Molecules With Antigen Binding And Polyvalent Fc Gamma Receptor Binding Activity

Abstract

The current invention involves biologically active proteins termed stradobodies. The stradobodies have two or more domains that create stradobody multimers. The stradobodies have both antigen-binding capacity and the ability to bind Fc receptors (FcR), and are useful in the treatment and prevention of disease.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No. 13/971,584, filed Aug. 20, 2013, now U.S. Pat. No. 9,683,044, issued May 31, 2017, which claims priority to U.S. Provisional Application No. 61/691,057, filed Aug. 20, 2012, and U.S. Provisional Application No. 61/785,144, filed Mar. 14, 2013, the contents of which are herein incorporated by reference in their entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0002] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: GLIK_009_01US_310975_2048_SeqList_ST25.txt, date recorded: Mar. 12, 2013, file size 329 kilobytes).

FIELD OF THE INVENTION

[0003] This invention relates generally to the fields of immunology, autoimmunity, inflammation, infectious diseases, and tumor immunology. More specifically, the present invention relates to biologically active biomimetic molecules comprising immunoglobulin Fc domains and Fab domains, compositions comprising such biomimetics, and methods of making and using such biomimetics.

BACKGROUND OF THE INVENTION

[0004] Monoclonal antibody (mAb) therapy is an important and growing part of medicine. Over 30 monoclonal antibodies have been approved for various immunological diseases, infectious diseases, and cancers either in the United States or Europe, and hundreds more are under investigation. However, a common problem in monoclonal antibody therapy development is lack of adequate efficacy despite Fab and FcR binding. Because of the high doses that are often necessary in order to achieve efficacy, adverse side effects are commonly associated with therapeutic antibodies. Further, low or altered expression of tumor and other target antigens, as well as genetic mutations that affect antibody targets or downstream effects of antibody binding, can render antibody therapies ineffective. As an example, the monoclonal antibody trastuzumab is a mAb directed specifically against the HER2/neu breast cancer antigen and commercially available under the trade name Herceptin.RTM., is approved by the United States Food and Drug Administration for the treatment of breast cancer. Trastuzumab can be effective in patients in which HER2/neu is highly expressed; however, approximately 90% of breast cancer patients have tumors that are not classified as HER2/neu high expressing. As another example, cetuximab, a mAb directed specifically against the epidermal growth factor receptor (EGFR) and commercially available under the trade name Erbitux.RTM., is approved by the United States Food and Drug Administration for the treatment of colon cancer. Cetuximab blocks the EGFR and arrests a downstream KRAS protein-dependent tumor proliferation pathway. From a clinical perspective, cetuximab can improve overall response rates as well as progression-free survival in patients whose tumors have wild type (WT) KRAS. Unfortunately, 30-60% of colon cancer patients have tumors with codon 12 or 13 KRAS mutations, and recent clinical trials suggest that patients with mutated KRAS do not benefit from treatment with cetuximab (summarized in Allegra et. al., Journal of Clinical Oncology, 2009 Apr. 20; 27(12):2091-6). Thus, there is a need for new antibody-like-based therapeutics in the treatment of cancers, as well as in the treatment of autoimmune disorders and inflammatory diseases.

[0005] Engagement and aggregation of Fc receptors, particularly low affinity receptors such as Fc.gamma.RIIIa, on immune cells and especially on natural killer (NK) cells by antibodies results in activation, degranulation, and lysis of the target tumor or cell, in a process known as antibody dependent cellular cytoxicity (ADCC). Tumor cells and other cells targeted by the immune system may also be killed through complement-dependent cytoxicity (CDC), in which an antibody binds complement, leading to cell cytotoxicity; or through direct cytotoxicity (DC) resulting from direct antibody binding to antigen in the absence of NK cells or complement; or by other mechanisms such as induction of apoptosis, or interference with cellular growth or processes. There is presently a need in the art to identify means of increasing ADCC, CDC, DC, and other mechanisms of killing tumor cells or other cells, thereby increasing the efficacy of mAb therapies. In particular, when complement-dependent pathways for cell killing are fully functional, CDC can be an effective method for killing cancer cells and other target cells. However, many cells are resistant to CDC due to cell membrane repair mechanisms and regulatory proteins such as CD59, which inhibits the complement pathway. For example, despite the high levels of expression of CD20 on B cell lymphoma and leukemia cells, many patients with B cell malignancies are unresponsive to, or become resistant to, treatment with the anti-CD20 monoclonal antibody rituximab, at least in part due to mechanisms of complement inhibition (Harjunpaa et al., Scand. J. Immunol, 2000 51; 634-641). Therefore, there is a particular need for molecules that are capable of increasing CDC.

