Cisbio Bioassays). Specific binding of fluorescently labeled SDF-1 to labeled SNAP-tag-CXCR4 results in a HTRF signal. The binding constant (Kd) between fluorescently labeled SDF-1 and the Tag-lite CXCR4 receptor was determined to be 14.2.+-.1.2 nM (FIG. 49). A dose dependent competition was observed between the engineered antibodies and 50 nM of labeled SDF-1 (FIG. 50A). Assuming a competitive binding mode, the K.sub.is of bAb-AC1, bAb-AC2 and bAb-AC3 to CXCR4 were calculated to be 2.1 nM, 5.4 nM and 19.8 nM, respectively. These results indicate that bAb-AC1 with a more flexible glycine at i+1 position of the hairpin turn binds the best to CXCR4, which is consistent with the flow cytometry analysis results. On the other hand, bAb-AC3 which has a .beta.-turn promoting sequence (Asn-Gly) added at the end of the .beta.-hairpin, has a decreased affinity compared to bAb-AC1 and bAb-AC2 that is probably due to spatial constraints within the CXCR4 ligand binding pocket.

[0466] Monoclonal antibody 12G5 is commonly used to assess CXCR4 expression as well as functionally inhibit the SDF1-CXCR4 interaction. The binding epitope of 12G5 includes extracellular loop (ECL) 2, as well as the N-terminus and ECL3. Because bAb-ACs were designed to bind the CXCR4 pocket, they should compete with binding of 12G5 to the receptor. To confirm this notion, a competition assay was performed between 12G5 and bAb-AC1 by flow cytometry. A dose dependent inhibition was observed for 12G5 binding to Jurkat cells by increasing concentrations of bAb-AC1 (FIG. 51). Flow cytometry analysis (FIG. 50B) indicated that a three-fold excess of bAb-AC1 is sufficient to completely block the binding of 12G5 to CXCR4 on Jurkat cells. FIGS. 59A and 59B show additional Tag-lite HTRF binding assays similarly performed for both bovine and human fusions.

[0467] The Tag-lite HTRF binding assay was performed by following manufacturer's suggested procedure. Briefly, 10.sup.6 Tag-lite labeled CXCR4 cells were thawed at 37.degree. C., centrifuged for 5 min at 1200 g, and re-suspended in 2.7 ml 1.times.Tag-lite buffer after removal of supernatant. The cells were incubated with increasing concentrations of antibodies and 50 nM of fluorescent ligand (Chemokine CXCR4 receptor red agonist) for 3 h at room temperature. The signal was recorded by an EnVision multi-label plate reader (PerkinElmer) at 620 nm and 665 nm with 340 nm excitation. The binding between CXCR4 and SDF-1 was represented by ratio of signal 665/620*10000. The K.sub.is between antibodies and CXCR4 were calculated based on the Cheng-Prusoff equation: K.sub.i=IC.sub.50/([A]/EC.sub.50+1), where [A] is the fixed concentration of SDF-1 and EC.sub.50 is the concentration of SDF-1 that results in half maximal activation of the CXCR4 receptor. Binding assay results for bovine and human summarized in Table 4 and FIGS. 59A-B. Ki=IC.sub.50/(([A]/EC.sub.50)+1) is the Cheng-Prusoff equation: where [A] is the fixed concentration of agonist and EC.sub.50 is the concentration of agonist that results in half maximal activation of the receptor.

TABLE-US-00004 TABLE 4 bAb- bAb- bAb- bAb- AC1 AC2 AC3 AC4 HSCX HMCX HLCX 12G5 IC50 9.58 24.37 89.33 4.16 >300 113.30 9.36 4.40 (nM) Ki (nM) 2.12 5.39 19.76 0.92 ND 25.06 2.07 0.97

Example 21

BVL1H12-Beta BCCX2 HC 4-Antibody with Peptide Fused to CDRH2

[0468] BVL1H12-beta BCCX2 HC 4 fusion was designed by grafting the CDRH3 sequence from BVLH12-beta BCCX2 HC 1 into the CDRH2 of the BLV1H12 scaffold. The truncated CDRH3 of the resulting antibody was capped with a GGGGS linker (SEQ ID NO: 164) to give a new CDRH3 sequence, TSVHQGGGGSWHVDV (SEQ ID NO: 234). BLV1H12-beta BCCX2 HC 4 IgG was expressed in 293 cells with a much higher yield (17 mg/L) compared to BLV1H12-beta BCCX2 HC 1 IgG. This may be due to the fact that CDRH2 makes no direct contact with the rest of the antibody, and therefore has less effect on heavy chain and light chain packing compared to the CDRH3 fusion. Binding between BLV1H12-beta BCCX2 HC 4 IgG and CXCR4 was confirmed by both flow cytometry (FIG. 52) and a Tag-lite HTRF assay as described above (FIG. 53) to give a Ki value of 0.92 nM against the receptor. This result indicates that the CDRH2 is indeed a viable alternative to CDRH3 for functional peptide grafting and suggests that it may be possible to simultaneously graft two polypeptide agonists or antagonists into two distinct CDRs of a single antibody fusion protein.

Example 22

Beta Fusion CXCR4 Antibody Inhibits SDF-1 Induced Chemotaxis

[0469] The physiological function of SDF-1 is to trigger the migration and recruitment of CXCR4 expressing cells. A chemotaxis assay was used to test if bAb-ACs can block SDF-1 dependent cell migration (FIG. 54). An HTS transwell plate with 5.0 .mu.m pore polycarbonate membrane (Corning Incorporated) was coated with human fibronectin (20 .mu.g/ml) in PBS for 2 h at 37.degree. C. Ramos cells were washed with PBS and re-suspended in assay medium (1% BSA in HEPES buffered RPMI) at a concentration of 10.sup.6 cells/ml. Cells were starved in assay medium for 4 h at 37.degree. C. and then incubated with various concentrations of antibodies for 1 h. After pre-incubation, 5.times.10.sup.5 cells were loaded onto the top chamber of the transwell plate in a volume of 100 .mu.L. The bottom wells were filled with 80 .mu.l of SDF-1 (10 ng/ml) and antibodies at the same concentration as the corresponding top wells. Cell migration was allowed to proceed for 3 h at 37.degree. C. Migrated cells were quantified by the addition of 10 .mu.l prestoblue (Life Technologies, CA) and 10 .mu.l FBS and fluorescent signal was recorded on a Spectramax fluorescence plate reader at 590 nm with 550 nm excitation.

[0470] Pre-incubation with the antibodies potently inhibited the migration of Ramos cells in a dose dependent manner (FIG. 55B) with EC50 values of 2.1 nM, 8.5 nM and 3.2 nM for 12G5, bAb-AC1 and bAb-AC4, respectively. 30 nM of bAb-AC4 completely neutralized SDF-1 induced migration of Ramos cells; while 12G5, even at its saturating concentration, could not 100% block the migration (FIGS. 55B and 55C). FIG. 58 shows a migration assay similarly performed for the human fusions.

Example 23

Beta Fusion CXCR4 Antibody Calcium Flux Assay

[0471] The engineered antibodies were tested for their ability to block CXCR4 dependent intracellular signaling. Activation of CXCR4 by SDF1 can be measured by intracellular calcium flux, a secondary messenger involved in GPCR signaling. Ramos cells, a non-Hodgkin lymphoma cell line, that highly express CXCR4, were washed with HBSS/HEPES (30 mM), and re-suspended in Fluo-4 direct labeling solution (Life Technologies, CA). The labeling reaction proceeded for 30 min at 37.degree. C. and then room temperature for an additional 30 min Fluo-4 loaded cells were washed with HBSS/HEPES twice and re-suspended in the assay buffer (HBSS with 30 mM HEPES and 2.5 mM probenecid) at a density of 10.sup.6 cells/ml. Antibodies were added and incubated with loaded cells for 1 h before reading the plate. Calcium flux signals were recorded on a fluorescence laser-imaging plate reader (FLIPR; Molecular Devices) immediately upon addition of SDF-1 at a final concentration of 50 nM. Cells loaded with Fluo-4 calcium indicators were incubated with 300 nM bAb-AC1, bAb-AC4 and the control antibody; SDF-1 mediated release of intracellular calcium was monitored by a fluorescence increase. bAb-AC1 significantly reduced calcium flux induced by 50 nM of SDF-1, whereas the same concentration of bAb-AC4 completely blocked the calcium signaling post SDF-1 activation (FIG. 55A and FIG. 56). These results indicate that these engineered antibodies are CXCR4 antagonists.

Example 24

Beta Fusion Anti-CXCR4 Antibody: Cell Culture and Maintenance

[0472] Jurkat and Ramos cells were maintained in RPMI-1640 (Life Technologies, CA) containing 10% (vol/vol) FBS (Life Technologies, CA) in 37.degree. C. incubator with 5% CO.sub.2. CHO-S and 293-F cells were maintained between 0.2.times.10.sup.6 and 2.times.10.sup.6 cells/ml in FreeStyle medium (Life Technologies, CA) in Minitron shakers at 37.degree. C.

Example 25

Expression and Purification of Beta Fusion Elastase Inhibitor Antibodies

[0473] BLV1H12 heavy chain or human antibody BVK heavy chain genes containing different CDR3s were cloned as C-terminal His6-tag (SEQ ID NO: 319) into the pFuse backbone vector (InvivoGen, CA). CDRs contained sequences encoding trypsin (control BLV1H12-tryspin inhibitor fusion antibody (BTI)) or neutrophil elastase inhibitor (BLV1H12-elastase inhibitor fusion antibody (BEI) and BVK elastase inhibitor fusion antibody (HEI). The antibodies were expressed through transient transfection of FreeStyle 293F cells using FreeStyle.TM. 293 Expression System (Life technologies Co., CA). Briefly, 293-F cells were maintained between 0.2.times.10.sup.6 to 2.times.10.sup.6/ml in 8% CO.sub.2 with 125 rpm shaking in Minitron Incubation Shakers at 37.degree. C. Cells were transfected with heavy chain plasmid, light chain plasmid and 293fectin ratio 2:1:6 as suggested by Life technologies. Medium (FreeStyle 293 expression medium) containing secreted proteins was harvested every 48 hours twice after transfection. His6-tag (SEQ ID NO: 319) Fab antibodies were purified by Ni-NTA affinity chromatography (Qiagen, CA) according to the manufacturer's instructions and buffer exchanged four times with 10 KDa Amicon Ultra-15 (1).

Example 26

Beta Fusion Elastase Inhibitor Antibodies: Trypsin Inhibition Assay

[0474] BLV1H12 heavy chain genes containing different CDR3 were cloned as C-terminal His6-tag (SEQ ID NO: 319) into the pFuse backbone vector (InvivoGen, CA). The antibodies were expressed through transient transfection of FreeStyle 293F cells using FreeStyle.TM. 293 Expression System (Life technologies Co., CA). Briefly, 293-F cells were maintained between 0.2.times.10.sup.6 to 2.times.10.sup.6/ml in 8% CO.sub.2 with 125 rpm shaking in Minitron Incubation Shakers at 37.degree. C. Cells were transfected with heavy chain plasmid, light chain plasmid and 293fectin ratio 2:1:6 as suggested by Life technologies. Medium (FreeStyle 293 expression medium) containing secreted proteins was harvested every 48 hours twice after transfection. His6-tag (SEQ ID NO: 319) Fab antibodies were purified by Ni-NTA affinity chromatography (Qiagen, CA) according to the manufacturer's instructions and buffer exchanged four times with 10 KDa Amicon Ultra-15 (Millipore) and were analyzed by SDS-PAGE (see FIGS. 60A, 61 and 63).

Example 27

Beta Fusion Elastase Inhibitor Antibodies: Biolayer Interferometry

[0475] Biolayer interferometry experiment was performed using an Octet RED instrument (ForteBio, Inc.). Briefly, his-tag labeled BEI Fab at 50 .mu.g/ml in kinetics buffer (PBS, 0.01% BSA and 0.002% Tween 20) was immobilized onto Ni-NTA coated biosensor. Each biosensor was incubated with a different concentration of bovine trypsin ranging from (12.5 nM to 200 nM). The binding kinetics was monitored in real time with 4 min association and 4 min dissociation time. Kinetics parameters Kon, Koff and Kd was obtained by fitting the data into 1:1 binding mode using Octet system software. The K.sub.on and K.sub.off values were measured in real time at room temperature by Octet RED instrument (ForteBio, Inc.), and were determined to be 9.68.times.10.sup.4.+-.4.70.times.102 M.sup.-1 s.sup.-1 and 3.26.times.10.sup.-4.+-.6.84.times.10.sup.-6 s.sup.-1 respectively. The calculated dissociation constant between BTI and trypsin is 3.37 nM (see FIG. 60B for plotted data).

Example 28

Elastase Inhibition Assay

[0476] Human neutrophil elastase was purchased from Elastin Products Company, Inc. Increasing concentration of BEI1 and BEI2 were incubated with 10 nM human NE for 20 min at room temperature, the residue activity of NE was analyzed by the addition of fluorogenic elastase substrate MeOSuc-AAPV-AMC (EMD Millipore) at a final concentration of 100 .mu.M. The slope of reaction was obtained by monitoring at 420 nm wavelength with 325 nm excitation on Spectramax fluorescence plate reader. Each data point was triplicated and fit into morrison equation using Et=10 nM, S=100 .mu.M, Km=130 .mu.M as constant value: Q=(Ki*(1+(S/Km))). Y=Vo*(1-((((Et+X+Q)-(((Et+X+Q) 2)-4*Et*X) 0.5))/(2*Et))). FIGS. 62 and 64 show the inhibition of elastase by the bovine and human elastase inhibitor fusion antibodies.

Example 29

Construction of Trastuzumab GCSF/EPO Dual Fusion Protein

[0477] Bovine CDR3H fusion proteins were humanized using trastuzumab-based scaffold. Therapeutic polypeptides (EPO) fused to the bovine ultralong CDR3H region was grafted onto the CDR3H of trastuzumab and paired with GCSF fused to the CDR3L region of trastuzumab along with the engineered coiled coil and beta sheet "stalks." The generated humanized biologically active fusion proteins potentially improve pharmacological propertied for treatment of relevant diseases.

Example 30

In Vitro Proliferative Activity of Trastuzumab GCSF/EPO Dual Fusion Protein on NFS-60 Cells

[0478] Mouse NFS-60 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 0.05 mM 2-mercapoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). For proliferation assay, mouse NFS-60 cells were washed three times with RPMI-1640 medium and resuspended in RPMI-1640 medium with 10% FBS and 0.05 mM 2-mercapoethanol at a density of 1.5.times.10.sup.5 cells/ml. In 96-well plates, 100 .mu.l of cell suspension was added into each well, followed by the addition of varied concentrations of hGCSF, His-tagged hGCSF, trastuzumab-H3-beta/hEPO-L3-coil/hGCSF dual fusion. The plates were incubated at 37.degree. C. in a 5% CO2 incubator for 72 hours. Cells were then treated with AlamarBlue (Invitrogen) ( 1/10 volume of cell suspension) for 4 hours at 37.degree. C. Fluorescence at 595 nm for each well was read to indicate the cell viability. See FIG. 66A for plotted data.

Example 31

In Vitro Proliferative Activity Assay of Trastuzumab GCSF/EPO Dual Fusion Protein on TF-1 Cells

[0479] Human TF-1 cells were cultured at 37.degree. C. with 5% CO.sub.2 in RPMI-1640 medium containing 10% fetal bovine serum (FBS), penicillin and streptomycin (50 U/mL), and 2 ng/ml human granulocyte macrophage colony stimulating factor (GM-CSF). To examine the proliferative activity of trastuzumab-hEPO fusion proteins, cells were washed three times with RPMI-1640 medium with 10% FBS, resuspended in RPMI-1640 medium with 10% FBS at a density of 1.5.times.10.sup.5 cells/ml, plated in 96-well plates (1.5.times.10.sup.4 cells per well) with various concentrations of hEPO, trastuzumab, and trastuzumab-hEPO fusion proteins (SEQ ID NOs: 304 and 21), and then incubated for 72 hours at 37.degree. C. with 5% CO.sub.2. Cells were then treated with Alamar Blue (Life Technologies, CA) for 4 hours at 37.degree. C. Fluorescence intensity measured at 595 nm is proportional to cell viability. The EC.sub.50 values were determined by fitting data into a logistic sigmoidal function: y=A.sub.2+(A.sub.1-A.sub.2)/(1 (x/x.sub.0.sup.p), where A.sub.1 is the initial value, A.sub.2 is the final value, x.sub.0 is the inflection point of the curve, and p is the power. See Table 5 for EC50 values of the dual fusion and related controls, and FIG. 66B for plotted data.

TABLE-US-00005 TABLE 5 Trastuzumab-H3- beta/hEPO-L3- His-tagged coil/hGCSF hGCSF hGCSF EC50 (ng/mL) 36.1 +/- 8.0 1.0 +/- 0.0 10.7 +/- 0.5

Example 32

Electrospray Ionization Mass Spectrometry (ESI-MS) of Immunoglobulin Fusion Proteins

[0480] Purified immunoglobulin fusion proteins were treated overnight at 37.degree. C. with Peptide-N-Glycosidase (NEB), followed by the addition of DTT. The fusion proteins were analyzed by ESI-MS using a 6520 Q-TOF LC/MS from Agilent Technology. A chromatograph for the ESI-MS of trastuzumab-CDR3H-beta-hEPO fusion protein (SEQ ID NOs: 304 and 21) is shown in FIG. 13.

Example 33

Construction and Purification of Bovine-Beta Fusion Proteins

[0481] To generate BLV1H12-beta Moka fusion proteins, the gene encoding Moka was synthesized by Genscript or IDT, and amplified by PCR. To generate a Moka1 L1 fusion protein, flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the Moka1 gene. Extender peptide sequences having beta strand secondary structure were added to both sides of the Moka1 L1 gene and Moka1 L0 (no linkers). The fragments were grafted into the BLV1H12 heavy chain to generate BLV1H12-beta Moka1 L0 HC and BLV1H12-beta Moka1 L1 HC. The BLV1H12 expression vectors were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0482] BLV1H12-beta Moka1 L0 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta Moka1 L0 protein heavy chain (SEQ ID NO: 261) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta Moka1 L1 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta Moka1 L1 protein heavy chain (SEQ ID NO: 262) and the BLV1H12 light chain (SEQ ID NO: 40).

[0483] Purified BLV1H12-beta Moka1 L0 IgG (SEQ ID NOs: 261 and 40) and BLV1H12-beta Moka1 L1 (SEQ ID NOs: 262 and 40) are shown in FIG. 18. Lane 1 is a protein molecular weight marker, lane 2 is purified BLV1H12-beta Moka1 L0 IgG, lane 3 is purified BLV1H12-beta Moka1 L0 IgG treated with DTT, lane 4 is purified BLV1H12-beta Moka1 L1 IgG, and lane 5 is purified BLV1H12-beta Moka1 L1 IgG treated with DTT.

[0484] To generate BLV1H12-beta VM24 fusion proteins, the gene encoding VM24 was synthesized by Genscript or IDT, and amplified by PCR. To generate a VM24 L1 fusion protein, flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the VM24 gene. To generate a VM24 L2 fusion protein, flexible linkers of GGGGSGGGGS (SEQ ID NO: 320) were added on both ends of the VM24 gene. Extender peptide sequences having beta strand secondary structure were added to both sides of the VM24 L1 and VM24 L2 genes. The fragments were grafted into the BLV1H12 heavy chain to generate BLV1H12-beta VM24 L1 HC and BLV1H12-beta VM24 L2 HC. The BLV1H12 expression vectors were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0485] BLV1H12-beta VM24 L1 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta VM24 L1 protein heavy chain (SEQ ID NO: 263) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta VM24 L2 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta VM24 L2 protein heavy chain (SEQ ID NO: 264) and the BLV1H12 light chain (SEQ ID NO: 40).

[0486] Purified BLV1H12-beta VM24 L1 IgG (SEQ ID NOs: 263 and 40) and BLV1H12-beta VM24 L2 (SEQ ID NOs: 264 and 40) are shown in FIG. 21. Lane 1 is a protein molecular weight marker, lane 2 is purified BLV1H12-beta VM24 L1 IgG, lane 3 is purified BLV1H12-beta VM24 L1 IgG treated with DTT, lane 4 is purified BLV1H12-beta VM24 L2 IgG, and lane 5 is purified BLV1H12-beta VM24 L2 IgG treated with DTT.

[0487] To generate BLV1H12-beta hEPO fusion proteins, the gene encoding hEPO was synthesized by Genscript or IDT, and amplified by PCR. To generate a hEPO fusion protein, flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the hEPO gene. Extender peptide sequences having beta strand secondary structure were added to both sides of the hEPO gene. The fragment was grafted into the BLV1H12 heavy chain to generate BLV1H12-beta hEPO HC. The BLV1H12 expression vector was generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0488] BLV1H12-beta hEPO IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta hEPO protein heavy chain (SEQ ID NO: 267) and the BLV1H12 light chain (SEQ ID NO: 40).

[0489] Purified BLV1H12-beta hEPO IgG (SEQ ID NOs: 267 and 40) are shown in FIG. 24. Lane 1 is a protein molecular weight marker, lane 2 is purified BLV1H12-beta hEPO IgG, and lane 3 is purified BLV1H12-beta hEPO IgG treated with DTT.

[0490] To generate BLV1H12-beta GLP-1 fusion proteins, the gene encoding GLP-1 was synthesized by Genscript or IDT, and amplified by PCR. To generate a GLP-1 RN (released N-terminus) heavy chain fusion protein, a Factor Xa cleavage site of IEGR was added to the N-terminus of the GLP-1 gene to generate a GLP-1 RN fragment. Flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the GLP-1 RN fragment. Extender peptide sequences having beta strand secondary structure were added to both sides of the GLP-1 RN fragment having linker peptide sequences. The GLP-1 RN, linker, extender peptide fragment was grafted into the BLV1H12 heavy chain to generate BLV1H12-beta GLP-1 RN HC. The BLV1H12 expression vector was generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0491] BLV1H12-beta GLP-1 RN IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta GLP-1 RN protein heavy chain (SEQ ID NO: 265) and the BLV1H12 light chain (SEQ ID NO: 40). The fusion proteins were purified and cleaved with Factor Xa to generated a clipped fusion protein.

[0492] Purified BLV1H12-beta GLP-1 RN IgG (SEQ ID NOs: 265 and 40) are shown in FIG. 29. Lane 1 is a protein molecular weight marker, lane 2 is purified BLV1H12-beta GLP-1 RN IgG, lane 3 is purified BLV1H12-beta GLP-1 RN IgG treated with DTT, lane 6 is purified BLV1H12-beta GLP-1 RN IgG cleaved with Factor Xa, and lane 7 is purified BLV1H12-beta GLP-1 RN IgG cleaved with Factor Xa and treated with DTT.

[0493] To generate BLV1H12-beta Ex-4 fusion proteins, the gene encoding Ex-4 was synthesized by Genscript or IDT, and amplified by PCR. To generate an Ex-4 RN (released N-terminus) heavy chain fusion protein, a Factor Xa cleavage site of IEGR was added to the N-terminus of the Ex-4 gene to generate an Ex-4 RN fragment. Flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the Ex-4 RN fragment. Extender peptide sequences having beta strand secondary structure were added to both sides of the Ex-4 RN fragment having linker peptide sequences. The Ex-4 RN, linker, extender peptide fragment was grafted into the BLV1H12 heavy chain to generate BLV1H12-beta Ex-4 RN HC. The BLV1H12 expression vector was generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0494] BLV1H12-beta Ex-4 RN IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta Ex-4 RN protein heavy chain (SEQ ID NO: 266) and the BLV1H12 light chain (SEQ ID NO: 40). The fusion proteins were purified and cleaved with Factor Xa to generate a clipped fusion protein.

[0495] Purified BLV1H12-beta Ex-4 RN IgG (SEQ ID NOs: 266 and 40) are shown in FIG. 29. Lane 1 is a protein molecular weight marker, lane 4 is purified BLV1H12-beta Ex-4 RN IgG, lane 5 is purified BLV1H12-beta Ex-4 RN IgG treated with DTT, lane 8 is purified BLV1H12-beta Ex-4 RN IgG cleaved with Factor Xa, and lane 9 is purified BLV1H12-beta Ex-4 RN IgG cleaved with Factor Xa and treated with DTT.

[0496] To generate BLV1H12-beta hLeptin fusion proteins, the gene encoding hLeptin was synthesized by Genscript or IDT, and amplified by PCR. Flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the hLeptin fragment. Extender peptide sequences having beta strand secondary structure were added to both sides of the hLeptin fragment having linker peptide sequences. The hLeptin, linker, extender peptide fragment was grafted into the BLV1H12 heavy chain to generate BLV1H12-beta hLeptin HC. The BLV1H12 expression vector was generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0497] BLV1H12-beta hLeptin IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta hLeptin protein heavy chain (SEQ ID NO: 230) and the BLV1H12 light chain (SEQ ID NO: 40).

[0498] Purified BLV1H12-beta hLeptin IgG (SEQ ID NOs: 230 and 40) are shown in FIG. 43A. Lane 1 is a protein molecular weight marker, lane 2 is purified BLV1H12-beta hLeptin IgG, and lane 3 is purified BLV1H12-beta hLeptin IgG treated with DTT.

[0499] To generate BLV1H12-beta relaxin fusion proteins, fragments encoding relaxin2, relaxin2 (GGSIEGR (SEQ ID NO: 307)), and relaxin2 (IEGRCpeptideIEGR (SEQ ID NO: 321)) were synthesized by Genscript or IDT, and amplified by PCR. Linker peptides encoding GGGGS (SEQ ID NO: 164) were added to the N-terminus and C-terminus of the relaxin fragments. Extender peptide ETKKYQS (SEQ ID NO: 111) was then added to the N-terminus of relaxin-linker fragments and extender peptide SYTYNYE (SEQ ID NO: 119) was added to the C-terminus of the relaxin-linker fragments. The relaxin, linker, extender peptide fragments were grafted into the BLV1H12 heavy chain to generate BLV1H12-beta relaxin HC fusions. The BLV1H12 expression vectors were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0500] BLV1H12-beta relaxin2 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta relaxin2 heavy chain (SEQ ID NO: 274) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta relaxin2 (GGSIEGR (SEQ ID NO: 307)) IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta relaxin2 (GGSIEGR (SEQ ID NO: 307)) heavy chain (SEQ ID NO: 275) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta relaxin2 (IEGRCpepIEGR (SEQ ID NO: 321)) IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta relaxin2 (IEGRCpepIEGR (SEQ ID NO: 321)) heavy chain (SEQ ID NO: 276) and the BLV1H12 light chain (SEQ ID NO: 40). The fusion proteins were purified and some were cleaved with Factor Xa to generated a clipped fusion protein.

[0501] Purified BLV1H12-beta relaxin IgGs are shown in FIGS. 44 A-C: (A) BLV1H12-CDR3H-beta human relaxin2 clip fusion protein (SEQ ID NOs: 274 and 40), with and without reducing agent; (B) BLV1H12-CDR3H-beta human relaxin clip fusion protein with engineered connector peptide (SEQ ID NOs: 276 and 40), with and without reducing agent; and (C) BLV1H12-CDR3H-beta human relaxin clip fusion protein with GGSIEGR linker (SEQ ID NO: 307) (SEQ ID NOs: 275 and 40), with and without reducing agent.

[0502] To generate BLV1H12-beta BCCX fusion proteins, fragments encoding BCCX2 were synthesized by Genscript or IDT, and amplified by PCR. Peptides encoding ETKKYQS (SEQ ID NO: 111) were added to the N-terminus and peptides encoding SYTYNYE (SEQ ID NO: 119) were added to the C-terminus of the BCCX2 fragments. The fragments were grafted into the BLV1H12 heavy chain to generate BLV1H12-beta BCCX2 HC fusions. The BLV1H12 expression vectors were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0503] BLV1H12-beta BCCX2 HC 1 IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta BCCX2 HC 1 (SEQ ID NO: 92) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta BCCX2 HC 4 fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta HC4 (SEQ ID NO: 95) and the BLV1H12 light chain (SEQ ID NO: 40).

[0504] Purified BLV1H12-beta BCCX2 IgGs are shown in FIG. 46. Lane 1 is a protein molecular weight marker, lane 2 is BLV1H12-beta BCCX2 HC4 (bAb-AC4) IgG (SEQ ID NOs: 94 and 40), lane 3 is BLV1H12-beta BCCX2 HC4 (bAb-AC4) IgG (SEQ ID NOs: 94 and 40) treated with DTT, lane 4 is BLV1H12-beta BCCX2 HCl (bAb-AC1) IgG (SEQ ID NOs: 92 and 40), and lane 5 is BLV1H12-beta BCCX2 HCl (bAb-AC1) IgG (SEQ ID NOs: 92 and 40) treated with DTT.

Example 34

In Vitro Study of BLV1H12-Beta-Strand bGCSF Fusion Protein Proliferative Activity on Mouse NFS-60 Cells

[0505] Mouse NFS-60 cells were obtained from American Type Culture Collection (ATCC), VA, and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 0.05 mM 2-mercapoethanol and 62 ng/ml human macrophage colony stimulating factor (M-CSF). For proliferation assays, mouse NFS-60 cells were washed three times with RPMI-1640 medium and re-suspended in RPMI-1640 medium with 10% FBS and 0.05 mM 2-mercapoethanol at a density of 1.5.times.10.sup.5 cells/ml. In 96-well plates, 100 .mu.l of cell suspension was added into each well, followed by the addition of varied concentrations of bGCSF (SEQ ID NO: 200), hGCSF, BLV1H12 IgG, BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0), and BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1). The plates were incubated at 37.degree. C. in a 5% CO.sub.2 incubator for 72 hours. Cells were then treated with AlamarBlue (Invitrogen) ( 1/10 volume of cell suspension) for 4 hours at 37.degree. C. Fluorescence at 595 nm for each well was read to indicate the cell viability. FIGS. 37 A-E shows the fluorescence of the NFS-60 cells treated with various concentrations of bGCSF (SEQ ID NO: 200), hGCSF, BLV1H12 IgG, BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0), and BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1).

Example 35

In Vitro Study of BLV1H12-Beta-Strand Moka1 Fusion Protein Inhibitory Activities on Human Peripheral Blood Mononuclear Cells (PBMCs)/T Cells Activation

[0506] Human PBMCs were isolated from fresh venous blood of healthy donors through ficoll gradient centrifugation, followed by re-suspension in RPMI1640 medium with 10% FBS and plating in 96-well plates at a density of 1.times.10.sup.6 cells/mL. PBMCs and T cells were pretreated for 1 h at 37.degree. C. and 5% CO.sub.2 with various concentrations of BLV1H12 IgG, purified BLV1H12-beta Moka1L0 fusion protein (SEQ ID NOs: 261 and 40) and purified BLV1H12-beta Moka L1 fusion protein (SEQ ID NOs:262 and 40), and then activated by anti-CD3 and CD28 antibodies. After 24 h treatment, supernatants were collected and the levels of secreted TNF-.alpha. measured using an ELISA kit. A tabular representation of the data is shown in FIG. 19.

Example 36

In Vitro Study of BLV1H12-Beta-Strand Moka1 Fusion Protein Inhibitory Activities on Human Peripheral Blood Mononuclear Cells (PBMCs)/T Cells Activation

[0507] Human PBMCs were isolated from fresh venous blood of healthy donors through ficoll gradient centrifugation, followed by re-suspension in RPMI1640 medium with 10% FBS and plating in 96-well plates at a density of 1.times.10.sup.6 cells/mL. Human T cells were purified from the isolated PBMCs using T cell enrichment kit. Purified PBMCs and T cells were pretreated for 1 h at 37.degree. C. and 5% CO.sub.2 with various concentrations of purified BLV1H12-beta Moka L1 fusion protein (SEQ ID NOs:262 and 40), and then activated by anti-CD3 and CD28 antibodies. After 24 h treatment, supernatants were collected and the levels of secreted TNF-.alpha. measured using an ELISA kit. A graphical representation of the data is shown in FIG. 20.

Example 37

In Vitro Study of BLV1H12-Beta-Strand VM24 Fusion Protein Inhibitory Activities on Human Peripheral Blood Mononuclear Cells (PBMCs)/T Cells Activation

[0508] Human PBMCs were isolated from fresh venous blood of healthy donors through ficoll gradient centrifugation, followed by re-suspension in RPMI1640 medium with 10% FBS and plating in 96-well plates at a density of 1.times.10.sup.6 cells/mL. Human T cells were purified from the isolated PBMCs using T cell enrichment kit. Purified PBMCs and T cells were pretreated for 1 h at 37.degree. C. and 5% CO.sub.2 with various concentrations of purified BLV1H12-beta VM24 L1 fusion protein (SEQ ID NOs:263 and 40) and BLV1H12-beta VM24 L2 fusion protein (SEQ ID NOs: 264 and 40), and then activated by anti-CD3 and CD28 antibodies. After 24 h treatment, supernatants were collected and the levels of secreted TNF-.alpha. measured using an ELISA kit. A graphical representation of the data is shown in FIGS. 22A and 22B.

Example 38

In Vitro Proliferative Activity Assay of BLV1H12-Beta hEPO Fusion Protein on TF-1 Cells

[0509] Human TF-1 cells were cultured at 37.degree. C. with 5% CO.sub.2 in RPMI-1640 medium containing 10% fetal bovine serum (FBS), penicillin and streptomycin (50 U/mL), and 2 ng/ml human granulocyte macrophage colony stimulating factor (GM-CSF). To examine the proliferative activity of BLV1H12-hEPO fusion proteins, cells were washed three times with RPMI-1640 medium with 10% FBS, resuspended in RPMI-1640 medium with 10% FBS at a density of 1.5.times.10.sup.5 cells/ml, plated in 96-well plates (1.5.times.10.sup.4 cells per well) with various concentrations of hEPO (SEQ ID NO: 206), BLV1H12 IgG, and BLV1H12-beta hEPO fusion protein (SEQ ID NOs: 267 and 40), and then incubated for 72 hours at 37.degree. C. with 5% CO.sub.2. Cells were then treated with Alamar Blue (Life Technologies, CA) for 4 hours at 37.degree. C. A graphical representation of the data is shown in FIG. 25.

Example 39

Pharmacokinetics of BLV1H12-Beta hEPO Fusion Proteins in Mice

[0510] hEPO (0.18 mg/kg) and BLV1H12-beta hEPO IgG (SEQ ID NOs: 267 and 40) (1.5 mg/kg) in PBS (pH 7.4) were administrated by intravenous (i.v.) injection into three CD1 mice per group. Blood was collected from day 0 to day 14 and analyzed by ELISA using anti-human IgG Fc (Abcam) and anti-hEPO (R&D systems) antibodies. Data were normalized by taking the maximal concentration at the first time point (30 minutes). The percentage of maximal concentration was plotted versus time, and the half-lives were determined by fitting data into the first-order equation, A=A0e-kt, where A0 is the initial concentration, t is the time, and k is the first order rate constant. A graphical representation of the data is shown in FIG. 26.

Example 40

Pharmacodynamics of BLV1H12-hEPO Fusion Proteins in Mice

[0511] Vehicle (PBS, pH 7.4), BLV1H12 IgG (810 .mu.g/kg), hEPO (90 .mu.g/kg) and BLV1H12-beta hEPO IgG (SEQ ID NOs: 267 and 40) (810 .mu.g/kg) were administrated by subcutaneous (s.c.) injection into CD1 mice (three per group) at day 0 and day 2. Blood was collected at different time points and the hematocrit levels were measured by centrifugation in micro-hematocrit capillary tubes. A graphical representation of the data is shown in FIG. 27.

Example 41

In Vitro BLV1H12-Beta GLP-1 and BLV1H12-Beta Exendin-4 Based Fusion Proteins Activation Activities on GLP-1 Receptor

[0512] HEK 293 cells overexpressing GLP-1 receptor (GLP-1R) and cAMP responsive element (CRE)-luciferase (Luc) reporter were grown in DMEM with 10% FBS at 37.degree. C. with 5% CO.sub.2. Cells were seeded in 384-well plates at a density of 5000 cells per well and treated with various concentrations of Ex-4 peptide (SEQ ID NO: 201), BLV1H12-beta Ex-4 (SEQ ID NOs: 266 and 40), BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, treated with Factor Xa), BLV1H12-beta GLP-1 (SEQ ID NOs: 265 and 40), and BLV1H12-beta GLP RN (SEQ ID NOs: 265 and 40, treated with Factor Xa) for 24 hours at 37.degree. C. with 5% CO.sub.2. An immunoglobulin fusion protein which may be cleaved to release the amino-terminus of a therapeutic agent is referred to as RN, for released N-terminus. Luminescence intensities were then measured using One-Glo (Promega, WI) luciferase reagent by following manufacturer's instruction. A graphical representation of the data is shown in FIG. 30.

Example 42

In Vitro Stability Assay of BLV1H12-Beta Exendin-4 Fusion Proteins

[0513] Exendin-4 (200 nM), BLV1H12-beta Ex-4 (SEQ ID NOs: 266 and 40) (1 uM) and BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, treated with Factor Xa) (200 nM) were incubated in fresh mouse and human plasma at 37.degree. C. The mixtures were collected at times between 0 and 96 hours, and the remaining activities on GLP-1R activation were measured using HEK293-GLP-1R-CRE-Luc cells. A graphical depiction of the data is shown in FIGS. 31A and 31B.

Example 43

Pharmacokinetics of BLV1H12-Beta Ex-4 RN Fusion Proteins in Mice

[0514] Exendin-4 (1.6 mg/kg) and BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, cleaved with Factor Xa) fusion protein (2.8 mg/kg) were administrated by injection into CD1 mice (N=3). Blood samples were collected from day 0 to day 8. The remaining activities were analyzed using HEK 293-GLP-1R-CRE-Luc cells. Data were normalized by taking the maximal concentration at the first time point (30 minutes). Percentages of the maximal concentration were plotted versus time points of blood sample collection, and half-lives were determined by fitting data into the first-order equation, A=A0e-kt, where A0 is the initial concentration, t is the time, and k is the first-order rate constant. FIG. 32 depicts a graphical representation of the data. The t.sub.1/2 of Exendin-4 was 1.5.+-.0.2 hours. The t.sub.1/2 of BLV1H12-beta Ex-4 RN was 2.2.+-.1.1 days.

Example 44

Pharmacodynamics of BLV1H12-Beta Ex-4 RN Fusion Proteins in Mice

[0515] Doses of Exendin-4 (0.5 .mu.g), BLV1H12, PBS, and BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, cleaved with Factor Xa) (100 .mu.g) were administrated by intravenous injection into CD1 mice (N=5). Glucose (3 g/kg, p.o.) was given post treatment, followed by blood glucose measurements. FIGS. 33A and 33B depicts a graphical representation of the data.

Example 45

Pharmacodynamics of BLV1H12-Beta Ex-4 RN Fusion Proteins in Mice

[0516] Doses of Exendin-4 (0.5 .mu.g), BLV1H12 (100, 200 .mu.g), PBS, and BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, cleaved with Factor Xa) (100, 200 .mu.g) were administrated by subcutaneous injection into CD1 mice (N=5). Glucose (3 g/kg, p.o.) was given 24 hr post treatment, followed by blood glucose measurements. FIGS. 34A and 34B depicts a graphical representation of the data.

Example 46

Pharmacodynamics of BLV1H12-Beta Ex-4 RN Fusion Proteins in Mice

[0517] Doses of Exendin-4 (0.5 .mu.g), BLV1H12 (100, 200 .mu.g), PBS, and BLV1H12-beta Ex-4 RN (SEQ ID NOs: 266 and 40, cleaved with Factor Xa) (100, 200 .mu.g) were administrated by subcutaneous injection into CD1 mice (N=5). Glucose (3 g/kg, p.o.) was given 48 hr post treatment, followed by blood glucose measurements. FIGS. 35A and 35B depicts a graphical representation of the data.

Example 47

In Vitro Study of BLV1H12-Beta-Strand bGCSF Fusion Protein Proliferative Activity on Human Granulocyte Progenitors

[0518] Human mobilized peripheral blood CD34+ cells were purchased from AllCells (Emeryville, Calif.). Cells were resuspended in HSC expansion medium (StemSpan SFEM, StemCell Technologies), and supplemented with 1.times. antibiotics and the following recombinant human cytokines: thrombopoietin, IL6, Flt3 ligand, and stem cell factor (100 ng/mL, R&D Systems). The cells were then plated in 96-well plates (1000 cells per well) with various concentrations of bGCSF (SEQ ID NO: 200), hGCSF, BLV1H12 full-length IgG, BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0), and BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1). Cells were cultured for 7 days at 37.degree. C. with 5% CO2, and then analyzed by flow cytometry to measure cell number and expression of CD45ra and CD41 using PE-Cy7 anti-CD45ra and eFluor 450 anti-CD41 (eBiosciences) antibodies. FIGS. 38 A-E show the fluorescence of the cells treated with various concentrations of bGCSF (SEQ ID NO: 200), hGCSF, BLV1H12 full-length IgG, BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0), and BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1).

Example 48

Pharmacokinetics of BLV1H12-Beta bGCSF Fusion Proteins in Mice

[0519] BLV1H12 full-length IgG (2.8 mg/kg), BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0) (2.8 mg/kg), BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1) (2.8 mg/kg) and bGCSF (8 mg/kg) were administrated by intravenous (i.v.) injection into 3 BALB/c mice per group. Blood was collected from day 0 to day 14 and analyzed by ELISA using anti-human IgG Fc antibody (KPL) for BLV1H12 full-length IgG and anti-bGCSF antibody (Abbiotec) for Ab-bGCSF fusion proteins and bGCSF. Data were normalized by taking maximal concentration at the first time point (30 minutes). FIGS. 39A and 39B depicts a graphical representation of the data. The t.sub.1/2 of bGCSF was 4.8 hours. The t.sub.1/2 of BLV1H12 full-length IgG was 12.6 days. The t.sub.1/2 of BLV1H12-beta bGCSF L0 IgG was 8.1 days. The t.sub.1/2 of BLV1H12-beta bGCSF L1 IgG was 9.2 days.

Example 49

Pharmacodynamics of BLV1H12-Beta bGCSF Fusion Proteins in Mice

[0520] Single doses of bGCSF (10 .mu.g/kg), BLV1H12 IgG, BLV1H12-beta bGCSF L0 fusion protein (Ab-bGCSF L0) (50 .mu.g/kg), and BLV1H12-beta bGCSF L1 fusion protein (Ab-bGCSF L1) (50 .mu.g/kg) were administrated by subcutaneous (s.c.) injection into 3 BALB/c mice per group. Blood was collected from day 0 to day 21 and analyzed by flow cytometry to measure percentages of neutrophil populations in white blood cells using FITC anti-CD45 (Miltenyi Biotec), PE anti-CD11b (Miltenyi Biotec), and APC anti-Ly-6G antibodies (BD Biosciences). FIG. 40A depicts a graphical representation of the data. FIG. 40B depicts stained monocytes and neutrophils.

Example 50

Construction and Purification of Bovine-Beta hGH Fusion Proteins

[0521] To generate BLV1H12-beta hGH fusion proteins, the gene encoding hGH was synthesized by Genscript or IDT, and amplified by PCR. Flexible linkers of GGGGS (SEQ ID NO: 164) were added on both ends of the hGH gene. Extender peptide sequences having beta strand secondary structure were added to both sides of the hGH-linker fragment. The fragment was grafted into the BLV1H12 Fab heavy chain CDR3H to generate BLV1H12-beta Fab hGH (CDR3H). The fragment was grafted into the BLV1H12 hFc (IgG) heavy chain CDR3H to generate BLV1H12-beta hFc (IgG) hGH (CDR3H). The BLV1H12 expression vectors were generated by in-frame ligation of the amplified fusion genes to the pFuse backbone vector (InvivoGen, CA). Similarly, the gene encoding the light chain of BLV1H12 was cloned to the pFuse backbone vector. The obtained expression vectors were confirmed by DNA sequencing.