SUMMARY OF THE INVENTION

[0006] The present invention relates to biologically active biomimetic molecules comprising immunoglobulin Fc domains, Fab domains, and multimerization domains; compositions comprising such biomimetics; and methods of making and using such biomimetics. These biomimetics have broad application for treating cancers, inflammatory, autoimmune, and infectious disease conditions in which a monoclonal antibody may be used or is already in clinical use. The biomimetics of the present invention have the advantages of more potent antibody-mediated cell cytoxicity, complementmediated cell cytotoxicity, and complement clq binding compared to a mAb whose Fab is identical to the Fab comprised in the biomimetics of the present invention. The biomimetics of the present invention also have the advantage of more potent complement-dependent cell cytoxicity and direct cytotoxicity compared to a mAb whose Fab is specific for the same antigen.

[0007] WO 2008/151088 discloses using biomimetic molecules comprising two or more Fc domains, preferably in the context of a stradomer, to which one or more Fab domains is attached, for the treatment of pathological conditions including cancers, autoimmune diseases and other inflammatory conditions, and infectious diseases. WO 2008/151088 is incorporated herein by reference in its entirety. The molecules comprising an Fab disclosed in WO 2008/151088 are termed "stradobodies" and possess the antigen binding properties of the Fab portion of a monoclonal antibody and the Fc receptor binding properties of stradomers. Thus, these stradobodies bind, cross-link, and activate multiple Fc.gamma. receptors on effector cells simultaneously, creating avidity that cannot be accomplished by an individual mAb or immunoglobulin Fc backbone binding to an individual Fc.gamma. receptor, even if optimized via Fc mutagenesis, defucosylation, or other methods that improve affinity between an individual mAb and an individual Fc.gamma. receptor. Polyvalent binding of Fc.gamma. receptors on effector cells is particularly important in the environment of low epitope expression. Low epitope expression leads to mAb Fab binding events too isolated to result in a sufficient density of Fc-Fc.gamma. receptor binding events in close enough proximity on the effector cell to cause downstream activation of low affinity Fc.gamma. receptors on effector cells. However, as disclosed herein, the inclusion of one or more multimerization domains in addition to the Fab and Fc domains enhances the Fc.gamma.R binding activity of the stradobodies, resulting in slow dissociation characteristic of avidity, as well as antibody-dependent cell cytoxicity (ADCC), complement-mediated cytoxicity (CDC), direct cytotoxicity (DC), strong complement clq binding, and/or other mechanisms of cellular toxicity. In particular, the multimerization domains are located between two Fc domains or at the carboxy end of the Fc region in the stradobodies disclosed herein. Surprisingly, a stradobody comprising two particular multimerization domains, an isoleucine zipper and an IgG2 hinge, resulted in particularly strong multimerization, high cellular toxicity against target cells, and high clq binding.

[0008] Nagashima et al. (Journal of Bioscience and Bioengineering 111(4): 391-6 (2011) and Molecular Immunology 45(10):2752-63 (2008)) described serial stradobodies with tandem repeats of Fc domains, as anticipated by WO 2008/151088, which resulted in enhanced ADCC relative to the parent monoclonal antibodies from which they were derived, i.e. comprising the identical Fab region. The stradobodies of the present invention, however, by virtue of the multimerization domain(s), lead to multimerization of the stradobody homodimers which in turn enhances the number of Fc domains capable of simultaneously binding Fc.gamma.R and ultimately leads to far superior binding and cytotoxicity when compared with non-multimerizing compounds, such as those described in Nagashima and elsewhere.

[0009] In one aspect, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains. In a further embodiment, the one or more multimerization domains is capable of multimerizing said stradobody. In one embodiment, at least one of the one or more multimerization domains separates two or more Fc domains. In another embodiment, the at least one of the one or more multimerization domains is located at the carboxy end of the Fc region. In a preferred embodiment, one or more Fc domains is an IgG1 Fc domain.

[0010] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody. In another embodiment, the multimerization domains are independently selected from the group consisting of an isoleucine zipper, an IgG2 hinge, and a GPP repeat. In another embodiment, the stradobody comprises two multimerization domains. In a further embodiment, the two multimerization domains are independently selected from the group consisting of an isoleucine zipper, an IgG2 hinge, and a GPP repeat. In a still further embodiment, the two multimerization domains are an isoleucine zipper and an IgG2 hinge. In a still further embodiment, the two multimerization domains are both an IgG2 hinge. In another embodiment, the two multimerization domains are both an isoleucine zipper. In another embodiment, the stradobody comprises three multimerization domains. In still another embodiment, the stradobody comprises four or more multimerization domains.

[0011] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein at least one of the one or more multimerization domains is an isoleucine zipper. In a further embodiment, the at least one isoleucine zipper is according to SEQ ID NO: 32, and is capable of multimerizing the stradobody. In another embodiment, at least one of the one or more multimerization domains is an IgG2 hinge domain. In a further embodiment, the at least one IgG2 hinge domain is according to SEQ ID NO: 3 and is capable of multimerizing the stradobody. In another embodiment, at least one of the one or more multimerization domains is a GPP domain. In a further embodiment, the at least one GPP domain comprises an amino acid sequence according to SEQ ID NO:26 and is capable of multimerizing the stradobody.

[0012] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody. In a further embodiment, at least one Fc domain is an IgG1 Fc domain, and the least one Fc domain comprises an IgG1 CH2, and an IgG1 CH3. In a further embodiment, the Fc domain comprises an IgG1 hinge, an IgG1 CH2, and an IgG1 CH3. In another embodiment, the stradobody comprises more than one Fc domain. In a further embodiment, each of the more than one Fc domains is an IgG1 Fc domain. In a further embodiment, each of the more than one Fc domains is an IgG3 Fc domain. In a further embodiment, each of the more than one Fc domains is an IgG2 Fc domain. In a further embodiment, each of the more than one Fc domains is an IgG4 Fc domain. In a further embodiment, the more than one Fc domains is comprised of an IgG1 Fc domain and an IgG2 Fc domain, IgG3 Fc domain, or IgG4 Fc domain.

[0013] In one embodiment, the current invention relates to a stradobody wherein the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a first multimerization domain, a second multimerization domain, and a second Fc domain. In a further embodiment, at least one of the Fc domains is an IgG1 Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an IgG2 hinge, an isoleucine zipper, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an isoleucine zipper, an IgG2 hinge, and a second Fc domain. In one especially preferred embodiment, the first Fc domain, isoleucine zipper, IgG2 hinge, and second Fc domain together comprise an amino acid sequence according to SEQ ID NO: 69. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an IgG2 hinge, a second IgG2 hinge, and a second Fc. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an isoleucine zipper, a second isoleucine zipper, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an isoleucine zipper, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an IgG2 hinge; and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a G4S domain, an IgG2 hinge, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an IgG2 hinge, a G4S domain, a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a G4S domain, an isoleucine zipper, a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an isoleucine zipper, a G4S domain, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a GPP domain, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a GPP domain, an IgG2 hinge, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an IgG2 hinge, a GPP domain, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, a GPP domain, an isoleucine zipper, and a second Fc domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, an isoleucine zipper, a GPP domain, and a second Fc domain. A skilled artisan will recognize that other multimerization domains can be used in place of the multimerization domains described here.

[0014] In a further embodiment, the first and the second Fc domains are IgG1 Fc domains. In another embodiment, at least one IgG1 Fc domain comprises an IgG1 CH2 and an IgG1 CH3. In a further embodiment, the IgG1 Fc domain further comprises an IgG1 hinge.

[0015] In one embodiment, the current invention relates to a composition comprising multimerized stradobodies, wherein the stradobodies comprise, from amino to carboxy terminus, an Fab domain, a first Fc domain, a first multimerization domain, a second multimerization domain, and a second Fc domain.