[0522] BLV1H12-beta hGH IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta Fab hGH protein heavy chain (SEQ ID NO: 300) and the BLV1H12 light chain (SEQ ID NO: 40). BLV1H12-beta hGH IgG fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding BLV1H12-beta hFc (IgG) hGH protein heavy chain (SEQ ID NO: 302) and the BLV1H12 light chain (SEQ ID NO: 40).

[0523] Purified BLV1H12-beta Fab hGH IgG (SEQ ID NOs: 300 and 40) and BLV1H12-beta hFc (IgG) (SEQ ID NOs: 302 and 40) are shown in FIGS. 41A and 41B. FIG. 41A depicts purified BLV1H12-beta Fab hGH IgG (SEQ ID NOs: 300 and 40), with and without DTT. FIG. 41B depicts purified BLV1H12-beta hFc (IgG) hGH IgG (SEQ ID NOs: 302 and 40), with and without DTT.

Example 51

BLV1H12-Beta hGH hGHR-Ba/F3 Proliferation Assay

[0524] Murine Ba/F3 cells cell lines were stably transduced with hGHR under EF1.alpha. promoter. Clonal selected hGHR-Ba/F3 were maintained in 10% FBS in RPMI1640 with 50 ng/mL of hGH. The proliferation assay was performed in 96 well culture plate with 20,000 cells in 200 uL assay medium (10% FBS in RPMI1640) per well. Increasing concentrations of BLV1H12-beta Fab hGH IgG (SEQ ID NOs: 300 and 40) and BLV1H12-beta hFc (IgG) (SEQ ID NOs: 302 and 40) were incubated with cells for 72 hours. At the end of the incubation period, 20 ul of Prestoblue was added to each well, and the fluorescent signal recorded on a Spectramax fluorescence plate reader at 590 nm with 550 nm excitation. FIG. 42 B depicts a graphical representation of the data.

Example 52

BLV1H12-Beta hGH NB2 Proliferation Assay

[0525] Rat Nb2-11 cell lines (Sigma) were maintained in 10% FBS, 10% horse serum (HS) in RPMI with 55 uM .beta.-ME. A proliferation assay was performed in a 96 well culture plate with 50,000 cells in 200 uL assay medium (10% HS in RPMI with 55 uM .beta.-ME) per well. Increasing concentrations of BLV1H12-beta Fab hGH IgG (SEQ ID NOs: 300 and 40) and BLV1H12-beta hFc (IgG) (SEQ ID NOs: 302 and 40) were incubated with cells for 72 hours. At the end of the incubation period, 20 ul of Prestoblue was added to each well, and the fluorescent signal recorded on a Spectramax fluorescence plate reader at 590 nm with 550 nm excitation. FIG. 42 A depicts a graphical representation of the data.

Example 53

BLV1H12-Beta hGH Stat5 Phosphorylation Assay

[0526] Human IM9 cells from ATCC were maintained in 10% FBS in RPMI1640. The night before the assay, 2.times.10e.sup.5 IM9 cells were seeded into V bottom 96 well plate in 200 uL assay medium (1% charcoal stripped FBS in RPMI) and starved overnight. On the day of the experiment, starved cells were stimulated with hGH, BLV1H12-beta Fab hGH IgG (SEQ ID NOs: 300 and 40) and BLV1H12-beta hFc (IgG) (SEQ ID NOs: 302 and 40) at various concentrations for 10 min at 37.degree. C. After stimulation, cells were fixed by 4% formaldehyde at 37.degree. C. for 10 min, and permeabalized with 90% methanol. Cells were then blocked with 5% BSA at room temperature for 10 min and stained with Alexa Fluor.RTM. 488 conjugated anti-pStat5 (Tyr694) (C71E5) Rabbit mAb (Cell Signaling Technology, Inc.) following the manufacturer's suggested protocol. Cells were then washed with PBS and analyzed by a flow cytometer. FIG. 42 C depicts a graphical representation of the data.

Example 54

BLV1H12-Beta hLeptin IgG Leptin Receptor Activity

[0527] Baf3 stable cells overexpressed with Leptin receptor (LepR) were seeded in a 96-well plate and subsequently treated with different doses of hLeptin and BLV1H12-beta hLeptin IgG (SEQ ID NOs: 230 and 40) for 72 hours. AlamarBlue regent was added as 1/10 volume, the plate was incubated for 2 hrs, and the fluorescent read at 590 nm under excitation at 560 nm. Data were analyzed using GraphPad Prism 6. A graphical depiction of the data is shown in FIG. 43B.

Example 55

Expression and Purification of Trastuzumab-Beta BCCX2 Fusion Proteins

[0528] Trastuzumab-beta BCCX2 fusion proteins were expressed through transient transfections of free style HEK293 cells with vectors encoding trastuzumab-beta BCCX2 fusion protein heavy chain (SEQ ID NOs: 96, 97, or 98) and the trastuzumab light chain (SEQ ID NO: 21). Expressed fusion proteins were secreted into the culture medium and harvested every 48 hours for twice after transfection. The fusion proteins were purified by Protein A/G chromatography (Thermo Fisher Scientific, IL), and analyzed by SDS-PAGE gel.

[0529] Purified trastuzumab-beta BCCX2 IgGs are shown in FIG. 47: trastuzumab-beta BCCX2 HC long (HLCX) (SEQ ID NOs: 96 and 40), trastuzumab-beta BCCX2 HC medium HMCX (SEQ ID NOs: 97 and 40), and trastuzumab-beta BCCX2 HC short (HSCX) (SEQ ID NOs: 98 and 40), with or without reducing reagent DTT.

Example 56

Flow Cytometry Analysis of CXCR4 Antibodies and BLV1H12-Beta BCCX2 Fusion Proteins

[0530] As shown in FIG. 48, engineered antibodies (A) bind to CXCR4 positive Jurkat cells, (B) do not bind to CXCR4 negative CHO cells (C) and bind to CXCR4 transfected CHO cells. In all cases, the control antibody (BLV1H12) showed no peak shift by flow cytometry analysis. The shaded peaks are cells without antibody treatment. The engineered antibodies include BLV1H12-beta BCCX2 HC 1 (bAb-AC1) (SEQ ID NOs: 92 and 40), BLV1H12-beta BCCX2 HC 2 (bAb-AC2) (SEQ ID NOs: 93 and 40), and BLV1H12-beta BCCX2 HC 3 (bAb-AC3) (SEQ ID NOs: 94 and 40).

Example 57

BLV12H12-Beta BCCX2IgG Binding to CXCR4

[0531] A Tag-lite HTFR binding assay was performed to determine binding between BLV1H12-beta BCCX2 fusion proteins and CXCR4. The binding affinities were calculated based on the Cheng-Prusoff equation to give Ki values of 2.1 nM, 5.4 nM and 19.8 nM for BLV1H12-beta BCCX2 HC 1, BLV1H12-beta BCCX2 HC 2 and BLV1H12-beta BCCX2 HC 3, respectively. FIG. 50B depicts a flow cytometry histogram demonstrating nearly complete inhibition of 12G5 binding to CXCR4 by a three-fold excess of BLV1H12-beta BCCX2 HC 1.

Example 58

BLV12H12-Beta BCCX2IgG FACS Competition

[0532] Jurkat cells were incubated with increasing concentrations of BLVH12-beta BCCX2 HC 1 (SEQ ID NOs: 92 and 40) in blocking buffer (PBS supplemented with 3% BSA) at 4.degree. C. for 30 min followed by fluorescein conjugated 12G5 treatment at a final concentration of 10 .mu.g/mL for an additional 30 min. Cells were then washed with PBS and analyzed by a flow cytometer. A graph representing the data is shown in FIG. 51.

[0533] The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims.

[0534] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0535] All references cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

TABLE-US-00006 TABLE 6 Immunoglobulin Light Chain (LC) and Heavy Chain (HC)- Nucleotide Sequence SEQ ID NAME NO SEQUENCE BVK heavy 1 CAGGTCCAGCTCCAGGAAAGCGGTCCCGGCCTCGTGCGTCCCAGCC chain (HC) AGACTCTCTCCCTCACTTGTACTGTGTCAGGTTTTAGCCTCACTGGC TACGGAGTGAACTGGGTCCGCCAGCCACCTGGTAGGGGACTGGAG TGGATCGGCATGATTTGGGGAGACGGTAACACCGATTATAATTCTG CTCTGAAGTCAAGAGTGACAATGCTCAAGGACACCTCCAAAAATC AGTTCTCTCTGCGTCTCTCCAGCGTGACCGCCGCTGATACTGCAGTC TACTATTGCGCCCGCGAAAGAGATTATCGTCTGGATTATTGGGGTC AGGGTAGTCTGGTCACAGTGTCCTCAGCCTCCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA GCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGA CGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACTGTGCCCTCTAGCAGCTTGGGCACCCAGACCTACATCTGCA ACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT Trastuzumab LC 2 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGATGTGAATA CCGCGGTCGCATGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGC TCCTGATCTATTCTGCATCCTTCTTGTATAGTGGGGTCCCATCAAGG TTCAGTGGCAGTAGATCTGGGACAGATTTCACTCTCACCATCAGCA GTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGCATTA CACTACCCCTCCGACGTTCGGCCAAGGTACCAAGCTTGAGATCAAA CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA GCAGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTGCTGAATAAC TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGC AAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAA GCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT CAGGGCCTGTCCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAG TGT Trastuzumab N- 3 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG terminal LC GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAG Trastuzumab C- 4 ACCGCGGTCGCATGGTATCAGCAGAAACCAGGGAAAGCCCCTAAG terminal LC CTCCTGATCTATTCTGCATCCTTCTTGTATAGTGGGGTCCCATCAAG GTTCAGTGGCAGTAGATCTGGGACAGATTTCACTCTCACCATCAGC AGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGCATT ACACTACCCCTCCGACGTTCGGCCAAGGTACCAAGCTTGAGATCAA ACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATG AGCAGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTGCTGAATAA CTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCA TCAGGGCCTGTCCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT Trastuzumab HC 5 GAAGTGCAGCTGGTGGAAAGCGGCGGCGGCCTGGTGCAGCCGGGC GGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCTTTAACATTAAAG ATACCTATATTCATTGGGTGCGCCAGGCGCCGGGCAAAGGCCTGGA ATGGGTGGCGCGCATTTATCCGACCAACGGCTATACCCGCTATGCG GATAGCGTGAAAGGCCGCTTTACCATTAGCGCGGATACCAGCAAA AACACCGCGTATCTGCAGATGAACAGCCTGCGCGCGGAAGATACC GCGGTGTATTATTGCAGCCGCTGGGGCGGCGATGGCTTTTATGCGA TGGATTATTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGCGCGA GCACCAAAGGCCCGAGCGTGTTTCCGCTGGCGCCGAGCAGCAAAA GCACCAGCGGCGGCACCGCGGCGCTGGGCTGCCTGGTGAAAGATT ATTTTCCGGAACCGGTGACCGTGAGCTGGAACAGCGGCGCGCTGAC CAGCGGCGTGCATACCTTTCCGGCGGTGCTGCAGAGCAGCGGCCTG TATAGCCTGAGCAGCGTGGTGACCGTGCCGAGCAGCAGCCTGGGC ACCCAGACCTATATTTGCAACGTGAACCATAAACCGAGCAACACCA AAGTGGATAAAAAAGTGGAACCGCCGAAAAGCTGCGATAAAACCC ATACCTGCCCGCCGTGCCCGGCGCCGGAACTGCTGGGCGGCCCGAG CGTGTTTCTGTTTCCGCCGAAACCGAAAGATACCCTGATGATTAGC CGCACCCCGGAAGTGACCTGCGTGGTGGTGGATGTGAGCCATGAA GATCCGGAAGTGAAATTTAACTGGTATGTGGATGGCGTGGAAGTGC ATAACGCGAAAACCAAACCGCGCGAAGAACAGTATAACAGCACCT ATCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAA CGGCAAAGAATATAAATGCAAAGTGAGCAACAAAGCGCTGCCGGC GCCGATTGAAAAAACCATTAGCAAAGCGAAAGGCCAGCCGCGCGA ACCGCAGGTGTATACCCTGCCGCCGAGCCGCGATGAACTGACCAA AAACCAGGTGAGCCTGACCTGCCTGGTGAAAGGCTTTTATCCGAGC GATATTGCGGTGGAATGGGAAAGCAACGGCCAGCCGGAAAACAAC TATAAAACCACCCCGCCGGTGCTGGATAGCGATGGCAGCTTTTTTC TGTATAGCAAACTGACCGTGGATAAAAGCCGCTGGCAGCAGGGCA ACGTGTTTAGCTGCAGCGTGATGCATGAAGCGCTGCATAACCATTA TACCCAGAAAAGCCTGAGCCTGAGCCCGGGCAAA Trastuzumab wt 6 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG hIgG1 HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGATGGGGCGGTGACGGCTTCTATGCCA TGGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCTC CACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAAT GCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGT GTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACA GGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGA CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGA AGAGCCTCTCCCTGTCTCCGGGTAAA Trastuzumab 7 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG heptad mutation GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG in hIgG1 HC ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGATGGGGCGGTGACGGCTTCTATGCCA TGGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCTC CACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTCCAGTCGCCGGACCGTCAGTCTTCCT CTTCCCTCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAG GTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAAGCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG TACACCCTGCCTCCATCCCGGGATGAGCTGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTAAA Trastuzumab 8 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG triple mutations GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG in hIgG4 HC ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGATGGGGCGGTGACGGCTTCTATGCCA TGGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCAG CACTAAAGGTCCATCTGTGTTCCCTCTGGCTCCTTGCAGCCGGAGC ACCTCCGAGTCCACAGCCGCTCTGGGATGTCTGGTGAAAGATTACT TCCCCGAGCCCGTCACCGTGAGCTGGAATAGCGGAGCACTGACCTC CGGCGTCCACACATTCCCCGCCGTGCTCCAAAGCTCCGGCCTGTAC AGCCTCTCCTCCGTGGTCACCGTGCCCAGCAGCTCTCTGGGCACAA AGACCTATACCTGTAACGTGGATCACAAGCCTAGCAACACCAAAGT GGATAAGCGGGTGGAGAGCAAGTACGGCCCTCCCTGTCCCCCTTGC CCCGCTCCTGAGGCCGCTGGCGGACCTTCCGTGTTCCTGTTTCCCCC TAAGCCCAAGGACACCCTCATGATTAGCCGGACACCCGAAGTGAC CTGCGTGGTCGTGGATGTGTCCCAGGAGGACCCTGAAGTGCAATTT AACTGGTACGTGGACGGCGTCGAGGTGCACAACGCCAAGACCAAG CCTCGGGAAGAGCAGTTCAACAGCACCTACCGGGTGGTCAGCGTG CTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAG TGCAAGGTGAGCAACAAGGGCCTGCCCAGCTCCATCGAGAAGACC ATCAGCAAGGCCAAGGGCCAGCCCAGGGAACCCCAGGTGTATACC CTGCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTGAGCCTG ACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGT GGGAGAGCAACGGCCAGCCCGAGAACAATTACAAGACCACCCCTC CTGTGCTGGACAGCGACGGCTCCTTCTTTCTGTATAGCCGGCTGAC CGTGGACAAGAGCAGGTGGCAGGAGGGCAACGTGTTCTCCTGTAG CGTGATGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGCTTG AGCCTGAGCCTGGGCAAA Trastuzumab N- 9 GAAGTGCAGCTGGTGGAAAGCGGCGGCGGCCTGGTGCAGCCGGGC terminal HC GGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCTTTAACATTAAAG ATACCTATATTCATTGGGTGCGCCAGGCGCCGGGCAAAGGCCTGGA ATGGGTGGCGCGCATTTATCCGACCAACGGCTATACCCGCTATGCG GATAGCGTGAAAGGCCGCTTTACCATTAGCGCGGATACCAGCAAA AACACCGCGTATCTGCAGATGAACAGCCTGCGCGCGGAAGATACC GCGGTGTATTATTGCAGCCGC Trastuzumab C- 10 GATTATTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGCGCGAGC terminal HC ACCAAAGGCCCGAGCGTGTTTCCGCTGGCGCCGAGCAGCAAAAGC ACCAGCGGCGGCACCGCGGCGCTGGGCTGCCTGGTGAAAGATTATT TTCCGGAACCGGTGACCGTGAGCTGGAACAGCGGCGCGCTGACCA GCGGCGTGCATACCTTTCCGGCGGTGCTGCAGAGCAGCGGCCTGTA TAGCCTGAGCAGCGTGGTGACCGTGCCGAGCAGCAGCCTGGGCAC CCAGACCTATATTTGCAACGTGAACCATAAACCGAGCAACACCAA AGTGGATAAAAAAGTGGAACCGCCGAAAAGCTGCGATAAAACCCA TACCTGCCCGCCGTGCCCGGCGCCGGAACTGCTGGGCGGCCCGAGC GTGTTTCTGTTTCCGCCGAAACCGAAAGATACCCTGATGATTAGCC GCACCCCGGAAGTGACCTGCGTGGTGGTGGATGTGAGCCATGAAG ATCCGGAAGTGAAATTTAACTGGTATGTGGATGGCGTGGAAGTGCA TAACGCGAAAACCAAACCGCGCGAAGAACAGTATAACAGCACCTA TCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAAC GGCAAAGAATATAAATGCAAAGTGAGCAACAAAGCGCTGCCGGCG CCGATTGAAAAAACCATTAGCAAAGCGAAAGGCCAGCCGCGCGAA CCGCAGGTGTATACCCTGCCGCCGAGCCGCGATGAACTGACCAAA AACCAGGTGAGCCTGACCTGCCTGGTGAAAGGCTTTTATCCGAGCG ATATTGCGGTGGAATGGGAAAGCAACGGCCAGCCGGAAAACAACT ATAAAACCACCCCGCCGGTGCTGGATAGCGATGGCAGCTTTTTTCT GTATAGCAAACTGACCGTGGATAAAAGCCGCTGGCAGCAGGGCAA CGTGTTTAGCTGCAGCGTGATGCATGAAGCGCTGCATAACCATTAT ACCCAGAAAAGCCTGAGCCTGAGCCCGGGCAAA Palivizumab wt 11 CAGGTGACCCTGCGCGAGTCCGGCCCCGCCCTGGTGAAGCCCACCC hIgG1 HC AGACCCTGACCCTGACCTGCACCTTCTCCGGCTTCTCCCTGTCCACC TCCGGCATGTCCGTGGGCTGGATCCGCCAGCCCCCCGGCAAGGCCC TGGAGTGGCTGGCCGACATCTGGTGGGACGACAAGAAGGACTACA ACCCCTCCCTGAAGTCCCGCCTGACCATCTCCAAGGACACCTCCAA GAACCAGGTGGTGCTGAAGGTGACCAACATGGACCCCGCCGACAC CGCCACCTACTACTGCGCCCGCTCCATGATCACCAACTGGTACTTC GACGTGTGGGGCGCCGGCACCACCGTGACCGTGTCCTCCGCCTCCA CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGT GGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTG AGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTG TGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAA GGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG GTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGC CGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA AGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GAGCCTCTCCCTGTCTCCGGGTAAA Palivizumab 12 CAGGTGACCCTGCGCGAGTCCGGCCCCGCCCTGGTGAAGCCCACCC heptad mutation AGACCCTGACCCTGACCTGCACCTTCTCCGGCTTCTCCCTGTCCACC in hIgG1 HC TCCGGCATGTCCGTGGGCTGGATCCGCCAGCCCCCCGGCAAGGCCC TGGAGTGGCTGGCCGACATCTGGTGGGACGACAAGAAGGACTACA ACCCCTCCCTGAAGTCCCGCCTGACCATCTCCAAGGACACCTCCAA GAACCAGGTGGTGCTGAAGGTGACCAACATGGACCCCGCCGACAC CGCCACCTACTACTGCGCCCGCTCCATGATCACCAACTGGTACTTC GACGTGTGGGGCGCCGGCACCACCGTGACCGTGTCCTCCGCCTCCA

CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGT GGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTCCAGTCGCCGGACCGTCAGTCTTCCTC TTCCCTCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAAGCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCTCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAA Palivizumab 13 CAGGTGACCCTGCGCGAGTCCGGCCCCGCCCTGGTGAAGCCCACCC triple mutations AGACCCTGACCCTGACCTGCACCTTCTCCGGCTTCTCCCTGTCCACC in hIgG4 HC TCCGGCATGTCCGTGGGCTGGATCCGCCAGCCCCCCGGCAAGGCCC TGGAGTGGCTGGCCGACATCTGGTGGGACGACAAGAAGGACTACA ACCCCTCCCTGAAGTCCCGCCTGACCATCTCCAAGGACACCTCCAA GAACCAGGTGGTGCTGAAGGTGACCAACATGGACCCCGCCGACAC CGCCACCTACTACTGCGCCCGCTCCATGATCACCAACTGGTACTTC GACGTGTGGGGCGCCGGCACCACCGTGACCGTGTCCTCCGCCAGCA CTAAAGGTCCATCTGTGTTCCCTCTGGCTCCTTGCAGCCGGAGCAC CTCCGAGTCCACAGCCGCTCTGGGATGTCTGGTGAAAGATTACTTC CCCGAGCCCGTCACCGTGAGCTGGAATAGCGGAGCACTGACCTCCG GCGTCCACACATTCCCCGCCGTGCTCCAAAGCTCCGGCCTGTACAG CCTCTCCTCCGTGGTCACCGTGCCCAGCAGCTCTCTGGGCACAAAG ACCTATACCTGTAACGTGGATCACAAGCCTAGCAACACCAAAGTGG ATAAGCGGGTGGAGAGCAAGTACGGCCCTCCCTGTCCCCCTTGCCC CGCTCCTGAGGCCGCTGGCGGACCTTCCGTGTTCCTGTTTCCCCCTA AGCCCAAGGACACCCTCATGATTAGCCGGACACCCGAAGTGACCT GCGTGGTCGTGGATGTGTCCCAGGAGGACCCTGAAGTGCAATTTAA CTGGTACGTGGACGGCGTCGAGGTGCACAACGCCAAGACCAAGCC TCGGGAAGAGCAGTTCAACAGCACCTACCGGGTGGTCAGCGTGCT GACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGAGCAACAAGGGCCTGCCCAGCTCCATCGAGAAGACCAT CAGCAAGGCCAAGGGCCAGCCCAGGGAACCCCAGGTGTATACCCT GCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTGAGCCTGAC CTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAACGGCCAGCCCGAGAACAATTACAAGACCACCCCTCCT GTGCTGGACAGCGACGGCTCCTTCTTTCTGTATAGCCGGCTGACCG TGGACAAGAGCAGGTGGCAGGAGGGCAACGTGTTCTCCTGTAGCG TGATGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGCTTGA GCCTGAGCCTGGGCAAA BVK light chain 14 GACATTCAGATGACACAGAGCCCCAGCAGCCTCAGTGCCTCAGTCG (LC) GTGACAGAGTGACCATTACTTGCCGTGCCAGCGGAAACATTCACAA CTACCTGGCCTGGTATCAGCAGAAGCCCGGCAAAGCTCCTAAGCTG CTCATCTACTATACCACTACACTCGCAGACGGCGTGCCATCTCGCTT CTCTGGCTCAGGATCCGGTACAGACTACACCTTTACTATCTCCAGC CTGCAGCCCGAGGATATTGCTACCTACTATTGCCAGCATTTTTGGTC AACCCCCCGCACATTCGGTCAGGGCACTAAGGTGGAGATTAAGAG AACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTCGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCT CCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAA GGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGC AGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCA GGGCCTGTCCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT Palivizumab LC 15 GACATCCAGATGACCCAGTCCCCCTCCACCCTGTCCGCCTCCGTGG GCGACCGCGTGACCATCACCTGCAAGTGCCAGCTGTCCGTGGGCTA CATGCACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCT GATCTACGACACCTCCAAGCTGGCCTCCGGCGTGCCCTCCCGCTTC TCCGGCTCCGGCTCCGGCACCGAGTTCACCCTGACCATCTCCTCCCT GCAGCCCGACGACTTCGCCACCTACTACTGCTTCCAGGGCTCCGGC TACCCCTTCACCTTCGGCGGCGGCACCAAGCTGGAGATCAAACGAA CTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAG TTGAAATCTGGAACTGCCTCTGTCGTGTGCCTGCTGAATAACTTCTA TCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGA CAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGA CTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGG CCTGTCCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT Palivizumab N- 16 CAGGTGACCCTGCGCGAGTCCGGCCCTGCACTGGTGAAGCCCACCC terminal HC AGACCCTGACCCTGACCTGCACCTTCTCCGGCTTCTCCCTGTCCACC TCCGGCATGTCCGTGGGCTGGATCCGGCAGCCTCCCGGCAAGGCCC TGGAGTGGCTGGCTGACATCTGGTGGGACGACAAGAAGGACTACA ACCCCTCCCTGAAGTCCCGCCTGACCATCTCCAAGGACACCTCCAA GAACCAGGTGGTGCTGAAGGTGACCAACATGGACCCCGCCGACAC CGCCACCTACTACTGCGCCCGC Palivizumab C- 17 GACGTGTGGGGAGCCGGTACCACCGTGACCGTGTCTTCCGCCTCCA terminal HC CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGT GGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTCCAGTCGCCGGACCGTCAGTCTTCCTC TTCCCTCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAAGCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCTCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAATGATAAGTGCTAGCTGGCCAGA BLV1H12 N- 18 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC terminal HC AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATC CCGGACTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAA GTCAGGTGTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGC AACTTACTATTGCACCTCTGTGCACCAG BLV1H12 C- 19 TGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGTCTCTA terminal HC GTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCTGCTG TGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTCTCA AGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGCCC TGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTGG CCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCA GGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCA AAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACA CATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGAC CCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGC AGAAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12 LC 20 CAGGCCGTCCTGAACCAGCCAAGCAGCGTCTCCGGGTCTCTGGGGC AGCGGGTCTCAATCACCTGTAGCGGGTCTTCCTCCAATGTCGGCAA CGGCTACGTGTCTTGGTATCAGCTGATCCCTGGCAGTGCCCCACGA ACCCTGATCTACGGCGACACATCCAGAGCTTCTGGGGTCCCCGATC GGTTCTCAGGGAGCAGATCCGGAAACACAGCTACTCTGACCATCAG CTCCCTGCAGGCTGAGGACGAAGCAGATTATTTCTGCGCATCTGCC GAGGACTCTAGTTCAAATGCCGTGTTTGGAAGCGGCACCACACTGA CAGTCCTGGGGCAGCCCAAGAGTCCCCCTTCAGTGACTCTGTTCCC ACCCTCTACCGAGGAACTGAACGGAAACAAGGCCACACTGGTGTG TCTGATCAGCGACTTTTACCCTGGATCCGTCACTGTGGTCTGGAAG GCAGATGGCAGCACAATTACTAGGAACGTGGAAACTACCCGCGCC TCCAAGCAGTCTAATAGTAAATACGCCGCCAGCTCCTATCTGAGCC TGACCTCTAGTGATTGGAAGTCCAAAGGGTCATATAGCTGCGAAGT GACCCATGAAGGCTCAACCGTGACTAAGACTGTGAAACCATCCGA GTGCTCC

TABLE-US-00007 TABLE 7 Immunoglobulin Light Chain (LC) and Heavy Chain (HC)- Amino Acid Sequence SEQ ID Name NO Sequence Trastuzumab LC 21 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLI YSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF GQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC Trastuzumab N- 22 DIQMTQSPSSLSASVGDRVTITCRASQ terminal LC Trastuzumab C- 23 TAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQ terminal LC PEDFATYYCQQHYTTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Trastuzumab HC 24 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEW VARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVY YCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Trastuzumab wt 25 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEW hIgG1 HC VARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVY YCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Trastuzumab 26 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEW heptad mutation VARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVY in hIgG1 HC YCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPV AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK Trastuzumab 27 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEW triple mutations VARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVY in hIgG4 HC YCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSI EKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLGK Light chain 28 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLI paired with YSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF Trastuzumab Ab GQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC Trastuzumab N- 29 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEW terminal HC VARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVY YCSR Trastuzumab C- 30 DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE terminal HC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK Palivizumab wt 31 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALE hIgG1 HC WLADIWWDDKKDYNPSLKSRLTISKDTSKNQVVLKVTNMDPADTAT YYCARSMITNWYFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Palivizumab 32 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALE heptad mutation WLADIWWDDKKDYNPSLKSRLTISKDTSKNQVVLKVTNMDPADTAT in hIgG1 HC YYCARSMITNWYFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVA GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Palivizumab 33 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALE triple mutations WLADIWWDDKKDYNPSLKSRLTISKDTSKNQVVLKVTNMDPADTAT in hIgG4 HC YYCARSMITNWYFDVWGAGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSI EKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLGK Light chain 34 DIQMTQSPSTLSASVGDRVTITCKCQLSVGYMHWYQQKPGKAPKLLI paired with YDTSKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCFQGSGYPFTF Palivizumab Ab GGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC Palivizumab LC 35 DIQMTQSPSTLSASVGDRVTITCKCQLSVGYMHWYQQKPGKAPKLLI YDTSKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCFQGSGYPFTF GGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC Palivizumab N- 36 QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALE terminal HC WLADIWWDDKKDYNPSLKSRLTISKDTSKNQVVLKVTNMDPADTAT YYCAR Palivizumab C- 37 DVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE terminal HC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK BLV1H12 N- 38 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW terminal HC LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT SVHQ BLV1H12 C- 39 WHVDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCLVSS terminal HC YMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTSGQ TFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK BLV1H12 LC 40 QAVLNQPSSVSGSLGQRVSITCSGSSSNVGNGYVSWYQLIPGSAPRTLI YGDTSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYFCASAEDSSSN AVFGSGTTLTVLGQPKSPPSVTLFPPSTEELNGNKATLVCLISDFYPGSV TVVWKADGSTITRNVETTRASKQSNSKYAASSYLSLTSSDWKSKGSYS CEVTHEGSTVTKTVKPSECS

TABLE-US-00008 TABLE 8 Immunoglobulin fusion protein-Nucleotide Sequence SEQ ID NAME NO SEQUENCE Trastuzumab- beta hEPO LC 41 ##STR00003## ##STR00004## ##STR00005## Trastuzumab- 42 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta bGCSF HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGAGAAACTAAGAAATACCAGAGCGGT GGCGGAGGATCTACCCCCCTTGGCCCTGCCCGATCCCTGCCCCAGA GCTTCCTGCTCAAGTGCTTAGAGCAAGTGAGGAAAATCCAGGCTGA TGGCGCCGAGCTGCAGGAGAGGCTGTGTGCCGCCCACAAGCTGTG CCACCCGGAGGAGCTGATGCTGCTCAGGCACTCTCTGGGCATCCCC CAGGCTCCCCTAAGCAGCTGCTCCAGCCAGTCCCTGCAGCTGACGA GCTGCCTGAACCAACTACACGGCGGCCTCTTTCTCTACCAGGGCCT CCTGCAGGCCCTGGCGGGCATCTCCCCAGAGCTGGCCCCCACCTTG GACACACTGCAGCTGGACGTCACTGACTTTGCCACGAACATCTGGC TGCAGATGGAGGACCTGGGGGCGGCCCCCGCTGTGCAGCCCACCC AGGGCGCCATGCCGACCTTCACTTCAGCCTTCCAACGCAGAGCAGG AGGGGTCCTGGTTGCTTCCCAGCTGCATCGTTTCCTGGAGCTGGCA TACCGTGGCCTGCGCTACCTTGCTGAGCCCGGTGGCGGAGGATCTT CTTATACCTACAATTATGAAGACTACTGGGGCCAAGGAACCCTGGT CACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTG GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACTGTGCCCT CTAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAA GCCCAGCAACACCAAGGTGGACAAGAAAGTTGAACCCAAATCTTG CGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTG GGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC TCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGG CGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA CAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA GCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGC ACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA Trastuzumab- 43 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta Exendin-4 GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG HC ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCQAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGAGAAACTAAGAAATACCAGAGCTGCG GGGGTGGCGGAAGCATCGAAGGTCGTCACGGAGAAGGAACATTTA CCAGCGACCTCAGCAAGCAGATGGAGGAAGAGGCCGTGAGGCTGT TCATCGAGTGGCTGAAGAACGGCGGACCCTCCTCTGGCGCTCCACC CCCTAGCGGCGGAGGTGGGAGTTGCTCTTATACCTACAATTATGAA GACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCTCCA CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGT GGACAAGAAAGTTGAACCCAAATCTTGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTCCAGTCGCCGGACCGTCAGTCTTCCTC TTCCCTCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAAGCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCTCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAA Trastuzumab- beta Moka1 HC 44 ##STR00006## ##STR00007## ##STR00008## Trastuzumab- beta VM24 HC 45 ##STR00009## ##STR00010## ##STR00011## Trastuzumab- 46 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta hGCSF HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGAGAAACTAAGAAATACCAGAGCGCC ACACCTCTGGGCCCCGCCTCCTCCCTGCCTCAGAGCTTTCTGCTCAA ATGTCTGGAGCAGGTGCGGAAGATCCAGGGCGACGGCGCCGCTCT GCAAGAGAAACTGGTCAGCGAATGCGCCACATATAAGCTGTGTCA CCCCGAGGAACTGGTCCTCTTGGGCCACAGCCTGGGCATCCCCTGG GCCCCTCTCAGCTCCTGCCCCTCCCAAGCTCTCCAACTCGGCTGGATG TCTGTCCCAACTGCACTCCGGCCTCTTCCTGTACCAGGGACTCCTCC AGGCTCTCGAAGGGATCAGCCCCGAACTGGGCCCCACACTGGACA CCTTGCAACTCGATGTGGCCGATTTCGCCACAACCATCTGGCAGCA GATGGAAGAACTCGGAATGGCTCCTGCTCTCCAGCCCACACAGGG AGCTATGCCTGCTTTCGCCTCTGCTTTCCAGCGGAGAGCTGGTGGT GTGCTCGTCGCATCCCACCTCCAGAGCTTCTTGGAGGTGTCCTATCG GGTGCTCCGGCATCTGGCCCAACCCTCTTATACCTACAATTATGAA GACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCAGCA CTAAAGGTCCATCTGTGTTCCCTCTGGCTCCTTGCAGCCGGAGCAC CTCCGAGTCCACAGCCGCTCTGGGATGTCTGGTGAAAGATTACTTC CCCGAGCCCGTCACCGTGAGCTGGAATAGCGGAGCACTGACCTCCG GCGTCCACACATTCCCCGCCGTGCTCCAAAGCTCCGGCCTGTACAG CCTCTCCTCCGTGGTCACCGTGCCCAGCAGCTCTCTGGGCACAAAG ACCTATACCTGTAACGTGGATCACAAGCCTAGCAACACCAAAGTGG ATAAGCGGGTGGAGAGCAAGTACGGCCCTCCCTGTCCCCCTTGCCC CGCTCCTGAGGCCGCTGGCGGACCTTCCGTGTTCCTGTTTCCCCCTA AGCCCAAGGACACCCTCATGATTAGCCGGACACCCGAAGTGACCT GCGTGGTCGTGGATGTGTCCCAGGAGGACCCTGAAGTGCAATTTAA CTGGTACGTGGACGGCGTCGAGGTGCACAACGCCAAGACCAAGCC TCGGGAAGAGCAGTTCAACAGCACCTACCGGGTGGTCAGCGTGCT GACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGAGCAACAAGGGCCTGCCCAGCTCCATCGAGAAGACCAT CAGCAAGGCCAAGGGCCAGCCCAGGGAACCCCAGGTGTATACCCT GCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTGAGCCTGAC CTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAACGGCCAGCCCGAGAACAATTACAAGACCACCCCTCCT GTGCTGGACAGCGACGGCTCCTTCTTTCTGTATAGCCGGCTGACCG TGGACAAGAGCAGGTGGCAGGAGGGCAACGTGTTCTCCTGTAGCG TGATGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGCTTGA GCCTGAGCCTGGGCAAA Trastuzumab- beta hGH CDRH3 HC 47 ##STR00012## ##STR00013## ##STR00014## ##STR00015## Trastuzumab- beta hGH CDRH2 HC 48 ##STR00016## ##STR00017## ##STR00018## ##STR00019## Trastuzumab- beta hLeptin HC 49 ##STR00020## ##STR00021## ##STR00022## ##STR00023## Trastuzumab- beta hIFNalpha HC 50 ##STR00024## GAGGACCTTGATGCTCCTGGCACAGATGAGGAGAATCTCTCTTTTCTCC TGCTTGAAGGACAGACATGACTTTGGATTTCCCCAGGAGGAGTTTGGCA ACCAGTTCCAAAAGGCTGAAACCATCCCTGTCCTCCATGAGATGATCCA GCAGATCTTCAATCTCTTCAGCACAAAGGACTCATCTGCTGCTTGGGAT GAGACCCTCCTAGACAAATTCTACACTGAACTCTACCAGCAGCTGAATG ACCTGGAAGCCTGTGTGATACAGGGGGTGGGGGTGACAGAGACTCCCC TGATGAAGGAGGACTCCATTCTGGCTGTGAGGAAATACTTCCAAAGAAT CACTCTCTATCTGAAAGAGAAGAAATACAGCCCTTGTGCCTGGGAGGTT GTCAGAGCAGAAATCATGAGATCTTTTTCTTTGTCAACAAACTTGCAAGA ##STR00025## ##STR00026## ##STR00027## Trastuzumab- beta GLP1 HC 51 ##STR00028## ##STR00029## ##STR00030## ##STR00031## Trastuzumab- beta Elafin HC 52 ##STR00032## GCCTGGCTCCTGCCCCATTATCTTGATCCGGTGCGCCATGTTGAATCCC CCTAACCGCTGCTTGAAAGATACTGACTGCCCAGGAATCAAGAAGTGCT ##STR00033## ##STR00034## ##STR00035## Trastuzumab- beta Mambalgin HC 53 ##STR00036## GAGATATGAAGTTTTGCTATCATAACACTGGCATGCCTTTTCGAAATCTC AAGCTCATCCTACAGGGATGTTCTTCTTCGTGCAGTGAAACAGAAAACAA ##STR00037## ##STR00038## Trastuzumab- beta betatrophin HC 54 ##STR00039## ##STR00040## ##STR00041## ##STR00042## Trastuzumab- beta hGH fusion HC 55 ##STR00043## CTATGCTCCGCGCCCATCGTCTGCACCAGCTGGCCTTTGACACCTACCA GGAGTTTGAAGAAGCCTATATCCCAAAGGAACAGAAGTATTCATTCCTG CAGAACCCCCAGACCTCCCTCTGTTTCTCAGAGTCTATTCCGACACCCT CCAACAGGGAGGAAACACAACAGAAATCCAACCTAGAGCTGCTCCGCAT CTCCCTGCTGCTCATCCAGTCGTGGCTGGAGCCCGTGCAGTTCCTCAG GAGTGTCTTCGCCAACAGCCTGGTGTACGGCGCCTCTGACAGCAACGT CTATGACCTCCTAAAGGACCTAGAGGAAGGCATCCAAACGCTGATGGG GAGGCTGGAAGATGGCAGCCCCCGGACTGGGCAGATCTTCAAGCAGAC CTACAGCAAGTTCGACACAAACTCACACAACGATGACGCACTACTCAAG AACTACGGGCTGCTCTACTGCTTCAGGAAGGACATGGACAAGGTCGAG ACATTCCTGCGCATCGTGCAGTGCCGCTCTGTGGAGGGCAGCTGTGGC ##STR00044## ##STR00045## Trastuzumab- beta hIFNB1 HC 56 ##STR00046## AGCAATTTTCAGTGTCAGAAGCTCCTGTGGCAATTGAATGGGAGGCTTG AATACTGCCTCAAGGACAGGATGAACTTTGACATCCCTGAGGAGATTAA GCAGCTGCAGCAGTTCCAGAAGGAGGACGCCGCATTGACCATCTATGA GATGCTCCAGAACATCTTTGCTATTTTCAGACAAGATTCATCTAGCACTG GCTGGAATGAGACTATTGTTGAGAACCTCCTGGCTAATGTCTATCATCAG ATAAACCATCTGAAGACAGTCCTGGAAGAAAAACTGGAGAAAGAAGATT TCACCAGGGGAAAACTCATGAGCAGTCTGCACCTGAAAAGATATTATGG GAGGATTCTGCATTACCTGAAGGCCAAGGAGTACAGTCACTGTGCCTGG

ACCATAGTCAGAGTGGAAATCCTAAGGAACTTTTACTTCATTAACAGACT ##STR00047## ##STR00048## Trastuzumab- beta Mambalgin HC 57 ##STR00049## ##STR00050## ##STR00051## Palivizumab- beta Mambalgin HC 58 ##STR00052## ##STR00053## ##STR00054## BLV1H12-beta- HEI 1 59 ##STR00055## ##STR00056## BLV1H12-beta- HEI 2 60 ##STR00057## ##STR00058## Human BVK antibody -beta- HEI LC 61 ##STR00059## ##STR00060## Human BVK antibody -beta- HEI HC 4 62 ##STR00061## ##STR00062## Human BVK antibody -beta- HEI HC 5 63 ##STR00063## ##STR00064## Human BVK- beta-HEI HC 6 64 ##STR00065## ##STR00066## Human BVK antibody -beta- HEI HC 7 65 ##STR00067## ##STR00068## Human BVK antibody -beta- HEI HC 8 66 ##STR00069## ##STR00070## Human BVK antibody -beta- HEI HC 9 67 ##STR00071## ##STR00072## BLV1H12-beta 68 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC trypsin inhibitor AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATC CCGGACTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAA GTCAGGTGTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGC AACTTACTATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAG AGCAGATGTACCAAGAGCATACCACCCATCTGCTTCTCTTATACCTAC AATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGA CAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTC AAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGC CTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACT CAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCA GTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGC AGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCA GCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGC BLV1H12-beta 69 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC BCCX2 HC 1 AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG (bAB-AC1) ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATC CCGGACTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAA GTCAGGTGTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGC AACTTACTATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAG AGCTATCGCAAATGTAGAGGAGGCAACGGACGAAGGTGGTGCTACCAA AAGTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGGAC AGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAA GGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACC GTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGA CTGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTT CCCAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATG GTGACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATG TGGCCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAAC CCAAATCTTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACC TGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGT ACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGT CTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA TCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCA ATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTC CGGGTAAATGATAA BLV1H12-beta 70 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC BCCX2 HC 2 AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG (bAb-AC2) ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATC CCGGACTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAA GTCAGGTGTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGC AACTTACTATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAG AGCTATCGCAAATGTAGAGGACCTCGAAGGTGGTGCTACCAAAAGTCTT ATACCTACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCT GCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTAC CCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACAC TGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCAC CTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCT GTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAG TCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCA TCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCT TGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCC TGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGAC GGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAG TACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGG ATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAG GCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTA AATGATAA BLV1H12-beta 71 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC BCCX2 HC 3 AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG (bAb-AC3) ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATC CCGGACTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAA GTCAGGTGTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGC AACTTACTATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAG AGCTATCGCAAATGTAGAGGAGGCAACGGACGAAGGTGGTGCTACCAA AAGTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGGAC AGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAA GGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACC GTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGA CTGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTT CCCAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATG GTGACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATG TGGCCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAAC CCAAATCTTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACC TGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGT ACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGT CTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA TCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCA ATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTC CGGGTAAATGATAA BLV1H12-beta 72 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCC BCCX2 HC 4 AGACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCG (bAB-AC4) ACAAGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGG AATGGCTGGGCAGCATCGATGAAACTAAGAAATACCAGAGCTATCG CAAATGTAGAGGAGGCCGAAGGTGGTGCTACCAAAAGTCTTATACCTA CAATTATGAAACAGGGTACAATCCCGGACTGAAGAGCAGACTGTC CATTACCAAGGACAACTCTAAAAGTCAGGTGTCACTGAGCGTGAGC TCCGTCACCACAGAGGATAGTGCAACTTACTATTGCACCTCTGTGC ACCAGGGAGGTGGCGGAAGCTGGCATGTGGATGTCTGGGGACAGG GCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGT GTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTG ACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTG TCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCC AGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTG ACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGG CCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCA AATCTTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG TGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGA GCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCC CGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC AAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAATGATAA Trastuzumab- 73 CAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta BCCX2 HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG long (HLCX) ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGAGAAACTAAGAAATACCAGAGCTATC GCAAATGTAGAGGAGGCCGAAGGTGGTGCTACCAAAAGTCTTATACCT ACAATTATGAAGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTC CTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCT CCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACTGTGCCCTCTAGCAGCT TGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCA ACACCAAGGTGGACAAGAAAGTTGAACCCAAATCTTGCGACAAAA CTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCT CCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCA CGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCT GAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACA ACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTT CCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGATAA Trastuzumab- 74 CAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta BCCX2 HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG medium ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG (HMCX) AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGAGAAACTAAGAAATATCGCAAATGTAG AGGAGGCCGAAGGTGGTGCTACCAAAAGTACAATTATGAAGACTACT GGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGG CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC ACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC AGCGTGGTGACTGTGCCCTCTAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA AAGTTGAACCCAAATCTTGCGACAAAACTCACACATGCCCACCGTG CCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAA

GTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGA CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC CGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCC GTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCT CCCTGTCTCCGGGTAAATGATAA Trastuzumab- 75 CAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGG beta BCCX2 HC GGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGG short (HSCX) ACACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGC AGACTCCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAG AACACGGCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACG GCCGTGTATTACTGTTCGAGATATCGCAAATGTAGAGGAGGCCGAAG GTGGTGCTACCAAAAGGACTACTGGGGCCAAGGAACCCTGGTCACC GTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCAC CCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGT CCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACTGTGCCCTCTAG CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC AGCAACACCAAGGTGGACAAGAAAGTTGAACCCAAATCTTGCGAC AAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGC CACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCC TCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGATAA ##STR00073##

TABLE-US-00009 TABLE 9 Immunoglobulin fusion protein - Amino Acid Sequence Name SEQ ID NO Sequence Trastuzumat- 76 ##STR00074## beta hEPO VLERYLLEAKEAENITTGCAEHCSLNENITBPDTKVNFYAWKRMEVGQQAV LC EVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRAL GAQKEAISPPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTG ##STR00075## ##STR00076## ##STR00077## ##STR00078## Trastuzumab- 77 ##STR00079## beta ##STR00080## bGCSF HC ##STR00081## RLCAAHKLCHPEELMLLRHSLGIPQAPLSSCSSQSLQLTSCLNQLHGGLFL YQGLLQALAGISPELAPTLDTLQLDVTDFATNIWLQMEDLGAAPAVQPTQ ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## Trastuzumab- 78 ##STR00090## beta ##STR00091## Exendin-4 ##STR00092## HC ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## Trastuzumab- 79 ##STR00101## beta ##STR00102## MokalHC ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## Trastuzumab- 80 ##STR00112## beta VM24 ##STR00113## HC ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## Trastuzumab- 81 ##STR00123## beta ##STR00124## hGCSF HC ##STR00125## ##STR00126## GLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQQMEELGMAPAL ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## Trastuzumab- 82 ##STR00136## beta hGH ##STR00137## HC ##STR00138## AYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWL EPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQI FKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGS ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## Trastuzumab- 83 ##STR00147## beta ##STR00148## hLeptin HC ##STR00149## VTGLDFIPGLHPILTISKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLL HVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLW ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## Trastuzumab- 84 ##STR00158## beta ##STR00159## hlFNalpha ##STR00160## HC HDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDK FYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKY ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## Trastuzumab- 85 ##STR00169## beta GLP1 ##STR00170## HC ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## Trastuzumab- 86 ##STR00180## beta Elafin ##STR00181## HC ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## Trastuzumab- 87 ##STR00191## beta ##STR00192## Mambalgin ##STR00193## HC ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## Trastuzumab- 88 ##STR00202## beta ##STR00203## betatrophin ##STR00204## HC RATEARLTEAGHSLGLYDRALEFLGTEVRQGQDATQELRTSLSEIQVEEDS LHLRAEATARSLGEVARAQQALRDTVRRLQVQRGAWLGQAIIGEFETLKA ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## Trastuzumab- 89 ##STR00214## beta hGH ##STR00215## HC ##STR00216## AYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWL EPVQFLRSVFANSLVYGASDSNYVDLLKDLEEGIQTLMGRLEDGSPRTGQI FKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGS ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223## ##STR00224## Trastuzumab- 90 ##STR00225## beta ##STR00226## hIFNB1 HC ##STR00227## KDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETIV ENLLANVYHQIHLKTVLEEKLELEDFTRGLMSSLHLKRYYGRILHYLKA ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## Palivizumab- 91 ##STR00237## beta ##STR00238## Mambalgin ##STR00239## HC ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## BLV1H12- 92 ##STR00248## beta BCCX2 ##STR00249## HC 1 (bAb- ##STR00250## AC1) ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## BLV1H12- 93 ##STR00258## beta BCCX2 ##STR00259## HC 2 (bAb- ##STR00260## AC2) ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## BLV1H12- 94 ##STR00268## beta BCCX2 ##STR00269## HC 3 (bAb- ##STR00270## AC3) ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## BLV1H12- 95 ##STR00278## beta BCCX2 ##STR00279## HC 4 (bAb- ##STR00280## AC4) ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## Trastuzumab- 96 ##STR00288## beta ##STR00289## BCCX2 HC ##STR00290## long ##STR00291## (HLCX) ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## Trastuzumab- 97 ##STR00298##

beta ##STR00299## BCCX2 HC ##STR00300## medium ##STR00301## (HMCX) ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## Trastuzumab- 98 ##STR00308## beta ##STR00309## BCCX2 HC ##STR00310## short ##STR00311## (HSCX) ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## BLV1H12- 99 ##STR00318## beta trypsin ##STR00319## inhibitor ##STR00320## ##STR00321## ##STR00322## ##STR00323## BLV1H12- 100 ##STR00324## beta-EI 1 ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## BLV1H12- 101 ##STR00330## beta-EI 2 ##STR00331## ##STR00332## ##STR00333## ##STR00334## Human 102 ##STR00335## BVK- beta ##STR00336## HEI LC ##STR00337## ##STR00338## ##STR00339## Human 103 ##STR00340## BVK- beta ##STR00341## HEI HC 4 ##STR00342## ##STR00343## ##STR00344## Human 104 ##STR00345## BVK- beta ##STR00346## HEI HC 5 ##STR00347## ##STR00348## ##STR00349## Human 105 ##STR00350## BVK- beta ##STR00351## HEI HC 6 ##STR00352## ##STR00353## ##STR00354## Human 106 ##STR00355## BVK- beta ##STR00356## HEI HC 7 ##STR00357## ##STR00358## ##STR00359## Human 107 ##STR00360## BVK- beta ##STR00361## HEI HC 8 ##STR00362## ##STR00363## ##STR00364## Human 108 ##STR00365## BVK- beta ##STR00366## HEI HC 9 ##STR00367## ##STR00368## ##STR00369## ##STR00370##

TABLE-US-00010 TABLE 10 Extender Peptide Sequences SEQ ID Name NO Sequence Beta strand 1A 109 X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7, wherein X.sup.1 may be a negatively charged amino acid; X.sup.2 may be a polar, uncharged amino acid; X.sup.3 may be a positively charged amino acid; X.sup.4 may be a positively charged amino acid; X.sup.5 may be a hydrophobic amino acid; X.sup.6 may be a polar, uncharged amino acid; and X.sup.7 may be a polar, uncharged amino acid Beta strand 1B 110 ETKKYQX.sub.nS Beta strand 1C 111 ETKKYQS Beta Strand 1D 112 ETKKYQKHRHS Beta Strand 1E 113 ETKKYQKHKNS Beta Strand 1F 114 ETKKYQKHRHTTERS Beta strand 2A 115 X.sup.1TX.sup.2NX.sup.3 Beta strand 2B 116 SX.sup.1TX.sup.2NX.sup.3E Beta strand 2C 117 SX.sup.1TX.sup.2NX.sup.3X.sup.4 Beta strand 2D 118 SX.sup.nX.sup.1TX.sup.2NX.sup.3X.sup.4 Beta strand 2E 119 SYTYNYE Beta strand 2F 120 SATYNYE Beta strand 2G 121 SATANAE Beta strand 2H 122 SYTANYE Beta strand 2I 123 SYTYNAE Beta strand 2J 124 SYTYNYA Beta strand 2K 125 SYTYDYTYNYE Beta strand 2L 126 SYTYDYTYNYE Beta strand 2M 127 SITYNYTYDYTYNYE Beta Strand 2N 128 YX.sup.1YX.sup.2Y; wherein X.sup.1 and X.sup.2 may be independently selected from a polar amino acid Alpha Helix 1A 129 X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7X.sup.8X.sup.9X.sup.10X.- sup.11X.sup.12X.sup.13X.sup.14; wherein in X1-X14 may be independently selected from a positively charged amino acid or a hydrophobic amino acid; wherein X1-X14 may be independently selected from the group comprising A, L and K; wherein A may comprise at least about 30% of the total amino acid composition; wherein A may comprise less than about 70% of the total amino acid composition; wherein L may comprise at least about 20% of the total amino acid composition; wherein L may comprise less than about 50% of the total amino acid composition; wherein K may comprise at least about 20% of the total amino acid composition; wherein K may comprise less than about 50% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 50% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 60% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 70% of the total amino acid composition; wherein the hydrophobic amino acids may comprise less than about 90% of the total amino acid composition Alpha Helix 1B 130 (X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7).sub.n Alpha Helix 1C 131 X.sup.aX.sup.bX.sup.cX.sup.d(X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.- sup.7).sub.n; wherein n may be 1-3; wherein X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid; wherein X.sup.c may be a polar, uncharged amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be the same amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be different amino acids. Alpha Helix 1D 132 X.sup.aX.sup.bX.sup.cX.sup.d (AKLAALK).sub.n; wherein n may be 1-3; wherein X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid; wherein X.sup.c may be a polar, uncharged amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be the same amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be different amino acids. Alpha Helix 1E 133 (AKLAALK).sub.n Alpha Helix 1F 134 GGSG(AKLAALK).sub.n Alpha Helix 1G 135 AKLAALKAKLAALK Alpha Helix 1H 136 GGSGAKLAALKAKLAALK Alpha Helix 1I 137 CAALKSKVSALKSKVASLKSKVAAL Alpha Helix 1J 138 ALKKELQANKKELAQLKKELQALKKELAQ Alpha Helix 2A 139 X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7X.sup.8X.sup.9X.sup.10X.- sup.11X.sup.12X.sup.13X.sup.14; wherein in X1-X14 may be independently selected from a negatively charged amino acid or a hydrophobic amino acid; wherein X1-X14 may be independently selected from the group comprising A, L and E; wherein A may comprise at least about 30% of the total amino acid composition; wherein A may comprise less than about 70% of the total amino acid composition; wherein L may comprise at least about 20% of the total amino acid composition; wherein L may comprise less than about 50% of the total amino acid composition; wherein E may comprise at least about 20% of the total amino acid composition; wherein E may comprise less than about 50% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 50% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 60% of the total amino acid composition; wherein the hydrophobic amino acids may comprise at least about 70% of the total amino acid composition; wherein the hydrophobic amino acids may comprise less than about 90% of the total amino acid composition Alpha Helix 2B 140 (X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7).sub.n Alpha Helix 2C 141 (X.sup.1X.sup.2X.sup.3X.sup.4X.sup.5X.sup.6X.sup.7).sub.n X.sup.aX.sup.bX.sup.cX.sup.d; wherein n may be 1-3; wherein X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid; wherein X.sup.c may be a polar, uncharged amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be the same amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be different amino acids. Alpha Helix 2D 142 (ELAALEA).sub.n X.sup.aX.sup.bX.sup.cX.sup.d; wherein n may be 1-3; wherein X.sup.a, X.sup.b and X.sup.d may be independently selected from a hydrophobic amino acid; wherein X.sup.c may be a polar, uncharged amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be the same amino acid; wherein X.sup.a, X.sup.b and X.sup.d may be different amino acids. Alpha Helix 2E 143 (ELAALEA).sub.n Alpha Helix 2F 144 (ELAALEA).sub.nGGSG Alpha Helix 2G 145 ELAALEA ELAALEA Alpha Helix 2H 146 ELAALEA ELAALEAGGSG Alpha Helix 2I 147 LAAVESELSAVESELASVESELAAC Alpha Helix 2J 148 QLEKKLQALEKKLAQLEKKNQALEKKLAQ Alpha Helix 3 149 CAALKSKVSALKSKVASLKSKVAAL Alpha Helix 4 150 LAAVESELSAVESELASVESELAAC Alpha Helix 5 151 ALKKELQANKKELAQLKKELQALKKELAQ Alpha Helix 6 152 QLEKKLQALEKKLAQLEKKNQALEKKLAQ Alpha Helix 7 153 LKLELQLIKQYREAL Alpha Helix 8 154 LAKILEDEEKHIEWL Alpha Helix 9 155 LSDLHRQVSRLV Alpha Helix 10 156 LQDAKVLLEAAL Alpha Helix 11 157 LQQKIHELEGLIAQH Alpha Helix 12 158 AAQIRDQLHQLRELF Alpha Helix 13 159 ELARLIRLYFAL Alpha Helix 14 160 QESLYVDLFDKF

TABLE-US-00011 TABLE 11 Linker sequences SEQ ID Name NO Sequence Linker 1 161 X.sup.eX.sup.fX.sup.gX.sup.h; wherein X.sup.e, X.sup.f and X.sup.g may be independently selected from a hydrophobic amino acid; wherein X.sup.h may be a polar, uncharged amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be the same amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be different amino acids. Linker 2 162 CX.sup.eX.sup.fX.sup.gX.sup.h; wherein X.sup.e, X.sup.f and X.sup.g may be independently selected from a hydrophobic amino acid; wherein X.sup.h may be a polar, uncharged amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be the same amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be different amino acids. Linker 3 163 X.sup.eX.sup.fX.sup.gX.sup.hC; wherein X.sup.e, X.sup.f and X.sup.g may be independently selected from a hydrophobic amino acid; wherein X.sup.h may be a polar, uncharged amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be the same amino acid; wherein X.sup.e, X.sup.f and X.sup.g may be different amino acids. Linker 4 164 (GGGGS).sub.n Linker 5 165 GGGSGGGGS Linker 6 166 GGGGSGGGS

TABLE-US-00012 TABLE 12 Therapeutic agents-Nucleic acid sequence SEQ ID Name NO Sequence bGCSF 167 ACCCCCCTTGGCCCTGCCCGATCCCTGCCCCAGAGCTTCCTGCTCAAG TGCTTAGAGCAAGTGAGGAAAATCCAGGCTGATGGCGCCGAGCTGCA GGAGAGGCTGTGTGCCGCCCACAAGCTGTGCCACCCGGAGGAGCTGA TGCTGCTCAGGCACTCTCTGGGCATCCCCCAGGCTCCCCTAAGCAGCT GCTCCAGCCAGTCCCTGCAGCTGACGAGCTGCCTGAACCAACTACACG GCGGCCTCTTTCTCTACCAGGGCCTCCTGCAGGCCCTGGCGGGCATCT CCCCAGAGCTGGCCCCCACCTTGGACACACTGCAGCTGGACGTCACTG ACTTTGCCACGAACATCTGGCTGCAGATGGAGGACCTGGGGGCGGCC CCCGCTGTGCAGCCCACCCAGGGCGCCATGCCGACCTTCACTTCAGCC TTCCAACGCAGAGCAGGAGGGGTCCTGGTTGCTTCCCAGCTGCATCGT TTCCTGGAGCTGGCATACCGTGGCCTGCGCTACCTTGCTGAGCCC hGCSF 168 GCCACACCTCTGGGCCCCGCCTCCTCCCTGCCTCAGAGCTTTCTGCTCA AATGTCTGGAGCAGGTGCGGAAGATCCAGGGCGACGGCGCCGCTCTG CAAGAGAAACTGGTCAGCGAATGCGCCACATATAAGCTGTGTCACCC CGAGGAACTGGTCCTCTTGGGCCACAGCCTGGGCATCCCCTGGGCCCC TCTCAGCTCCTGCCCCTCCCAAGCTCTCCAACTGGCTGGATGTCTGTCC CAACTGCACTCCGGCCTCTTCCTGTACCAGGGACTCCTCCAGGCTCTC GAAGGGATCAGCCCCGAACTGGGCCCCACACTGGACACCTTGCAACT CGATGTGGCCGATTTCGCCACAACCATCTGGCAGCAGATGGAAGAAC TCGGAATGGCTCCTGCTCTCCAGCCCACACAGGGAGCTATGCCTGCTT TCGCCTCTGCTTTCCAGCGGAGAGCTGGTGGTGTGCTCGTCGCATCCC ACCTCCAGAGCTTCTTGGAGGTGTCCTATCGGGTGCTCCGGCATCTGG CCCAACCC Exendin-4 169 CACGGAGAAGGAACATTTACCAGCGACCTCAGCAAGCAGATGGAGGA AGAGGCCGTGAGGCTGTTCATCGAGTGGCTGAAGAACGGCGGACCCT CCTCTGGCGCTCCACCCCCTAGC Moka1 170 ATCAACGTGAAGTGCAGCCTGCCCCAGCAGTGCATCAAGCCCTGCAA GGACGCCGGCATGCGGTTCGGCAAGTGCATGAACAAGAAGTGCAGGT GCTACAGC VM24 171 GCCGCTGCAATCTCCTGCGTCGGCAGCCCCGAATGTCCTCCCAAGTGC CGGGCTCAGGGATGCAAGAACGGCAAGTGTATGAACCGGAAGTGCAA GTGCTACTATTGC hGLP-1 172 CATGCGGAAGGCACCTTTACCAGCGATGTGAGCAGCTATCTGGAAGG CCAGGCGGCGAAAGAATTTATTGCGTGGCTGGTGAAAGGCCGC hEPO 173 GCCCCACCACGCCTCATCTGTGACAGCCGAGTCCTGGAGAGGTACCTC TTGGAGGCCAAGGAGGCCGAGAATATCACGACGGGCTGTGCTGAACA CTGCAGCTTGAATGAGAATATCACTGTCCCAGACACCAAAGTTAATTT CTATGCCTGGAAGAGGATGGAGGTCGGGCAGCAGGCCGTAGAAGTCT GGCAGGGCCTGGCCCTGCTGTCGGAAGCTGTCCTGCGGGGCCAGGCC CTGTTGGTCAACTCTTCCCAGCCGTGGGAGCCCCTGCAGCTGCATGTG GATAAAGCCGTCAGTGGCCTTCGCAGCCTCACCACTCTGCTTCGGGCT CTGGGAGCCCAGAAGGAAGCCATCTCCCCTCCAGATGCGGCCTCAGC TGCTCCACTCCGAACAATCACTGCTGACACTTTCCGCAAACTCTTCCG AGTCTACTCCAATTTCCTCCGGGGAAAGCTGAAGCTGTACACAGGGG AGGCCTGCAGGACAGGGGACAGA GMCSF 174 GCGCCGGCGCGCAGCCCGAGCCCGAGCACCCAGCCGTGGGAACATGT GAACGCGATTCAGGAAGCGCGCCGCCTGCTGAACCTGAGCCGCGATA CCGCGGCGGAAATGAACGAAACCGTGGAAGTGATTAGCGAAATGTTT GATCTGCAGGAACCGACCTGCCTGCAGACCCGCCTGGAACTGTATAA ACAGGGCCTGCGCGGCAGCCTGACCAAACTGAAAGGCCCGCTGACCA TGATGGCGAGCCATTATAAACAGCATTGCCCGCCGACCCCGGAAACC AGCTGCGCGACCCAGATTATTACCTTTGAAAGCTTTAAAGAAAACCTG AAAGATTTTCTGCTGGTGATTCCGTTTGATTGCTGGGAACCGGTGCAG GAA IFN-beta 175 ATGAGCTATAACCTGCTGGGCTTTCTGCAGCGCAGCAGCAACTTTCAG TGCCAGAAACTGCTGTGGCAGCTGAACGGCCGCCTGGAATATTGCCTG AAAGATCGCATGAACTTTGATATTCCGGAAGAAATTAAACAGCTGCA GCAGTTTCAGAAAGAAGATGCGGCGCTGACCATTTATGAAATGCTGC AGAACATTTTTGCGATTTTTCGCCAGGATAGCAGCAGCACCGGCTGGA ACGAAACCATTGTGGAAAACCTGCTGGCGAACGTGTATCATCAGATT AACCATCTGAAAACCGTGCTGGAAGAAAAACTGGAAAAAGAAGATTT TACCCGCGGCAAACTGATGAGCAGCCTGCATCTGAAACGCTATTATGG CCGCATTCTGCATTATCTGAAAGCGAAAGAATATAGCCATTGCGCGTG GACCATTGTGCGCGTGGAAATTCTGCGCAACTTTTATTTTATTAACCG CCTGACCGGCTATCTGCGCAAC Oxyntomodulin 176 CACTCTCAGGGTACCTTCACCTCTGACTACTCTAAATACCTGGACTCTC GTCGTGCTCAGGACTTCGTTCAGTGGCTGATGAACACCAAACGTAACC GTAACAACATCGCT Leptin 177 GTTCCAATTCAAAAGGTTCAAGATGATACCAAAACTCTGATTAAAACT ATTGTCACGCGTATAAACGACATCAGCCATACCCAGTCGGTTAGCTCA AAGCAAAAAGTTACCGGTTTGGACTTTATTCCGGGACTGCACCCGATC CTGACCCTTAGTAAAATGGACCAGACACTGGCCGTCTACCAGCAAATC CTGACATCGATGCCATCCAGAAATGTGATACAAATTAGCAACGATTTG GAAAACCTTCGCGATCTGCTGCACGTGCTGGCCTTCAGTAAGTCCTGT CATCTGCCGTGGGCGTCGGGACTGGAGACTCTTGACTCGCTGGGTGGA GTGTTAGAGGCCTCTGGCTATTCTACTGAAGTCGTTGCGCTGTCACGC CTCCAGGGGAGCCTGCAGGACATGCTGTGGCAGCTGGACCTGTCACCT GGCTGC Betatrophin 178 GCTCCTCTGGGCGGTCCTGAACCAGCACAGTACGAGGAACTGACACT GTTGTTCCATGGAGCCTTGCAGCTGGGCCAGGCCCTCAACGGCGTGTA CCGCGCCACAGAGGCACGTTTGACCGAGGCCGGACACAGCCTGGGTT TGTACGACAGAGCCCTGGAGTTTCTGGGTACCGAAGTGCGTCAGGGC CAGGACGCAACTCAGGAGCTGAGAACCTCCCTCTCTGAGATCCAGGT GGAGGAGGACGCCCTGCACCTGCGCGCCGAGGCGACAGCACGCTCTT TGGGAGAAGTTGCTCGCGCTCAGCAGGCCCTGCGTGATACCGTGCGG AGACTCCAAGTTCAGCTCAGAGGCGCTTGGCTCGGACAGGCGCATCA GGAGTTCGAGACCCTGAAAGCTCGTGCCGACAAACAGTCCCACCTGC TGTGGGCGCTCACCGGTCACGTCCAGCGCCAGCAACGCGAAATGGCC GAGCAGCAGCAATGGCTGCGCCAAATCCAGCAGCGCCTGCATACCGC GGCCCTGCCAGCGTAA GDF11 179 AACCTGGGTCTGGACTGCGACGAACACTCTTCTGAATCTCGTTGCTGC CGTTACCCGCTGACCGTTGACTTCGAGGCGTTCGGTTGGGACTGGATC ATCGCTCCGAAACGTTACAAAGCTAACTACTGCTCTGGTCAGTGCGAA TACATGTTCATGCAGAAATACCCGCACACCCACCTGGTTCAGCAGGCT AACCCGCGTGGTTCTGCTGGTCCGTGCTGCACCCCGACCAAAATGTCT CCGATCAACATGCTGTACTTCAACGACAAACAGCAGATCATCTACGGT AAAATCCCGGGTATGGTTGTTGACCGTTGCGGTTGCTCTTAA ANGPTL3 180 GGATCCGGTGGTTTCACCATCAAACTGCTGCTGTTCATCGTTCCGCTG GTTATCTCTTCTCGTATCGACCAGGACAACTCTTCTTTCGACTCTCTGT CTCCGGAACCGAAATCTCGTTTCGCTATGCTGGACGACGTTAAAATCC TGGCTAACGGTCTGCTGCAGCTGGGTCACGGTCTGAAAGACTTCGTTC ACAAAACCAAAGGTCAGATCAACGACATCTTCCAGAAACTGAACATC TTCGACCAGTCTTTCTACGACCTGTCTCTGCAGACCTCTGAAATCAAA GAAGAAGAAAAAGAACTGCGTCGTACCACCTACAAACTGCAGGTTAA AAACGAAGAAGTTAAAAACATGTCTCTGGAACTGAACTCTAAACTGG AATCTCTGCTGGAAGAAAAAATCCTGCTGCAGCAGAAAGTTAAATAC CTGGAAGAACAGCTGACCAACCTGATCCAGAACCAGCCGGAAACCCC GGAACACCCGGAAGTTACCTCTCTGAAAACCTTCGTTGAAAAACAGG ACAACTCTATCAAAGACCTGCTGCAGACCGTTGAAGACCAGTACAAA CAGCTGAACCAGCAGCACTCTCAGATCAAAGAAATCGAAAACCAGCT GCGTCGTACCTCTATCCAGGAACCGACCGAAATCTCTCTGTCTTCTAA ACCGCGTGCTCCGCGTACCACCCCGTTCCTGCAGCTGAACGAAATCCG TAACGTTAAACACGACGGTATCCCGGCTGAATGCACCACCATCTACAA CCGTGGTGAACACACCTCTGGTATGTACGCTATCCGTCCGTCTAACTC TCAGGTTTTCCACGTTTACTGCGACGTTATCTCTGGTTCTCCGTGGACC CTGATCCAGCACCGTATCGACGGTTCTCAGAACTTCAACGAAACCTGG GAAAACTACAAATACGGTTTCGGTCGTCTGGACGGTGAATTCTGGCTG GGTCTGGAAAAAATCTACTCTATCGTTAAACAGTCTAACTACGTTCTG CGTATCGAACTGGAAGACTGGAAAGACAACAAACACTACATCGAATA CTCTTTCTACCTGGGTAACCACGAAACCAACTACACCCTGCACCTGGT TGCTATCACCGGTAACGTTCCGAACGCTATCCCGAAGAAGAAGAAGA AAAAAAAGAAGAAGAAAT hGH 181 TTCCCAACCATTCCCTTATCCAGGCTTTTTGACAACGCTATGCTCCGCG CCCATCGTCTGCACCAGCTGGCCTTTGACACCTACCAGGAGTTTGAAG AAGCCTATATCCCAAAGGAACAGAAGTATTCATTCCTGCAGAACCCCC AGACCTCCCTCTGTTTCTCAGAGTCTATTCCGACACCCTCCAACAGGG AGGAAACACAACAGAAATCCAACCTAGAGCTGCTCCGCATCTCCCTG CTGCTCATCCAGTCGTGGCTGGAGCCCGTGCAGTTCCTCAGGAGTGTC TTCGCCAACAGCCTGGTGTACGGCGCCTCTGACAGCAACGTCTATGAC CTCCTAAAGGACCTAGAGGAAGGCATCCAAACGCTGATGGGGAGGCT GGAAGATGGCAGCCCCCGGACTGGGCAGATCTTCAAGCAGACCTACA GCAAGTTCGACACAAACTCACACAACGATGACGCACTACTCAAGAAC TACGGGCTGCTCTACTGCTTCAGGAAGGACATGGACAAGGTCGAGAC ATTCCTGCGCATCGTGCAGTGCCGCTCTGTGGAGGGCAGCTGTGGCTTC hIFN-alpha 182 TGTGATCTGCCTCAAACCCACAGCCTGGGTAGCAGGAGGACCTTGATG CTCCTGGCACAGATGAGGAGAATCTCTCTTTTCTCCTGCTTGAAGGAC AGACATGACTTTGGATTTCCCCAGGAGGAGTTTGGCAACCAGTTCCAA AAGGCTGAAACCATCCCTGTCCTCCATGAGATGATCCAGCAGATCTTC AATCTCTTCAGCACAAAGGACTCATCTGCTGCTTGGGATGAGACCCTC CTAGACAAATTCTACACTGAACTCTACCAGCAGCTGAATGACCTGGAA GCCTGTGTGATACAGGGGGTGGGGGTGACAGAGACTCCCCTGATGAA GGAGGACTCCATTCTGGCTGTGAGGAAATACTTCCAAAGAATCACTCT CTATCTGAAAGAGAAGAAATACAGCCCTTGTGCCTGGGAGGTTGTCA GAGCAGAAATCATGAGATCTTTTTCTTTGTCAACAAACTTGCAAGAAA GTTTAAGAAGTAAGGAA Mamba 183 CTGAAATGTTACCAACATGGTAAAGTTGTGACTTGTCATCGAGATATG AAGTTTTGCTATCATAACACTGGCATGCCTTTTCGAAATCTCAAGCTC ATCCTACAGGGATGTTCTTCTTCGTGCAGTGAAACAGAAAACAATAAG TGTTGCTCAACAGACAGATGCAACAA Parathyroid 184 TCTGTGAGTGAAATACAGCTTATGCATAACCTGGGAAAACATCTGAAC hormone TCGATGGAGAGAGTAGAATGGCTGCGTAAGAAGCTGCAGGATGTGCA CAATTTTGTTGCCCTTGGAGCTCCTCTAGCTCCCAGAGATGCTGGTTCC CAGAGGCCCCGAAAAAAGGAAGACAATGTCTTGGTTGAGAGCCATGA AAAAAGTCTTGGAGAGGCAGACAAAGCTGATGTGAATGTATTAACTA AAGCTAAATCCCAG IL-11 185 ATGAACTGCGTGTGCCGCCTGGTGCTGGTGGTGCTGAGCCTGTGGCCG GATACCGCGGTGGCGCCGGGCCCGCCGCCGGGCCCGCCGCGCGTGAG CCCGGATCCGCGCGCGGAACTGGATAGCACCGTGCTGCTGACCCGCA GCCTGCTGGCGGATACCCGCCAGCTGGCGGCGCAGCTGCGCGATAAA TTTCCGGCGGATGGCGATCATAACCTGGATAGCCTGCCGACCCTGGCG ATGAGCGCGGGCGCGCTGGGCGCGCTGCAGCTGCCGGGCGTGCTGAC CCGCCTGCGCGCGGATCTGCTGAGCTATCTGCGCCATGTGCAGTGGCT GCGCCGCGCGGGCGGCAGCAGCCTGAAAACCCTGGAACCGGAACTGG GCACCCTGCAGGCGCGCCTGGATCGCCTGCTGCGCCGCCTGCAGCTGC TGATGAGCCGCCTGGCGCTGCCGCAGCCGCCGCCGGATCCGCCGGCG CCGCCGCTGGCGCCGCCGAGCAGCGCGTGGGGCGGCATTCGCGCGGC GCTGGCGATTCTGGGCGGCCTGCATCTGACCCTGGATTGGGCGGTGCG CGGCCTGCTGCTGCTGAAAACCCGCCTG Relaxin 186 GACTCTTGGATGGAAGAAGTTATCAAACTGTGCGGTCGTGAACTGGTT CGTGCTCAGATCGCTATCTGCGGTATGTCTACCTGGTCTGGTGGCGGT CGTGGCGGTCGTCAGCTGTACTCTGCTCTGGCTAACAAATGCTGCCAC GTTGGTTGCACCAAACGTTCTCTGGCTCGTTTCTGCTAA Relaxin- 187 GATAGCTGGATGGAAGAAGTGATTAAACTGTGCGGCCGCGAACTGGT FactorXa GCGCGCGCAGATTGCGATTTGCGGCATGAGCACCTGGAGCATTGAAG GCCGCAGCCTGAGCCAGGAAGATGCGCCGCAGACCCCGCGCCCGGTG GCGGAAATTGTGCCGAGCTTTATTAACAAAGATACCGAAACCATTAA CATGATGAGCGAATTTGTGGCGAACCTGCCGCAGGAACTGAAACTGA CCCTGAGCGAAATGCAGCCGGCGCTGCCGCAGCTGCAGCAGCATGTG CCGGTGCTGAAAGATAGCAGCCTGCTGTTTGAAGAATTTAAAAAACT GATTCGCAACCGCCAGAGCGAAGCGGCGGATAGCAGCCCGAGCGAAC TGAAATATCTGGGCCTGGATACCCATAGCATTGAAGGCCGCCAGCTGT ATAGCGCGCTGGCGAACAAATGCTGCCATGTGGGCTGCACCAAACGC AGCCTGGCGCGCTTTTGC Relaxin 188 AGCCTGAGCCAGGAAGATGCGCCGCAGACCCCGCGCCCGGTGGCGGA fragment AATTGTGCCGAGCTTTATTAACAAAGATACCGAAACCATTAACATGAT GAGCGAATTTGTGGCGAACCTGCCGCAGGAACTGAAACTGACCCTGA GCGAAATGCAGCCGGCGCTGCCGCAGCTGCAGCAGCATGTGCCGGTG CTGAAAGATAGCAGCCTGCTGTTTGAAGAATTTAAAAAACTGATTCGC AACCGCCAGAGCGAAGCGGCGGATAGCAGCCCGAGCGAACTGAAAT ATCTGGGCCTGGATACCCATAGC Relaxin2 A 189 GACTCTTGGATGGAAGAAGTTATCAAACTGTGCGGTCGTGAACTGGTT chain CGTGCTCAGATCGCTATCTGCGGTATGTCTACCTGGTCTAAACGTTCTC TGTCTCAGGAAGACGCTCCGCAGACCCCGCGTCCGGTT Relaxin2 B 190 CAGCTGTACTCTGCTCTGGCTAACAAATGCTGCCACGTTGGTTGCACC chain AAACGTTCTCTGGCTCGTTTCTGC IL8 191 CCGCGCAGCGCGAAAGAACTGCGCTGCCAGTGCATTAAAACCTATAG CAAACCGTTTCATCCGAAATTTATTAAAGAACTGCGCGTGATTGAAAG CGGCCCGCATTGCGCGAACACCGAAATTATTGTGAAACTGAGCGATG GCCGCGAACTGTGCCTGGATCCGAAAGAAAACTGGGTGCAGCGCGTG GTGGAAAAATTTCTGAAACGCGCGGAAAACAGC ziconotide 192 TGCAAAGGCAAAGGCGCGAAATGCAGCCGCCTGATGTATGATTGCTG CACCGGCAGCTGCCGCAGCGGCAAATGC somatostatin 193 GCGGGCTGCAAAAACTTTTTTTGGAAAACCTTTACCAGCTGCGGC chlorotoxin 194 ATGTGCATGCCGTGCTTTACCACCGATCATCAGATGGCGCGCAAATGC GATGATTGCTGCGGCGGCAAAGGCCGCGGCAAATGCTATGGCCCGCA GTGCCTG SDF1(alpha) 195 AAACCGGTGAGCCTGAGCTATCGCTGCCCGTGCCGCTTTTTTGAAAGC CATGTGGCGCGCGCGAACGTGAAACATCTGAAAATTCTGAACACCCC GAACTGCGCGCTGCAGATTGTGGCGCGCCTGAAAAACAACAACCGCC AGGTGTGCATTGATCCGAAACTGAAATGGATTCAGGAATATCTGGAA AAAGCGCTGAACAAA IL21 196 CAGGGCCAGGATCGCCATATGATTCGCATGCGCCAGCTGATTGATATT GTGGATCAGCTGAAAAACTATGTGAACGATCTGGTGCCGGAATTTCTG CCGGCGCCGGAAGATGTGGAAACCAACTGCGAATGGAGCGCGTTTAG CTGCTTTCAGAAAGCGCAGCTGAAAAGCGCGAACACCGGCAACAACG

AACGCATTATTAACGTGAGCATTAAAAAACTGAAACGCAAACCGCCG AGCACCAACGCGGGCCGCCGCCAGAAACATCGCCTGACCTGCCCGAG CTGCGATAGCTATGAAAAAAAACCGCCGAAAGAATTTCTGGAACGCT TTAAAAGCCTGCTGCAGAAAATGATTCATCAGCATCTGAGCAGCCGC ACCCATGGCAGCGAAGATAGC Elafin 197 GCGCAAGAGCCAGTCAAAGGTCCAGTCTCCACTAAGCCTGGCTCCTGC CCCATTATCTTGATCCGGTGCGCCATGTTGAATCCCCCTAACCGCTGCT TGAAAGATACTGACTGCCCAGGAATCAAGAAGTGCTGTGAAGGCTCT TGCGGGATGGCCTGTTTCGTTCCCCAG BCCX2 (of 198 TATCGCAAATGTAGAGGAGGCCGAAGGTGGTGCTACCAAAAG bAb-AC1) Elastase 199 ATGTGTACCGCAAGCATACCACCCCAATGCTAC inhibitor

TABLE-US-00013 TABLE 13 Therapeutic agents - Amino acid sequences SEQ ID Name NO Sequence bGCSF 200 TPLGPARSLPQSFLLKCLEQVRKIQADGAELQERLCAAHKLCHPEELMLL RHSLGIPQAPLSSCSSQSLQLTSCLNQLHGGLFLYQGLLQALAGISPELAPT LDTLQLDVTDFATNIWLQMEDLGAAPAVQPTQGAMPTFTSAFQRRAGG VLVASQLHRFLELAYRGLRYLAEP Exendin-4 201 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Moka1 202 INVKCSLPQQCIKPCKDAGMRFGKCMNKKCRCYS VM24 203 AAAISCVGSPECPPKCRAQGCKNGKCMNRKCKCYYC hGCSF 204 ATPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLVSECATYKLCHPEE LVLLGHSLGIPWAPLSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISP ELGPTLDTLQLDVADFATTIWQQMEELGMAPALQPTQGAMPAFASAFQR RAGGVLVASHLQSFLEVSYRVLRHLAQP hGLP-1 205 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR hEPO 206 APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYA WKRMEVGQQAVEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDK AVSGLRSLTTLLRALGAQKEAISPPDAASAAPLRTITADTFRKLFRVYSNF LRGKLKLYTGEACRTGDR GMCSF 207 APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQ EPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQI ITFESFKENLKDFLLVIPFDCWEPVQE IFN-beta 208 MSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQ FQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKT VLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEI LRNFYFINRLTGYLRN Oxyntomodulin 209 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA Leptin 210 VPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSK MDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASG LETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC Betatrophin 211 APLGGPEPAQYEELTLLFHGALQLGQALNGVYRATEARLTEAGHSLGLY DRALEFLGTEVRQGQDATQELRTSLSEIQVEEDALHLRAEATARSLGEVA RAQQALRDTVRRLQVQLRGAWLGQAHQEFETLKARADKQSHLLWALT GHVQRQQREMAEQQQWLRQIQQRLHTAALPA GDF11 212 NLGLDCDEHSSESRCCRYPLTVDFEAFGWDWIIAPKRYKANYCSGQCEY MFMQKYPHTHLVQQANPRGSAGPCCTPTKMSPINMLYFNDKQQIIYGKIP GMVVDRCGCS ANGPTL3 213 GSGGFTIKLLLFIVPLVISSRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGL LQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRR TTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQN QPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQ LRRTSIQEPTEISLSSKPRAPRTTPFLQLNEIRNVKHDGIPAECTTIYNRGEH TSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWENYKYG FGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHE TNYTLHLVAITGNVPNAIPKKKKKKKKKK hGH 214 FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTS LCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVY GASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHND DALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF hIFN-alpha 215 CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKA ETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQ GVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSF SLSTNLQESLRSKE Mamba 216 LKCYQHGKVVTCHRDMKFCYHNTGMPFRNLKLILQGCSSSCSETENNKC CSTDRCN Parathyroid 217 SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGS Hormone QRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ IL-11 218 MNCVCRLVLVVLSLWPDTAVAPGPPPGPPRVSPDPRAELDSTVLLTRSLL ADTRQLAAQLRDKFPADGDHNLDSLPTLAMSAGALGALQLPGVLTRLR ADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRL ALPQPPPDPPAPPLAPPSSAWGGIRAALAILGGLHLTLDWAVRGLLLLKT RL Relaxin 219 DSWMEEVIKLCGRELVRAQIAICGMSTWSGGGRGGRQLYSALANKCCH VGCTKRSLARFC Relaxin- 220 DSWMEEVIKLCGRELVRAQIAICGMSTWSIEGRSLSQEDAPQTPRPVAEIV FactorXa PSFINKDTETINMMSEFVANLPQELKLTLSEMQPALPQLQQHVPVLKDSS LLFEEFKKLIRNRQSEAADSSPSELKYLGLDTHSIEGRQLYSALANKCCHV GCTKRSLARFC Relaxin 221 SLSQEDAPQTPRPVAEIVPSFINKDTETINMMSEFVANLPQELKLTLSEMQ fragment PALPQLQQHVPVLKDSSLLFEEFKKLIRNRQSEAADSSPSELKYLGLDTHS Relaxin2 A 222 DSWMEEVIKLCGRELVRAQIAICGMSTWS chain Relaxin2 B 223 QLYSALANKCCHVGCTKRSLARFC chain IL8 224 PRSAKELRCQCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELC LDPKENWVQRVVEKFLKRAENS ziconotide 225 CKGKGAKCSRLMYDCCTGSCRSGKC somatostatin 226 AGCKNFFWKTFTSCG chlorotoxin 227 MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCL SDF1(alpha) 228 KPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVC IDPKLKWIQEYLEKALNK IL21 229 QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSC FQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSY EKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS Elafin 230 AQEPVKGPVSTKPGSCPIILIRCAMLNPPNRCLKDTDCPGIKKCCEGSCGM ACFVPQ BCCX2 (of 231 YRKCRGGRRWCYQK bAb-AC1) BCCX2 (of 232 YRKCRGPRRWCYQK bAB-AC2) BCCX2 (of 233 YRKCRGGNGRRWCYQK bAB-AC3) BCCX2 (of 234 TSVHQGGGGSWHVDV bAB-AC4) Elastase 235 MCTASIPPQCY inhibitor

TABLE-US-00014 TABLE 14 Miscellaneous sequences SEQ ID Name NO Sequence Factor Xa nucleotide 236 ATCGAAGGTCGT Factor Xa peptide 237 IEGR PC2 Cleavage Site - Nucleotide 238 CGTAAAAAACGT PC2 Cleavage Site - Amino acid 239 RKKR