[0016] In one embodiment, the current invention relates to a stradobody wherein the stradobody comprises, from amino to carboxy terminus, an Fab domain, a single Fc domain, a first multimerization domain, and a second multimerization domain. In a further embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, a single Fc domain, an isoleucine zipper, and an IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an IgG2 hinge, and an isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, and an IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an IgG2 hinge, and a second IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, and an isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an isoleucine zipper, and a second isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a G4S domain, and an IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an IgG2 hinge, and a G4S domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a G4S domain, and an isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an isoleucine zipper, and a G4S domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a domain linkage, and an IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a domain linkage, and an isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an IgG2 hinge, and a domain linkage. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an isoleucine zipper and a domain linkage. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, and a GPP domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a GPP domain, and an IgG2 hinge. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an IgG2 hinge, and a GPP domain. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, a GPP domain, and an isoleucine zipper. In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, an Fc domain, an isoleucine zipper, and a GPP domain. A skilled artisan will recognize that other multimerization domains can be used in place of the multimerization domains described here.

[0017] In a further embodiment, the Fc domain is an IgG1 Fc domain. In a further embodiment, the IgG1 Fc domain comprises an IgG1 CH2 and an IgG1 CH3. In a still further embodiment, the IgG1 Fc domain further comprises an IgG1 hinge.

[0018] In one embodiment, the current invention relates to a composition comprising multimerized stradobodies, wherein the stradobodies comprise, from amino to carboxy terminus, an Fab domain, an Fc domain, a first multimerization domain, and a second multimerization domain.

[0019] In another embodiment, the stradobody comprises, from amino to carboxy terminus, an Fab domain, two or more Fc domains, and one or more multimerization domains. In a further embodiment, the Fc domain is an IgG1 Fc domain.

[0020] In one embodiment, the current invention relates to a stradobody wherein the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, one or more multimerization domains, and a second Fc domain. In another embodiment, the current invention relates to a stradobody wherein the stradobody comprises, from amino to carboxy terminus, an Fab domain, a first Fc domain, and one or more multimerization domains. In a further embodiment, the stradobody further comprises one or more multimerization domains at the C-terminal end of the Fc region. In a further embodiment, one or more of the Fc domains is an IgG1 Fc domain.

[0021] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the Fab domain is specific for EGFR. In one embodiment, the amino acid sequence of the Fab domain is at least 80% homologous to SEQ ID NO: 31. In a further embodiment, the amino acid sequence of the Fab domain is at least 90% homologous to SEQ ID NO: 31. In still a further embodiment, the amino acid sequence of the Fab domain is at least 95% homologous to SEQ ID NO: 31. In yet a further embodiment, the amino acid sequence of the Fab domain is at least 99% homologous to SEQ ID NO: 31. In a yet further embodiment, the amino acid sequence of the Fab domain is SEQ ID NO: 31. In some embodiments, the one or more Fc domain is an IgG1 Fc domain.

[0022] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 33. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 33. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 33. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 33. In a yet further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 33. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 33.

[0023] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 70. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 70. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 70. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 70. In a yet further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 70. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 70.

[0024] In another embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the Fab domain is specific for HER2/neu antigen. In one embodiment, the amino acid sequence of the Fab domain is at least 80% homologous to SEQ ID NO: 34. In a further embodiment, the amino acid sequence of the Fab domain is at least 90% homologous to SEQ ID NO: 34. In still a further embodiment, the amino acid sequence of the Fab domain is at least 95% homologous to SEQ ID NO: 34. In yet a further embodiment, the amino acid sequence of the Fab domain is at least 99% homologous to SEQ ID NO: 34. In a yet further embodiment, the amino acid sequence of the Fab domain is SEQ ID NO: 34. In some embodiments, the one or more Fc domain is an IgG1 Fc domain.

[0025] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 35. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 35. In a still further embodiment, the amino acid sequence of the stradobody is t least 90% homologous to SEQ ID NO: 35. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 35. In yet a further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 35. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 35. The skilled artisan would understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab directed against any tumor antigen.

[0026] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 91. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 91. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 91. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 91. In a yet further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 91. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 91.

[0027] In another embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the Fab domain is specific for CD20. In one embodiment, the amino acid sequence of the Fab domain is at least 80% homologous to SEQ ID NO: 36. In a further embodiment, the amino acid sequence of the Fab domain is at least 90% homologous to SEQ ID NO: 36. In still a further embodiment, the amino acid sequence of the Fab domain is at least 95% homologous to SEQ ID NO: 36. In yet a further embodiment, the amino acid sequence of the Fab domain is at least 99% homologous to SEQ ID NO: 36. In a yet further embodiment, the amino acid sequence of the Fab domain is SEQ ID NO: 36. In some embodiments, the one or more Fc domain is an IgG1 Fc domain.