TABLE-US-00015 TABLE 15 Immunoglobulin Fusion Proteins for Dual Fusions SEQ ID Name NO Sequence Trastuzumab-coil hEPO LC 240 ##STR00371## ##STR00372## NITTGCAEHCSLNENITVPDTKVNFYAWRMEVGQQ AVEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHV DKAVSGLRSLTTLLRALGAQKEAISPPDAASAAPLRTTT ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## Trastuzumab-coil bGCSF HC 241 ##STR00379## ##STR00380## ##STR00381## ##STR00382## EQVRKLQADGAELQERLCSSHKLCHPEELMLLRHSL GIPQAPLSSCSSQSLQLTSCLNQLHGGLFLYQGLLQAL AGISPELAPTLDTLQLDVTDFATNIWLQMEDLGAAPA VPTQGAMPTFTSAFQRRAGGVLVASQLHRFLELAY ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## Trastuzumab-coil hGCSF HC 242 ##STR00394## ##STR00395## ##STR00396## ##STR00397## LEQVRKIQGDGAALQEKLVSECATVKLCHPEELVLLG HSLGIPWAPLSSCPSQALQLAGCLSQLHSGLFLYQGL LQALEGISPELGPTLDTLQLDVADFATTIWQQMEELG MAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFL ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## Trastuzumab-coil hLeptin HC 243 ##STR00409## ##STR00410## ##STR00411## ##STR00412## TRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQ TLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKS CHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGS ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## Trastuzumab-direct-hEPO LC 244 ##STR00424## LICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVP DTKVNFYAWKRMEVGQQAVEVWQGLALLSEAVLRG QALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGA QKEAISPPDAASAAPLRTITADTFRKLFRVYSNFLRGK ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## Trastuzumab-direct-bGCSF HC 245 ##STR00431## ##STR00432## ##STR00433## ##STR00434## AAHKLCHPEELMLLRHSLGIPQAPLSSCSSQSLQLTSC LNQLHGGLFLYQGLLQALAGISPELAPTLDTLQLDVT DFATNIWLQMEDIGAAPAVQPTQGAMPTFTSAFQRR ##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## Trastuzumab-direct hGCSF HC 246 ##STR00446## ##STR00447## ##STR00448## ##STR00449## VSECATYKLCHPEELVLLGHSLGIPWAPLSSCPSQALQ LAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQ LDVADFATTIWQQMEELGMAPALQPTQGAMPAFASA ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## Trastuzumab-direct hLeptin HC 247 ##STR00461## ##STR00462## ##STR00463## ##STR00464## LDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQIS NDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVL ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476##

TABLE-US-00016 TABLE 16 Ultralong CDR3 containing bovine antibody heavy chain and light chain amino acid sequences SEQ ID Name NO Sequence BLV1H1 248 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEWLGS 2 HC IDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCTSVHQE TKKYQSCPDGYRERSDCSNRPACGTSDCCRVSVFGNCLTTLPVSYSYTYN YEWHVDVWGQGLLVTVSS BLV5B8 249 QVQLRESGPSLVQPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEWLGS HC IDTGGSTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCTTVHQET RKTCSDGYIAVDSCGRGQSDGCVNDCNSCYYGWRNCRRQPAIHSYEFHV DAWGRGLLVTVSS BLV5D3 250 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRRAPGKALEWLGT HC TDTGGSAAYNPGLKSRLSITKDNSKSQVSLSVSNVATEDSATYYCSSVTQR THVSRSCPDGCSDGDGCVDGCCCSAYRCYTPGVRDLSCTSYSITYTYEWN VDAWGQGLLVTVSS BLV1H1 251 QAVLNQPSSVSGSLGQRVSITCSGSSSNVGNGYVSWYQLIPGSAPRTLIYG 2 LC DTSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYFCASAEDSSSNAVFG SGTTLTVLGQPKSPPSVTLFPPSTEELNGNKATLVCLISDFYPGSVTVVWK ADGSTITRNVETTRASKQSNSKYAASSYLSLTSSDWKSKGSYSCEVTHEGS TVTKTVKPSECS BLV5B8 252 QAVLNQPSSVSGSLGQRVSITCSGSSSNVGNGYVSWYQLIPGSAPRTLIYG LC DTSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYFCASAEDSSSNAVFG SGTTLTVLGQPKSPPSVTLFPPSTEELNGNKATLVCLISDFYPGSVTVVWK ADGSTITRNVETTRASKQSNSKYAASSYLSLTSSDWKSKGSYSCEVTHEGS TVTKTVKPSECS BLV5D3 253 QAVLNQPSSVSGSLGQRVSITCSGSSSNVGNGYVSWYQLIPGSAPRTLIYG LC DTSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYFCASAEDSSSNAVFG SGTTLTVLGQPKSPPSVTLFPPSTEELNGNKATLVCLISDFYPGSVTVVWK ADGSTITRNVETTRASKQSNSKYAASSYLSLTSSDWKSKGSYSCEVTHEGS TVTKTVKPSECS For select SEQ ID NOs, the Ultralong CDR3 Stalks are underlined and knobs are double underlined

TABLE-US-00017 TABLE 17 Ultralong CDR3 containing bovine antibody heavy chain and light chain nucleotide sequences SEQ ID Name NO Sequence BLV1H12 Fab 254 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA heavy chain GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA (VH + CH1) AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCTGTCCT GACGGCTATCGGGAGAGATCTGATTGCAGTAATAGGCCAGCTTGTGG CACATCCGACTGCTGTCGCGTGTCTGTCTTCGGGAACTGCCTGACTAC CCTGCCTGTGTCCTACTCTTATACCTACAATTATGAATGGCATGTGGA TGTCTGGGGACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAA CTGCACCAAAGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCC TCTAGTACCGTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGA GCCTGTGACTGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGC ACACCTTCCCAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTT CAATGGTGACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGT AATGTGGCCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGA ACCCAAATCTTGCGACGGCAGCCATCACCATCATCATCAC BLV5B8 Fab 255 CAGGTCCAGCTGAGAGAGAGCGGGCCTTCACTGGTCCAGCCTTCACA heavy chain GACACTGAGCCTGACTTGTACTGCCTCCGGGTTTTCACTGTCTGACAA (VH + CH1) GGCTGTGGGATGGGTCCGACAGGCACCAGGGAAAGCTCTGGAGTGG CTGGGAAGTATCGATACCGGCGGGTCAACAGGGTACAACCCTGGACT GAAGTCCAGACTGTCTATTACTAAGGACAATTCTAAAAGTCAGGTGT CACTGAGCGTGAGCTCCGTCACCACAGAGGATTCTGCAACATACTAT TGCACTACCGTGCACCAGGAAACAAGGAAAACTTGTAGTGACGGCTA TATCGCAGTGGATAGCTGCGGACGAGGACAGTCCGACGGATGCGTG AACGATTGCAATAGCTGTTACTATGGATGGCGAAACTGCCGGAGACA GCCAGCAATTCATTCATACGAGTTTCATGTGGATGCTTGGGGGCGGG GGCTGCTGGTCACCGTCTCCTCAGCTTCCACAACTGCACCAAAGGTG TACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGAC ACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCA CCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCT GTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTC CCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCC TGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCG ACGGCAGCCATCACCATCATCATCAC BLV5D3 Fab 256 CAGGTCCAGCTGAGGGAATCCGGCCCATCACTGGTCAAGCCTTCACA heavy chain GACACTGAGCCTGACATGTACTGCAAGCGGGTTTTCACTGAGTGACA (VH + CH1) AGGCAGTGGGATGGGTCCGGAGAGCACCAGGAAAAGCCCTGGAGTG GCTGGGAACCACAGATACTGGAGGATCCGCCGCTTACAACCCTGGCC TGAAGTCCCGGCTGTCTATCACCAAGGACAACTCTAAAAGTCAGGTG TCACTGAGCGTGTCCAATGTCGCTACAGAAGATTCTGCAACTTACTAT TGTAGCTCCGTGACTCAGAGGACCCACGTCTCTCGCAGTTGTCCAGA CGGGTGCAGTGACGGAGATGGCTGCGTGGATGGATGCTGTTGCTCAG CTTACCGATGTTATACACCCGGGGTCAGAGACCTGAGCTGCACCTCA TATAGCATTACATACACTTACGAATGGAATGTGGATGCTTGGGGACA GGGACTGCTGGTGACCGTCTCTTCAGCTTCCACAACTGCACCAAAGG TGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTG ACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGT CACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAG CTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAG TCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCAT CCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTG CGACGGCAGCCATCACCATCATCATCAC BLV1H12 Fab 257 CAGGCCGTCCTGAACCAGCCAAGCAGCGTCTCCGGGTCTCTGGGGCA light chain GCGGGTCTCAATCACCTGTAGCGGGTCTTCCTCCAATGTCGGCAACG (VL + CL) GCTACGTGTCTTGGTATCAGCTGATCCCTGGCAGTGCCCCACGAACC CTGATCTACGGCGACACATCCAGAGCTTCTGGGGTCCCCGATCGGTT CTCAGGGAGCAGATCCGGAAACACAGCTACTCTGACCATCAGCTCCC TGCAGGCTGAGGACGAAGCAGATTATTTCTGCGCATCTGCCGAGGAC TCTAGTTCAAATGCCGTGTTTGGAAGCGGCACCACACTGACAGTCCT GGGGCAGCCCAAGAGTCCCCCTTCAGTGACTCTGTTCCCACCCTCTAC CGAGGAACTGAACGGAAACAAGGCCACACTGGTGTGTCTGATCAGC GACTTTTACCCTGGATCCGTCACTGTGGTCTGGAAGGCAGATGGCAG CACAATTACTAGGAACGTGGAAACTACCCGCGCCTCCAAGCAGTCTA ATAGTAAATACGCCGCCAGCTCCTATCTGAGCCTGACCTCTAGTGATT GGAAGTCCAAAGGGTCATATAGCTGCGAAGTGACCCATGAAGGCTC AACCGTGACTAAGACTGTGAAACCATCCGAGTGCTCC BLV5B8 Fab 258 CAGGCCGTCCTGAACCAGCCAAGCAGCGTCTCCGGGTCTCTGGGGCA light chain GCGGGTCTCAATCACCTGTAGCGGGTCTTCCTCCAATGTCGGCAACG (VL + CL) GCTACGTGTCTTGGTATCAGCTGATCCCTGGCAGTGCCCCACGAACC CTGATCTACGGCGACACATCCAGAGCTTCTGGGGTCCCCGATCGGTT CTCAGGGAGCAGATCCGGAAACACAGCTACTCTGACCATCAGCTCCC TGCAGGCTGAGGACGAAGCAGATTATTTCTGCGCATCTGCCGAGGAC TCTAGTTCAAATGCCGTGTTTGGAAGCGGCACCACACTGACAGTCCT GGGGCAGCCCAAGAGTCCCCCTTCAGTGACTCTGTTCCCACCCTCTAC CGAGGAACTGAACGGAAACAAGGCCACACTGGTGTGTCTGATCAGC GACTTTTACCCTGGATCCGTCACTGTGGTCTGGAAGGCAGATGGCAG CACAATTACTAGGAACGTGGAAACTACCCGCGCCTCCAAGCAGTCTA ATAGTAAATACGCCGCCAGCTCCTATCTGAGCCTGACCTCTAGTGATT GGAAGTCCAAAGGGTCATATAGCTGCGAAGTGACCCATGAAGGCTC AACCGTGACTAAGACTGTGAAACCATCCGAGTGCTCC BLV5D3 Fab 259 CAGGCCGTCCTGAACCAGCCAAGCAGCGTCTCCGGGTCTCTGGGGCA light chain GCGGGTCTCAATCACCTGTAGCGGGTCTTCCTCCAATGTCGGCAACG (VL + CL) GCTACGTGTCTTGGTATCAGCTGATCCCTGGCAGTGCCCCACGAACC CTGATCTACGGCGACACATCCAGAGCTTCTGGGGTCCCCGATCGGTT CTCAGGGAGCAGATCCGGAAACACAGCTACTCTGACCATCAGCTCCC TGCAGGCTGAGGACGAAGCAGATTATTTCTGCGCATCTGCCGAGGAC TCTAGTTCAAATGCCGTGTTTGGAAGCGGCACCACACTGACAGTCCT GGGGCAGCCCAAGAGTCCCCCTTCAGTGACTCTGTTCCCACCCTCTAC CGAGGAACTGAACGGAAACAAGGCCACACTGGTGTGTCTGATCAGC GACTTTTACCCTGGATCCGTCACTGTGGTCTGGAAGGCAGATGGCAG CACAATTACTAGGAACGTGGAAACTACCCGCGCCTCCAAGCAGTCTA ATAGTAAATACGCCGCCAGCTCCTATCTGAGCCTGACCTCTAGTGATT GGAAGTCCAAAGGGTCATATAGCTGCGAAGTGACCCATGAAGGCTC AACCGTGACTAAGACTGTGAAACCATCCGAGTGCTCC

TABLE-US-00018 TABLE 18 Bovine Immunoglobulin Fusion Protein Amino Acid Sequences Name SEQ ID NO Sequence BLV1H1 260 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT hLeptin SVHQETKKYQSGGGGSVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSK HC QKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLEN LRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQ GSLQDMLWQLDLSPGCGGGGSSYTYNYEWHVDVWGQGLLVTVSSA STTAPKVYPLSSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSG VHTFPAVLQSSGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 261 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Moka1 SVHQETKKYQSINVKCSLPQQCIKPCKDAGMRFGKCMNKKCRCYSSY L0 HC TYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLG CLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGS TSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK BLV1H1 262 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Moka1 SVHQETKKYQSGGGGSINVKCSLPQQCIKPCKDAGMRFGKCMNKKCR L1 HC CYSGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCC GDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLY SLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 263 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT VM24 L1 SVHQETKKYQSGGGGSAAAISCVGSPECPPKCRAQGCKNGKCMNRKC HC KCYYCGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSS CCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSG LYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 264 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT VM24 L2 SVHQETKKYQSGGGSGGGGSAAAISCVGSPECPPKCRAQGCKNGKCM HC NRKCKCYYCGGGGSGGGSSYTYNYEWHVDVWGQGLLVTVSSASTT APKVYPLSSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHT FPAVLQSSGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 265 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT GLP-1 SVHQETKKYQSCGGGGSIEGRHAEGTFTSDVSSYLEGQAAKEFIAWLV HC KGRGGGGSCSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSC CGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGL YSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 266 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Exendin- SVHQETKKYQSCGGGGSIEGRHGEGTFTSDLSKQMEEEAVRLFIEWLK 4 HC NGGPSSGAPPPSGGGGSCSYTYNYEWHVDVWGQGLLVTVSSASTTAP KVYPLSSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFP AVLQSSGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 267 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT EPO HC SVHQETKKYQSGGGGSAPPRLICDSRVLERYLLEAKEAENITTGCAEH CSLNENITVPDTKVNFYAWKRMEVGQQAVEVWQGLALLSEAVLRGQ ALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAISPPDAAS AAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDRGGGGSSYT YNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGC LVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGST SGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK BLV1H1 268 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2- LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT betaoxyntomodulin SVHQETKKYQSGGGGSHSQGTFTSDYSKYLDSRRAQDFVQWLMNTK HC RNRNNIAGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPL SSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQS SGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 269 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Mamba1 SVHQETKKYQSGGGGSLKCYQHGKVVTCHRDMKFCYHNTGMPFRNL HC KLILQGCSSSCSETENNKCCSTDRCNKGGGGSSYTYNYEWHVDVWGQ GLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCLVSSYMPEPVTVT WNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTSGQTFTCNVAHP ASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK BLV1H1 270 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT GMCSF SVHQETKKYQSGGGGSAPARSPSPSTQPWEHVNAIQEARRLLNLSRDT HC AAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTM MASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQEG GGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSS STVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSM VTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK BLV1H1 271 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT IL11 HC SVHQETKKYQSGGGGSPGPPPGPPRVSPDPRAELDSTVLLTRSLLADTR QLAAQLRDKFPADGDHNLDSLPTLAMSAGALGALQLPGVLTRLRADL LSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRLA LPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLLLKT RLGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCCG DKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYS LSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 272 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT IFN beta SVHQETKKYQSGGGGSMSYNLLGFLQRSSNFQCQKLLWQLNGRLEY HC CLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGW NETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYG RILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRNGGGGSSYTY NYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCL VSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTS GQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK BLV1H1 273 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT parathyroid SVHQETKKYQSGGGGSSVSEIQLMHNLGKHLNSMERVEWLRKKLQD hormone VHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVN HC VLTKAKSQGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYP LSSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQ SSGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H1 274 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Relaxin2 SVHQETKKYQSGGGGSDSWMEEVIKLCGRELVRAQIAICGMSTWSKR HC SLSQEDAPQTPRPVAEIVPSFINKDTETINMMSEFVANLPQELKLTLSE MQPALPQLQQHVPVLKDSSLLFEEFKKLIRNRQSEAADSSPSELKYLGL DTHSRKKRQLYSALANKCCHVGCTKRSLARFCGGGGSSYTYNYEWH VDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCLVSSYMP EPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTSGQTFTC NVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK BLV1H1 275 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Relaxin2 SVHQETKKYQSGGGGSDSWMEEVIKLCGRELVRAQIAICGMSTWSGG (GGSIEGR) SIEGRQLYSALANKCCHVGCTKRSLARFCGGGGSSYTYNYEWHVDV HC WGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCLVSSYMPEPV TVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTSGQTFTCNVA HPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK BLV1H1 276 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT Relaxin2 SVHQETKKYQSGGGGSDSWMEEVIKLCGRELVRAQIAICGMSTWSIE (IEGRCpep GRSLSQEDAPQTPRPVAEIVPSFINKDTETINMMSEFVANLPQELKLTLS IEGR) EMQPALPQLQQHVPVLKDSSLLFEEFKKLIRNRQSEAADSSPSELKYLG HC LDTHSIEGRQLYSALANKCCHVGCTKRSLARFCGGGGSSYTYNYEWH VDVWGQGLLVTVSSASTTAPKVYPLSSCCGDKSSSTVTLGCLVSSYMP EPVTVTWNSGALKSGVHTFPAVLQSSGLYSLSSMVTVPGSTSGQTFTC NVAHPASSTKVDKAVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK BLV1H1 277 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEW 2-beta LGSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCT hGH SVHQETKKYQSGGGGSFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFE heavy EAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLI chain QSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLED GSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFL RIVQCRSVEGSCGFGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTA PKVYPLSSCCGDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTF PAVLQSSGLYSLSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BLV1H12 278 QAVLNQPSSVSGSLGQRVSITCSGSSSNVGNGYVSWYQLIPGSAPRTLI immunoglobulin YGDTSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYFCASAEDSSSN fusion AVFGSGTTLTVLGQPKSPPSVTLFPPSTEELNGNKATLVCLISDFYPGSV protein TVVWKADGSTITRNVETTRASKQSNSKYAASSYLSLTSSDWKSKGSYS

LC CEVTHEGSTVTKTVKPSECS

TABLE-US-00019 TABLE 19 Bovine Immunoglobulin Fusion Protein Nucleotide Sequences Name SEQ ID NO Sequence BLV1H12-beta 279 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA hLeptin L1 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGTGGC GGAGGATCTGTTCCAATTCAAAAGGTTCAAGATGATACCAAAACTCT GATTAAAACTATTGTCACGCGTATAAACGACATCAGCCATACCCAGT CGGTTAGCTCAAAGCAAAAAGTTACCGGTTTGGACTTTATTCCGGGA CTGCACCCGATCCTGACCCTTAGTAAAATGGACCAGACACTGGCCGT CTACCAGCAAATCCTGACATCGATGCCATCCAGAAATGTGATACAAA TTAGCAACGATTTGGAAAACCTTCGCGATCTGCTGCACGTGCTGGCC TTCAGTAAGTCCTGTCATCTGCCGTGGGCGTCGGGACTGGAGACTCTT GACTCGCTGGGTGGAGTGTTAGAGGCCTCTGGCTATTCTACTGAAGT CGTTGCGCTGTCACGCCTCCAGGGGAGCCTGCAGGACATGCTGTGGC AGCTGGACCTGTCACCTGGCTGCGGAGGTGGTGGTTCATCTTATACCT ACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTG ACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTC AAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCC TGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCA GGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTC CTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTA CTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCA CCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCA CACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAG TCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGA CCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTA CACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCG TGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCT GTCTCCGGGTAAA BLV1H12-beta 280 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Moka1 L0 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCATCAAC GTGAAGTGCAGCCTGCCCCAGCAGTGCATCAAGCCCTGCAAGGACGC CGGCATGCGGTTCGGCAAGTGCATGAACAAGAAGTGCAGGTGCTAC AGCTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGGACA GGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGG TGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTG ACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGT CACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAG CTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAG TCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCAT CCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTG CGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG GGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTC ATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAG CCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG AGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAG CACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA GCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGA CATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCT TCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG AAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12-beta 281 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Moka1 L1 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGTGGC GGAGGATCTATCAACGTGAAGTGCAGCCTGCCCCAGCAGTGCATCAA GCCCTGCAAGGACGCCGGCATGCGGTTCGGCAAGTGCATGAACAAG AAGTGCAGGTGCTACAGCGGAGGTGGTGGTTCATCTTATACCTACAA TTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAG TCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCT GCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTC TCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGC CCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTG GCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCA GGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAA AGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACA TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAG GTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGA CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTC TCCGGGTAAA BLV1H12-beta 282 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA VM24 L1 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGCCGCTGCAATCTCCTGCGTCGGCAGCCCCGAATGTCC TCCCAAGTGCCGGGCTCAGGGATGCAAGAACGGCAAGTGTATGAAC CGGAAGTGCAAGTGCTACTATTGCGGCGGAGGTGGGAGTTCTTATAC CTACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGG TGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGT CAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGC CTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTC AGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGT CCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGT ACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCC ACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTC ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA BLV1H12-beta 283 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA VM24 L2 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGCGGT GGATCTGGGGGTGGCGGAAGCGCCGCTGCAATCTCCTGCGTCGGCAG CCCCGAATGTCCTCCCAAGTGCCGGGCTCAGGGATGCAAGAACGGCA AGTGTATGAACCGGAAGTGCAAGTGCTACTATTGCGGCGGAGGTGGG AGTGGAGGCGGTAGCTCTTATACCTACAATTATGAATGGCATGTGGA TGTCTGGGGACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAA CTGCACCAAAGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCC TCTAGTACCGTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGA GCCTGTGACTGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGC ACACCTTCCCAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTT CAATGGTGACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGT AATGTGGCCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGA ACCCAAATCTTGCGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTG GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCA CCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGG GCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGG AGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12-beta 284 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA GLP-1 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCTGCGGG GGTGGCGGAAGCATCGAAGGTCGTCACGCTGAGGGAACATTCACTTC CGATGTGTCCTCCTACCTGGAGGGCCAGGCTGCCAAAGAGTTCATCG CTTGGCTCGTCAAGGGCAGGGGCGGAGGTGGGAGTTGCTCTTATACC TACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGT GACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGT CAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGC CTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTC AGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGT CCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGT ACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCC ACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTC ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA BLV1H12-beta 285 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Exendin-4 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCTGCGGG GGTGGCGGAAGCATCGAAGGTCGTCACGCTGAGGGAACATTCACTTC CGATGTGTCCTCCTACCTGGAGGGCCAGGCTGCCAAAGAGTTCATCG CTTGGCTCGTCAAGGGCAGGGGCGGAGGTGGGAGTTGCTCTTATACC TACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGT GACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGT CAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGC CTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTC AGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGT CCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGT ACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCC ACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTC ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAA BLV1H12-beta 286 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA

EPO HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGCCCCACCACGCCTCATCTGTGACAGCCGAGTCCTGGA GAGGTACCTCTTGGAGGCCAAGGAGGCCGAGAATATCACGACGGGC TGTGCTGAACACTGCAGCTTGAATGAGAATATCACTGTCCCAGACAC CAAAGTTAATTTCTATGCCTGGAAGAGGATGGAGGTCGGGCAGCAGG CCGTAGAAGTCTGGCAGGGCCTGGCCCTGCTGTCGGAAGCTGTCCTG CGGGGCCAGGCCCTGTTGGTCAACTCTTCCCAGCCGTGGGAGCCCCT GCAGCTGCATGTGGATAAAGCCGTCAGTGGCCTTCGCAGCCTCACCA CTCTGCTTCGGGCTCTGGGAGCCCAGAAGGAAGCCATCTCCCCTCCA GATGCGGCCTCAGCTGCTCCACTCCGAACAATCACTGCTGACACTTTC CGCAAACTCTTCCGAGTCTACTCCAATTTCCTCCGGGGAAAGCTGAA GCTGTACACAGGGGAGGCCTGCAGGACAGGGGACAGAGGCGGAGGT GGGAGTTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGG ACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAA AGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACC GTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGAC TGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCC CAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGA CAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCC CATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATC TTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCC TGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACC CTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACA ACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCT CCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCC GAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGC AGAAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12- 287 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA betaoxyntomodulin GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA HC AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCCACTCTCAGGGTACCTTCACCTCTGACTACTCTAAATA CCTGGACTCTCGTCGTGCTCAGGACTTCGTTCAGTGGCTGATGAACAC CAAACGTAACCGTAACAACATCGCTGGCGGAGGTGGGAGTTCTTATA CCTACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTG GTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCT GTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGAT GCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAAC TCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCA GTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCA GTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCT CCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAAC TCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGT CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCC GGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCG TGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGG TGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTC ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCT CCCTGTCTCCGGGTAAA BLV1H12-beta 288 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Mamba1 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCCTGAAATGTTACCAACATGGTAAAGTTGTGACTTGTCA TCGAGATATGAAGTTTTGCTATCATAACACTGGCATGCCTTTTCGAAA TCTCAAGCTCATCCTACAGGGATGTTCTTCTTCGTGCAGTGAAACAGA AAACAATAAGTGTTGCTCAACAGACAGATGCAACAAAGGCGGAGGT GGGAGTTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGG ACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAA AGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACC GTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGAC TGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCC CAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGA CAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCC CATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATC TTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCC TGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACC CTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACA ACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCT CCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCC GAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGC AGAAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12-beta 289 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA GMCSF HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGCACCCGCCCGCTCGCCCAGCCCCAGCACGCAGCCCTG GGAGCATGTGAATGCCATCCAGGAGGCCCGGCGTCTCCTGAACCTGA GTAGAGACACTGCTGCTGAGATGAATGAAACAGTAGAAGTCATCTCA GAAATGTTTGACCTCCAGGAGCCGACCTGCCTACAGACCCGCCTGGA GCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAGCTCAAGGGC CCCTTGACCATGATGGCCAGCCACTACAAGCAGCACTGCCCTCCAAC CCCGGAAACTTCCTGTGCAACCCAGATTATCACCTTTGAAAGTTTCAA AGAGAACCTGAAGGACTTTCTGCTTGTCATCCCCTTTGACTGCTGGGA GCCAGTCCAGGAGGGCGGAGGTGGGAGTTCTTATACCTACAATTATG AATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGTCTCT AGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCTGCTG TGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTCTCAA GCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGCCCTG AAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTGGCCT GTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCAGGGC AGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAAAGTG GACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACATGCCC ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT CCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGG TCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAG TTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTG CAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCT CCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC CCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCC TGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGC AATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAG AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA BLV1H12-beta 290 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA IL11 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCCCTGGGCCACCACCTGGCCCCCCTCGAGTTTCCCCAGA CCCTCGGGCCGAGCTGGACAGCACCGTGCTCCTGACCCGCTCTCTCCT GGCGGACACGCGGCAGCTGGCTGCACAGCTGAGGGACAAATTCCCA GCTGACGGGGACCACAACCTGGATTCCCTGCCCACCCTGGCCATGAG TGCGGGGGCACTGGGAGCTCTACAGCTCCCAGGTGTGCTGACAAGGC TGCGAGCGGACCTACTGTCCTACCTGCGGCACGTGCAGTGGCTGCGC CGGGCAGGTGGCTCTTCCCTGAAGACCCTGGAGCCCGAGCTGGGCAC CCTGCAGGCCCGACTGGACCGGCTGCTGCGCCGGCTGCAGCTCCTGA TGTCCCGCCTGGCCCTGCCCCAGCCACCCCCGGACCCGCCGGCGCCC CCGCTGGCGCCCCCCTCCTCAGCCTGGGGGGGCATCAGGGCCGCCCA CGCCATCCTGGGGGGGCTGCACCTGACACTTGACTGGGCCGTGAGGG GACTGCTGCTGCTGAAGACTCGGCTGGGCGGAGGTGGGAGTTCTTAT ACCTACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCT GGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCC TGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGA TGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAA CTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGC AGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGC AGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAG CTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAA ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC CCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG GTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCT CCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC TCCCTGTCTCCGGGTAAA BLV1H12-beta 291 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA IFN beta HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCATGAGCTACAACTTGCTTGGATTCCTACAAAGAAGCAG CAATTTTCAGTGTCAGAAGCTCCTGTGGCAATTGAATGGGAGGCTTG AATACTGCCTCAAGGACAGGATGAACTTTGACATCCCTGAGGAGATT AAGCAGCTGCAGCAGTTCCAGAAGGAGGACGCCGCATTGACCATCTA TGAGATGCTCCAGAACATCTTTGCTATTTTCAGACAAGATTCATCTAG CACTGGCTGGAATGAGACTATTGTTGAGAACCTCCTGGCTAATGTCT ATCATCAGATAAACCATCTGAAGACAGTCCTGGAAGAAAAACTGGA GAAAGAAGATTTCACCAGGGGAAAACTCATGAGCAGTCTGCACCTG AAAAGATATTATGGGAGGATTCTGCATTACCTGAAGGCCAAGGAGTA CAGTCACTGTGCCTGGACCATAGTCAGAGTGGAAATCCTAAGGAACT TTTACTTCATTAACAGACTTACAGGTTACCTCCGAAACGGCGGAGGT GGGAGTTCTTATACCTACAATTATGAATGGCATGTGGATGTCTGGGG ACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAA AGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACC GTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGAC TGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCC CAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGA CAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCC CATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATC TTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCC TGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACC CTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACA ACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCT CCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCC GAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGC AGAAGAGCCTCTCCCTGTCTCCGGGTAAA BLV1H12- 292 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA betaparathyroid GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA hormone HC AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCTCTGTGAGTGAAATACAGCTTATGCATAACCTGGGAAA ACATCTGAACTCGATGGAGAGAGTAGAATGGCTGCGTAAGAAGCTG CAGGATGTGCACAATTTTGTTGCCCTTGGAGCTCCTCTAGCTCCCAGA GATGCTGGTTCCCAGAGGCCCCGAAAAAAGGAAGACAATGTCTTGGT TGAGAGCCATGAAAAAAGTCTTGGAGAGGCAGACAAAGCTGATGTG AATGTATTAACTAAAGCTAAATCCCAGGGCGGAGGTGGGAGTTCTTA TACCTACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGC TGGTGACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCC CTGTCAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGG

ATGCCTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGA ACTCAGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTG CAGTCCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGG CAGTACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCA GCTCCACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCT CCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA TAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACA GGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCT CTCCCTGTCTCCGGGTAAA BLV1H12-beta 293 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Relaxin2 HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGACTCTTGGATGGAAGAAGTTATCAAACTGTGCGGTCG TGAACTGGTTCGTGCTCAGATCGCTATCTGCGGTATGTCTACCTGGTC TAAACGTTCTCTGTCTCAGGAAGACGCTCCGCAGACCCCGCGTCCGG TTGCTGAAATCGTTCCGTCTTTCATCAACAAAGACACCGAAACCATC AACATGATGTCTGAATTCGTTGCTAACCTGCCGCAGGAACTGAAACT GACCCTGTCTGAAATGCAGCCGGCTCTGCCGCAGCTGCAGCAGCACG TTCCGGTTCTGAAAGACTCTTCTCTGCTGTTCGAAGAATTCAAAAAAC TGATCCGTAACCGTCAGTCTGAAGCTGCTGACTCTTCTCCGTCTGAAC TGAAATACCTGGGTCTGGACACCCACTCTCGTAAAAAACGTCAGCTG TACTCTGCTCTGGCTAACAAATGCTGCCACGTTGGTTGCACCAAACGT TCTCTGGCTCGTTTCTGCGGCGGAGGTGGGAGTTCTTATACCTACAAT TATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGT CTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCT GCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTC TCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGC CCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTG GCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCA GGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAA AGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACA TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAG GTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGA CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTC TCCGGGTAAATGATAA BLV1H12-beta 294 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Relaxin2 GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA (GGSIEGR) AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG HC GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGACTCTTGGATGGAAGAAGTTATCAAACTGTGCGGTCG TGAACTGGTTCGTGCTCAGATCGCTATCTGCGGTATGTCTACCTGGTC TGGCGGAAGCATCGAGGGCCGCCAGCTGTACTCTGCTCTGGCTAACA AATGCTGCCACGTTGGTTGCACCAAACGTTCTCTGGCTCGTTTCTGCG GCGGAGGTGGGAGTTCTTATACCTACAATTATGAATGGCATGTGGAT GTCTGGGGACAGGGCCTGCTGGTGACAGTCTCTAGTGCTTCCACAAC TGCACCAAAGGTGTACCCCCTGTCAAGCTGCTGTGGGGACAAATCCT CTAGTACCGTGACACTGGGATGCCTGGTCTCAAGCTATATGCCCGAG CCTGTGACTGTCACCTGGAACTCAGGAGCCCTGAAAAGCGGAGTGCA CACCTTCCCAGCTGTGCTGCAGTCCTCTGGCCTGTATAGCCTGAGTTC AATGGTGACAGTCCCCGGCAGTACTTCAGGGCAGACCTTCACCTGTA ATGTGGCCCATCCTGCCAGCTCCACCAAAGTGGACAAAGCAGTGGAA CCCAAATCTTGCGACAAAACTCACACATGCCCACCGTGCCCAGCACC TGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTG GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCA CCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGG GCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGG AGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGATAA BLV1H12-beta 295 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Relaxin2 GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA (IEGRCpepIEGR) AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG HC GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCGACTCTTGGATGGAAGAAGTTATCAAACTGTGCGGTCG TGAACTGGTTCGTGCTCAGATCGCTATCTGCGGTATGTCTACCTGGTC TATCGAGGGCCGCTCTCTGTCTCAGGAAGACGCTCCGCAGACCCCGC GTCCGGTTGCTGAAATCGTTCCGTCTTTCATCAACAAAGACACCGAA ACCATCAACATGATGTCTGAATTCGTTGCTAACCTGCCGCAGGAACT GAAACTGACCCTGTCTGAAATGCAGCCGGCTCTGCCGCAGCTGCAGC AGCACGTTCCGGTTCTGAAAGACTCTTCTCTGCTGTTCGAAGAATTCA AAAAACTGATCCGTAACCGTCAGTCTGAAGCTGCTGACTCTTCTCCGT CTGAACTGAAATACCTGGGTCTGGACACCCACTCTATCGAGGGCCGC CAGCTGTACTCTGCTCTGGCTAACAAATGCTGCCACGTTGGTTGCACC AAACGTTCTCTGGCTCGTTTCTGCGGCGGAGGTGGGAGTTCTTATACC TACAATTATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGT GACAGTCTCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGT CAAGCTGCTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGC CTGGTCTCAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTC AGGAGCCCTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGT CCTCTGGCCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGT ACTTCAGGGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCC ACCAAAGTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTC ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC TGTCTCCGGGTAAATGATAA BLV1H12-beta 296 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA hGH HC GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCTTCCCAACCATTCCCTTATCCAGGCTTTTTGACAACGCT ATGCTCCGCGCCCATCGTCTGCACCAGCTGGCCTTTGACACCTACCAG GAGTTTGAAGAAGCCTATATCCCAAAGGAACAGAAGTATTCATTCCT GCAGAACCCCCAGACCTCCCTCTGTTTCTCAGAGTCTATTCCGACACC CTCCAACAGGGAGGAAACACAACAGAAATCCAACCTAGAGCTGCTC CGCATCTCCCTGCTGCTCATCCAGTCGTGGCTGGAGCCCGTGCAGTTC CTCAGGAGTGTCTTCGCCAACAGCCTGGTGTACGGCGCCTCTGACAG CAACGTCTATGACCTCCTAAAGGACCTAGAGGAAGGCATCCAAACGC TGATGGGGAGGCTGGAAGATGGCAGCCCCCGGACTGGGCAGATCTTC AAGCAGACCTACAGCAAGTTCGACACAAACTCACACAACGATGACG CACTACTCAAGAACTACGGGCTGCTCTACTGCTTCAGGAAGGACATG GACAAGGTCGAGACATTCCTGCGCATCGTGCAGTGCCGCTCTGTGGA GGGCAGCTGTGGCTTCGGCGGAGGTGGGAGTTCTTATACCTACAATT ATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGTC TCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCTG CTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTCT CAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGCC CTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTGG CCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCAG GGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAAA GTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAG ACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGA CAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAATGATAA BLV1H12 297 CAGGCCGTCCTGAACCAGCCAAGCAGCGTCTCCGGGTCTCTGGGGCA immunoglobulin GCGGGTCTCAATCACCTGTAGCGGGTCTTCCTCCAATGTCGGCAACG fusion protein GCTACGTGTCTTGGTATCAGCTGATCCCTGGCAGTGCCCCACGAACC LC CTGATCTACGGCGACACATCCAGAGCTTCTGGGGTCCCCGATCGGTT CTCAGGGAGCAGATCCGGAAACACAGCTACTCTGACCATCAGCTCCC TGCAGGCTGAGGACGAAGCAGATTATTTCTGCGCATCTGCCGAGGAC TCTAGTTCAAATGCCGTGTTTGGAAGCGGCACCACACTGACAGTCCT GGGGCAGCCCAAGAGTCCCCCTTCAGTGACTCTGTTCCCACCCTCTAC CGAGGAACTGAACGGAAACAAGGCCACACTGGTGTGTCTGATCAGC GACTTTTACCCTGGATCCGTCACTGTGGTCTGGAAGGCAGATGGCAG CACAATTACTAGGAACGTGGAAACTACCCGCGCCTCCAAGCAGTCTA ATAGTAAATACGCCGCCAGCTCCTATCTGAGCCTGACCTCTAGTGATT GGAAGTCCAAAGGGTCATATAGCTGCGAAGTGACCCATGAAGGCTC AACCGTGACTAAGACTGTGAAACCATCCGAGTGCTCC

TABLE-US-00020 TABLE 20 Immunoglobulin Fusion Protein Nucleotide and Amino Acid Sequences Name SEQ ID NO Sequence Trastuzumab- 298 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWV beta hGH ARIETKKYQSGGGGSFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAY (CDR2H) HC IPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLE PVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQ IFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVE GSCGFGGGGSSYTYNYETRYADSVKGRFTISADTSKNTAYLQMNSLRAE DTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPP VAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSS IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK BLV1H12-beta 299 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA Fab hGH GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA (CDR3H) AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCTTCCCAACCATTCCCTTATCCAGGCTTTTTGACAACGCT ATGCTCCGCGCCCATCGTCTGCACCAGCTGGCCTTTGACACCTACCAG GAGTTTGAAGAAGCCTATATCCCAAAGGAACAGAAGTATTCATTCCT GCAGAACCCCCAGACCTCCCTCTGTTTCTCAGAGTCTATTCCGACACC CTCCAACAGGGAGGAAACACAACAGAAATCCAACCTAGAGCTGCTC CGCATCTCCCTGCTGCTCATCCAGTCGTGGCTGGAGCCCGTGCAGTTC CTCAGGAGTGTCTTCGCCAACAGCCTGGTGTACGGCGCCTCTGACAG CAACGTCTATGACCTCCTAAAGGACCTAGAGGAAGGCATCCAAACGC TGATGGGGAGGCTGGAAGATGGCAGCCCCCGGACTGGGCAGATCTTC AAGCAGACCTACAGCAAGTTCGACACAAACTCACACAACGATGACG CACTACTCAAGAACTACGGGCTGCTCTACTGCTTCAGGAAGGACATG GACAAGGTCGAGACATTCCTGCGCATCGTGCAGTGCCGCTCTGTGGA GGGCAGCTGTGGCTTCGGCGGAGGTGGGAGTTCTTATACCTACAATT ATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGTC TCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCTG CTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTCT CAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGCC CTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTGG CCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCAG GGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAAA GTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACAC ATCACCATCATCATCACTAGTGA BLV1H12-beta 300 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEWL Fab hGH GSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCTSV (CDR3H) HQETKKYQSGGGGSFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAY IPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLE PVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQ IFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVE GSCGFGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCC GDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYS LSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTHHHHHH BLV1H12-beta 301 CAGGTCCAGCTGAGAGAGAGCGGCCCTTCACTGGTCAAGCCATCCCA hFc (IgG) hGH GACACTGAGCCTGACATGCACAGCAAGCGGGTTTTCACTGAGCGACA (CDR3H) AGGCAGTGGGATGGGTCCGACAGGCACCAGGAAAAGCCCTGGAATG GCTGGGCAGCATCGATACCGGCGGGAACACAGGGTACAATCCCGGA CTGAAGAGCAGACTGTCCATTACCAAGGACAACTCTAAAAGTCAGGT GTCACTGAGCGTGAGCTCCGTCACCACAGAGGATAGTGCAACTTACT ATTGCACCTCTGTGCACCAGGAAACTAAGAAATACCAGAGCGGGGGT GGCGGAAGCTTCCCAACCATTCCCTTATCCAGGCTTTTTGACAACGCT ATGCTCCGCGCCCATCGTCTGCACCAGCTGGCCTTTGACACCTACCAG GAGTTTGAAGAAGCCTATATCCCAAAGGAACAGAAGTATTCATTCCT GCAGAACCCCCAGACCTCCCTCTGTTTCTCAGAGTCTATTCCGACACC CTCCAACAGGGAGGAAACACAACAGAAATCCAACCTAGAGCTGCTC CGCATCTCCCTGCTGCTCATCCAGTCGTGGCTGGAGCCCGTGCAGTTC CTCAGGAGTGTCTTCGCCAACAGCCTGGTGTACGGCGCCTCTGACAG CAACGTCTATGACCTCCTAAAGGACCTAGAGGAAGGCATCCAAACGC TGATGGGGAGGCTGGAAGATGGCAGCCCCCGGACTGGGCAGATCTTC AAGCAGACCTACAGCAAGTTCGACACAAACTCACACAACGATGACG CACTACTCAAGAACTACGGGCTGCTCTACTGCTTCAGGAAGGACATG GACAAGGTCGAGACATTCCTGCGCATCGTGCAGTGCCGCTCTGTGGA GGGCAGCTGTGGCTTCGGCGGAGGTGGGAGTTCTTATACCTACAATT ATGAATGGCATGTGGATGTCTGGGGACAGGGCCTGCTGGTGACAGTC TCTAGTGCTTCCACAACTGCACCAAAGGTGTACCCCCTGTCAAGCTG CTGTGGGGACAAATCCTCTAGTACCGTGACACTGGGATGCCTGGTCT CAAGCTATATGCCCGAGCCTGTGACTGTCACCTGGAACTCAGGAGCC CTGAAAAGCGGAGTGCACACCTTCCCAGCTGTGCTGCAGTCCTCTGG CCTGTATAGCCTGAGTTCAATGGTGACAGTCCCCGGCAGTACTTCAG GGCAGACCTTCACCTGTAATGTGGCCCATCCTGCCAGCTCCACCAAA GTGGACAAAGCAGTGGAACCCAAATCTTGCGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAG ACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGA CAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAATGATAA BLV1H12-beta 302 QVQLRESGPSLVKPSQTLSLTCTASGFSLSDKAVGWVRQAPGKALEWL hFc (IgG) hGH GSIDTGGNTGYNPGLKSRLSITKDNSKSQVSLSVSSVTTEDSATYYCTSV (CDR3H) HQETKKYQSGGGGSFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAY IPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLE PVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQ IFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVE GSCGFGGGGSSYTYNYEWHVDVWGQGLLVTVSSASTTAPKVYPLSSCC GDKSSSTVTLGCLVSSYMPEPVTVTWNSGALKSGVHTFPAVLQSSGLYS LSSMVTVPGSTSGQTFTCNVAHPASSTKVDKAVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK Trastuzumab- 303 GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGG beta CDRH3 GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAATATTAAGGAC EPO ACTTACATCCACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTG GGTCGCACGTATTTATCCTACCAATGGTTACACACGCTACGCAGACT CCGTGAAGGGCCGATTCACCATCTCCGCAGACACTTCCAAGAACACG GCGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTA TTACTGTTCGAGAGAAACTAAGAAATACCAGAGCGGGGGTGGCGGA AGCGCCCCACCACGCCTCATCTGTGACAGCCGAGTCCTGGAGAGGTA CCTCTTGGAGGCCAAGGAGGCCGAGAATATCACGACGGGCTGTGCTG AACACTGCAGCTTGAATGAGAATATCACTGTCCCAGACACCAAAGTT AATTTCTATGCCTGGAAGAGGATGGAGGTCGGGCAGCAGGCCGTAG AAGTCTGGCAGGGCCTGGCCCTGCTGTCGGAAGCTGTCCTGCGGGGC CAGGCCCTGTTGGTCAACTCTTCCCAGCCGTGGGAGCCCCTGCAGCT GCATGTGGATAAAGCCGTCAGTGGCCTTCGCAGCCTCACCACTCTGC TTCGGGCTCTGGGAGCCCAGAAGGAAGCCATCTCCCCTCCAGATGCG GCCTCAGCTGCTCCACTCCGAACAATCACTGCTGACACTTTCCGCAA ACTCTTCCGAGTCTACTCCAATTTCCTCCGGGGAAAGCTGAAGCTGTA CACAGGGGAGGCCTGCAGGACAGGGGACAGAGGCGGAGGTGGGAGT TCTTATACCTACAATTATGAAGACTACTGGGGCCAAGGAACCCTGGT CACCGTCTCCTCAGCCAGCACTAAAGGTCCATCTGTGTTCCCTCTGGC TCCTTGCAGCCGGAGCACCTCCGAGTCCACAGCCGCTCTGGGATGTC TGGTGAAAGATTACTTCCCCGAGCCCGTCACCGTGAGCTGGAATAGC GGAGCACTGACCTCCGGCGTCCACACATTCCCCGCCGTGCTCCAAAG CTCCGGCCTGTACAGCCTCTCCTCCGTGGTCACCGTGCCCAGCAGCTC TCTGGGCACAAAGACCTATACCTGTAACGTGGATCACAAGCCTAGCA ACACCAAAGTGGATAAGCGGGTGGAGAGCAAGTACGGCCCTCCCTG TCCCCCTTGCCCCGCTCCTGAGGCCGCTGGCGGACCTTCCGTGTTCCT GTTTCCCCCTAAGCCCAAGGACACCCTCATGATTAGCCGGACACCCG AAGTGACCTGCGTGGTCGTGGATGTGTCCCAGGAGGACCCTGAAGTG CAATTTAACTGGTACGTGGACGGCGTCGAGGTGCACAACGCCAAGAC CAAGCCTCGGGAAGAGCAGTTCAACAGCACCTACCGGGTGGTCAGC GTGCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACA AGTGCAAGGTGAGCAACAAGGGCCTGCCCAGCTCCATCGAGAAGAC CATCAGCAAGGCCAAGGGCCAGCCCAGGGAACCCCAGGTGTATACC CTGCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTGAGCCTGA CCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAACGGCCAGCCCGAGAACAATTACAAGACCACCCCTCCTGT GCTGGACAGCGACGGCTCCTTCTTTCTGTATAGCCGGCTGACCGTGG ACAAGAGCAGGTGGCAGGAGGGCAACGTGTTCTCCTGTAGCGTGATG CACGAGGCCCTGCACAACCATTACACCCAGAAGAGCTTGAGCCTGAG CCTGGGCAAA Trastuzumab- 304 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWV beta CDRH3 ARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCS EPO RETKKYQSGGGGSAPPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNE NITVPDTKVNFYAWKRMEVGQQAVEVWQGLALLSEAVLRGQALLVNS SQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAISPPDAASAAPLRTIT ADTFRKLFRVYSNFLRGKLKLYTGEACRTGDRGGGGSSYTYNYEDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Sequence CWU 1

1

3231642DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 1caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcgcccg cgaaagagat 300tatcgtctgg attattgggg tcagggtagt ctggtcacag tgtcctcagc ctccaccaag 360ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540ctcagcagcg tggtgactgt gccctctagc agcttgggca cccagaccta catctgcaac 600gtgaatcaca agcccagcaa caccaaggtg gacaagaaag tt 6422642DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 2gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca ggatgtgaat accgcggtcg catggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctattct gcatccttct tgtatagtgg ggtcccatca 180aggttcagtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag cattacacta cccctccgac gttcggccaa 300ggtaccaagc ttgagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgtcgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgtcctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642381DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 3gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca g 814552DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 4accgcggtcg catggtatca gcagaaacca gggaaagccc ctaagctcct gatctattct 60gcatccttct tgtatagtgg ggtcccatca aggttcagtg gcagtagatc tgggacagat 120ttcactctca ccatcagcag tctgcaacct gaagattttg caacttacta ctgtcaacag 180cattacacta cccctccgac gttcggccaa ggtaccaagc ttgagatcaa acgaactgtg 240gctgcaccat ctgtcttcat cttcccgcca tctgatgagc agttgaaatc tggaactgcc 300tctgtcgtgt gcctgctgaa taacttctat cccagagagg ccaaagtaca gtggaaggtg 360gataacgccc tccaatcggg taactcccag gagagtgtca cagagcagga cagcaaggac 420agcacctaca gcctcagcag caccctgacg ctgagcaaag cagactacga gaaacacaaa 480gtctacgcct gcgaagtcac ccatcagggc ctgtcctcgc ccgtcacaaa gagcttcaac 540aggggagagt gt 55251353DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 5gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60agctgcgcgg cgagcggctt taacattaaa gatacctata ttcattgggt gcgccaggcg 120ccgggcaaag gcctggaatg ggtggcgcgc atttatccga ccaacggcta tacccgctat 180gcggatagcg tgaaaggccg ctttaccatt agcgcggata ccagcaaaaa caccgcgtat 240ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcag ccgctggggc 300ggcgatggct tttatgcgat ggattattgg ggccagggca ccctggtgac cgtgagcagc 360gcgagcacca aaggcccgag cgtgtttccg ctggcgccga gcagcaaaag caccagcggc 420ggcaccgcgg cgctgggctg cctggtgaaa gattattttc cggaaccggt gaccgtgagc 480tggaacagcg gcgcgctgac cagcggcgtg catacctttc cggcggtgct gcagagcagc 540ggcctgtata gcctgagcag cgtggtgacc gtgccgagca gcagcctggg cacccagacc 600tatatttgca acgtgaacca taaaccgagc aacaccaaag tggataaaaa agtggaaccg 660ccgaaaagct gcgataaaac ccatacctgc ccgccgtgcc cggcgccgga actgctgggc 720ggcccgagcg tgtttctgtt tccgccgaaa ccgaaagata ccctgatgat tagccgcacc 780ccggaagtga cctgcgtggt ggtggatgtg agccatgaag atccggaagt gaaatttaac 840tggtatgtgg atggcgtgga agtgcataac gcgaaaacca aaccgcgcga agaacagtat 900aacagcacct atcgcgtggt gagcgtgctg accgtgctgc atcaggattg gctgaacggc 960aaagaatata aatgcaaagt gagcaacaaa gcgctgccgg cgccgattga aaaaaccatt 1020agcaaagcga aaggccagcc gcgcgaaccg caggtgtata ccctgccgcc gagccgcgat 1080gaactgacca aaaaccaggt gagcctgacc tgcctggtga aaggctttta tccgagcgat 1140attgcggtgg aatgggaaag caacggccag ccggaaaaca actataaaac caccccgccg 1200gtgctggata gcgatggcag cttttttctg tatagcaaac tgaccgtgga taaaagccgc 1260tggcagcagg gcaacgtgtt tagctgcagc gtgatgcatg aagcgctgca taaccattat 1320acccagaaaa gcctgagcct gagcccgggc aaa 135361350DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 6gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320cagaagagcc tctccctgtc tccgggtaaa 135071347DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 7gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 720tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 780gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320aagagcctct ccctgtctcc gggtaaa 134781341DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 8gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatggggc 300ggtgacggct tctatgccat ggactactgg ggccaaggaa ccctggtcac cgtctcctca 360gccagcacta aaggtccatc tgtgttccct ctggctcctt gcagccggag cacctccgag 420tccacagccg ctctgggatg tctggtgaaa gattacttcc ccgagcccgt caccgtgagc 480tggaatagcg gagcactgac ctccggcgtc cacacattcc ccgccgtgct ccaaagctcc 540ggcctgtaca gcctctcctc cgtggtcacc gtgcccagca gctctctggg cacaaagacc 600tatacctgta acgtggatca caagcctagc aacaccaaag tggataagcg ggtggagagc 660aagtacggcc ctccctgtcc cccttgcccc gctcctgagg ccgctggcgg accttccgtg 720ttcctgtttc cccctaagcc caaggacacc ctcatgatta gccggacacc cgaagtgacc 780tgcgtggtcg tggatgtgtc ccaggaggac cctgaagtgc aatttaactg gtacgtggac 840ggcgtcgagg tgcacaacgc caagaccaag cctcgggaag agcagttcaa cagcacctac 900cgggtggtca gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 960tgcaaggtga gcaacaaggg cctgcccagc tccatcgaga agaccatcag caaggccaag 1020ggccagccca gggaacccca ggtgtatacc ctgcccccta gccaggagga aatgaccaaa 1080aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140tgggagagca acggccagcc cgagaacaat tacaagacca cccctcctgt gctggacagc 1200gacggctcct tctttctgta tagccggctg accgtggaca agagcaggtg gcaggagggc 1260aacgtgttct cctgtagcgt gatgcacgag gccctgcaca accattacac ccagaagagc 1320ttgagcctga gcctgggcaa a 13419294DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 9gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60agctgcgcgg cgagcggctt taacattaaa gatacctata ttcattgggt gcgccaggcg 120ccgggcaaag gcctggaatg ggtggcgcgc atttatccga ccaacggcta tacccgctat 180gcggatagcg tgaaaggccg ctttaccatt agcgcggata ccagcaaaaa caccgcgtat 240ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcag ccgc 294101032DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 10gattattggg gccagggcac cctggtgacc gtgagcagcg cgagcaccaa aggcccgagc 60gtgtttccgc tggcgccgag cagcaaaagc accagcggcg gcaccgcggc gctgggctgc 120ctggtgaaag attattttcc ggaaccggtg accgtgagct ggaacagcgg cgcgctgacc 180agcggcgtgc atacctttcc ggcggtgctg cagagcagcg gcctgtatag cctgagcagc 240gtggtgaccg tgccgagcag cagcctgggc acccagacct atatttgcaa cgtgaaccat 300aaaccgagca acaccaaagt ggataaaaaa gtggaaccgc cgaaaagctg cgataaaacc 360catacctgcc cgccgtgccc ggcgccggaa ctgctgggcg gcccgagcgt gtttctgttt 420ccgccgaaac cgaaagatac cctgatgatt agccgcaccc cggaagtgac ctgcgtggtg 480gtggatgtga gccatgaaga tccggaagtg aaatttaact ggtatgtgga tggcgtggaa 540gtgcataacg cgaaaaccaa accgcgcgaa gaacagtata acagcaccta tcgcgtggtg 600agcgtgctga ccgtgctgca tcaggattgg ctgaacggca aagaatataa atgcaaagtg 660agcaacaaag cgctgccggc gccgattgaa aaaaccatta gcaaagcgaa aggccagccg 720cgcgaaccgc aggtgtatac cctgccgccg agccgcgatg aactgaccaa aaaccaggtg 780agcctgacct gcctggtgaa aggcttttat ccgagcgata ttgcggtgga atgggaaagc 840aacggccagc cggaaaacaa ctataaaacc accccgccgg tgctggatag cgatggcagc 900ttttttctgt atagcaaact gaccgtggat aaaagccgct ggcagcaggg caacgtgttt 960agctgcagcg tgatgcatga agcgctgcat aaccattata cccagaaaag cctgagcctg 1020agcccgggca aa 1032111350DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 11caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320cagaagagcc tctccctgtc tccgggtaaa 1350121347DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 12caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 600tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 660aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 720tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 780gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1020gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1080accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320aagagcctct ccctgtctcc gggtaaa 1347131341DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 13caggtgaccc tgcgcgagtc cggccccgcc ctggtgaagc ccacccagac cctgaccctg 60acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgc 120cagccccccg gcaaggccct ggagtggctg gccgacatct ggtgggacga caagaaggac 180tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctcc 300atgatcacca actggtactt cgacgtgtgg ggcgccggca ccaccgtgac cgtgtcctcc 360gccagcacta aaggtccatc tgtgttccct ctggctcctt gcagccggag cacctccgag 420tccacagccg ctctgggatg tctggtgaaa gattacttcc ccgagcccgt caccgtgagc 480tggaatagcg gagcactgac ctccggcgtc cacacattcc ccgccgtgct ccaaagctcc 540ggcctgtaca gcctctcctc cgtggtcacc gtgcccagca gctctctggg cacaaagacc 600tatacctgta acgtggatca caagcctagc aacaccaaag tggataagcg ggtggagagc 660aagtacggcc ctccctgtcc cccttgcccc gctcctgagg ccgctggcgg accttccgtg 720ttcctgtttc cccctaagcc caaggacacc ctcatgatta gccggacacc cgaagtgacc 780tgcgtggtcg tggatgtgtc ccaggaggac cctgaagtgc aatttaactg gtacgtggac 840ggcgtcgagg tgcacaacgc caagaccaag cctcgggaag agcagttcaa cagcacctac 900cgggtggtca gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 960tgcaaggtga gcaacaaggg cctgcccagc tccatcgaga agaccatcag caaggccaag 1020ggccagccca gggaacccca ggtgtatacc ctgcccccta gccaggagga aatgaccaaa 1080aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140tgggagagca acggccagcc cgagaacaat tacaagacca cccctcctgt gctggacagc 1200gacggctcct tctttctgta tagccggctg accgtggaca agagcaggtg gcaggagggc 1260aacgtgttct cctgtagcgt gatgcacgag gccctgcaca accattacac ccagaagagc 1320ttgagcctga gcctgggcaa a 134114642DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 14gacattcaga tgacacagag ccccagcagc ctcagtgcct cagtcggtga cagagtgacc 60attacttgcc gtgccagcgg aaacattcac aactacctgg cctggtatca gcagaagccc 120ggcaaagctc ctaagctgct catctactat accactacac tcgcagacgg cgtgccatct 180cgcttctctg gctcaggatc cggtacagac tacaccttta ctatctccag cctgcagccc 240gaggatattg ctacctacta ttgccagcat ttttggtcaa ccccccgcac attcggtcag 300ggcactaagg tggagattaa gagaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgtcgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgtcctcgc ccgtcacaaa gagcttcaac aggggagagt gt 64215639DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 15gacatccaga tgacccagtc cccctccacc

ctgtccgcct ccgtgggcga ccgcgtgacc 60atcacctgca agtgccagct gtccgtgggc tacatgcact ggtaccagca gaagcccggc 120aaggccccca agctgctgat ctacgacacc tccaagctgg cctccggcgt gccctcccgc 180ttctccggct ccggctccgg caccgagttc accctgacca tctcctccct gcagcccgac 240gacttcgcca cctactactg cttccagggc tccggctacc ccttcacctt cggcggcggc 300accaagctgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gtcgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600tcctcgcccg tcacaaagag cttcaacagg ggagagtgt 63916297DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 16caggtgaccc tgcgcgagtc cggccctgca ctggtgaagc ccacccagac cctgaccctg 60acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgg 120cagcctcccg gcaaggccct ggagtggctg gctgacatct ggtgggacga caagaaggac 180tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgc 297171048DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 17gacgtgtggg gagccggtac caccgtgacc gtgtcttccg cctccaccaa gggcccatcg 60gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 120ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 180agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 240gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 300aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 360acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 420aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 480gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 540aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 600ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 660aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 720ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 780acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 840cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 900ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 960tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1020ggtaaatgat aagtgctagc tggccaga 104818300DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 18caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300191035DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 19tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 60gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 120ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 180gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 240ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg 300gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 360actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 420ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 480gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 540gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 600gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 660gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 720ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 780gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 840agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 900tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 960ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1020ctgtctccgg gtaaa 103520648DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 20caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300tttggaagcg gcaccacact gacagtcctg gggcagccca agagtccccc ttcagtgact 360ctgttcccac cctctaccga ggaactgaac ggaaacaagg ccacactggt gtgtctgatc 420agcgactttt accctggatc cgtcactgtg gtctggaagg cagatggcag cacaattact 480aggaacgtgg aaactacccg cgcctccaag cagtctaata gtaaatacgc cgccagctcc 540tatctgagcc tgacctctag tgattggaag tccaaagggt catatagctg cgaagtgacc 600catgaaggct caaccgtgac taagactgtg aaaccatccg agtgctcc 64821214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 21Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 2227PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 22Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 20 25 23184PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 23Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 1 5 10 15 Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 20 25 30 Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 35 40 45 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr 50 55 60 Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 65 70 75 80 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 85 90 95 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 100 105 110 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 115 120 125 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 130 135 140 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 145 150 155 160 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 165 170 175 Lys Ser Phe Asn Arg Gly Glu Cys 180 24451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 24Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 25450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 25Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 26449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 26Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210

215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys 27447PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 27Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 28214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 28Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 2998PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 29Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg 30344PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 30Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 1 5 10 15 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 20 25 30 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 35 40 45 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 50 55 60 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 65 70 75 80 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 85 90 95 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 100 105 110 Pro Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 115 120 125 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 130 135 140 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 145 150 155 160 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 165 170 175 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 180 185 190 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 195 200 205 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 210 215 220 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 225 230 235 240 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 245 250 255 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 260 265 270 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 275 280 285 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 290 295 300 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 305 310 315 320 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 325 330 335 Ser Leu Ser Leu Ser Pro Gly Lys 340 31450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 31Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 32449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 32Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys 33447PRTArtificial

SequenceDescription of Artificial Sequence Synthetic polypeptide 33Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 34213PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 34Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Cys Gln Leu Ser Val Gly Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 35213PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 35Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Cys Gln Leu Ser Val Gly Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 3699PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 36Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg 37342PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 37Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 1 5 10 15 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 20 25 30 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 35 40 45 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 50 55 60 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 65 70 75 80 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 85 90 95 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 100 105 110 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 115 120 125 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 130 135 140 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 145 150 155 160 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 165 170 175 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 180 185 190 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 195 200 205 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 210 215 220 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 225 230 235 240 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 245 250 255 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 260 265 270 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 275 280 285 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 290 295 300 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 305 310 315 320 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 325 330 335 Ser Leu Ser Pro Gly Lys 340 38100PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 38Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln 100 39345PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 39Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 1 5 10 15 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 20 25 30 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr 35 40 45 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 50 55 60 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 65 70 75 80 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 85 90 95 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 100 105 110 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 40216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 40Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 411203DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 41gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca ggaaactaag aaataccaga gcgggggtgg cggaagcgcc 120ccaccacgcc tcatctgtga cagccgagtc ctggagaggt acctcttgga ggccaaggag 180gccgagaata tcacgacggg ctgtgctgaa cactgcagct tgaatgagaa tatcactgtc 240ccagacacca aagttaattt ctatgcctgg aagaggatgg aggtcgggca gcaggccgta 300gaagtctggc agggcctggc cctgctgtcg gaagctgtcc tgcggggcca ggccctgttg 360gtcaactctt cccagccgtg ggagcccctg cagctgcatg tggataaagc cgtcagtggc 420cttcgcagcc tcaccactct gcttcgggct ctgggagccc agaaggaagc catctcccct 480ccagatgcgg cctcagctgc tccactccga acaatcactg ctgacacttt ccgcaaactc 540ttccgagtct actccaattt cctccgggga aagctgaagc tgtacacagg ggaggcctgc 600aggacagggg acagaggcgg aggtgggagt tcttatacct acaattatga aaccgcggtc 660gcatggtatc agcagaaacc agggaaagcc cctaagctcc tgatctattc tgcatccttc 720ttgtatagtg gggtcccatc aaggttcagt ggcagtagat ctgggacaga tttcactctc 780accatcagca gtctgcaacc tgaagatttt gcaacttact actgtcaaca gcattacact 840acccctccga cgttcggcca aggtaccaag cttgagatca aacgaactgt ggctgcacca 900tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgtcgtg 960tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 1020ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 1080agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 1140tgcgaagtca cccatcaggg cctgtcctcg cccgtcacaa agagcttcaa caggggagag 1200tgt 1203421917DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 42gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg

ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggtgg cggaggatct accccccttg gccctgcccg atccctgccc 360cagagcttcc tgctcaagtg cttagagcaa gtgaggaaaa tccaggctga tggcgccgag 420ctgcaggaga ggctgtgtgc cgcccacaag ctgtgccacc cggaggagct gatgctgctc 480aggcactctc tgggcatccc ccaggctccc ctaagcagct gctccagcca gtccctgcag 540ctgacgagct gcctgaacca actacacggc ggcctctttc tctaccaggg cctcctgcag 600gccctggcgg gcatctcccc agagctggcc cccaccttgg acacactgca gctggacgtc 660actgactttg ccacgaacat ctggctgcag atggaggacc tgggggcggc ccccgctgtg 720cagcccaccc agggcgccat gccgaccttc acttcagcct tccaacgcag agcaggaggg 780gtcctggttg cttcccagct gcatcgtttc ctggagctgg cataccgtgg cctgcgctac 840cttgctgagc ccggtggcgg aggatcttct tatacctaca attatgaaga ctactggggc 900caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 960gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 1020tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 1080accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 1140ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 1200accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac atgcccaccg 1260tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1320gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1380gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1440acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1500ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1560ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1620tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1680gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1740aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1800aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1860catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1917431527DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 43gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagctgcgg gggtggcgga agcatcgaag gtcgtcacgg agaaggaaca 360tttaccagcg acctcagcaa gcagatggag gaagaggccg tgaggctgtt catcgagtgg 420ctgaagaacg gcggaccctc ctctggcgct ccacccccta gcggcggagg tgggagttgc 480tcttatacct acaattatga agactactgg ggccaaggaa ccctggtcac cgtctcctca 540gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 600ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 660tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 720ggactctact ccctcagcag cgtggtgact gtgccctcta gcagcttggg cacccagacc 780tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgaaccc 840aaatcttgcg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 900tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 960gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 1020gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 1080acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1140tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1200gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1260accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1320gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1380gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1440caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1500aagagcctct ccctgtctcc gggtaaa 1527441498DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 44gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggtgg cggaggatct atcaacgtga agtgcagcct gccccagcag 360tgcatcaagc cctgcaagga cgccggcatg cggttcggca agtgcatgaa caagaagtgc 420aggtgctaca gcggtggcgg aggatcttct tatacctaca attatgaaga ctactggggc 480caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 540gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 600tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 660accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 720ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 780accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac catgcccacc 840gtgcccagca cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa 900ggacaccctc atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca 960cgaagaccct gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa 1020gacaaagccg cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt 1080cctgcaccag gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct 1140cccagccccc atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt 1200gtacaccctg cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct 1260ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga 1320gaacaactac aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag 1380caagctcacc gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat 1440gcatgaggct ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1498451504DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 45gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggtgg cggaggatct gccgctgcaa tctcctgcgt cggcagcccc 360gaatgtcctc ccaagtgccg ggctcaggga tgcaagaacg gcaagtgtat gaaccggaag 420tgcaagtgct actattgcgg tggcggagga tcttcttata cctacaatta tgaagactac 480tggggccaag gaaccctggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 540cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 600aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 660gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 720actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 780agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacaccatg 840cccaccgtgc ccagcacctg aactcctggg gggaccgtca gtcttcctct tccccccaaa 900acccaaggac accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt 960gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa 1020tgccaagaca aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct 1080caccgtcctg caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa 1140agccctccca gcccccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc 1200acaggtgtac accctgcccc catcccggga tgagctgacc aagaaccagg tcagcctgac 1260ctgcctggtc aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca 1320gccggagaac aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct 1380ctacagcaag ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc 1440cgtgatgcat gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg 1500taaa 1504461890DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 46gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcgccac acctctgggc cccgcctcct ccctgcctca gagctttctg 360ctcaaatgtc tggagcaggt gcggaagatc cagggcgacg gcgccgctct gcaagagaaa 420ctggtcagcg aatgcgccac atataagctg tgtcaccccg aggaactggt cctcttgggc 480cacagcctgg gcatcccctg ggcccctctc agctcctgcc cctcccaagc tctccaactg 540gctggatgtc tgtcccaact gcactccggc ctcttcctgt accagggact cctccaggct 600ctcgaaggga tcagccccga actgggcccc acactggaca ccttgcaact cgatgtggcc 660gatttcgcca caaccatctg gcagcagatg gaagaactcg gaatggctcc tgctctccag 720cccacacagg gagctatgcc tgctttcgcc tctgctttcc agcggagagc tggtggtgtg 780ctcgtcgcat cccacctcca gagcttcttg gaggtgtcct atcgggtgct ccggcatctg 840gcccaaccct cttataccta caattatgaa gactactggg gccaaggaac cctggtcacc 900gtctcctcag ccagcactaa aggtccatct gtgttccctc tggctccttg cagccggagc 960acctccgagt ccacagccgc tctgggatgt ctggtgaaag attacttccc cgagcccgtc 1020accgtgagct ggaatagcgg agcactgacc tccggcgtcc acacattccc cgccgtgctc 1080caaagctccg gcctgtacag cctctcctcc gtggtcaccg tgcccagcag ctctctgggc 1140acaaagacct atacctgtaa cgtggatcac aagcctagca acaccaaagt ggataagcgg 1200gtggagagca agtacggccc tccctgtccc ccttgccccg ctcctgaggc cgctggcgga 1260ccttccgtgt tcctgtttcc ccctaagccc aaggacaccc tcatgattag ccggacaccc 1320gaagtgacct gcgtggtcgt ggatgtgtcc caggaggacc ctgaagtgca atttaactgg 1380tacgtggacg gcgtcgaggt gcacaacgcc aagaccaagc ctcgggaaga gcagttcaac 1440agcacctacc gggtggtcag cgtgctgaca gtgctgcacc aggactggct gaacggcaag 1500gagtacaagt gcaaggtgag caacaagggc ctgcccagct ccatcgagaa gaccatcagc 1560aaggccaagg gccagcccag ggaaccccag gtgtataccc tgccccctag ccaggaggaa 1620atgaccaaaa accaggtgag cctgacctgc ctggtgaagg gcttctaccc cagcgacatc 1680gccgtggagt gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcctgtg 1740ctggacagcg acggctcctt ctttctgtat agccggctga ccgtggacaa gagcaggtgg 1800caggagggca acgtgttctc ctgtagcgtg atgcacgagg ccctgcacaa ccattacacc 1860cagaagagct tgagcctgag cctgggcaaa 1890471959DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 47gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc ttcccaacca ttcccttatc caggcttttt 360gacaacgcta tgctccgcgc ccatcgtctg caccagctgg cctttgacac ctaccaggag 420tttgaagaag cctatatccc aaaggaacag aagtattcat tcctgcagaa cccccagacc 480tccctctgtt tctcagagtc tattccgaca ccctccaaca gggaggaaac acaacagaaa 540tccaacctag agctgctccg catctccctg ctgctcatcc agtcgtggct ggagcccgtg 600cagttcctca ggagtgtctt cgccaacagc ctggtgtacg gcgcctctga cagcaacgtc 660tatgacctcc taaaggacct agaggaaggc atccaaacgc tgatggggag gctggaagat 720ggcagccccc ggactgggca gatcttcaag cagacctaca gcaagttcga cacaaactca 780cacaacgatg acgcactact caagaactac gggctgctct actgcttcag gaaggacatg 840gacaaggtcg agacattcct gcgcatcgtg cagtgccgct ctgtggaggg cagctgtggc 900ttcggcggag gtgggagttc ttatacctac aattatgaag actactgggg ccaaggaacc 960ctggtcaccg tctcctcagc cagcactaaa ggtccatctg tgttccctct ggctccttgc 1020agccggagca cctccgagtc cacagccgct ctgggatgtc tggtgaaaga ttacttcccc 1080gagcccgtca ccgtgagctg gaatagcgga gcactgacct ccggcgtcca cacattcccc 1140gccgtgctcc aaagctccgg cctgtacagc ctctcctccg tggtcaccgt gcccagcagc 1200tctctgggca caaagaccta tacctgtaac gtggatcaca agcctagcaa caccaaagtg 1260gataagcggg tggagagcaa gtacggccct ccctgtcccc cttgccccgc tcctgaggcc 1320gctggcggac cttccgtgtt cctgtttccc cctaagccca aggacaccct catgattagc 1380cggacacccg aagtgacctg cgtggtcgtg gatgtgtccc aggaggaccc tgaagtgcaa 1440tttaactggt acgtggacgg cgtcgaggtg cacaacgcca agaccaagcc tcgggaagag 1500cagttcaaca gcacctaccg ggtggtcagc gtgctgacag tgctgcacca ggactggctg 1560aacggcaagg agtacaagtg caaggtgagc aacaagggcc tgcccagctc catcgagaag 1620accatcagca aggccaaggg ccagcccagg gaaccccagg tgtataccct gccccctagc 1680caggaggaaa tgaccaaaaa ccaggtgagc ctgacctgcc tggtgaaggg cttctacccc 1740agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaatta caagaccacc 1800cctcctgtgc tggacagcga cggctccttc tttctgtata gccggctgac cgtggacaag 1860agcaggtggc aggagggcaa cgtgttctcc tgtagcgtga tgcacgaggc cctgcacaac 1920cattacaccc agaagagctt gagcctgagc ctgggcaaa 1959481980DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 48gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt attgaaacta agaaatacca gagcgggggt 180ggcggaagct tcccaaccat tcccttatcc aggctttttg acaacgctat gctccgcgcc 240catcgtctgc accagctggc ctttgacacc taccaggagt ttgaagaagc ctatatccca 300aaggaacaga agtattcatt cctgcagaac ccccagacct ccctctgttt ctcagagtct 360attccgacac cctccaacag ggaggaaaca caacagaaat ccaacctaga gctgctccgc 420atctccctgc tgctcatcca gtcgtggctg gagcccgtgc agttcctcag gagtgtcttc 480gccaacagcc tggtgtacgg cgcctctgac agcaacgtct atgacctcct aaaggaccta 540gaggaaggca tccaaacgct gatggggagg ctggaagatg gcagcccccg gactgggcag 600atcttcaagc agacctacag caagttcgac acaaactcac acaacgatga cgcactactc 660aagaactacg ggctgctcta ctgcttcagg aaggacatgg acaaggtcga gacattcctg 720cgcatcgtgc agtgccgctc tgtggagggc agctgtggct tcggcggagg tgggagttct 780tatacctaca attatgaaac acgctacgca gactccgtga agggccgatt caccatctcc 840gcagacactt ccaagaacac ggcgtatctt caaatgaaca gcctgagagc cgaggacacg 900gccgtgtatt actgttcgag atggggcggt gacggcttct atgccatgga ctactggggc 960caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 1020gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 1080tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 1140accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 1200ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 1260accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac atgcccaccg 1320tgcccagcac ctccagtcgc cggaccgtca gtcttcctct tccctccaaa acccaaggac 1380accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1440gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1500aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1560caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa aggcctccca 1620agctccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1680accctgcctc catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1740aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1800aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1860ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1920gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaatgataa 1980491824DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 49gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggtgg cggaggatct gttccaattc aaaaggttca agatgatacc 360aaaactctga ttaaaactat tgtcacgcgt ataaacgaca tcagccatac ccagtcggtt 420agctcaaagc aaaaagttac cggtttggac tttattccgg gactgcaccc gatcctgacc 480cttagtaaaa tggaccagac actggccgtc taccagcaaa tcctgacatc gatgccatcc 540agaaatgtga tacaaattag caacgatttg gaaaaccttc gcgatctgct gcacgtgctg 600gccttcagta agtcctgtca tctgccgtgg gcgtcgggac tggagactct tgactcgctg 660ggtggagtgt tagaggcctc tggctattct actgaagtcg ttgcgctgtc acgcctccag 720gggagcctgc aggacatgct gtggcagctg gacctgtcac ctggctgcgg aggtggtggt 780tcatcttata cctacaatta tgaagactac tggggccaag gaaccctggt caccgtctcc 840tcagccagca ctaaaggtcc atctgtgttc cctctggctc cttgcagccg gagcacctcc 900gagtccacag ccgctctggg atgtctggtg aaagattact tccccgagcc cgtcaccgtg 960agctggaata gcggagcact gacctccggc gtccacacat tccccgccgt gctccaaagc 1020tccggcctgt acagcctctc ctccgtggtc accgtgccca gcagctctct gggcacaaag 1080acctatacct gtaacgtgga tcacaagcct agcaacacca aagtggataa gcgggtggag 1140agcaagtacg gccctccctg tcccccttgc cccgctcctg aggccgctgg cggaccttcc 1200gtgttcctgt ttccccctaa gcccaaggac accctcatga ttagccggac acccgaagtg 1260acctgcgtgg tcgtggatgt gtcccaggag gaccctgaag tgcaatttaa ctggtacgtg 1320gacggcgtcg aggtgcacaa cgccaagacc aagcctcggg aagagcagtt caacagcacc 1380taccgggtgg tcagcgtgct gacagtgctg caccaggact ggctgaacgg caaggagtac 1440aagtgcaagg tgagcaacaa gggcctgccc agctccatcg agaagaccat cagcaaggcc 1500aagggccagc ccagggaacc ccaggtgtat accctgcccc ctagccagga ggaaatgacc 1560aaaaaccagg tgagcctgac ctgcctggtg aagggcttct accccagcga catcgccgtg 1620gagtgggaga gcaacggcca gcccgagaac aattacaaga ccacccctcc tgtgctggac 1680agcgacggct ccttctttct gtatagccgg ctgaccgtgg acaagagcag gtggcaggag 1740ggcaacgtgt tctcctgtag cgtgatgcac gaggccctgc acaaccatta cacccagaag 1800agcttgagcc tgagcctggg caaa 1824501881DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 50gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc

tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc tgtgatctgc ctcaaaccca cagcctgggt 360agcaggagga ccttgatgct cctggcacag atgaggagaa tctctctttt ctcctgcttg 420aaggacagac atgactttgg atttccccag gaggagtttg gcaaccagtt ccaaaaggct 480gaaaccatcc ctgtcctcca tgagatgatc cagcagatct tcaatctctt cagcacaaag 540gactcatctg ctgcttggga tgagaccctc ctagacaaat tctacactga actctaccag 600cagctgaatg acctggaagc ctgtgtgata cagggggtgg gggtgacaga gactcccctg 660atgaaggagg actccattct ggctgtgagg aaatacttcc aaagaatcac tctctatctg 720aaagagaaga aatacagccc ttgtgcctgg gaggttgtca gagcagaaat catgagatct 780ttttctttgt caacaaactt gcaagaaagt ttaagaagta aggaaggcgg aggtgggagt 840tcttatacct acaattatga agactactgg ggccaaggaa ccctggtcac cgtctcctca 900gccagcacta aaggtccatc tgtgttccct ctggctcctt gcagccggag cacctccgag 960tccacagccg ctctgggatg tctggtgaaa gattacttcc ccgagcccgt caccgtgagc 1020tggaatagcg gagcactgac ctccggcgtc cacacattcc ccgccgtgct ccaaagctcc 1080ggcctgtaca gcctctcctc cgtggtcacc gtgcccagca gctctctggg cacaaagacc 1140tatacctgta acgtggatca caagcctagc aacaccaaag tggataagcg ggtggagagc 1200aagtacggcc ctccctgtcc cccttgcccc gctcctgagg ccgctggcgg accttccgtg 1260ttcctgtttc cccctaagcc caaggacacc ctcatgatta gccggacacc cgaagtgacc 1320tgcgtggtcg tggatgtgtc ccaggaggac cctgaagtgc aatttaactg gtacgtggac 1380ggcgtcgagg tgcacaacgc caagaccaag cctcgggaag agcagttcaa cagcacctac 1440cgggtggtca gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 1500tgcaaggtga gcaacaaggg cctgcccagc tccatcgaga agaccatcag caaggccaag 1560ggccagccca gggaacccca ggtgtatacc ctgcccccta gccaggagga aatgaccaaa 1620aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 1680tgggagagca acggccagcc cgagaacaat tacaagacca cccctcctgt gctggacagc 1740gacggctcct tctttctgta tagccggctg accgtggaca agagcaggtg gcaggagggc 1800aacgtgttct cctgtagcgt gatgcacgag gccctgcaca accattacac ccagaagagc 1860ttgagcctga gcctgggcaa a 1881511500DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 51gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagctgcgg gggtggcgga agcatcgaag gtcgtcacgc tgagggaaca 360ttcacttccg atgtgtcctc ctacctggag ggccaggctg ccaaagagtt catcgcttgg 420ctcgtcaagg gcaggggcgg aggtgggagt tgctcttata cctacaatta tgaagactac 480tggggccaag gaaccctggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 540cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 600aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 660gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 720actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 780agcaacacca aggtggacaa gaaagttgaa cccaaatctt gcgacaaaac tcacacatgc 840ccaccgtgcc cagcacctcc agtcgccgga ccgtcagtct tcctcttccc tccaaaaccc 900aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 960cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1020aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1080gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaaggc 1140ctcccaagct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1200gtgtacaccc tgcctccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1260ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1320gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1380agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1440atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1500521563DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 52gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc gcgcaagagc cagtcaaagg tccagtctcc 360actaagcctg gctcctgccc cattatcttg atccggtgcg ccatgttgaa tccccctaac 420cgctgcttga aagatactga ctgcccagga atcaagaagt gctgtgaagg ctcttgcggg 480atggcctgtt tcgttcccca gggcggaggt gggagttctt atacctacaa ttatgaagac 540tactggggcc aaggaaccct ggtcaccgtc tcctcagcct ccaccaaggg cccatcggtc 600ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 660gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 720ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 780gtgactgtgc cctctagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 840cccagcaaca ccaaggtgga caagaaagtt gaacccaaat cttgcgacaa aactcacaca 900tgcccaccgt gcccagcacc tccagtcgcc ggaccgtcag tcttcctctt ccctccaaaa 960cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1020agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1080gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1140accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1200ggcctcccaa gctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1260caggtgtaca ccctgcctcc atcccgggat gagctgacca agaaccaggt cagcctgacc 1320tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1380ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1440tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1500gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1560aaa 1563531560DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 53gaagtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc ggaaactaag 300aaataccaga gcgggggtgg cggaagcctg aaatgttacc aacatggtaa agttgtgact 360tgtcatcgag atatgaagtt ttgctatcat aacactggca tgccttttcg aaatctcaag 420ctcatcctac agggatgttc ttcttcgtgc agtgaaacag aaaacaataa gtgttgctca 480acagacagat gcaacaaagg cggaggtggg agttcttata cctacaatta tgaatggggc 540caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 600gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 660tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 720accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 780ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 840accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac atgcccaccg 900tgcccagcac ctccagtcgc cggaccgtca gtcttcctct tccctccaaa acccaaggac 960accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1020gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1080aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1140caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa aggcctccca 1200agctccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1260accctgcctc catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1320aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1380aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1440ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1500gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaatgataa 1560541923DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 54gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc gctcctctgg gcggtcctga accagcacag 360tacgaggaac tgacactgtt gttccatgga gccttgcagc tgggccaggc cctcaacggc 420gtgtaccgcg ccacagaggc acgtttgacc gaggccggac acagcctggg tttgtacgac 480agagccctgg agtttctggg taccgaagtg cgtcagggcc aggacgcaac tcaggagctg 540agaacctccc tctctgagat ccaggtggag gaggacgccc tgcacctgcg cgccgaggcg 600acagcacgct ctttgggaga agttgctcgc gctcagcagg ccctgcgtga taccgtgcgg 660agactccaag ttcagctcag aggcgcttgg ctcggacagg cgcatcagga gttcgagacc 720ctgaaagctc gtgccgacaa acagtcccac ctgctgtggg cgctcaccgg tcacgtccag 780cgccagcaac gcgaaatggc cgagcagcag caatggctgc gccaaatcca gcagcgcctg 840cataccgcgg ccctgccagc gggcggaggt gggagttctt atacctacaa ttatgaagac 900tactggggcc aaggaaccct ggtcaccgtc tcctcagcct ccaccaaggg cccatcggtc 960ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 1020gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 1080ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 1140gtgactgtgc cctctagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 1200cccagcaaca ccaaggtgga caagaaagtt gaacccaaat cttgcgacaa aactcacaca 1260tgcccaccgt gcccagcacc tccagtcgcc ggaccgtcag tcttcctctt ccctccaaaa 1320cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1380agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1440gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1500accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1560ggcctcccaa gctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1620caggtgtaca ccctgcctcc atcccgggat gagctgacca agaaccaggt cagcctgacc 1680tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1740ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1800tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1860gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1920aaa 1923551971DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 55gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc ttcccaacca ttcccttatc caggcttttt 360gacaacgcta tgctccgcgc ccatcgtctg caccagctgg cctttgacac ctaccaggag 420tttgaagaag cctatatccc aaaggaacag aagtattcat tcctgcagaa cccccagacc 480tccctctgtt tctcagagtc tattccgaca ccctccaaca gggaggaaac acaacagaaa 540tccaacctag agctgctccg catctccctg ctgctcatcc agtcgtggct ggagcccgtg 600cagttcctca ggagtgtctt cgccaacagc ctggtgtacg gcgcctctga cagcaacgtc 660tatgacctcc taaaggacct agaggaaggc atccaaacgc tgatggggag gctggaagat 720ggcagccccc ggactgggca gatcttcaag cagacctaca gcaagttcga cacaaactca 780cacaacgatg acgcactact caagaactac gggctgctct actgcttcag gaaggacatg 840gacaaggtcg agacattcct gcgcatcgtg cagtgccgct ctgtggaggg cagctgtggc 900ttcggcggag gtgggagttc ttatacctac aattatgaag actactgggg ccaaggaacc 960ctggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 1020tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1080gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1140gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgactgt gccctctagc 1200agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1260gacaagaaag ttgaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 1320cctccagtcg ccggaccgtc agtcttcctc ttccctccaa aacccaagga caccctcatg 1380atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1440gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1500gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1560tggctgaatg gcaaggagta caagtgcaag gtctccaaca aaggcctccc aagctccatc 1620gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgcct 1680ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1740tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1800accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1860gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1920cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatgata a 1971561896DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 56gaggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagcggggg tggcggaagc atgagctaca acttgcttgg attcctacaa 360agaagcagca attttcagtg tcagaagctc ctgtggcaat tgaatgggag gcttgaatac 420tgcctcaagg acaggatgaa ctttgacatc cctgaggaga ttaagcagct gcagcagttc 480cagaaggagg acgccgcatt gaccatctat gagatgctcc agaacatctt tgctattttc 540agacaagatt catctagcac tggctggaat gagactattg ttgagaacct cctggctaat 600gtctatcatc agataaacca tctgaagaca gtcctggaag aaaaactgga gaaagaagat 660ttcaccaggg gaaaactcat gagcagtctg cacctgaaaa gatattatgg gaggattctg 720cattacctga aggccaagga gtacagtcac tgtgcctgga ccatagtcag agtggaaatc 780ctaaggaact tttacttcat taacagactt acaggttacc tccgaaacgg cggaggtggg 840agttcttata cctacaatta tgaagactac tggggccaag gaaccctggt caccgtctcc 900tcagcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 960gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 1020tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 1080tcaggactct actccctcag cagcgtggtg actgtgccct ctagcagctt gggcacccag 1140acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgaa 1200cccaaatctt gcgacaaaac tcacacatgc ccaccgtgcc cagcacctcc agtcgccgga 1260ccgtcagtct tcctcttccc tccaaaaccc aaggacaccc tcatgatctc ccggacccct 1320gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 1380tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 1440agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1500gagtacaagt gcaaggtctc caacaaaggc ctcccaagct ccatcgagaa aaccatctcc 1560aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcctccatc ccgggatgag 1620ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1680gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1740ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1800cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1860cagaagagcc tctccctgtc tccgggtaaa tgataa 1896571560DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 57gaagtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc ggaaactaag 300aaataccaga gcgggggtgg cggaagcctg aaatgttacc aacatggtaa agttgtgact 360tgtcatcgag atatgaagtt ttgctatcat aacactggca tgccttttcg aaatctcaag 420ctcatcctac agggatgttc ttcttcgtgc agtgaaacag aaaacaataa gtgttgctca 480acagacagat gcaacaaagg cggaggtggg agttcttata cctacaatta tgaatggggc 540caaggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 600gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 660tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 720accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 780ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 840accaaggtgg acaagaaagt tgaacccaaa tcttgcgaca aaactcacac atgcccaccg 900tgcccagcac ctccagtcgc cggaccgtca gtcttcctct tccctccaaa acccaaggac 960accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1020gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1080aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1140caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa aggcctccca 1200agctccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1260accctgcctc catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1320aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1380aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1440ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1500gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaatgataa 1560581563DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 58caggtgaccc tgcgcgagtc cggccctgca ctggtgaagc ccacccagac cctgaccctg 60acctgcacct tctccggctt ctccctgtcc acctccggca tgtccgtggg ctggatccgg 120cagcctcccg gcaaggccct ggagtggctg gctgacatct ggtgggacga caagaaggac 180tacaacccct ccctgaagtc ccgcctgacc atctccaagg acacctccaa gaaccaggtg 240gtgctgaagg tgaccaacat ggaccccgcc gacaccgcca cctactactg cgcccgctct 300gaaactaaga aagggggtgg cggaagcctg aaatgttacc aacatggtaa agttgtgact 360tgtcatcgag atatgaagtt ttgctatcat aacactggca tgccttttcg aaatctcaag 420ctcatcctac agggatgttc ttcttcgtgc agtgaaacag aaaacaataa gtgttgctca 480acagacagat gcaacaaagg cggaggtggg