[0028] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 37. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 37. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 37. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 37. In yet a further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 37. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 37.

[0029] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 76. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 76. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 76. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 76. In a yet further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 76. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 76.

[0030] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the Fab domain is specific for a TNF superfamily member. Members of the TNF superfamily include, without limitation, TNF, TNF-.alpha., TNF-.beta., Lymphotoxin (LT), Lymphotoxin.beta. (LT.beta.), OX40 Ligand, CD40 Ligand, CD95/Fas Ligand, CD27 Ligand (CD70), CD30 Ligand, CD137/4-1BB Ligand, TRAIL, TRANCE/RANKL, TWEAK/Apo-3, APRIL, BAFF/Blys, LIGHT, TL1A/VEGI, GITR Ligand, EDA-A1, and EDA-A2. In one embodiment, the stradobody comprises an Fab domain that is specific for TNF (i.e., an anti-TNF stradobody; for example, the stradobody GB7542). In another embodiment, the stradobody comprises an Fab domain that is specific for Blys (i.e., an anti-Blys stradobody). In another embodiment, the stradobody comprises an Fab domain that is specific for TRAIL (i.e., an anti-TRAIL stradobody). In another embodiment, the stradobody comprises an Fab domain that is specific for OX40L (i.e., an anti-OX40L stradobody). In another embodiment, the stradobody comprises an Fab domain that is specific for 4-1BB (i.e., an anti-4-1BB stradobody). In another embodiment, the stradobody comprises a Fab domain that is specific for APRIL, (i.e., an anti-APRIL stradobody). In another embodiment, the stradobody comprises a Fab domain that is specific for TRANCE (i.e., an anti-TRANCE stradobody). In another embodiment, the stradobody comprises a Fab domain that is specific for LT.beta. (i.e., an anti-LT.beta. stradobody), In another embodiment, the stradobody comprises a Fab domain that is specific for CD40L (i.e., an anti-CD40L stradobody). The skilled artisan would understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab directed against any immune cell surface receptor.

[0031] In another embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the Fab domain is specific for TNF. In one embodiment, the amino acid sequence of the Fab domain is at least 80% homologous to SEQ ID NO: 67. In a further embodiment, the amino acid sequence of the Fab domain is at least 90% homologous to SEQ ID NO: 67. In still a further embodiment, the amino acid sequence of the Fab domain is at least 95% homologous to SEQ ID NO: 67. In yet a further embodiment, the amino acid sequence of the Fab domain is at least 99% homologous to SEQ ID NO: 67. In a yet further embodiment, the amino acid sequence of the Fab domain is SEQ ID NO: 67. In some embodiments, the one or more Fc domain is an IgG1 Fc domain.

[0032] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 66. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 66. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 66. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 66. In yet a further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 66. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 66. The skilled artisan would understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab directed against any cytokine or soluble receptor.

[0033] In one embodiment, the current invention relates to a stradobody wherein the amino acid sequence of the stradobody is at least 80% homologous to SEQ ID NO: 87. In a further embodiment, the amino acid sequence of the stradobody is at least 85% homologous to SEQ ID NO: 87. In a still further embodiment, the amino acid sequence of the stradobody is at least 90% homologous to SEQ ID NO: 87. In a yet further embodiment, the amino acid sequence of the stradobody is at least 95% homologous to SEQ ID NO: 87. In a yet further embodiment, the amino acid sequence is at least 99% homologous to SEQ ID NO: 87. In a yet further embodiment, the amino acid sequence is SEQ ID NO: 87.

[0034] In one embodiment, the stradobody of the current invention comprises an Fab domain that is specific for IFN.gamma., IFN.alpha., IFN.beta., IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, or IL-23. In one embodiment, the stradobody of the current invention comprises an Fab domain that is specific for a cytokine, wherein the stradobody is useful for treatment or prevention of an inflammatory or autoimmune disease. For example, in one embodiment, the stradobody is an anti-IL-2, anti-IL-8, or anti-IL-17 stradobody. The skilled artisan would understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab directed against any interleukin or interferon.

[0035] In one embodiment, the current invention relates to a stradobody wherein the stradobody comprises an Fab directed against one or more infectious disease antigens. The skilled artisan would understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab directed against any infectious disease antigen. The skilled artisan would further understand that stradobodies and in particular multimerizing stradobodies can be readily produced with an Fab derived from a monoclonal antibody that may be used or is already in clinical use for treatment or prevention of infectious disease.