agttacaatt atgaatactt tgacgtgtgg 540ggagccggta ccaccgtgac cgtgtcttcc gcctccacca agggcccatc ggtcttcccc 600ctggcaccct cctccaagag cacctctggg ggcacagcgg ccctgggctg cctggtcaag 660gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgccctgac cagcggcgtg 720cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgact 780gtgccctcta gcagcttggg cacccagacc tacatctgca acgtgaatca caagcccagc 840aacaccaagg tggacaagaa agttgaaccc aaatcttgcg acaaaactca cacatgccca 900ccgtgcccag cacctccagt cgccggaccg tcagtcttcc tcttccctcc aaaacccaag 960gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1020gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1080acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1140ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaaggcctc 1200ccaagctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1260tacaccctgc ctccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1320gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1380aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1440aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1500catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 1560taa 156359729DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 59caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag catgtgtacc gcaagcatac caccccaatg ctactcttat 360acctacaatt atgaatggca tgtggatgtc tggggacagg gcctgctggt gacagtctct 420agtgcttcca caactgcacc aaaggtgtac cccctgtcaa gctgctgtgg ggacaaatcc 480tctagtaccg tgacactggg atgcctggtc tcaagctata tgcccgagcc tgtgactgtc 540acctggaact caggagccct gaaaagcgga gtgcacacct tcccagctgt gctgcagtcc 600tctggcctgt atagcctgag ttcaatggtg acagtccccg gcagtacttc agggcagacc 660ttcacctgta atgtggccca tcctgccagc tccaccaaag tggacaaagc agtggaaccc 720aaatcttgc 72960711DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 60caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aaatgtgtac cgcaagcata ccaccccaat gctactacaa ttatgaatgg 360catgtggatg tctggggaca gggcctgctg gtgacagtct ctagtgcttc cacaactgca 420ccaaaggtgt accccctgtc aagctgctgt ggggacaaat cctctagtac cgtgacactg 480ggatgcctgg tctcaagcta tatgcccgag cctgtgactg tcacctggaa ctcaggagcc 540ctgaaaagcg gagtgcacac cttcccagct gtgctgcagt cctctggcct gtatagcctg 600agttcaatgg tgacagtccc cggcagtact tcagggcaga ccttcacctg taatgtggcc 660catcctgcca gctccaccaa agtggacaaa gcagtggaac ccaaatcttg c 71161642DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 61gacattcaga tgacacagag ccccagcagc ctcagtgcct cagtcggtga cagagtgacc 60attacttgcc gtgccagcgg aaacattcac aactacctgg cctggtatca gcagaagccc 120ggcaaagctc ctaagctgct catctactat accactacac tcgcagacgg cgtgccatct 180cgcttctctg gctcaggatc cggtacagac tacaccttta ctatctccag cctgcagccc 240gaggatattg ctacctacta ttgccagcat ttttggtcaa ccccccgcac attcggtcag 300ggcactaagg tggagattaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 64262684DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 62caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcacatg 300tgtaccgcaa gcataccacc ccaatgctac catgtggatg tctggggaca gggcctgctg 360gtgacagtct ctagtgctag caccaagggc ccatcggtct tccccctggc accctcctcc 420aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct 540gtcctacagt cctcaggact ctactccctc agcagcgtgg tgactgtgcc ctctagcagc 600ttgggcaccc agacctacat ctgcaacgtg aatcacaagc ccagcaacac caaggtggac 660aagaaagttg agcccaaatc ttgt 68463690DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 63caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcaccag 300atgtgtaccg caagcatacc accccaatgc tactggcatg tggatgtctg gggacagggc 360ctgctggtga cagtctctag tgctagcacc aagggcccat cggtcttccc cctggcaccc 420tcctccaaga gcacctctgg gggcacagcg gccctgggct gcctggtcaa ggactacttc 480cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 540ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac tgtgccctct 600agcagcttgg gcacccagac ctacatctgc aacgtgaatc acaagcccag caacaccaag 660gtggacaaga aagttgagcc caaatcttgt 69064696DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 64caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcaccag 300gaaatgtgta ccgcaagcat accaccccaa tgctacgaat ggcatgtgga tgtctgggga 360cagggcctgc tggtgacagt ctctagtgct agcaccaagg gcccatcggt cttccccctg 420gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 480tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 540accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgactgtg 600ccctctagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 660accaaggtgg acaagaaagt tgagcccaaa tcttgt 69665702DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 65caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcaccag 300gaaactatgt gtaccgcaag cataccaccc caatgctact atgaatggca tgtggatgtc 360tggggacagg gcctgctggt gacagtctct agtgctagca ccaagggccc atcggtcttc 420cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 480aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 540gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 600actgtgccct ctagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 660agcaacacca aggtggacaa gaaagttgag cccaaatctt gt 70266708DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 66caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcaccag 300gaaactaaga tgtgtaccgc aagcatacca ccccaatgct acaattatga atggcatgtg 360gatgtctggg gacagggcct gctggtgaca gtctctagtg ctagcaccaa gggcccatcg 420gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 480ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 540agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 600gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 660aagcccagca acaccaaggt ggacaagaaa gttgagccca aatcttgt 70867714DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 67caggtccagc tccaggaaag cggtcccggc ctcgtgcgtc ccagccagac tctctccctc 60acttgtactg tgtcaggttt tagcctcact ggctacggag tgaactgggt ccgccagcca 120cctggtaggg gactggagtg gatcggcatg atttggggag acggtaacac cgattataat 180tctgctctga agtcaagagt gacaatgctc aaggacacct ccaaaaatca gttctctctg 240cgtctctcca gcgtgaccgc cgctgatact gcagtctact attgcacctc tgtgcaccag 300gaaactaaga aaatgtgtac cgcaagcata ccaccccaat gctactacaa ttatgaatgg 360catgtggatg tctggggaca gggcctgctg gtgacagtct ctagtgctag caccaagggc 420ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 480ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600agcagcgtgg tgactgtgcc ctctagcagc ttgggcaccc agacctacat ctgcaacgtg 660aatcacaagc ccagcaacac caaggtggac aagaaagttg agcccaaatc ttgt 71468729DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 68caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cagatgtacc aagagcatac cacccatctg cttctcttat 360acctacaatt atgaatggca tgtggatgtc tggggacagg gcctgctggt gacagtctct 420agtgcttcca caactgcacc aaaggtgtac cccctgtcaa gctgctgtgg ggacaaatcc 480tctagtaccg tgacactggg atgcctggtc tcaagctata tgcccgagcc tgtgactgtc 540acctggaact caggagccct gaaaagcgga gtgcacacct tcccagctgt gctgcagtcc 600tctggcctgt atagcctgag ttcaatggtg acagtccccg gcagtacttc agggcagacc 660ttcacctgta atgtggccca tcctgccagc tccaccaaag tggacaaagc agtggaaccc 720aaatcttgc 729691431DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 69caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctatcgcaaa tgtagaggag gcaacggacg aaggtggtgc 360taccaaaagt cttataccta caattatgaa tggcatgtgg atgtctgggg acagggcctg 420ctggtgacag tctctagtgc ttccacaact gcaccaaagg tgtaccccct gtcaagctgc 480tgtggggaca aatcctctag taccgtgaca ctgggatgcc tggtctcaag ctatatgccc 540gagcctgtga ctgtcacctg gaactcagga gccctgaaaa gcggagtgca caccttccca 600gctgtgctgc agtcctctgg cctgtatagc ctgagttcaa tggtgacagt ccccggcagt 660acttcagggc agaccttcac ctgtaatgtg gcccatcctg ccagctccac caaagtggac 720aaagcagtgg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 780gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 900gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 960gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1020tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1080gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1140ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatgata a 1431701425DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 70caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctatcgcaaa tgtagaggac ctcgaaggtg gtgctaccaa 360aagtcttata cctacaatta tgaatggcat gtggatgtct ggggacaggg cctgctggtg 420acagtctcta gtgcttccac aactgcacca aaggtgtacc ccctgtcaag ctgctgtggg 480gacaaatcct ctagtaccgt gacactggga tgcctggtct caagctatat gcccgagcct 540gtgactgtca cctggaactc aggagccctg aaaagcggag tgcacacctt cccagctgtg 600ctgcagtcct ctggcctgta tagcctgagt tcaatggtga cagtccccgg cagtacttca 660gggcagacct tcacctgtaa tgtggcccat cctgccagct ccaccaaagt ggacaaagca 720gtggaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 780ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 840cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 900ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 960cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1020aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1080accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1140cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1200agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1260cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1320agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1380cactacacgc agaagagcct ctccctgtct ccgggtaaat gataa 1425711431DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 71caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctatcgcaaa tgtagaggag gcaacggacg aaggtggtgc 360taccaaaagt cttataccta caattatgaa tggcatgtgg atgtctgggg acagggcctg 420ctggtgacag tctctagtgc ttccacaact gcaccaaagg tgtaccccct gtcaagctgc 480tgtggggaca aatcctctag taccgtgaca ctgggatgcc tggtctcaag ctatatgccc 540gagcctgtga ctgtcacctg gaactcagga gccctgaaaa gcggagtgca caccttccca 600gctgtgctgc agtcctctgg cctgtatagc ctgagttcaa tggtgacagt ccccggcagt 660acttcagggc agaccttcac ctgtaatgtg gcccatcctg ccagctccac caaagtggac 720aaagcagtgg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 780gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 900gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 960gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1020tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1080gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1140ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatgata a 1431721428DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 72caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgatgaaa ctaagaaata ccagagctat 180cgcaaatgta gaggaggccg aaggtggtgc taccaaaagt cttataccta caattatgaa 240acagggtaca atcccggact gaagagcaga ctgtccatta ccaaggacaa ctctaaaagt 300caggtgtcac tgagcgtgag ctccgtcacc acagaggata gtgcaactta ctattgcacc 360tctgtgcacc agggaggtgg cggaagctgg catgtggatg tctggggaca gggcctgctg 420gtgacagtct ctagtgcttc cacaactgca ccaaaggtgt accccctgtc aagctgctgt 480ggggacaaat cctctagtac cgtgacactg ggatgcctgg tctcaagcta tatgcccgag 540cctgtgactg tcacctggaa ctcaggagcc ctgaaaagcg gagtgcacac cttcccagct 600gtgctgcagt cctctggcct gtatagcctg agttcaatgg tgacagtccc cggcagtact 660tcagggcaga ccttcacctg taatgtggcc catcctgcca gctccaccaa agtggacaaa 720gcagtggaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc agcacctgaa 780ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 840tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 900aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 960gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1020ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1080aaaaccatct ccaaagccaa agggcagccc

cgagaaccac aggtgtacac cctgccccca 1140tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1200cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1260acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1320aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1380aaccactaca cgcagaagag cctctccctg tctccgggta aatgataa 1428731413DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 73caggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatacc agagctatcg caaatgtaga ggaggccgaa ggtggtgcta ccaaaagtct 360tatacctaca attatgaaga ctactggggc caaggaaccc tggtcaccgt ctcctcagcc 420tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600ctctactccc tcagcagcgt ggtgactgtg ccctctagca gcttgggcac ccagacctac 660atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgaacccaaa 720tcttgcgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 1140accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1200gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380aagagcctct ccctgtctcc gggtaaatga taa 1413741395DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 74caggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagagaaact 300aagaaatatc gcaaatgtag aggaggccga aggtggtgct accaaaagta caattatgaa 360gactactggg gccaaggaac cctggtcacc gtctcctcag cctccaccaa gggcccatcg 420gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 480ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 540agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 600gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 660aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 720acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 780ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 840gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 900cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 960gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1020aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1080gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1140ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1200gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1260ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380ccgggtaaat gataa 1395751371DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 75caggtgcagc tggtggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctgggtt caatattaag gacacttaca tccactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtcgcacgt atttatccta ccaatggtta cacacgctac 180gcagactccg tgaagggccg attcaccatc tccgcagaca cttccaagaa cacggcgtat 240cttcaaatga acagcctgag agccgaggac acggccgtgt attactgttc gagatatcgc 300aaatgtagag gaggccgaag gtggtgctac caaaaggact actggggcca aggaaccctg 360gtcaccgtct cctcagcctc caccaagggc ccatcggtct tccccctggc accctcctcc 420aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct 540gtcctacagt cctcaggact ctactccctc agcagcgtgg tgactgtgcc ctctagcagc 600ttgggcaccc agacctacat ctgcaacgtg aatcacaagc ccagcaacac caaggtggac 660aagaaagttg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 720gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 780atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 840gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 900gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 960tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1020gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1080ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1140tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1200accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1260gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1320cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatgata a 137176401PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 76Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Thr Lys Lys Tyr 20 25 30 Gln Ser Gly Gly Gly Gly Ser Ala Pro Pro Arg Leu Ile Cys Asp Ser 35 40 45 Arg Val Leu Glu Arg Tyr Leu Leu Glu Ala Lys Glu Ala Glu Asn Ile 50 55 60 Thr Thr Gly Cys Ala Glu His Cys Ser Leu Asn Glu Asn Ile Thr Val 65 70 75 80 Pro Asp Thr Lys Val Asn Phe Tyr Ala Trp Lys Arg Met Glu Val Gly 85 90 95 Gln Gln Ala Val Glu Val Trp Gln Gly Leu Ala Leu Leu Ser Glu Ala 100 105 110 Val Leu Arg Gly Gln Ala Leu Leu Val Asn Ser Ser Gln Pro Trp Glu 115 120 125 Pro Leu Gln Leu His Val Asp Lys Ala Val Ser Gly Leu Arg Ser Leu 130 135 140 Thr Thr Leu Leu Arg Ala Leu Gly Ala Gln Lys Glu Ala Ile Ser Pro 145 150 155 160 Pro Asp Ala Ala Ser Ala Ala Pro Leu Arg Thr Ile Thr Ala Asp Thr 165 170 175 Phe Arg Lys Leu Phe Arg Val Tyr Ser Asn Phe Leu Arg Gly Lys Leu 180 185 190 Lys Leu Tyr Thr Gly Glu Ala Cys Arg Thr Gly Asp Arg Gly Gly Gly 195 200 205 Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Thr Ala Val Ala Trp Tyr Gln 210 215 220 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe 225 230 235 240 Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr 245 250 255 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 260 265 270 Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly 275 280 285 Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 290 295 300 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 305 310 315 320 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 325 330 335 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 340 345 350 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 355 360 365 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 370 375 380 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 385 390 395 400 Cys 77639PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 77Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Thr Pro 100 105 110 Leu Gly Pro Ala Arg Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu 115 120 125 Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu Arg 130 135 140 Leu Cys Ala Ala His Lys Leu Cys His Pro Glu Glu Leu Met Leu Leu 145 150 155 160 Arg His Ser Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser Cys Ser Ser 165 170 175 Gln Ser Leu Gln Leu Thr Ser Cys Leu Asn Gln Leu His Gly Gly Leu 180 185 190 Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro Glu 195 200 205 Leu Ala Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Thr Asp Phe Ala 210 215 220 Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Gly Ala Ala Pro Ala Val 225 230 235 240 Gln Pro Thr Gln Gly Ala Met Pro Thr Phe Thr Ser Ala Phe Gln Arg 245 250 255 Arg Ala Gly Gly Val Leu Val Ala Ser Gln Leu His Arg Phe Leu Glu 260 265 270 Leu Ala Tyr Arg Gly Leu Arg Tyr Leu Ala Glu Pro Gly Gly Gly Gly 275 280 285 Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr Leu 290 295 300 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 305 310 315 320 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 325 330 335 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 340 345 350 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 355 360 365 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 370 375 380 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 385 390 395 400 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 405 410 415 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 420 425 430 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 435 440 445 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 450 455 460 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 465 470 475 480 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 485 490 495 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 500 505 510 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 515 520 525 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 530 535 540 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 545 550 555 560 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 565 570 575 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 580 585 590 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 595 600 605 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 610 615 620 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 625 630 635 78510PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 78Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Cys Gly Gly Gly Gly Ser Ile 100 105 110 Glu Gly Arg His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln 115 120 125 Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly 130 135 140 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Cys 145 150 155 160 Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr Leu Val 165 170 175 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 180 185 190 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 195 200 205 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 210 215 220 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 225 230 235 240 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 245 250 255 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 260 265 270 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 275 280 285 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 290 295 300 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 305 310 315 320 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 325 330 335 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 340 345 350 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 355 360 365 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 370 375 380 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 385 390 395 400 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 405 410 415 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 420 425 430 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 435 440 445 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 450 455 460 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 465 470 475 480 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

485 490 495 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 510 79499PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 79Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Ile Asn 100 105 110 Val Lys Cys Ser Leu Pro Gln Gln Cys Ile Lys Pro Cys Lys Asp Ala 115 120 125 Gly Met Arg Phe Gly Lys Cys Met Asn Lys Lys Cys Arg Cys Tyr Ser 130 135 140 Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly 145 150 155 160 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 165 170 175 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 180 185 190 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 195 200 205 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 210 215 220 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 225 230 235 240 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 245 250 255 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 260 265 270 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 275 280 285 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 290 295 300 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 305 310 315 320 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 325 330 335 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 340 345 350 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 355 360 365 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 370 375 380 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 385 390 395 400 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 405 410 415 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 420 425 430 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 435 440 445 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 450 455 460 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 465 470 475 480 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 485 490 495 Pro Gly Lys 80501PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 80Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Ala Ala 100 105 110 Ala Ile Ser Cys Val Gly Ser Pro Glu Cys Pro Pro Lys Cys Arg Ala 115 120 125 Gln Gly Cys Lys Asn Gly Lys Cys Met Asn Arg Lys Cys Lys Cys Tyr 130 135 140 Tyr Cys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr 145 150 155 160 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 165 170 175 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 180 185 190 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 195 200 205 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 210 215 220 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 225 230 235 240 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 245 250 255 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 260 265 270 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 275 280 285 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 290 295 300 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 305 310 315 320 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 325 330 335 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 340 345 350 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 355 360 365 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 370 375 380 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 385 390 395 400 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 405 410 415 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 420 425 430 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 435 440 445 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 450 455 460 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 465 470 475 480 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 485 490 495 Leu Ser Pro Gly Lys 500 81643PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 81Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Ala Thr 100 105 110 Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys 115 120 125 Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu 130 135 140 Lys Leu Val Ser Glu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu 145 150 155 160 Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser 165 170 175 Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu 180 185 190 His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly 195 200 205 Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val 210 215 220 Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met 225 230 235 240 Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser 245 250 255 Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln 260 265 270 Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro 275 280 285 Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly 290 295 300 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 305 310 315 320 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 325 330 335 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 340 345 350 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 355 360 365 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 370 375 380 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 385 390 395 400 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 405 410 415 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 420 425 430 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 435 440 445 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 450 455 460 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 465 470 475 480 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 485 490 495 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 500 505 510 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 515 520 525 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 530 535 540 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 545 550 555 560 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 565 570 575 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 580 585 590 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 595 600 605 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 610 615 620 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 625 630 635 640 Pro Gly Lys 82653PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 82Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Phe Pro 100 105 110 Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His 115 120 125 Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala 130 135 140 Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr 145 150 155 160 Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu 165 170 175 Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu 180 185 190 Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala 195 200 205 Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu 210 215 220 Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp 225 230 235 240 Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe 245 250 255 Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu 260 265 270 Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg 275 280 285 Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly 290 295 300 Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr 305 310 315 320 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 325 330 335 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 340 345 350 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 355 360 365 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 370 375 380 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 385 390 395 400 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 405 410 415 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 420 425 430 Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu 435 440 445 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 450 455 460 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 465 470 475 480 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 485 490 495 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 500 505 510 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 515 520 525 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 530 535 540 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 545 550 555 560 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 565 570 575 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 580 585 590 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

Ser Asp Gly 595 600 605 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 610 615 620 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 625 630 635 640 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 645 650 83608PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 83Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Val Pro 100 105 110 Ile Gln Lys Val Gln Asp Asp Thr Lys Thr Leu Ile Lys Thr Ile Val 115 120 125 Thr Arg Ile Asn Asp Ile Ser His Thr Gln Ser Val Ser Ser Lys Gln 130 135 140 Lys Val Thr Gly Leu Asp Phe Ile Pro Gly Leu His Pro Ile Leu Thr 145 150 155 160 Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln Ile Leu Thr 165 170 175 Ser Met Pro Ser Arg Asn Val Ile Gln Ile Ser Asn Asp Leu Glu Asn 180 185 190 Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys His Leu 195 200 205 Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly Val Leu 210 215 220 Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg Leu Gln 225 230 235 240 Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro Gly Cys 245 250 255 Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly 260 265 270 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 275 280 285 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 290 295 300 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 305 310 315 320 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 325 330 335 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 340 345 350 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 355 360 365 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 370 375 380 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 385 390 395 400 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 405 410 415 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro 420 425 430 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 435 440 445 Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val 450 455 460 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 465 470 475 480 Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr 485 490 495 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 500 505 510 Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 515 520 525 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 530 535 540 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 545 550 555 560 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser 565 570 575 Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 580 585 590 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 595 600 605 84627PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 84Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Cys Asp 100 105 110 Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met Leu Leu 115 120 125 Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu Lys Asp Arg His 130 135 140 Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln Lys Ala 145 150 155 160 Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe Asn Leu 165 170 175 Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu Leu Asp 180 185 190 Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu Ala Cys 195 200 205 Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys Glu Asp 210 215 220 Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu Tyr Leu 225 230 235 240 Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu 245 250 255 Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser Leu Arg 260 265 270 Ser Lys Glu Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp 275 280 285 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 290 295 300 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 305 310 315 320 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 325 330 335 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 340 345 350 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 355 360 365 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 370 375 380 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 385 390 395 400 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 405 410 415 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 420 425 430 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 435 440 445 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 450 455 460 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 465 470 475 480 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 485 490 495 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 500 505 510 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 515 520 525 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 530 535 540 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 545 550 555 560 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 565 570 575 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 580 585 590 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 595 600 605 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 610 615 620 Leu Gly Lys 625 85500PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 85Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Cys Gly Gly Gly Gly Ser Ile 100 105 110 Glu Gly Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr 115 120 125 Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 130 135 140 Arg Gly Gly Gly Gly Ser Cys Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr 145 150 155 160 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 165 170 175 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 180 185 190 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 195 200 205 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 210 215 220 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 225 230 235 240 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 245 250 255 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 260 265 270 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val 275 280 285 Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 290 295 300 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305 310 315 320 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 325 330 335 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 340 345 350 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 355 360 365 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 370 375 380 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 385 390 395 400 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 405 410 415 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 420 425 430 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 435 440 445 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 450 455 460 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 465 470 475 480 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 485 490 495 Ser Pro Gly Lys 500 86521PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 86Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Ala Gln 100 105 110 Glu Pro Val Lys Gly Pro Val Ser Thr Lys Pro Gly Ser Cys Pro Ile 115 120 125 Ile Leu Ile Arg Cys Ala Met Leu Asn Pro Pro Asn Arg Cys Leu Lys 130 135 140 Asp Thr Asp Cys Pro Gly Ile Lys Lys Cys Cys Glu Gly Ser Cys Gly 145 150 155 160 Met Ala Cys Phe Val Pro Gln Gly Gly Gly Gly Ser Ser Tyr Thr Tyr 165 170 175 Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 180 185 190 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 195 200 205 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 210 215 220 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 225 230 235 240 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 245 250 255 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 260 265 270 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 275 280 285 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 290 295 300 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 305 310 315 320 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 325 330 335 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 340 345 350 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 355 360 365 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 370 375 380 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 385 390 395 400 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 405 410 415 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 420 425 430 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 435 440 445 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 450 455 460 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

Gly Ser Phe Phe Leu 465 470 475 480 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 485 490 495 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 500 505 510 Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 87518PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 87Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Leu Lys Cys 100 105 110 Tyr Gln His Gly Lys Val Val Thr Cys His Arg Asp Met Lys Phe Cys 115 120 125 Tyr His Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu Ile Leu Gln 130 135 140 Gly Cys Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys Cys Cys Ser 145 150 155 160 Thr Asp Arg Cys Asn Lys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn 165 170 175 Tyr Glu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 180 185 190 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 195 200 205 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 210 215 220 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 225 230 235 240 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 245 250 255 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 260 265 270 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 275 280 285 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 290 295 300 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 305 310 315 320 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 325 330 335 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 340 345 350 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 355 360 365 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 370 375 380 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 385 390 395 400 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 405 410 415 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 420 425 430 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 435 440 445 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 450 455 460 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 465 470 475 480 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 485 490 495 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 500 505 510 Ser Leu Ser Pro Gly Lys 515 88641PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 88Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Ala Pro 100 105 110 Leu Gly Gly Pro Glu Pro Ala Gln Tyr Glu Glu Leu Thr Leu Leu Phe 115 120 125 His Gly Ala Leu Gln Leu Gly Gln Ala Leu Asn Gly Val Tyr Arg Ala 130 135 140 Thr Glu Ala Arg Leu Thr Glu Ala Gly His Ser Leu Gly Leu Tyr Asp 145 150 155 160 Arg Ala Leu Glu Phe Leu Gly Thr Glu Val Arg Gln Gly Gln Asp Ala 165 170 175 Thr Gln Glu Leu Arg Thr Ser Leu Ser Glu Ile Gln Val Glu Glu Asp 180 185 190 Ala Leu His Leu Arg Ala Glu Ala Thr Ala Arg Ser Leu Gly Glu Val 195 200 205 Ala Arg Ala Gln Gln Ala Leu Arg Asp Thr Val Arg Arg Leu Gln Val 210 215 220 Gln Leu Arg Gly Ala Trp Leu Gly Gln Ala His Gln Glu Phe Glu Thr 225 230 235 240 Leu Lys Ala Arg Ala Asp Lys Gln Ser His Leu Leu Trp Ala Leu Thr 245 250 255 Gly His Val Gln Arg Gln Gln Arg Glu Met Ala Glu Gln Gln Gln Trp 260 265 270 Leu Arg Gln Ile Gln Gln Arg Leu His Thr Ala Ala Leu Pro Ala Gly 275 280 285 Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln 290 295 300 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 305 310 315 320 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 325 330 335 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 340 345 350 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 355 360 365 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 370 375 380 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 385 390 395 400 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 405 410 415 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 420 425 430 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 435 440 445 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 450 455 460 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 465 470 475 480 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 485 490 495 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 500 505 510 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 515 520 525 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 530 535 540 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 545 550 555 560 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 565 570 575 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 580 585 590 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 595 600 605 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 610 615 620 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 625 630 635 640 Lys 89655PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 89Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Phe Pro 100 105 110 Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg Ala His 115 120 125 Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu Glu Ala 130 135 140 Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro Gln Thr 145 150 155 160 Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg Glu Glu 165 170 175 Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu Leu Leu 180 185 190 Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val Phe Ala 195 200 205 Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp Leu Leu 210 215 220 Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu Glu Asp 225 230 235 240 Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser Lys Phe 245 250 255 Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr Gly Leu 260 265 270 Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe Leu Arg 275 280 285 Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe Gly Gly Gly 290 295 300 Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr 305 310 315 320 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 325 330 335 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 340 345 350 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 355 360 365 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 370 375 380 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 385 390 395 400 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 405 410 415 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 420 425 430 His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 435 440 445 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 450 455 460 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 465 470 475 480 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 485 490 495 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 500 505 510 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 515 520 525 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 530 535 540 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 545 550 555 560 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 565 570 575 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 580 585 590 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 595 600 605 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 610 615 620 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 625 630 635 640 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 645 650 655 90630PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 90Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser Met Ser 100 105 110 Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln 115 120 125 Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu Lys Asp 130 135 140 Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe 145 150 155 160 Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile 165 170 175 Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr 180 185 190 Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu 195 200 205 Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly 210 215 220 Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu 225 230 235 240 His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val 245 250 255 Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly 260 265 270 Tyr Leu Arg Asn Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu 275 280 285 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 290 295 300 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 305 310 315 320 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 325 330 335 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 340 345 350 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 355 360 365 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 370 375 380 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 385

390 395 400 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 405 410 415 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 420 425 430 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 435 440 445 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 450 455 460 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 465 470 475 480 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 485 490 495 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 500 505 510 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 515 520 525 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 530 535 540 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 545 550 555 560 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 565 570 575 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 580 585 590 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 595 600 605 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 610 615 620 Ser Leu Ser Pro Gly Lys 625 630 91519PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 91Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Glu Thr Lys Lys Gly Gly Gly Gly Ser Leu Lys Cys 100 105 110 Tyr Gln His Gly Lys Val Val Thr Cys His Arg Asp Met Lys Phe Cys 115 120 125 Tyr His Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu Ile Leu Gln 130 135 140 Gly Cys Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys Cys Cys Ser 145 150 155 160 Thr Asp Arg Cys Asn Lys Gly Gly Gly Gly Ser Tyr Asn Tyr Glu Tyr 165 170 175 Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser 180 185 190 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 195 200 205 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 210 215 220 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 225 230 235 240 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 245 250 255 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 260 265 270 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 275 280 285 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 290 295 300 Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 305 310 315 320 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 325 330 335 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 340 345 350 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 355 360 365 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 370 375 380 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 385 390 395 400 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 405 410 415 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 420 425 430 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 435 440 445 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 450 455 460 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 465 470 475 480 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 485 490 495 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 500 505 510 Leu Ser Leu Ser Pro Gly Lys 515 92475PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 92Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Tyr Arg Lys Cys Arg 100 105 110 Gly Gly Asn Gly Arg Arg Trp Cys Tyr Gln Lys Ser Tyr Thr Tyr Asn 115 120 125 Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val 130 135 140 Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys 145 150 155 160 Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser 165 170 175 Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu 180 185 190 Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 195 200 205 Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln 210 215 220 Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 225 230 235 240 Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 370 375 380 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 93473PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 93Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Tyr Arg Lys Cys Arg 100 105 110 Gly Pro Arg Arg Trp Cys Tyr Gln Lys Ser Tyr Thr Tyr Asn Tyr Glu 115 120 125 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 130 135 140 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 145 150 155 160 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr 165 170 175 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 180 185 190 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 195 200 205 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 210 215 220 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 225 230 235 240 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 245 250 255 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 275 280 285 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 290 295 300 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 325 330 335 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 355 360 365 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 370 375 380 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 385 390 395 400 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 405 410 415 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 420 425 430 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 435 440 445 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 450 455 460 Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 94475PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 94Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Tyr Arg Lys Cys Arg 100 105 110 Gly Gly Asn Gly Arg Arg Trp Cys Tyr Gln Lys Ser Tyr Thr Tyr Asn 115 120 125 Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val 130 135 140 Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys 145 150 155 160 Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser 165 170 175 Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu 180 185 190 Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 195 200 205 Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln 210 215 220 Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 225 230 235 240 Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 370 375 380 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 95474PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 95Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Glu Thr Lys Lys Tyr Gln Ser Tyr Arg Lys Cys Arg 50 55 60 Gly Gly Arg Arg Trp Cys Tyr Gln Lys Ser Tyr Thr Tyr

Asn Tyr Glu 65 70 75 80 Thr Gly Tyr Asn Pro Gly Leu Lys Ser Arg Leu Ser Ile Thr Lys Asp 85 90 95 Asn Ser Lys Ser Gln Val Ser Leu Ser Val Ser Ser Val Thr Thr Glu 100 105 110 Asp Ser Ala Thr Tyr Tyr Cys Thr Ser Val His Gln Gly Gly Gly Gly 115 120 125 Ser Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys 145 150 155 160 Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser 165 170 175 Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr 210 215 220 Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys 225 230 235 240 Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 245 250 255 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 260 265 270 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 275 280 285 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 290 295 300 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 305 310 315 320 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 325 330 335 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 340 345 350 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 355 360 365 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 370 375 380 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 385 390 395 400 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 405 410 415 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 420 425 430 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 435 440 445 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 450 455 460 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 96469PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 96Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Gln Ser Tyr Arg Lys Cys Arg Gly Gly 100 105 110 Arg Arg Trp Cys Tyr Gln Lys Ser Tyr Thr Tyr Asn Tyr Glu Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 145 150 155 160 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 225 230 235 240 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 305 310 315 320 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 385 390 395 400 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460 Leu Ser Pro Gly Lys 465 97463PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 97Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Glu Thr Lys Lys Tyr Arg Lys Cys Arg Gly Gly Arg Arg Trp 100 105 110 Cys Tyr Gln Lys Tyr Asn Tyr Glu Asp Tyr Trp Gly Gln Gly Thr Leu 115 120 125 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 130 135 140 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 145 150 155 160 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 165 170 175 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 195 200 205 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 210 215 220 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 225 230 235 240 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 245 250 255 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265 270 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 275 280 285 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 98455PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 98Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Tyr Arg Lys Cys Arg Gly Gly Arg Arg Trp Cys Tyr Gln Lys 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 290 295 300 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 305 310 315 320 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 340 345 350 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 385 390 395 400 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 420 425 430 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 435 440 445 Leu Ser Leu Ser Pro Gly Lys 450 455 99243PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 99Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Arg Cys Thr Lys Ser 100 105 110 Ile Pro Pro Ile Cys Phe Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val 115 120 125 Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser 145 150 155 160 Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu 165 170 175 Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn 210 215 220 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro 225 230 235 240 Lys Ser Cys 100243PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 100Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Met Cys Thr Ala Ser 100 105 110 Ile Pro Pro Gln Cys Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val 115 120 125 Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser 145 150 155 160 Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu 165 170 175 Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Met Val Thr Val Pro Gly Ser

Thr Ser Gly Gln Thr Phe Thr Cys Asn 210 215 220 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro 225 230 235 240 Lys Ser Cys 101237PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 101Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Met Cys Thr Ala Ser Ile Pro Pro 100 105 110 Gln Cys Tyr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly 115 120 125 Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr 130 135 140 Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu 145 150 155 160 Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp 165 170 175 Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly 195 200 205 Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser 210 215 220 Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys 225 230 235 102214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 102Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Thr Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Ser Thr Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 103228PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 103Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Met Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr His Val 100 105 110 Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 Pro Lys Ser Cys 225 104230PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 104Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Met Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr Trp 100 105 110 His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala 115 120 125 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 130 135 140 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 195 200 205 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys 210 215 220 Val Glu Pro Lys Ser Cys 225 230 105232PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 105Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Met Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr 100 105 110 Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser 115 120 125 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 130 135 140 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 145 150 155 160 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 165 170 175 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 180 185 190 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 195 200 205 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 210 215 220 Lys Lys Val Glu Pro Lys Ser Cys 225 230 106234PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 106Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Met Cys Thr Ala Ser Ile Pro Pro Gln Cys 100 105 110 Tyr Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 195 200 205 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Lys Val Glu Pro Lys Ser Cys 225 230 107236PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 107Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Met Cys Thr Ala Ser Ile Pro Pro Gln 100 105 110 Cys Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu 115 120 125 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 130 135 140 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 145 150 155 160 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 165 170 175 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 180 185 190 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 195 200 205 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 210 215 220 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 225 230 235 108238PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 108Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Val Thr Met Leu Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Met Cys Thr Ala Ser Ile Pro Pro 100 105 110 Gln Cys Tyr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly 115 120 125 Leu Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 225 230 235 1097PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 109Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 1108PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 110Glu Thr Lys Lys Tyr Gln Xaa Ser 1 5 1117PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 111Glu Thr Lys Lys Tyr Gln Ser 1 5 11211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 112Glu Thr Lys Lys Tyr Gln Lys His Arg His Ser 1 5 10 11311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 113Glu Thr Lys Lys Tyr Gln Lys His Lys Asn Ser 1 5 10 11415PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 114Glu Thr Lys Lys Tyr Gln Lys His Arg His Thr Thr Glu Arg Ser 1 5 10 15 1155PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 115Xaa Thr Xaa Asn Xaa 1 5 1167PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 116Ser Xaa Thr Xaa Asn Xaa Glu 1 5 1177PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 117Ser Xaa Thr Xaa Asn Xaa Xaa 1 5 1188PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 118Ser Xaa Xaa Thr Xaa Asn Xaa Xaa 1 5 1197PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 119Ser Tyr Thr Tyr Asn Tyr Glu 1 5 1207PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 120Ser Ala Thr Tyr Asn Tyr Glu 1 5 1217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 121Ser Ala Thr Ala Asn Ala Glu 1 5 1227PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 122Ser Tyr Thr Ala Asn Tyr Glu 1 5 1237PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 123Ser Tyr Thr Tyr Asn Ala Glu 1 5 1247PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 124Ser Tyr Thr Tyr Asn Tyr Ala 1 5 12511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 125Ser Tyr Thr Tyr Asp Tyr Thr Tyr Asn Tyr Glu 1

5 10 12611PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 126Ser Tyr Thr Tyr Asp Tyr Thr Tyr Asn Tyr Glu 1 5 10 12715PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 127Ser Ile Thr Tyr Asn Tyr Thr Tyr Asp Tyr Thr Tyr Asn Tyr Glu 1 5 10 15 1285PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 128Tyr Xaa Tyr Xaa Tyr 1 5 12914PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 129Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 1307PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 130Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 13125PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 131Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 13225PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 132Xaa Xaa Xaa Xaa Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala 1 5 10 15 Leu Lys Ala Lys Leu Ala Ala Leu Lys 20 25 1337PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 133Ala Lys Leu Ala Ala Leu Lys 1 5 13411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 134Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys 1 5 10 13514PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 135Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys 1 5 10 13618PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 136Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala 1 5 10 15 Leu Lys 13725PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 137Cys Ala Ala Leu Lys Ser Lys Val Ser Ala Leu Lys Ser Lys Val Ala 1 5 10 15 Ser Leu Lys Ser Lys Val Ala Ala Leu 20 25 13829PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 138Ala Leu Lys Lys Glu Leu Gln Ala Asn Lys Lys Glu Leu Ala Gln Leu 1 5 10 15 Lys Lys Glu Leu Gln Ala Leu Lys Lys Glu Leu Ala Gln 20 25 13914PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 139Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 1407PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 140Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 14125PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 141Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 14225PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 142Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Glu Leu 1 5 10 15 Ala Ala Leu Glu Ala Xaa Xaa Xaa Xaa 20 25 1437PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 143Glu Leu Ala Ala Leu Glu Ala 1 5 14411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 144Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly 1 5 10 14514PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 145Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala 1 5 10 14618PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 146Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 1 5 10 15 Ser Gly 14725PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 147Leu Ala Ala Val Glu Ser Glu Leu Ser Ala Val Glu Ser Glu Leu Ala 1 5 10 15 Ser Val Glu Ser Glu Leu Ala Ala Cys 20 25 14829PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 148Gln Leu Glu Lys Lys Leu Gln Ala Leu Glu Lys Lys Leu Ala Gln Leu 1 5 10 15 Glu Lys Lys Asn Gln Ala Leu Glu Lys Lys Leu Ala Gln 20 25 14925PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 149Cys Ala Ala Leu Lys Ser Lys Val Ser Ala Leu Lys Ser Lys Val Ala 1 5 10 15 Ser Leu Lys Ser Lys Val Ala Ala Leu 20 25 15025PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 150Leu Ala Ala Val Glu Ser Glu Leu Ser Ala Val Glu Ser Glu Leu Ala 1 5 10 15 Ser Val Glu Ser Glu Leu Ala Ala Cys 20 25 15129PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 151Ala Leu Lys Lys Glu Leu Gln Ala Asn Lys Lys Glu Leu Ala Gln Leu 1 5 10 15 Lys Lys Glu Leu Gln Ala Leu Lys Lys Glu Leu Ala Gln 20 25 15229PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 152Gln Leu Glu Lys Lys Leu Gln Ala Leu Glu Lys Lys Leu Ala Gln Leu 1 5 10 15 Glu Lys Lys Asn Gln Ala Leu Glu Lys Lys Leu Ala Gln 20 25 15315PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 153Leu Lys Leu Glu Leu Gln Leu Ile Lys Gln Tyr Arg Glu Ala Leu 1 5 10 15 15415PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 154Leu Ala Lys Ile Leu Glu Asp Glu Glu Lys His Ile Glu Trp Leu 1 5 10 15 15512PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 155Leu Ser Asp Leu His Arg Gln Val Ser Arg Leu Val 1 5 10 15612PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 156Leu Gln Asp Ala Lys Val Leu Leu Glu Ala Ala Leu 1 5 10 15715PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 157Leu Gln Gln Lys Ile His Glu Leu Glu Gly Leu Ile Ala Gln His 1 5 10 15 15815PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 158Ala Ala Gln Ile Arg Asp Gln Leu His Gln Leu Arg Glu Leu Phe 1 5 10 15 15912PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 159Glu Leu Ala Arg Leu Ile Arg Leu Tyr Phe Ala Leu 1 5 10 16012PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 160Gln Glu Ser Leu Tyr Val Asp Leu Phe Asp Lys Phe 1 5 10 1614PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 161Xaa Xaa Xaa Xaa 1 1625PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 162Cys Xaa Xaa Xaa Xaa 1 5 1635PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 163Xaa Xaa Xaa Xaa Cys 1 5 1645PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 164Gly Gly Gly Gly Ser 1 5 1659PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 165Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 1669PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 166Gly Gly Gly Gly Ser Gly Gly Gly Ser 1 5 167522DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 167accccccttg gccctgcccg atccctgccc cagagcttcc tgctcaagtg cttagagcaa 60gtgaggaaaa tccaggctga tggcgccgag ctgcaggaga ggctgtgtgc cgcccacaag 120ctgtgccacc cggaggagct gatgctgctc aggcactctc tgggcatccc ccaggctccc 180ctaagcagct gctccagcca gtccctgcag ctgacgagct gcctgaacca actacacggc 240ggcctctttc tctaccaggg cctcctgcag gccctggcgg gcatctcccc agagctggcc 300cccaccttgg acacactgca gctggacgtc actgactttg ccacgaacat ctggctgcag 360atggaggacc tgggggcggc ccccgctgtg cagcccaccc agggcgccat gccgaccttc 420acttcagcct tccaacgcag agcaggaggg gtcctggttg cttcccagct gcatcgtttc 480ctggagctgg cataccgtgg cctgcgctac cttgctgagc cc 522168534DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 168gccacacctc tgggccccgc ctcctccctg cctcagagct ttctgctcaa atgtctggag 60caggtgcgga agatccaggg cgacggcgcc gctctgcaag agaaactggt cagcgaatgc 120gccacatata agctgtgtca ccccgaggaa ctggtcctct tgggccacag cctgggcatc 180ccctgggccc ctctcagctc ctgcccctcc caagctctcc aactggctgg atgtctgtcc 240caactgcact ccggcctctt cctgtaccag ggactcctcc aggctctcga agggatcagc 300cccgaactgg gccccacact ggacaccttg caactcgatg tggccgattt cgccacaacc 360atctggcagc agatggaaga actcggaatg gctcctgctc tccagcccac acagggagct 420atgcctgctt tcgcctctgc tttccagcgg agagctggtg gtgtgctcgt cgcatcccac 480ctccagagct tcttggaggt gtcctatcgg gtgctccggc atctggccca accc 534169117DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 169cacggagaag gaacatttac cagcgacctc agcaagcaga tggaggaaga ggccgtgagg 60ctgttcatcg agtggctgaa gaacggcgga ccctcctctg gcgctccacc ccctagc 117170102DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 170atcaacgtga agtgcagcct gccccagcag tgcatcaagc cctgcaagga cgccggcatg 60cggttcggca agtgcatgaa caagaagtgc aggtgctaca gc 102171108DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 171gccgctgcaa tctcctgcgt cggcagcccc gaatgtcctc ccaagtgccg ggctcaggga 60tgcaagaacg gcaagtgtat gaaccggaag tgcaagtgct actattgc 10817290DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 172catgcggaag gcacctttac cagcgatgtg agcagctatc tggaaggcca ggcggcgaaa 60gaatttattg cgtggctggt gaaaggccgc 90173498DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 173gccccaccac gcctcatctg tgacagccga gtcctggaga ggtacctctt ggaggccaag 60gaggccgaga atatcacgac gggctgtgct gaacactgca gcttgaatga gaatatcact 120gtcccagaca ccaaagttaa tttctatgcc tggaagagga tggaggtcgg gcagcaggcc 180gtagaagtct ggcagggcct ggccctgctg tcggaagctg tcctgcgggg ccaggccctg 240ttggtcaact cttcccagcc gtgggagccc ctgcagctgc atgtggataa agccgtcagt 300ggccttcgca gcctcaccac tctgcttcgg gctctgggag cccagaagga agccatctcc 360cctccagatg cggcctcagc tgctccactc cgaacaatca ctgctgacac tttccgcaaa 420ctcttccgag tctactccaa tttcctccgg ggaaagctga agctgtacac aggggaggcc 480tgcaggacag gggacaga 498174381DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 174gcgccggcgc gcagcccgag cccgagcacc cagccgtggg aacatgtgaa cgcgattcag 60gaagcgcgcc gcctgctgaa cctgagccgc gataccgcgg cggaaatgaa cgaaaccgtg 120gaagtgatta gcgaaatgtt tgatctgcag gaaccgacct gcctgcagac ccgcctggaa 180ctgtataaac agggcctgcg cggcagcctg accaaactga aaggcccgct gaccatgatg 240gcgagccatt ataaacagca ttgcccgccg accccggaaa ccagctgcgc gacccagatt 300attacctttg aaagctttaa agaaaacctg aaagattttc tgctggtgat tccgtttgat 360tgctgggaac cggtgcagga a 381175498DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 175atgagctata acctgctggg ctttctgcag cgcagcagca actttcagtg ccagaaactg 60ctgtggcagc tgaacggccg cctggaatat tgcctgaaag atcgcatgaa ctttgatatt 120ccggaagaaa ttaaacagct gcagcagttt cagaaagaag atgcggcgct gaccatttat 180gaaatgctgc agaacatttt tgcgattttt cgccaggata gcagcagcac cggctggaac 240gaaaccattg tggaaaacct gctggcgaac gtgtatcatc agattaacca tctgaaaacc 300gtgctggaag aaaaactgga aaaagaagat tttacccgcg gcaaactgat gagcagcctg 360catctgaaac gctattatgg ccgcattctg cattatctga aagcgaaaga atatagccat 420tgcgcgtgga ccattgtgcg cgtggaaatt ctgcgcaact tttattttat taaccgcctg 480accggctatc tgcgcaac 498176111DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 176cactctcagg gtaccttcac ctctgactac tctaaatacc tggactctcg tcgtgctcag 60gacttcgttc agtggctgat gaacaccaaa cgtaaccgta acaacatcgc t 111177438DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 177gttccaattc aaaaggttca agatgatacc aaaactctga ttaaaactat tgtcacgcgt 60ataaacgaca tcagccatac ccagtcggtt agctcaaagc aaaaagttac cggtttggac 120tttattccgg gactgcaccc gatcctgacc cttagtaaaa tggaccagac actggccgtc 180taccagcaaa tcctgacatc gatgccatcc agaaatgtga tacaaattag caacgatttg 240gaaaaccttc gcgatctgct gcacgtgctg gccttcagta agtcctgtca tctgccgtgg 300gcgtcgggac tggagactct tgactcgctg ggtggagtgt tagaggcctc tggctattct 360actgaagtcg ttgcgctgtc acgcctccag gggagcctgc aggacatgct gtggcagctg 420gacctgtcac ctggctgc 438178534DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 178gctcctctgg gcggtcctga accagcacag tacgaggaac tgacactgtt gttccatgga 60gccttgcagc tgggccaggc cctcaacggc gtgtaccgcg ccacagaggc acgtttgacc 120gaggccggac acagcctggg tttgtacgac agagccctgg agtttctggg taccgaagtg 180cgtcagggcc aggacgcaac tcaggagctg agaacctccc tctctgagat ccaggtggag 240gaggacgccc tgcacctgcg cgccgaggcg acagcacgct ctttgggaga agttgctcgc 300gctcagcagg ccctgcgtga taccgtgcgg agactccaag ttcagctcag aggcgcttgg 360ctcggacagg cgcatcagga gttcgagacc ctgaaagctc gtgccgacaa acagtcccac 420ctgctgtggg cgctcaccgg tcacgtccag cgccagcaac gcgaaatggc cgagcagcag 480caatggctgc gccaaatcca gcagcgcctg cataccgcgg ccctgccagc gtaa 534179330DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 179aacctgggtc tggactgcga cgaacactct tctgaatctc gttgctgccg ttacccgctg 60accgttgact tcgaggcgtt cggttgggac tggatcatcg ctccgaaacg ttacaaagct 120aactactgct ctggtcagtg cgaatacatg ttcatgcaga aatacccgca cacccacctg 180gttcagcagg ctaacccgcg tggttctgct ggtccgtgct gcaccccgac caaaatgtct 240ccgatcaaca tgctgtactt caacgacaaa cagcagatca tctacggtaa aatcccgggt 300atggttgttg accgttgcgg ttgctcttaa 3301801162DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 180ggatccggtg gtttcaccat caaactgctg ctgttcatcg ttccgctggt tatctcttct 60cgtatcgacc aggacaactc ttctttcgac tctctgtctc cggaaccgaa atctcgtttc 120gctatgctgg acgacgttaa aatcctggct aacggtctgc tgcagctggg tcacggtctg 180aaagacttcg ttcacaaaac caaaggtcag atcaacgaca tcttccagaa actgaacatc 240ttcgaccagt ctttctacga cctgtctctg cagacctctg aaatcaaaga agaagaaaaa 300gaactgcgtc gtaccaccta caaactgcag gttaaaaacg aagaagttaa aaacatgtct 360ctggaactga actctaaact ggaatctctg ctggaagaaa aaatcctgct gcagcagaaa 420gttaaatacc tggaagaaca gctgaccaac ctgatccaga accagccgga aaccccggaa 480cacccggaag ttacctctct gaaaaccttc gttgaaaaac aggacaactc tatcaaagac 540ctgctgcaga ccgttgaaga ccagtacaaa cagctgaacc agcagcactc tcagatcaaa 600gaaatcgaaa accagctgcg tcgtacctct atccaggaac cgaccgaaat ctctctgtct 660tctaaaccgc gtgctccgcg taccaccccg ttcctgcagc tgaacgaaat ccgtaacgtt 720aaacacgacg gtatcccggc tgaatgcacc accatctaca accgtggtga acacacctct 780ggtatgtacg ctatccgtcc gtctaactct caggttttcc acgtttactg cgacgttatc 840tctggttctc cgtggaccct gatccagcac cgtatcgacg gttctcagaa cttcaacgaa 900acctgggaaa actacaaata cggtttcggt cgtctggacg gtgaattctg gctgggtctg 960gaaaaaatct actctatcgt taaacagtct aactacgttc tgcgtatcga actggaagac 1020tggaaagaca acaaacacta catcgaatac tctttctacc tgggtaacca cgaaaccaac 1080tacaccctgc acctggttgc tatcaccggt aacgttccga acgctatccc gaagaagaag 1140aagaaaaaaa agaagaagaa at 1162181573DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 181ttcccaacca ttcccttatc caggcttttt gacaacgcta tgctccgcgc ccatcgtctg 60caccagctgg cctttgacac ctaccaggag tttgaagaag cctatatccc aaaggaacag 120aagtattcat tcctgcagaa cccccagacc tccctctgtt tctcagagtc tattccgaca 180ccctccaaca gggaggaaac acaacagaaa tccaacctag agctgctccg catctccctg 240ctgctcatcc agtcgtggct ggagcccgtg cagttcctca ggagtgtctt cgccaacagc 300ctggtgtacg gcgcctctga cagcaacgtc tatgacctcc taaaggacct agaggaaggc 360atccaaacgc tgatggggag gctggaagat ggcagccccc ggactgggca gatcttcaag 420cagacctaca gcaagttcga cacaaactca cacaacgatg acgcactact caagaactac 480gggctgctct actgcttcag gaaggacatg gacaaggtcg agacattcct gcgcatcgtg 540cagtgccgct ctgtggaggg cagctgtggc ttc 573182495DNAArtificial SequenceDescription of Artificial Sequence

Synthetic polynucleotide 182tgtgatctgc ctcaaaccca cagcctgggt agcaggagga ccttgatgct cctggcacag 60atgaggagaa tctctctttt ctcctgcttg aaggacagac atgactttgg atttccccag 120gaggagtttg gcaaccagtt ccaaaaggct gaaaccatcc ctgtcctcca tgagatgatc 180cagcagatct tcaatctctt cagcacaaag gactcatctg ctgcttggga tgagaccctc 240ctagacaaat tctacactga actctaccag cagctgaatg acctggaagc ctgtgtgata 300cagggggtgg gggtgacaga gactcccctg atgaaggagg actccattct ggctgtgagg 360aaatacttcc aaagaatcac tctctatctg aaagagaaga aatacagccc ttgtgcctgg 420gaggttgtca gagcagaaat catgagatct ttttctttgt caacaaactt gcaagaaagt 480ttaagaagta aggaa 495183170DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 183ctgaaatgtt accaacatgg taaagttgtg acttgtcatc gagatatgaa gttttgctat 60cataacactg gcatgccttt tcgaaatctc aagctcatcc tacagggatg ttcttcttcg 120tgcagtgaaa cagaaaacaa taagtgttgc tcaacagaca gatgcaacaa 170184252DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 184tctgtgagtg aaatacagct tatgcataac ctgggaaaac atctgaactc gatggagaga 60gtagaatggc tgcgtaagaa gctgcaggat gtgcacaatt ttgttgccct tggagctcct 120ctagctccca gagatgctgg ttcccagagg ccccgaaaaa aggaagacaa tgtcttggtt 180gagagccatg aaaaaagtct tggagaggca gacaaagctg atgtgaatgt attaactaaa 240gctaaatccc ag 252185597DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 185atgaactgcg tgtgccgcct ggtgctggtg gtgctgagcc tgtggccgga taccgcggtg 60gcgccgggcc cgccgccggg cccgccgcgc gtgagcccgg atccgcgcgc ggaactggat 120agcaccgtgc tgctgacccg cagcctgctg gcggataccc gccagctggc ggcgcagctg 180cgcgataaat ttccggcgga tggcgatcat aacctggata gcctgccgac cctggcgatg 240agcgcgggcg cgctgggcgc gctgcagctg ccgggcgtgc tgacccgcct gcgcgcggat 300ctgctgagct atctgcgcca tgtgcagtgg ctgcgccgcg cgggcggcag cagcctgaaa 360accctggaac cggaactggg caccctgcag gcgcgcctgg atcgcctgct gcgccgcctg 420cagctgctga tgagccgcct ggcgctgccg cagccgccgc cggatccgcc ggcgccgccg 480ctggcgccgc cgagcagcgc gtggggcggc attcgcgcgg cgctggcgat tctgggcggc 540ctgcatctga ccctggattg ggcggtgcgc ggcctgctgc tgctgaaaac ccgcctg 597186183DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 186gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60gctatctgcg gtatgtctac ctggtctggt ggcggtcgtg gcggtcgtca gctgtactct 120gctctggcta acaaatgctg ccacgttggt tgcaccaaac gttctctggc tcgtttctgc 180taa 183187489DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 187gatagctgga tggaagaagt gattaaactg tgcggccgcg aactggtgcg cgcgcagatt 60gcgatttgcg gcatgagcac ctggagcatt gaaggccgca gcctgagcca ggaagatgcg 120ccgcagaccc cgcgcccggt ggcggaaatt gtgccgagct ttattaacaa agataccgaa 180accattaaca tgatgagcga atttgtggcg aacctgccgc aggaactgaa actgaccctg 240agcgaaatgc agccggcgct gccgcagctg cagcagcatg tgccggtgct gaaagatagc 300agcctgctgt ttgaagaatt taaaaaactg attcgcaacc gccagagcga agcggcggat 360agcagcccga gcgaactgaa atatctgggc ctggataccc atagcattga aggccgccag 420ctgtatagcg cgctggcgaa caaatgctgc catgtgggct gcaccaaacg cagcctggcg 480cgcttttgc 489188306DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 188agcctgagcc aggaagatgc gccgcagacc ccgcgcccgg tggcggaaat tgtgccgagc 60tttattaaca aagataccga aaccattaac atgatgagcg aatttgtggc gaacctgccg 120caggaactga aactgaccct gagcgaaatg cagccggcgc tgccgcagct gcagcagcat 180gtgccggtgc tgaaagatag cagcctgctg tttgaagaat ttaaaaaact gattcgcaac 240cgccagagcg aagcggcgga tagcagcccg agcgaactga aatatctggg cctggatacc 300catagc 306189135DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 189gactcttgga tggaagaagt tatcaaactg tgcggtcgtg aactggttcg tgctcagatc 60gctatctgcg gtatgtctac ctggtctaaa cgttctctgt ctcaggaaga cgctccgcag 120accccgcgtc cggtt 13519072DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 190cagctgtact ctgctctggc taacaaatgc tgccacgttg gttgcaccaa acgttctctg 60gctcgtttct gc 72191222DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 191ccgcgcagcg cgaaagaact gcgctgccag tgcattaaaa cctatagcaa accgtttcat 60ccgaaattta ttaaagaact gcgcgtgatt gaaagcggcc cgcattgcgc gaacaccgaa 120attattgtga aactgagcga tggccgcgaa ctgtgcctgg atccgaaaga aaactgggtg 180cagcgcgtgg tggaaaaatt tctgaaacgc gcggaaaaca gc 22219275DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 192tgcaaaggca aaggcgcgaa atgcagccgc ctgatgtatg attgctgcac cggcagctgc 60cgcagcggca aatgc 7519345DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 193gcgggctgca aaaacttttt ttggaaaacc tttaccagct gcggc 45194102DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 194atgtgcatgc cgtgctttac caccgatcat cagatggcgc gcaaatgcga tgattgctgc 60ggcggcaaag gccgcggcaa atgctatggc ccgcagtgcc tg 102195204DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 195aaaccggtga gcctgagcta tcgctgcccg tgccgctttt ttgaaagcca tgtggcgcgc 60gcgaacgtga aacatctgaa aattctgaac accccgaact gcgcgctgca gattgtggcg 120cgcctgaaaa acaacaaccg ccaggtgtgc attgatccga aactgaaatg gattcaggaa 180tatctggaaa aagcgctgaa caaa 204196399DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 196cagggccagg atcgccatat gattcgcatg cgccagctga ttgatattgt ggatcagctg 60aaaaactatg tgaacgatct ggtgccggaa tttctgccgg cgccggaaga tgtggaaacc 120aactgcgaat ggagcgcgtt tagctgcttt cagaaagcgc agctgaaaag cgcgaacacc 180ggcaacaacg aacgcattat taacgtgagc attaaaaaac tgaaacgcaa accgccgagc 240accaacgcgg gccgccgcca gaaacatcgc ctgacctgcc cgagctgcga tagctatgaa 300aaaaaaccgc cgaaagaatt tctggaacgc tttaaaagcc tgctgcagaa aatgattcat 360cagcatctga gcagccgcac ccatggcagc gaagatagc 399197171DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 197gcgcaagagc cagtcaaagg tccagtctcc actaagcctg gctcctgccc cattatcttg 60atccggtgcg ccatgttgaa tccccctaac cgctgcttga aagatactga ctgcccagga 120atcaagaagt gctgtgaagg ctcttgcggg atggcctgtt tcgttcccca g 17119842DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 198tatcgcaaat gtagaggagg ccgaaggtgg tgctaccaaa ag 4219933DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 199atgtgtaccg caagcatacc accccaatgc tac 33200174PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 200Thr Pro Leu Gly Pro Ala Arg Ser Leu Pro Gln Ser Phe Leu Leu Lys 1 5 10 15 Cys Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu Gln 20 25 30 Glu Arg Leu Cys Ala Ala His Lys Leu Cys His Pro Glu Glu Leu Met 35 40 45 Leu Leu Arg His Ser Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser Cys 50 55 60 Ser Ser Gln Ser Leu Gln Leu Thr Ser Cys Leu Asn Gln Leu His Gly 65 70 75 80 Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile Ser 85 90 95 Pro Glu Leu Ala Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Thr Asp 100 105 110 Phe Ala Thr Asn Ile Trp Leu Gln Met Glu Asp Leu Gly Ala Ala Pro 115 120 125 Ala Val Gln Pro Thr Gln Gly Ala Met Pro Thr Phe Thr Ser Ala Phe 130 135 140 Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser Gln Leu His Arg Phe 145 150 155 160 Leu Glu Leu Ala Tyr Arg Gly Leu Arg Tyr Leu Ala Glu Pro 165 170 20139PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 201His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 20234PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 202Ile Asn Val Lys Cys Ser Leu Pro Gln Gln Cys Ile Lys Pro Cys Lys 1 5 10 15 Asp Ala Gly Met Arg Phe Gly Lys Cys Met Asn Lys Lys Cys Arg Cys 20 25 30 Tyr Ser 20336PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 203Ala Ala Ala Ile Ser Cys Val Gly Ser Pro Glu Cys Pro Pro Lys Cys 1 5 10 15 Arg Ala Gln Gly Cys Lys Asn Gly Lys Cys Met Asn Arg Lys Cys Lys 20 25 30 Cys Tyr Tyr Cys 35 204178PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 204Ala Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu 1 5 10 15 Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu 20 25 30 Gln Glu Lys Leu Val Ser Glu Cys Ala Thr Tyr Lys Leu Cys His Pro 35 40 45 Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro 50 55 60 Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser 65 70 75 80 Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu 85 90 95 Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu 100 105 110 Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu 115 120 125 Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe 130 135 140 Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His 145 150 155 160 Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala 165 170 175 Gln Pro 20530PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 205His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25 30 206166PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 206Ala Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg Tyr Leu 1 5 10 15 Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala Glu His 20 25 30 Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val Asn Phe 35 40 45 Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp 50 55 60 Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu 65 70 75 80 Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His Val Asp 85 90 95 Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu 100 105 110 Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser Ala Ala 115 120 125 Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val 130 135 140 Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala 145 150 155 160 Cys Arg Thr Gly Asp Arg 165 207127PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 207Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val 1 5 10 15 Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr 20 25 30 Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp 35 40 45 Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln 50 55 60 Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met 65 70 75 80 Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys 85 90 95 Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp 100 105 110 Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 115 120 125 208166PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 208Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln 1 5 10 15 Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu 20 25 30 Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln 35 40 45 Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln 50 55 60 Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn 65 70 75 80 Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn 85 90 95 His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr 100 105 110 Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg 115 120 125 Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr 130 135 140 Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu 145 150 155 160 Thr Gly Tyr Leu Arg Asn 165 20937PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 209His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn 20 25 30 Arg Asn Asn Ile Ala 35 210146PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 210Val Pro Ile Gln Lys Val Gln Asp Asp Thr Lys Thr Leu Ile Lys Thr 1 5 10 15 Ile Val Thr Arg Ile Asn Asp Ile Ser His Thr Gln Ser Val Ser Ser 20 25 30 Lys Gln Lys Val Thr Gly Leu Asp Phe Ile Pro Gly Leu His Pro Ile 35 40 45 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln Ile 50 55 60 Leu Thr Ser Met Pro Ser Arg Asn Val Ile Gln Ile Ser Asn Asp Leu 65 70 75 80 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 85 90 95 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 100 105 110 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 115 120 125 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 130 135 140 Gly Cys 145 211177PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 211Ala Pro Leu Gly Gly Pro Glu Pro Ala Gln Tyr Glu Glu Leu Thr Leu 1 5 10 15 Leu Phe His Gly Ala Leu Gln Leu Gly Gln Ala Leu Asn Gly Val Tyr 20 25 30 Arg Ala Thr Glu Ala Arg Leu Thr Glu Ala Gly His Ser Leu Gly Leu 35 40 45 Tyr Asp Arg Ala Leu Glu Phe Leu Gly Thr Glu Val Arg Gln Gly Gln 50 55 60 Asp Ala Thr Gln Glu Leu Arg Thr Ser Leu Ser Glu Ile Gln Val Glu 65 70 75 80 Glu Asp Ala Leu His Leu Arg Ala Glu Ala Thr Ala

Arg Ser Leu Gly 85 90 95 Glu Val Ala Arg Ala Gln Gln Ala Leu Arg Asp Thr Val Arg Arg Leu 100 105 110 Gln Val Gln Leu Arg Gly Ala Trp Leu Gly Gln Ala His Gln Glu Phe 115 120 125 Glu Thr Leu Lys Ala Arg Ala Asp Lys Gln Ser His Leu Leu Trp Ala 130 135 140 Leu Thr Gly His Val Gln Arg Gln Gln Arg Glu Met Ala Glu Gln Gln 145 150 155 160 Gln Trp Leu Arg Gln Ile Gln Gln Arg Leu His Thr Ala Ala Leu Pro 165 170 175 Ala 212109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 212Asn Leu Gly Leu Asp Cys Asp Glu His Ser Ser Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile 20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu 35 40 45 Tyr Met Phe Met Gln Lys Tyr Pro His Thr His Leu Val Gln Gln Ala 50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly 85 90 95 Lys Ile Pro Gly Met Val Val Asp Arg Cys Gly Cys Ser 100 105 213387PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 213Gly Ser Gly Gly Phe Thr Ile Lys Leu Leu Leu Phe Ile Val Pro Leu 1 5 10 15 Val Ile Ser Ser Arg Ile Asp Gln Asp Asn Ser Ser Phe Asp Ser Leu 20 25 30 Ser Pro Glu Pro Lys Ser Arg Phe Ala Met Leu Asp Asp Val Lys Ile 35 40 45 Leu Ala Asn Gly Leu Leu Gln Leu Gly His Gly Leu Lys Asp Phe Val 50 55 60 His Lys Thr Lys Gly Gln Ile Asn Asp Ile Phe Gln Lys Leu Asn Ile 65 70 75 80 Phe Asp Gln Ser Phe Tyr Asp Leu Ser Leu Gln Thr Ser Glu Ile Lys 85 90 95 Glu Glu Glu Lys Glu Leu Arg Arg Thr Thr Tyr Lys Leu Gln Val Lys 100 105 110 Asn Glu Glu Val Lys Asn Met Ser Leu Glu Leu Asn Ser Lys Leu Glu 115 120 125 Ser Leu Leu Glu Glu Lys Ile Leu Leu Gln Gln Lys Val Lys Tyr Leu 130 135 140 Glu Glu Gln Leu Thr Asn Leu Ile Gln Asn Gln Pro Glu Thr Pro Glu 145 150 155 160 His Pro Glu Val Thr Ser Leu Lys Thr Phe Val Glu Lys Gln Asp Asn 165 170 175 Ser Ile Lys Asp Leu Leu Gln Thr Val Glu Asp Gln Tyr Lys Gln Leu 180 185 190 Asn Gln Gln His Ser Gln Ile Lys Glu Ile Glu Asn Gln Leu Arg Arg 195 200 205 Thr Ser Ile Gln Glu Pro Thr Glu Ile Ser Leu Ser Ser Lys Pro Arg 210 215 220 Ala Pro Arg Thr Thr Pro Phe Leu Gln Leu Asn Glu Ile Arg Asn Val 225 230 235 240 Lys His Asp Gly Ile Pro Ala Glu Cys Thr Thr Ile Tyr Asn Arg Gly 245 250 255 Glu His Thr Ser Gly Met Tyr Ala Ile Arg Pro Ser Asn Ser Gln Val 260 265 270 Phe His Val Tyr Cys Asp Val Ile Ser Gly Ser Pro Trp Thr Leu Ile 275 280 285 Gln His Arg Ile Asp Gly Ser Gln Asn Phe Asn Glu Thr Trp Glu Asn 290 295 300 Tyr Lys Tyr Gly Phe Gly Arg Leu Asp Gly Glu Phe Trp Leu Gly Leu 305 310 315 320 Glu Lys Ile Tyr Ser Ile Val Lys Gln Ser Asn Tyr Val Leu Arg Ile 325 330 335 Glu Leu Glu Asp Trp Lys Asp Asn Lys His Tyr Ile Glu Tyr Ser Phe 340 345 350 Tyr Leu Gly Asn His Glu Thr Asn Tyr Thr Leu His Leu Val Ala Ile 355 360 365 Thr Gly Asn Val Pro Asn Ala Ile Pro Lys Lys Lys Lys Lys Lys Lys 370 375 380 Lys Lys Lys 385 214191PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 214Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg 1 5 10 15 Ala His Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu 20 25 30 Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro 35 40 45 Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg 50 55 60 Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu 65 70 75 80 Leu Leu Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val 85 90 95 Phe Ala Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp 100 105 110 Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu 115 120 125 Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser 130 135 140 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr 145 150 155 160 Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe 165 170 175 Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe 180 185 190 215165PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 215Cys Asp Leu Pro Gln Thr His Ser Leu Gly Ser Arg Arg Thr Leu Met 1 5 10 15 Leu Leu Ala Gln Met Arg Arg Ile Ser Leu Phe Ser Cys Leu Lys Asp 20 25 30 Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Gly Asn Gln Phe Gln 35 40 45 Lys Ala Glu Thr Ile Pro Val Leu His Glu Met Ile Gln Gln Ile Phe 50 55 60 Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu Thr Leu 65 70 75 80 Leu Asp Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp Leu Glu 85 90 95 Ala Cys Val Ile Gln Gly Val Gly Val Thr Glu Thr Pro Leu Met Lys 100 105 110 Glu Asp Ser Ile Leu Ala Val Arg Lys Tyr Phe Gln Arg Ile Thr Leu 115 120 125 Tyr Leu Lys Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val Val Arg 130 135 140 Ala Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln Glu Ser 145 150 155 160 Leu Arg Ser Lys Glu 165 21656PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 216Leu Lys Cys Tyr Gln His Gly Lys Val Val Thr Cys His Arg Asp Met 1 5 10 15 Lys Phe Cys Tyr His Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu 20 25 30 Ile Leu Gln Gly Cys Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys 35 40 45 Cys Cys Ser Thr Asp Arg Cys Asn 50 55 21784PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 217Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 65 70 75 80 Ala Lys Ser Gln 218199PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 218Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Thr Ala Val Ala Pro Gly Pro Pro Pro Gly Pro Pro Arg Val Ser 20 25 30 Pro Asp Pro Arg Ala Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Leu Arg Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Gly Val Leu Thr Arg 85 90 95 Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Gly Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr 115 120 125 Leu Gln Ala Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro Pro 145 150 155 160 Leu Ala Pro Pro Ser Ser Ala Trp Gly Gly Ile Arg Ala Ala Leu Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 21960PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 219Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Gly Gly Gly 20 25 30 Arg Gly Gly Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His 35 40 45 Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 50 55 60 220163PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 220Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ile Glu Gly 20 25 30 Arg Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala 35 40 45 Glu Ile Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met 50 55 60 Met Ser Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu 65 70 75 80 Ser Glu Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val 85 90 95 Leu Lys Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg 100 105 110 Asn Arg Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr 115 120 125 Leu Gly Leu Asp Thr His Ser Ile Glu Gly Arg Gln Leu Tyr Ser Ala 130 135 140 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 145 150 155 160 Arg Phe Cys 221102PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 221Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala Glu 1 5 10 15 Ile Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met Met 20 25 30 Ser Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu Ser 35 40 45 Glu Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val Leu 50 55 60 Lys Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg Asn 65 70 75 80 Arg Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr Leu 85 90 95 Gly Leu Asp Thr His Ser 100 22229PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 222Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 22324PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 223Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 22474PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 224Pro Arg Ser Ala Lys Glu Leu Arg Cys Gln Cys Ile Lys Thr Tyr Ser 1 5 10 15 Lys Pro Phe His Pro Lys Phe Ile Lys Glu Leu Arg Val Ile Glu Ser 20 25 30 Gly Pro His Cys Ala Asn Thr Glu Ile Ile Val Lys Leu Ser Asp Gly 35 40 45 Arg Glu Leu Cys Leu Asp Pro Lys Glu Asn Trp Val Gln Arg Val Val 50 55 60 Glu Lys Phe Leu Lys Arg Ala Glu Asn Ser 65 70 22525PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 225Cys Lys Gly Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys 1 5 10 15 Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25 22615PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 226Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly 1 5 10 15 22734PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 227Met Cys Met Pro Cys Phe Thr Thr Asp His Gln Met Ala Arg Lys Cys 1 5 10 15 Asp Asp Cys Cys Gly Gly Lys Gly Arg Gly Lys Cys Tyr Gly Pro Gln 20 25 30 Cys Leu 22868PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 228Lys Pro Val Ser Leu Ser Tyr Arg Cys Pro Cys Arg Phe Phe Glu Ser 1 5 10 15 His Val Ala Arg Ala Asn Val Lys His Leu Lys Ile Leu Asn Thr Pro 20 25 30 Asn Cys Ala Leu Gln Ile Val Ala Arg Leu Lys Asn Asn Asn Arg Gln 35 40 45 Val Cys Ile Asp Pro Lys Leu Lys Trp Ile Gln Glu Tyr Leu Glu Lys 50 55 60 Ala Leu Asn Lys 65 229133PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 229Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 23057PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 230Ala Gln Glu Pro Val Lys Gly Pro Val Ser Thr Lys Pro Gly Ser Cys 1 5 10 15 Pro Ile Ile Leu Ile Arg Cys Ala Met Leu Asn Pro Pro Asn Arg Cys 20 25 30 Leu Lys Asp Thr Asp Cys Pro Gly Ile Lys Lys Cys Cys Glu Gly Ser 35 40 45 Cys Gly Met Ala Cys Phe Val Pro Gln 50 55 23114PRTArtificial SequenceDescription

of Artificial Sequence Synthetic peptide 231Tyr Arg Lys Cys Arg Gly Gly Arg Arg Trp Cys Tyr Gln Lys 1 5 10 23214PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 232Tyr Arg Lys Cys Arg Gly Pro Arg Arg Trp Cys Tyr Gln Lys 1 5 10 23316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 233Tyr Arg Lys Cys Arg Gly Gly Asn Gly Arg Arg Trp Cys Tyr Gln Lys 1 5 10 15 23415PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 234Thr Ser Val His Gln Gly Gly Gly Gly Ser Trp His Val Asp Val 1 5 10 15 23511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 235Met Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr 1 5 10 23612DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 236atcgaaggtc gt 122374PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 237Ile Glu Gly Arg 1 23812DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 238cgtaaaaaac gt 122394PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 239Arg Lys Lys Arg 1 240423PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 240Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Gly Ser Gly Ala 20 25 30 Lys Leu Ala Ala Leu Lys Ala Lys Leu Ala Ala Leu Lys Gly Gly Gly 35 40 45 Gly Ser Ala Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg 50 55 60 Tyr Leu Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala 65 70 75 80 Glu His Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val 85 90 95 Asn Phe Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu 100 105 110 Val Trp Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln 115 120 125 Ala Leu Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His 130 135 140 Val Asp Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg 145 150 155 160 Ala Leu Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser 165 170 175 Ala Ala Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe 180 185 190 Arg Val Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly 195 200 205 Glu Ala Cys Arg Thr Gly Asp Arg Gly Gly Gly Gly Ser Glu Leu Ala 210 215 220 Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Thr 225 230 235 240 Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 245 250 255 Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 260 265 270 Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 275 280 285 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro 290 295 300 Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 305 310 315 320 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 325 330 335 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 340 345 350 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 355 360 365 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 370 375 380 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 385 390 395 400 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 405 410 415 Ser Phe Asn Arg Gly Glu Cys 420 241661PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 241Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Thr Pro Leu Gly Pro Ala Arg 115 120 125 Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys 130 135 140 Ile Gln Ala Asp Gly Ala Glu Leu Gln Glu Arg Leu Cys Ala Ala His 145 150 155 160 Lys Leu Cys His Pro Glu Glu Leu Met Leu Leu Arg His Ser Leu Gly 165 170 175 Ile Pro Gln Ala Pro Leu Ser Ser Cys Ser Ser Gln Ser Leu Gln Leu 180 185 190 Thr Ser Cys Leu Asn Gln Leu His Gly Gly Leu Phe Leu Tyr Gln Gly 195 200 205 Leu Leu Gln Ala Leu Ala Gly Ile Ser Pro Glu Leu Ala Pro Thr Leu 210 215 220 Asp Thr Leu Gln Leu Asp Val Thr Asp Phe Ala Thr Asn Ile Trp Leu 225 230 235 240 Gln Met Glu Asp Leu Gly Ala Ala Pro Ala Val Gln Pro Thr Gln Gly 245 250 255 Ala Met Pro Thr Phe Thr Ser Ala Phe Gln Arg Arg Ala Gly Gly Val 260 265 270 Leu Val Ala Ser Gln Leu His Arg Phe Leu Glu Leu Ala Tyr Arg Gly 275 280 285 Leu Arg Tyr Leu Ala Glu Pro Gly Gly Gly Gly Ser Glu Leu Ala Ala 290 295 300 Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly Ser Gly Asp Tyr 305 310 315 320 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 325 330 335 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 340 345 350 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 355 360 365 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 370 375 380 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 385 390 395 400 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 405 410 415 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 420 425 430 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 435 440 445 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 450 455 460 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 465 470 475 480 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 485 490 495 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 500 505 510 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 515 520 525 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 530 535 540 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 545 550 555 560 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 565 570 575 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 580 585 590 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 595 600 605 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 610 615 620 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 625 630 635 640 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 645 650 655 Leu Ser Pro Gly Lys 660 242662PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 242Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Ala Thr Pro Leu Gly Pro Ala 115 120 125 Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg 130 135 140 Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Val Ser Glu 145 150 155 160 Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly 165 170 175 His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln 180 185 190 Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe 195 200 205 Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu 210 215 220 Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr 225 230 235 240 Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln 245 250 255 Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg 260 265 270 Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val 275 280 285 Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Gly Gly Gly Gly Ser 290 295 300 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 305 310 315 320 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 325 330 335 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 340 345 350 Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 355 360 365 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 370 375 380 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 385 390 395 400 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr 405 410 415 Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 420 425 430 Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 435 440 445 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 450 455 460 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 465 470 475 480 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 485 490 495 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 500 505 510 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 515 520 525 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 530 535 540 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 545 550 555 560 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 565 570 575 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 580 585 590 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 595 600 605 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 610 615 620 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 625 630 635 640 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 645 650 655 Ser Leu Ser Leu Gly Lys 660 243630PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 243Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Ser Gly Ala Lys Leu Ala Ala Leu Lys Ala Lys Leu 100 105 110 Ala Ala Leu Lys Gly Gly Gly Gly Ser Val Pro Ile Gln Lys Val Gln 115 120 125 Asp Asp Thr Lys Thr Leu Ile Lys Thr Ile Val Thr Arg Ile Asn Asp 130 135 140 Ile Ser His Thr Gln Ser Val Ser Ser Lys Gln Lys Val Thr Gly Leu 145 150 155 160 Asp Phe Ile Pro Gly Leu His Pro Ile Leu Thr Leu Ser Lys Met Asp 165 170 175 Gln Thr Leu Ala Val Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser Arg 180 185 190 Asn Val Ile Gln Ile Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu 195 200 205 His Val Leu Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly 210 215 220 Leu Glu Thr Leu Asp Ser Leu Gly Gly Val Leu Glu Ala Ser Gly Tyr 225 230 235 240 Ser Thr Glu Val Val Ala Leu Ser Arg Leu Gln Gly Ser Leu Gln Asp 245 250 255 Met Leu Trp Gln Leu Asp Leu Ser Pro Gly Cys Gly Gly Gly Gly Ser 260 265 270 Glu Leu Ala Ala Leu Glu Ala Glu Leu Ala Ala Leu Glu Ala Gly Gly 275 280 285 Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 290 295 300 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 305 310

315 320 Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 325 330 335 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 340 345 350 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 355 360 365 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr 370 375 380 Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 385 390 395 400 Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 405 410 415 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 420 425 430 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 435 440 445 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 450 455 460 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 465 470 475 480 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 485 490 495 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 500 505 510 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 515 520 525 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 530 535 540 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 545 550 555 560 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 565 570 575 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 580 585 590 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 595 600 605 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 610 615 620 Ser Leu Ser Leu Gly Lys 625 630 244387PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 244Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Gly Gly Gly Ser 20 25 30 Ala Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg Tyr Leu 35 40 45 Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala Glu His 50 55 60 Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val Asn Phe 65 70 75 80 Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp 85 90 95 Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu 100 105 110 Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His Val Asp 115 120 125 Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu 130 135 140 Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser Ala Ala 145 150 155 160 Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val 165 170 175 Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala 180 185 190 Cys Arg Thr Gly Asp Arg Gly Gly Gly Gly Ser Thr Ala Val Ala Trp 195 200 205 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala 210 215 220 Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 225 230 235 240 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 245 250 255 Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly 260 265 270 Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 275 280 285 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser 290 295 300 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 305 310 315 320 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 325 330 335 Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 340 345 350 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 355 360 365 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 370 375 380 Gly Glu Cys 385 245625PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 245Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Thr Pro Leu Gly Pro Ala Arg Ser Leu 100 105 110 Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile Gln 115 120 125 Ala Asp Gly Ala Glu Leu Gln Glu Arg Leu Cys Ala Ala His Lys Leu 130 135 140 Cys His Pro Glu Glu Leu Met Leu Leu Arg His Ser Leu Gly Ile Pro 145 150 155 160 Gln Ala Pro Leu Ser Ser Cys Ser Ser Gln Ser Leu Gln Leu Thr Ser 165 170 175 Cys Leu Asn Gln Leu His Gly Gly Leu Phe Leu Tyr Gln Gly Leu Leu 180 185 190 Gln Ala Leu Ala Gly Ile Ser Pro Glu Leu Ala Pro Thr Leu Asp Thr 195 200 205 Leu Gln Leu Asp Val Thr Asp Phe Ala Thr Asn Ile Trp Leu Gln Met 210 215 220 Glu Asp Leu Gly Ala Ala Pro Ala Val Gln Pro Thr Gln Gly Ala Met 225 230 235 240 Pro Thr Phe Thr Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val 245 250 255 Ala Ser Gln Leu His Arg Phe Leu Glu Leu Ala Tyr Arg Gly Leu Arg 260 265 270 Tyr Leu Ala Glu Pro Gly Gly Gly Gly Ser Asp Tyr Trp Gly Gln Gly 275 280 285 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 290 295 300 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 305 310 315 320 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 325 330 335 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 340 345 350 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 355 360 365 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 370 375 380 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 385 390 395 400 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 405 410 415 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 420 425 430 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 435 440 445 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 450 455 460 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 465 470 475 480 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 485 490 495 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 500 505 510 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 515 520 525 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 530 535 540 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 545 550 555 560 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 565 570 575 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 580 585 590 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 595 600 605 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 610 615 620 Lys 625 246626PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 246Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Ala Thr Pro Leu Gly Pro Ala Ser Ser 100 105 110 Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile 115 120 125 Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Val Ser Glu Cys Ala 130 135 140 Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser 145 150 155 160 Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu 165 170 175 Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr 180 185 190 Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro 195 200 205 Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile 210 215 220 Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr 225 230 235 240 Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly 245 250 255 Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr 260 265 270 Arg Val Leu Arg His Leu Ala Gln Pro Gly Gly Gly Gly Ser Asp Tyr 275 280 285 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 290 295 300 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 305 310 315 320 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 325 330 335 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 340 345 350 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 355 360 365 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 370 375 380 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 385 390 395 400 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 405 410 415 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 420 425 430 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 435 440 445 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 450 455 460 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 465 470 475 480 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 485 490 495 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 500 505 510 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 515 520 525 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 530 535 540 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 545 550 555 560 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 565 570 575 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 580 585 590 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 595 600 605 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 610 615 620 Gly Lys 625 247594PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 247Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Gly Gly Gly Gly Ser Val Pro Ile Gln Lys Val Gln Asp Asp 100 105 110 Thr Lys Thr Leu Ile Lys Thr Ile Val Thr Arg Ile Asn Asp Ile Ser 115 120 125 His Thr Gln Ser Val Ser Ser Lys Gln Lys Val Thr Gly Leu Asp Phe 130 135 140 Ile Pro Gly Leu His Pro Ile Leu Thr Leu Ser Lys Met Asp Gln Thr 145 150 155 160 Leu Ala Val Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser Arg Asn Val 165 170 175 Ile Gln Ile Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu His Val 180 185 190 Leu Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu 195 200 205 Thr Leu Asp Ser Leu Gly Gly Val Leu Glu Ala Ser Gly Tyr Ser Thr 210 215 220 Glu Val Val Ala Leu Ser Arg Leu Gln Gly Ser Leu Gln Asp Met Leu 225 230 235 240 Trp Gln Leu Asp Leu Ser Pro Gly Cys Gly Gly Gly Gly Ser Asp Tyr 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 260 265 270 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 275 280 285 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 290 295 300 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

Val His Thr Phe 305 310 315 320 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 325 330 335 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 340 345 350 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 355 360 365 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 370 375 380 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390 395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 405 410 415 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 500 505 510 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 545 550 555 560 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 580 585 590 Gly Lys 248169PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 248Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Pro Asp Gly Tyr 100 105 110 Arg Glu Arg Ser Asp Cys Ser Asn Arg Pro Ala Cys Gly Thr Ser Asp 115 120 125 Cys Cys Arg Val Ser Val Phe Gly Asn Cys Leu Thr Thr Leu Pro Val 130 135 140 Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly 145 150 155 160 Gln Gly Leu Leu Val Thr Val Ser Ser 165 249164PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 249Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Ser Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Thr Val His Gln Glu Thr Arg Lys Thr Cys Ser Asp Gly Tyr Ile Ala 100 105 110 Val Asp Ser Cys Gly Arg Gly Gln Ser Asp Gly Cys Val Asn Asp Cys 115 120 125 Asn Ser Cys Tyr Tyr Gly Trp Arg Asn Cys Arg Arg Gln Pro Ala Ile 130 135 140 His Ser Tyr Glu Phe His Val Asp Ala Trp Gly Arg Gly Leu Leu Val 145 150 155 160 Thr Val Ser Ser 250165PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 250Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Arg Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Thr Thr Asp Thr Gly Gly Ser Ala Ala Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Asn Val Ala Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Ser 85 90 95 Ser Val Thr Gln Arg Thr His Val Ser Arg Ser Cys Pro Asp Gly Cys 100 105 110 Ser Asp Gly Asp Gly Cys Val Asp Gly Cys Cys Cys Ser Ala Tyr Arg 115 120 125 Cys Tyr Thr Pro Gly Val Arg Asp Leu Ser Cys Thr Ser Tyr Ser Ile 130 135 140 Thr Tyr Thr Tyr Glu Trp Asn Val Asp Ala Trp Gly Gln Gly Leu Leu 145 150 155 160 Val Thr Val Ser Ser 165 251216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 251Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 252216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 252Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 253216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 253Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 254840DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 254caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctgtcctgac ggctatcggg agagatctga ttgcagtaat 360aggccagctt gtggcacatc cgactgctgt cgcgtgtctg tcttcgggaa ctgcctgact 420accctgcctg tgtcctactc ttatacctac aattatgaat ggcatgtgga tgtctgggga 480cagggcctgc tggtgacagt ctctagtgct tccacaactg caccaaaggt gtaccccctg 540tcaagctgct gtggggacaa atcctctagt accgtgacac tgggatgcct ggtctcaagc 600tatatgcccg agcctgtgac tgtcacctgg aactcaggag ccctgaaaag cggagtgcac 660accttcccag ctgtgctgca gtcctctggc ctgtatagcc tgagttcaat ggtgacagtc 720cccggcagta cttcagggca gaccttcacc tgtaatgtgg cccatcctgc cagctccacc 780aaagtggaca aagcagtgga acccaaatct tgcgacggca gccatcacca tcatcatcac 840255825DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 255caggtccagc tgagagagag cgggccttca ctggtccagc cttcacagac actgagcctg 60acttgtactg cctccgggtt ttcactgtct gacaaggctg tgggatgggt ccgacaggca 120ccagggaaag ctctggagtg gctgggaagt atcgataccg gcgggtcaac agggtacaac 180cctggactga agtccagact gtctattact aaggacaatt ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggattct gcaacatact attgcactac cgtgcaccag 300gaaacaagga aaacttgtag tgacggctat atcgcagtgg atagctgcgg acgaggacag 360tccgacggat gcgtgaacga ttgcaatagc tgttactatg gatggcgaaa ctgccggaga 420cagccagcaa ttcattcata cgagtttcat gtggatgctt gggggcgggg gctgctggtc 480accgtctcct cagcttccac aactgcacca aaggtgtacc ccctgtcaag ctgctgtggg 540gacaaatcct ctagtaccgt gacactggga tgcctggtct caagctatat gcccgagcct 600gtgactgtca cctggaactc aggagccctg aaaagcggag tgcacacctt cccagctgtg 660ctgcagtcct ctggcctgta tagcctgagt tcaatggtga cagtccccgg cagtacttca 720gggcagacct tcacctgtaa tgtggcccat cctgccagct ccaccaaagt ggacaaagca 780gtggaaccca aatcttgcga cggcagccat caccatcatc atcac 825256828DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 256caggtccagc tgagggaatc cggcccatca ctggtcaagc cttcacagac actgagcctg 60acatgtactg caagcgggtt ttcactgagt gacaaggcag tgggatgggt ccggagagca 120ccaggaaaag ccctggagtg gctgggaacc acagatactg gaggatccgc cgcttacaac 180cctggcctga agtcccggct gtctatcacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgtcca atgtcgctac agaagattct gcaacttact attgtagctc cgtgactcag 300aggacccacg tctctcgcag ttgtccagac gggtgcagtg acggagatgg ctgcgtggat 360ggatgctgtt gctcagctta ccgatgttat acacccgggg tcagagacct gagctgcacc 420tcatatagca ttacatacac ttacgaatgg aatgtggatg cttggggaca gggactgctg 480gtgaccgtct cttcagcttc cacaactgca ccaaaggtgt accccctgtc aagctgctgt 540ggggacaaat cctctagtac cgtgacactg ggatgcctgg tctcaagcta tatgcccgag 600cctgtgactg tcacctggaa ctcaggagcc ctgaaaagcg gagtgcacac cttcccagct 660gtgctgcagt cctctggcct gtatagcctg agttcaatgg tgacagtccc cggcagtact 720tcagggcaga ccttcacctg taatgtggcc catcctgcca gctccaccaa agtggacaaa 780gcagtggaac ccaaatcttg cgacggcagc catcaccatc atcatcac 828257648DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 257caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300tttggaagcg gcaccacact gacagtcctg gggcagccca agagtccccc ttcagtgact 360ctgttcccac cctctaccga ggaactgaac ggaaacaagg ccacactggt gtgtctgatc 420agcgactttt accctggatc cgtcactgtg gtctggaagg cagatggcag cacaattact 480aggaacgtgg aaactacccg cgcctccaag cagtctaata gtaaatacgc cgccagctcc 540tatctgagcc tgacctctag tgattggaag tccaaagggt catatagctg cgaagtgacc 600catgaaggct caaccgtgac taagactgtg aaaccatccg agtgctcc 648258648DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 258caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300tttggaagcg gcaccacact gacagtcctg gggcagccca agagtccccc ttcagtgact 360ctgttcccac cctctaccga ggaactgaac ggaaacaagg ccacactggt gtgtctgatc 420agcgactttt accctggatc cgtcactgtg gtctggaagg cagatggcag cacaattact 480aggaacgtgg aaactacccg cgcctccaag cagtctaata gtaaatacgc cgccagctcc 540tatctgagcc tgacctctag tgattggaag tccaaagggt catatagctg cgaagtgacc 600catgaaggct caaccgtgac taagactgtg aaaccatccg agtgctcc 648259648DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 259caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300tttggaagcg gcaccacact gacagtcctg gggcagccca agagtccccc ttcagtgact 360ctgttcccac cctctaccga ggaactgaac ggaaacaagg ccacactggt gtgtctgatc 420agcgactttt accctggatc cgtcactgtg gtctggaagg cagatggcag cacaattact 480aggaacgtgg aaactacccg cgcctccaag cagtctaata gtaaatacgc cgccagctcc 540tatctgagcc tgacctctag tgattggaag tccaaagggt catatagctg cgaagtgacc 600catgaaggct caaccgtgac taagactgtg aaaccatccg agtgctcc 648260615PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 260Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu

Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Val Pro Ile Gln Lys Val Gln Asp Asp Thr Lys Thr Leu Ile Lys Thr 115 120 125 Ile Val Thr Arg Ile Asn Asp Ile Ser His Thr Gln Ser Val Ser Ser 130 135 140 Lys Gln Lys Val Thr Gly Leu Asp Phe Ile Pro Gly Leu His Pro Ile 145 150 155 160 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln Ile 165 170 175 Leu Thr Ser Met Pro Ser Arg Asn Val Ile Gln Ile Ser Asn Asp Leu 180 185 190 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 195 200 205 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 210 215 220 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 225 230 235 240 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 245 250 255 Gly Cys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His 260 265 270 Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser 275 280 285 Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys 290 295 300 Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro 305 310 315 320 Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val 325 330 335 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 340 345 350 Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys 355 360 365 Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu 370 375 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385 390 395 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405 410 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420 425 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435 440 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450 455 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465 470 475 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485 490 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500 505 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515 520 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530 535 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545 550 555 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565 570 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580 585 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595 600 605 Leu Ser Leu Ser Pro Gly Lys 610 615 261493PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 261Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ile Asn Val Lys Cys 100 105 110 Ser Leu Pro Gln Gln Cys Ile Lys Pro Cys Lys Asp Ala Gly Met Arg 115 120 125 Phe Gly Lys Cys Met Asn Lys Lys Cys Arg Cys Tyr Ser Ser Tyr Thr 130 135 140 Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val 145 150 155 160 Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser 165 170 175 Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu 180 185 190 Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly 195 200 205 Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 210 215 220 Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser 225 230 235 240 Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys 245 250 255 Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 260 265 270 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 370 375 380 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 385 390 395 400 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 405 410 415 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 420 425 430 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 450 455 460 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 262503PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 262Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Ile Asn Val Lys Cys Ser Leu Pro Gln Gln Cys Ile Lys Pro Cys Lys 115 120 125 Asp Ala Gly Met Arg Phe Gly Lys Cys Met Asn Lys Lys Cys Arg Cys 130 135 140 Tyr Ser Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His 145 150 155 160 Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser 165 170 175 Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys 180 185 190 Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro 195 200 205 Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val 210 215 220 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 225 230 235 240 Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys 245 250 255 Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu 260 265 270 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 275 280 285 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 290 295 300 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 305 310 315 320 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 325 330 335 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 340 345 350 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 355 360 365 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 370 375 380 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 385 390 395 400 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 405 410 415 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 420 425 430 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 435 440 445 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 450 455 460 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 465 470 475 480 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 485 490 495 Leu Ser Leu Ser Pro Gly Lys 500 263505PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 263Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Ala Ala Ala Ile Ser Cys Val Gly Ser Pro Glu Cys Pro Pro Lys Cys 115 120 125 Arg Ala Gln Gly Cys Lys Asn Gly Lys Cys Met Asn Arg Lys Cys Lys 130 135 140 Cys Tyr Tyr Cys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu 145 150 155 160 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 165 170 175 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 180 185 190 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr 195 200 205 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 210 215 220 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 225 230 235 240 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 245 250 255 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 260 265 270 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 275 280 285 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 290 295 300 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 305 310 315 320 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 325 330 335 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 340 345 350 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 355 360 365 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 370 375 380 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 385 390 395 400 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 405 410 415 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 420 425 430 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 435 440 445 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 450 455 460 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 465 470 475 480 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 485 490 495 Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 264513PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 264Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Ala Ala Ala Ile Ser Cys Val Gly Ser Pro Glu Cys 115 120 125 Pro Pro Lys Cys Arg Ala Gln Gly Cys Lys Asn Gly Lys Cys Met Asn 130 135 140 Arg Lys Cys Lys Cys Tyr Tyr Cys Gly Gly Gly Gly Ser Gly Gly Gly 145 150 155

160 Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln 165 170 175 Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val 180 185 190 Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr 195 200 205 Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr 210 215 220 Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val 225 230 235 240 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro 245 250 255 Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala 260 265 270 Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Lys 275 280 285 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 290 295 300 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 305 310 315 320 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 325 330 335 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 340 345 350 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 355 360 365 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 370 375 380 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 385 390 395 400 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 405 410 415 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 420 425 430 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 435 440 445 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 450 455 460 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 465 470 475 480 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 485 490 495 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 500 505 510 Lys 265505PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 265Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Gly Gly Gly Gly 100 105 110 Ser Ile Glu Gly Arg His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser 115 120 125 Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val 130 135 140 Lys Gly Arg Gly Gly Gly Gly Ser Cys Ser Tyr Thr Tyr Asn Tyr Glu 145 150 155 160 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 165 170 175 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 180 185 190 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr 195 200 205 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 210 215 220 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 225 230 235 240 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 245 250 255 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 260 265 270 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 275 280 285 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 290 295 300 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 305 310 315 320 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 325 330 335 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 340 345 350 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 355 360 365 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 370 375 380 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 385 390 395 400 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 405 410 415 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 420 425 430 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 435 440 445 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 450 455 460 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 465 470 475 480 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 485 490 495 Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 266514PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 266Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Gly Gly Gly Gly 100 105 110 Ser Ile Glu Gly Arg His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser 115 120 125 Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys 130 135 140 Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly 145 150 155 160 Ser Cys Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly 165 170 175 Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys 180 185 190 Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val 195 200 205 Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val 210 215 220 Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala 225 230 235 240 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val 245 250 255 Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro 260 265 270 Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp 275 280 285 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 290 295 300 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 305 310 315 320 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 325 330 335 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 340 345 350 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 355 360 365 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 370 375 380 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 385 390 395 400 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 405 410 415 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 420 425 430 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 435 440 445 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 450 455 460 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 465 470 475 480 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 485 490 495 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 500 505 510 Gly Lys 267635PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 267Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Ala Pro Pro Arg Leu Ile Cys Asp Ser Arg Val Leu Glu Arg Tyr Leu 115 120 125 Leu Glu Ala Lys Glu Ala Glu Asn Ile Thr Thr Gly Cys Ala Glu His 130 135 140 Cys Ser Leu Asn Glu Asn Ile Thr Val Pro Asp Thr Lys Val Asn Phe 145 150 155 160 Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp 165 170 175 Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu 180 185 190 Leu Val Asn Ser Ser Gln Pro Trp Glu Pro Leu Gln Leu His Val Asp 195 200 205 Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu 210 215 220 Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser Ala Ala 225 230 235 240 Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val 245 250 255 Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala 260 265 270 Cys Arg Thr Gly Asp Arg Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn 275 280 285 Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val 290 295 300 Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys 305 310 315 320 Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser 325 330 335 Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu 340 345 350 Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 355 360 365 Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln 370 375 380 Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 385 390 395 400 Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 405 410 415 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 420 425 430 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 435 440 445 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 450 455 460 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 465 470 475 480 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 485 490 495 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 500 505 510 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 515 520 525 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 530 535 540 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 545 550 555 560 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 565 570 575 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 580 585 590 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 595 600 605 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 610 615 620 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 625 630 635 268506PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 268Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 115 120 125 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn 130 135 140 Arg Asn Asn Ile Ala Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr 145 150 155 160 Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser 165 170 175 Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys 180 185 190 Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser 195 200 205 Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys 210 215 220 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 225 230 235 240 Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr 245 250

255 Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys 260 265 270 Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 275 280 285 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 290 295 300 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 305 310 315 320 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 325 330 335 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 340 345 350 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 355 360 365 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 370 375 380 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 385 390 395 400 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 405 410 415 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 420 425 430 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 435 440 445 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 450 455 460 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 465 470 475 480 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 485 490 495 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 269526PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 269Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Leu Lys Cys Tyr Gln His Gly Lys Val Val Thr Cys His Arg Asp Met 115 120 125 Lys Phe Cys Tyr His Asn Thr Gly Met Pro Phe Arg Asn Leu Lys Leu 130 135 140 Ile Leu Gln Gly Cys Ser Ser Ser Cys Ser Glu Thr Glu Asn Asn Lys 145 150 155 160 Cys Cys Ser Thr Asp Arg Cys Asn Lys Gly Gly Gly Gly Ser Ser Tyr 165 170 175 Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu 180 185 190 Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu 195 200 205 Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys 210 215 220 Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser 225 230 235 240 Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 245 250 255 Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr 260 265 270 Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 275 280 285 Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 290 295 300 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 305 310 315 320 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 325 330 335 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 340 345 350 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 355 360 365 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 370 375 380 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 385 390 395 400 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 405 410 415 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 420 425 430 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 435 440 445 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 450 455 460 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 465 470 475 480 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 485 490 495 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 500 505 510 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 525 270596PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 270Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val 115 120 125 Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr 130 135 140 Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp 145 150 155 160 Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln 165 170 175 Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met 180 185 190 Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys 195 200 205 Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp 210 215 220 Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu Gly 225 230 235 240 Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val 245 250 255 Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala 260 265 270 Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser 275 280 285 Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val 290 295 300 Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe 305 310 315 320 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val 325 330 335 Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala 340 345 350 His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser 355 360 365 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 370 375 380 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 385 390 395 400 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 405 410 415 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 420 425 430 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 435 440 445 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 450 455 460 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 465 470 475 480 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 485 490 495 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 500 505 510 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 515 520 525 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 530 535 540 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 545 550 555 560 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 565 570 575 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 580 585 590 Ser Pro Gly Lys 595 271647PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 271Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Pro Gly Pro Pro Pro Gly Pro Pro Arg Val Ser Pro Asp Pro Arg Ala 115 120 125 Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser Leu Leu Ala Asp Thr 130 135 140 Arg Gln Leu Ala Ala Gln Leu Arg Asp Lys Phe Pro Ala Asp Gly Asp 145 150 155 160 His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met Ser Ala Gly Ala Leu 165 170 175 Gly Ala Leu Gln Leu Pro Gly Val Leu Thr Arg Leu Arg Ala Asp Leu 180 185 190 Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg Arg Ala Gly Gly Ser 195 200 205 Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr Leu Gln Ala Arg Leu 210 215 220 Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met Ser Arg Leu Ala Leu 225 230 235 240 Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro Pro Leu Ala Pro Pro Ser 245 250 255 Ser Ala Trp Gly Gly Ile Arg Ala Ala His Ala Ile Leu Gly Gly Leu 260 265 270 His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu Leu Leu Leu Lys Thr 275 280 285 Arg Leu Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His 290 295 300 Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser 305 310 315 320 Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys 325 330 335 Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro 340 345 350 Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val 355 360 365 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 370 375 380 Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys 385 390 395 400 Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu 405 410 415 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 420 425 430 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 435 440 445 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 450 455 460 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 465 470 475 480 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 485 490 495 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 500 505 510 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 515 520 525 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 530 535 540 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 545 550 555 560 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 565 570 575 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 580 585 590 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 595 600 605 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 610 615 620 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 625 630 635 640 Leu Ser Leu Ser Pro Gly Lys 645 272635PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 272Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln 115 120 125 Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu 130 135 140 Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln 145 150 155 160 Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln 165 170 175 Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn 180 185 190 Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn 195 200 205 His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr 210 215 220 Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg 225 230

235 240 Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr 245 250 255 Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu 260 265 270 Thr Gly Tyr Leu Arg Asn Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn 275 280 285 Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val 290 295 300 Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys 305 310 315 320 Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser 325 330 335 Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu 340 345 350 Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 355 360 365 Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln 370 375 380 Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 385 390 395 400 Lys Ala Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 405 410 415 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 420 425 430 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 435 440 445 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 450 455 460 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 465 470 475 480 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 485 490 495 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 500 505 510 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 515 520 525 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 530 535 540 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 545 550 555 560 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 565 570 575 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 580 585 590 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 595 600 605 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 610 615 620 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 625 630 635 273553PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 273Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 115 120 125 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 130 135 140 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 145 150 155 160 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 165 170 175 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys 180 185 190 Ala Lys Ser Gln Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu 195 200 205 Trp His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser 210 215 220 Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly 225 230 235 240 Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr 245 250 255 Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser 260 265 270 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 275 280 285 Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe 290 295 300 Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala 305 310 315 320 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 325 330 335 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 340 345 350 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 355 360 365 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 370 375 380 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 385 390 395 400 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 405 410 415 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 420 425 430 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 435 440 445 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 450 455 460 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 465 470 475 480 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 485 490 495 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 500 505 510 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 515 520 525 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 530 535 540 Lys Ser Leu Ser Leu Ser Pro Gly Lys 545 550 274630PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 274Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 115 120 125 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Lys Arg Ser 130 135 140 Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala Glu Ile 145 150 155 160 Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met Met Ser 165 170 175 Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu Ser Glu 180 185 190 Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val Leu Lys 195 200 205 Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg Asn Arg 210 215 220 Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr Leu Gly 225 230 235 240 Leu Asp Thr His Ser Arg Lys Lys Arg Gln Leu Tyr Ser Ala Leu Ala 245 250 255 Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe 260 265 270 Cys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val 275 280 285 Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr 290 295 300 Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser 305 310 315 320 Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu 325 330 335 Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His 340 345 350 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 355 360 365 Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn 370 375 380 Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro 385 390 395 400 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 405 410 415 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 420 425 430 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 435 440 445 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 450 455 460 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 465 470 475 480 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 485 490 495 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 500 505 510 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 515 520 525 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 530 535 540 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 545 550 555 560 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 565 570 575 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 580 585 590 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 595 600 605 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 610 615 620 Ser Leu Ser Pro Gly Lys 625 630 275529PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 275Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 115 120 125 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Gly Gly Ser 130 135 140 Ile Glu Gly Arg Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His 145 150 155 160 Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly 165 170 175 Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln 180 185 190 Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val 195 200 205 Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr 210 215 220 Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr 225 230 235 240 Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val 245 250 255 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro 260 265 270 Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala 275 280 285 Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Lys 290 295 300 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 305 310 315 320 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 325 330 335 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 340 345 350 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 355 360 365 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 370 375 380 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 385 390 395 400 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 405 410 415 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 420 425 430 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 435 440 445 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 450 455 460 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 465 470 475 480 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 485 490 495 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 500 505 510 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 515 520 525 Lys 276632PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 276Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 115 120 125 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ile Glu Gly 130 135 140 Arg Ser Leu Ser Gln Glu Asp Ala Pro Gln Thr Pro Arg Pro Val Ala 145

150 155 160 Glu Ile Val Pro Ser Phe Ile Asn Lys Asp Thr Glu Thr Ile Asn Met 165 170 175 Met Ser Glu Phe Val Ala Asn Leu Pro Gln Glu Leu Lys Leu Thr Leu 180 185 190 Ser Glu Met Gln Pro Ala Leu Pro Gln Leu Gln Gln His Val Pro Val 195 200 205 Leu Lys Asp Ser Ser Leu Leu Phe Glu Glu Phe Lys Lys Leu Ile Arg 210 215 220 Asn Arg Gln Ser Glu Ala Ala Asp Ser Ser Pro Ser Glu Leu Lys Tyr 225 230 235 240 Leu Gly Leu Asp Thr His Ser Ile Glu Gly Arg Gln Leu Tyr Ser Ala 245 250 255 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 260 265 270 Arg Phe Cys Gly Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp 275 280 285 His Val Asp Val Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala 290 295 300 Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp 305 310 315 320 Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met 325 330 335 Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly 340 345 350 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 355 360 365 Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr 370 375 380 Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val 385 390 395 400 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 405 410 415 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 420 425 430 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 435 440 445 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 450 455 460 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 465 470 475 480 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 485 490 495 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 500 505 510 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 515 520 525 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 530 535 540 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 545 550 555 560 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 565 570 575 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 580 585 590 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 595 600 605 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 610 615 620 Ser Leu Ser Leu Ser Pro Gly Lys 625 630 277660PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 277Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys 20 25 30 Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys 50 55 60 Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu 65 70 75 80 Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr 85 90 95 Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Gly Gly Gly Gly Ser 100 105 110 Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg 115 120 125 Ala His Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu 130 135 140 Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro 145 150 155 160 Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg 165 170 175 Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu 180 185 190 Leu Leu Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val 195 200 205 Phe Ala Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp 210 215 220 Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu 225 230 235 240 Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser 245 250 255 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr 260 265 270 Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe 275 280 285 Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe Gly 290 295 300 Gly Gly Gly Ser Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val 305 310 315 320 Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala 325 330 335 Pro Lys Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser 340 345 350 Thr Val Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val 355 360 365 Thr Val Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe 370 375 380 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val 385 390 395 400 Thr Val Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala 405 410 415 His Pro Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser 420 425 430 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 435 440 445 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 450 455 460 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 465 470 475 480 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 485 490 495 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 500 505 510 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 515 520 525 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 530 535 540 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 545 550 555 560 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 565 570 575 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 580 585 590 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 595 600 605 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 610 615 620 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 625 630 635 640 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 645 650 655 Ser Pro Gly Lys 660 278216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 278Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly 20 25 30 Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu 35 40 45 Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser 85 90 95 Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu 115 120 125 Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr 145 150 155 160 Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys 180 185 190 Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys 195 200 205 Thr Val Lys Pro Ser Glu Cys Ser 210 215 2791845DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 279caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cggtggcgga ggatctgttc caattcaaaa ggttcaagat 360gataccaaaa ctctgattaa aactattgtc acgcgtataa acgacatcag ccatacccag 420tcggttagct caaagcaaaa agttaccggt ttggacttta ttccgggact gcacccgatc 480ctgaccctta gtaaaatgga ccagacactg gccgtctacc agcaaatcct gacatcgatg 540ccatccagaa atgtgataca aattagcaac gatttggaaa accttcgcga tctgctgcac 600gtgctggcct tcagtaagtc ctgtcatctg ccgtgggcgt cgggactgga gactcttgac 660tcgctgggtg gagtgttaga ggcctctggc tattctactg aagtcgttgc gctgtcacgc 720ctccagggga gcctgcagga catgctgtgg cagctggacc tgtcacctgg ctgcggaggt 780ggtggttcat cttataccta caattatgaa tggcatgtgg atgtctgggg acagggcctg 840ctggtgacag tctctagtgc ttccacaact gcaccaaagg tgtaccccct gtcaagctgc 900tgtggggaca aatcctctag taccgtgaca ctgggatgcc tggtctcaag ctatatgccc 960gagcctgtga ctgtcacctg gaactcagga gccctgaaaa gcggagtgca caccttccca 1020gctgtgctgc agtcctctgg cctgtatagc ctgagttcaa tggtgacagt ccccggcagt 1080acttcagggc agaccttcac ctgtaatgtg gcccatcctg ccagctccac caaagtggac 1140aaagcagtgg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 1200gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1260atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1320gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1380gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1440tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1500gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1560ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1620tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1680accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1740gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1800cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 18452801479DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 280caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag catcaacgtg aagtgcagcc tgccccagca gtgcatcaag 360ccctgcaagg acgccggcat gcggttcggc aagtgcatga acaagaagtg caggtgctac 420agctcttata cctacaatta tgaatggcat gtggatgtct ggggacaggg cctgctggtg 480acagtctcta gtgcttccac aactgcacca aaggtgtacc ccctgtcaag ctgctgtggg 540gacaaatcct ctagtaccgt gacactggga tgcctggtct caagctatat gcccgagcct 600gtgactgtca cctggaactc aggagccctg aaaagcggag tgcacacctt cccagctgtg 660ctgcagtcct ctggcctgta tagcctgagt tcaatggtga cagtccccgg cagtacttca 720gggcagacct tcacctgtaa tgtggcccat cctgccagct ccaccaaagt ggacaaagca 780gtggaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 840ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 900cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 960ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1080aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1200cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1260agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1320cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1380agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1440cactacacgc agaagagcct ctccctgtct ccgggtaaa 14792811509DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 281caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cggtggcgga ggatctatca acgtgaagtg cagcctgccc 360cagcagtgca tcaagccctg caaggacgcc ggcatgcggt tcggcaagtg catgaacaag 420aagtgcaggt gctacagcgg aggtggtggt tcatcttata cctacaatta tgaatggcat 480gtggatgtct ggggacaggg cctgctggtg acagtctcta gtgcttccac aactgcacca 540aaggtgtacc ccctgtcaag ctgctgtggg gacaaatcct ctagtaccgt gacactggga 600tgcctggtct caagctatat gcccgagcct gtgactgtca cctggaactc aggagccctg 660aaaagcggag tgcacacctt cccagctgtg ctgcagtcct ctggcctgta tagcctgagt 720tcaatggtga cagtccccgg cagtacttca gggcagacct tcacctgtaa tgtggcccat 780cctgccagct ccaccaaagt ggacaaagca gtggaaccca aatcttgcga caaaactcac 840acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 900ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1140aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1320gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500ccgggtaaa 15092821515DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 282caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagcgccg ctgcaatctc ctgcgtcggc 360agccccgaat gtcctcccaa gtgccgggct cagggatgca agaacggcaa gtgtatgaac 420cggaagtgca agtgctacta ttgcggcgga ggtgggagtt cttataccta caattatgaa 480tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 540gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 600ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 660gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 720ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg

780gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 840actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 900ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 960gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1020gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1080gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1140gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1200ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 1260gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1320agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1380tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1440ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1500ctgtctccgg gtaaa 15152831539DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 283caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cggcggtgga tctgggggtg gcggaagcgc cgctgcaatc 360tcctgcgtcg gcagccccga atgtcctccc aagtgccggg ctcagggatg caagaacggc 420aagtgtatga accggaagtg caagtgctac tattgcggcg gaggtgggag tggaggcggt 480agctcttata cctacaatta tgaatggcat gtggatgtct ggggacaggg cctgctggtg 540acagtctcta gtgcttccac aactgcacca aaggtgtacc ccctgtcaag ctgctgtggg 600gacaaatcct ctagtaccgt gacactggga tgcctggtct caagctatat gcccgagcct 660gtgactgtca cctggaactc aggagccctg aaaagcggag tgcacacctt cccagctgtg 720ctgcagtcct ctggcctgta tagcctgagt tcaatggtga cagtccccgg cagtacttca 780gggcagacct tcacctgtaa tgtggcccat cctgccagct ccaccaaagt ggacaaagca 840gtggaaccca aatcttgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 900ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 960cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1020ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1080cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1140aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1200accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1260cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1320agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1380cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1440agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1500cactacacgc agaagagcct ctccctgtct ccgggtaaa 15392841515DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 284caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctgcgggggt ggcggaagca tcgaaggtcg tcacgctgag 360ggaacattca cttccgatgt gtcctcctac ctggagggcc aggctgccaa agagttcatc 420gcttggctcg tcaagggcag gggcggaggt gggagttgct cttataccta caattatgaa 480tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 540gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 600ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 660gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 720ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg 780gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 840actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 900ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 960gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1020gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1080gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1140gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1200ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 1260gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1320agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1380tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1440ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1500ctgtctccgg gtaaa 15152851515DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 285caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag ctgcgggggt ggcggaagca tcgaaggtcg tcacgctgag 360ggaacattca cttccgatgt gtcctcctac ctggagggcc aggctgccaa agagttcatc 420gcttggctcg tcaagggcag gggcggaggt gggagttgct cttataccta caattatgaa 480tggcatgtgg atgtctgggg acagggcctg ctggtgacag tctctagtgc ttccacaact 540gcaccaaagg tgtaccccct gtcaagctgc tgtggggaca aatcctctag taccgtgaca 600ctgggatgcc tggtctcaag ctatatgccc gagcctgtga ctgtcacctg gaactcagga 660gccctgaaaa gcggagtgca caccttccca gctgtgctgc agtcctctgg cctgtatagc 720ctgagttcaa tggtgacagt ccccggcagt acttcagggc agaccttcac ctgtaatgtg 780gcccatcctg ccagctccac caaagtggac aaagcagtgg aacccaaatc ttgcgacaaa 840actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 900ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 960gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1020gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1080gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1140gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1200ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 1260gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1320agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1380tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1440ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1500ctgtctccgg gtaaa 15152861905DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 286caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagcgccc caccacgcct catctgtgac 360agccgagtcc tggagaggta cctcttggag gccaaggagg ccgagaatat cacgacgggc 420tgtgctgaac actgcagctt gaatgagaat atcactgtcc cagacaccaa agttaatttc 480tatgcctgga agaggatgga ggtcgggcag caggccgtag aagtctggca gggcctggcc 540ctgctgtcgg aagctgtcct gcggggccag gccctgttgg tcaactcttc ccagccgtgg 600gagcccctgc agctgcatgt ggataaagcc gtcagtggcc ttcgcagcct caccactctg 660cttcgggctc tgggagccca gaaggaagcc atctcccctc cagatgcggc ctcagctgct 720ccactccgaa caatcactgc tgacactttc cgcaaactct tccgagtcta ctccaatttc 780ctccggggaa agctgaagct gtacacaggg gaggcctgca ggacagggga cagaggcgga 840ggtgggagtt cttataccta caattatgaa tggcatgtgg atgtctgggg acagggcctg 900ctggtgacag tctctagtgc ttccacaact gcaccaaagg tgtaccccct gtcaagctgc 960tgtggggaca aatcctctag taccgtgaca ctgggatgcc tggtctcaag ctatatgccc 1020gagcctgtga ctgtcacctg gaactcagga gccctgaaaa gcggagtgca caccttccca 1080gctgtgctgc agtcctctgg cctgtatagc ctgagttcaa tggtgacagt ccccggcagt 1140acttcagggc agaccttcac ctgtaatgtg gcccatcctg ccagctccac caaagtggac 1200aaagcagtgg aacccaaatc ttgcgacaaa actcacacat gcccaccgtg cccagcacct 1260gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1320atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1380gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1440gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1500tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1560gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1620ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1680tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1740accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1800gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1860cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 19052871518DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 287caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagccact ctcagggtac cttcacctct 360gactactcta aatacctgga ctctcgtcgt gctcaggact tcgttcagtg gctgatgaac 420accaaacgta accgtaacaa catcgctggc ggaggtggga gttcttatac ctacaattat 480gaatggcatg tggatgtctg gggacagggc ctgctggtga cagtctctag tgcttccaca 540actgcaccaa aggtgtaccc cctgtcaagc tgctgtgggg acaaatcctc tagtaccgtg 600acactgggat gcctggtctc aagctatatg cccgagcctg tgactgtcac ctggaactca 660ggagccctga aaagcggagt gcacaccttc ccagctgtgc tgcagtcctc tggcctgtat 720agcctgagtt caatggtgac agtccccggc agtacttcag ggcagacctt cacctgtaat 780gtggcccatc ctgccagctc caccaaagtg gacaaagcag tggaacccaa atcttgcgac 840aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 900ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 960gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1020gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1080gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1140aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1200cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1260caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1320gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1380ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1440gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1500tccctgtctc cgggtaaa 15182881578DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 288caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagcctga aatgttacca acatggtaaa 360gttgtgactt gtcatcgaga tatgaagttt tgctatcata acactggcat gccttttcga 420aatctcaagc tcatcctaca gggatgttct tcttcgtgca gtgaaacaga aaacaataag 480tgttgctcaa cagacagatg caacaaaggc ggaggtggga gttcttatac ctacaattat 540gaatggcatg tggatgtctg gggacagggc ctgctggtga cagtctctag tgcttccaca 600actgcaccaa aggtgtaccc cctgtcaagc tgctgtgggg acaaatcctc tagtaccgtg 660acactgggat gcctggtctc aagctatatg cccgagcctg tgactgtcac ctggaactca 720ggagccctga aaagcggagt gcacaccttc ccagctgtgc tgcagtcctc tggcctgtat 780agcctgagtt caatggtgac agtccccggc agtacttcag ggcagacctt cacctgtaat 840gtggcccatc ctgccagctc caccaaagtg gacaaagcag tggaacccaa atcttgcgac 900aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 960ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1020gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1080gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1140gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1200aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1260cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1320caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1380gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1440ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1500gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1560tccctgtctc cgggtaaa 15782891788DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 289caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagcgcac ccgcccgctc gcccagcccc 360agcacgcagc cctgggagca tgtgaatgcc atccaggagg cccggcgtct cctgaacctg 420agtagagaca ctgctgctga gatgaatgaa acagtagaag tcatctcaga aatgtttgac 480ctccaggagc cgacctgcct acagacccgc ctggagctgt acaagcaggg cctgcggggc 540agcctcacca agctcaaggg ccccttgacc atgatggcca gccactacaa gcagcactgc 600cctccaaccc cggaaacttc ctgtgcaacc cagattatca cctttgaaag tttcaaagag 660aacctgaagg actttctgct tgtcatcccc tttgactgct gggagccagt ccaggagggc 720ggaggtggga gttcttatac ctacaattat gaatggcatg tggatgtctg gggacagggc 780ctgctggtga cagtctctag tgcttccaca actgcaccaa aggtgtaccc cctgtcaagc 840tgctgtgggg acaaatcctc tagtaccgtg acactgggat gcctggtctc aagctatatg 900cccgagcctg tgactgtcac ctggaactca ggagccctga aaagcggagt gcacaccttc 960ccagctgtgc tgcagtcctc tggcctgtat agcctgagtt caatggtgac agtccccggc 1020agtacttcag ggcagacctt cacctgtaat gtggcccatc ctgccagctc caccaaagtg 1080gacaaagcag tggaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 1140cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1200atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1260gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1320cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1380gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1440atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1500cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1560ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1620aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1680gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1740ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 17882901941DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 290caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300gaaactaaga aataccagag cgggggtggc ggaagccctg ggccaccacc tggcccccct 360cgagtttccc cagaccctcg ggccgagctg gacagcaccg tgctcctgac ccgctctctc 420ctggcggaca cgcggcagct ggctgcacag ctgagggaca aattcccagc tgacggggac 480cacaacctgg attccctgcc caccctggcc atgagtgcgg gggcactggg agctctacag 540ctcccaggtg tgctgacaag gctgcgagcg gacctactgt cctacctgcg gcacgtgcag 600tggctgcgcc gggcaggtgg ctcttccctg aagaccctgg agcccgagct gggcaccctg 660caggcccgac tggaccggct gctgcgccgg ctgcagctcc tgatgtcccg cctggccctg 720ccccagccac ccccggaccc gccggcgccc ccgctggcgc ccccctcctc agcctggggg 780ggcatcaggg ccgcccacgc catcctgggg gggctgcacc tgacacttga ctgggccgtg 840aggggactgc tgctgctgaa gactcggctg ggcggaggtg ggagttctta tacctacaat 900tatgaatggc atgtggatgt ctggggacag ggcctgctgg tgacagtctc tagtgcttcc 960acaactgcac caaaggtgta ccccctgtca agctgctgtg gggacaaatc ctctagtacc 1020gtgacactgg gatgcctggt ctcaagctat atgcccgagc ctgtgactgt cacctggaac 1080tcaggagccc tgaaaagcgg agtgcacacc ttcccagctg tgctgcagtc ctctggcctg 1140tatagcctga gttcaatggt gacagtcccc ggcagtactt cagggcagac cttcacctgt 1200aatgtggccc atcctgccag ctccaccaaa gtggacaaag cagtggaacc caaatcttgc 1260gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 1320ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1380tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1440ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1500cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1560tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1620gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1680aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1740tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1800gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1860aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1920ctctccctgt ctccgggtaa a

19412911905DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 291caggtccagc tgagagagag cggcccttca ctgg

Claims

1.-61. (canceled)

62. An immunoglobulin fusion protein comprising: a) a first antibody region; and b) a first extender fusion region comprising a first therapeutic agent attached to a first extender peptide, wherein the first extender peptide comprises a first beta strand secondary structure region having a first beta strand secondary structure; wherein the first extender fusion region does not contain more than 7 consecutive amino acids from an ultralong complementary determining region 3 heavy chain of SEQ ID NO: 248.

63. The immunoglobulin fusion protein of claim 62, wherein the first extender fusion region comprises a second extender peptide comprising a second beta strand secondary structure region having a second beta strand secondary structure, and wherein the first beta strand secondary structure and second beta strand secondary structure form a beta sheet.

64. The immunoglobulin fusion protein of claim 62, wherein the first extender fusion region replaces a portion of a light chain of the first antibody region or a portion of the heavy chain of the first antibody region.

65. The immunoglobulin fusion protein of claim 62, wherein the first antibody region comprises an antibody selected from an anti-Her2 antibody, trastuzumab, an anti-CD47 antibody, palivizumab, and antigen binding fragments thereof.

66. The immunoglobulin fusion protein of claim 62, wherein the first antibody region comprises a heavy chain, wherein the heavy chain is represented by an amino acid sequence that is at least 90% homologous to a sequence selected from SEQ ID NOS: 24-27, 29-33, 36-39, and 251-253, and a light chain, wherein the light chain is represented by an amino acid sequence that is at least 90% homologous to a sequence selected from SEQ ID NOS: 21-23, 28, 34, 35, 40, 248-250 and 278.

67. The immunoglobulin fusion protein of claim 62, wherein the first beta strand secondary structure region comprises an amino acid sequence that is at least 90% homologous to a sequence selected from SEQ ID NOs: 109-128, 305-308.

68. The immunoglobulin fusion protein of claim 62, wherein the first beta strand secondary structure region comprises an amino acid sequence of ETKKYQX.sub.nS (SEQ ID NO:110), wherein n=1-8 and X is selected from a basic amino acid, an acidic amino acid, a polar amino acid, and a charged amino acid.

69. The immunoglobulin fusion protein of claim 63, wherein the first beta strand secondary structure region comprises an amino acid sequence of ETKKYQX.sub.nS (SEQ ID NO: 306), wherein n=1-8 and X is selected from a basic amino acid, an acidic amino acid, a polar amino acid, and a charged amino acid, and wherein the second beta strand secondary structure region comprises an amino acid sequence of SX.sup.1TX.sup.2NX.sup.3 (SEQ ID NO: 128), wherein X.sup.1, X.sup.2, and X.sup.3 are independently selected from polar amino acids.

70. The immunoglobulin fusion protein of claim 63, wherein the second beta strand secondary structure region comprises an amino acid sequence of YX.sup.1YX.sup.2Y, and wherein X.sup.1 and X.sup.2 are independently selected from polar amino acids.

71. The immunoglobulin fusion protein of claim 62, wherein the immunoglobulin fusion protein comprises an amino acid sequence that is at least about 90% identical to an amino acid sequence of any one of SEQ ID NOs: 76-108, 260-277, 298, 300, 302, and 304.

72. The immunoglobulin fusion protein of claim 62, wherein the immunoglobulin fusion protein further comprises a second therapeutic agent.

73. The immunoglobulin fusion protein of claim 72, wherein the immunoglobulin fusion protein further comprises a second antibody region, wherein the second antibody region comprises a second extender fusion region attached to the second antibody region, and wherein the second extender fusion region comprises the second therapeutic agent and an extender peptide comprising a) an amino acid sequence having an alpha helical secondary structure, or b) an amino acid sequence having a beta strand secondary structure, or c) an amino acid sequence having no regular secondary structure.

74. The immunoglobulin fusion protein of claim 72, further comprising a second antibody region, wherein the second therapeutic agent is directly attached to the second antibody region.

75. The immunoglobulin fusion protein of claim 62, wherein first therapeutic agent is selected from bGCSF, hGCSF, bGMCSF, hGMCSF, GDF11, interferon-beta, interferon-alpha, interleukin 11 (IL-11), exendin-4, GLP-1, relaxin, oxyntomodulin, leptin, betatrophin, bovine growth hormone (bGH), human growth hormone (hGH), parathyroid hormone, erythropoietin, Moka1, VM-24, Mamba1, angiopoeitin-like 3 (ANGPTL3), CVX15, a CXCR4 ligand, a neutrophil elastase inhibitor, and homologs thereof.

76. The immunoglobulin fusion protein of claim 62, wherein the first therapeutic agent is represented by an amino acid sequence that is at least 90% homologous to a sequence selected from any one of SEQ ID NOs: 200-235 and/or encoded by a nucleic acid sequence that is at least 90% homologous to a sequences selected from SEQ ID NOs: 167-199.

77. The immunoglobulin fusion protein of claim 62, wherein the first antibody region comprises a BVK antibody or antigen binding fragment thereof and the first therapeutic agent comprises a Moka1 peptide, and wherein the first extender fusion region is grafted into a heavy chain of the BVK antibody.

78. The immunoglobulin fusion protein of claim 77, wherein the Moka1 peptide is represented by an amino acid sequence that is at least about 90% homologous to SEQ ID NO. 202.

79. The immunoglobulin fusion protein of claim 77, wherein the heavy chain of the BVK antibody is encoded by a nucleotide sequence that is at least 90% homologous to SEQ ID NO. 1.

80. The immunoglobulin fusion protein of claim 77, wherein the first beta strand secondary structure is represented by an amino acid sequence selected from SEQ ID NOS: 111, 119, and combinations thereof.

81. The immunoglobulin fusion protein of claim 77, wherein: a) the BVK antibody comprises a heavy chain encoded by a nucleotide sequence of SEQ ID NO:1, and a light chain encoded by a nucleotide sequence of SEQ ID NO: 14; b) the Moka1 peptide is represented by an amino acid sequence of SEQ ID NO: 202; c) the first beta strand secondary structure is represented by an amino acid sequence of SEQ ID NO: 111; and d) a second beta strand secondary structure is represented by an amino acid sequence of SEQ ID NO: 119, wherein the Moka1 peptide is grafted into the heavy chain of the BVK antibody.