[0036] For Example, multimerizing stradobodies can be produced with an Fab derived from a monoclonal antibody that may be used or is already in clinical use for neutralization of viruses, neutralization of bacteria or bacterial toxins, blocking of viral entry into host cells, blocking immune inhibitory mechanisms triggered by pathogens, blocking of immunopathogenic responses triggered by pathogens, or other means of treating or preventing infectious disease. Exemplary monoclonal antibodies in clinical use or in development for clinical use for treatment or prevention of infectious disease include, but are not limited to, palivizumab and motavizumab, both of which are specific for respiratory syncitial virus (RSV) glycoprotein F; ibalizumab, an anti-CD4 antibody for blocking human immunodeficiency virus (HIV) entry into host cells; Pro-140 and CCR5mAb004, anti-CCR5 antibodies for blocking HIV entry into host cells; F105, an anti-gp120 antibody for neutralizing envelope glycoprotein gp120 of HIV, which is also used in viral entry; sevirumab, which is specific for cytomegalovirus (CMV) envelope glycoprotein H; bavituximab, an anti-phosphatidyl serine antibody used to neutralize Hepatitis C virus (HCV); nivolumab (also known as MDX1106/BMS936558/ONO-4538) and pidilizumab (also known as CT-011), both of which are specific for the immune inhibitory molecule PD-1 on immune cells and are used as immunomodulation antibodies in HCV infection; MBL-HCV1, an HCV neutralizing antibody specific for the HCV structural protein E2; foravirumab, a rabies virus neutralizing antibody specific for glycoprotein G; ETI-204 (anthim), raxibacumab, and AVP 21D9, each of which is a Bacillus anthracis toxin neutralization antibody specific for B. anthracis protective antigen; SAR279356 and other anti-poly-N-acetyl glucosamine (PNAG) antibodies, which are useful in Staphylococcus and other bacterial infections, particularly multi drug-resistant infections; pagibaximab, which is specific for anti-lipoteichoic acid and used for prevention of Staphylococcus infection; tefibazumab, which is specific for clumping factor A and is also useful for Staphylococcus infection; urtoxazumab, an anti-Shiga-like toxin 2B antibody for E. coli infection; shigamabs, which is a cocktail of two mAbs, caStx1 and caStx2, for neutralization of E. coli STEC toxins Stx1 and Stx2; actoxumab (anti-Clostridum difficile enterotoxin A) and bezlotoxumab (anti-C. difficile enterotoxin B), which may be administered together as a cocktail of two antibodies known as MK3415A; panobacumab, an anti-LPS antibody used in Pseudomonas aeruginosa infection; KB 001, an anti-type 3 secretion system antibody used in P. aeruginosa infection); and 18B7, anti-capsular polysaccharide antibody for Cyptococcus neoformans infection.

[0037] In one embodiment, the current invention relates to a stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody, and wherein the two or more Fc domains are capable of binding Fc.gamma.R. In a further embodiment, the Fc.gamma.R is Fc.gamma.RIIIa. In a further embodiment, the Fc.gamma.RIIIa are on effector cells. In a yet further embodiment, the Fc.gamma.RIIIa are on NK cells. In another embodiment, the Fc.gamma.RIIIa are on macrophages. In another embodiment, the Fc.gamma.R is Fc.gamma.RIIb. In a further embodiment, the Fc.gamma.RIIb are on B cells. In another embodiment, the Fc.gamma.RIIb are on dendritic cells.

[0038] In a further embodiment, the amino acid sequence of the two or more Fc domains is at least 80% homologous to SEQ ID NO: 2. In a further embodiment, the amino acid sequence of the two or more Fc domains is at least 90% homologous to SEQ ID NO: 2. In still a further embodiment, the amino acid sequence of the two or more Fc domains is at least 95% homologous to SEQ ID NO: 2. In yet a further embodiment, the amino acid sequence of the two or more Fc domains is at least 99% homologous to SEQ ID NO: 2. In a yet further embodiment, the amino acid sequence of the two or more Fc domains is SEQ ID NO: 2.

[0039] In one aspect, the current invention relates to a method of modulating an immune response in a subject comprising administering to the subject an effective amount of the stradobody comprising an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody.

[0040] In one embodiment, the current invention relates to a method of treating an inflammatory or autoimmune disease, an infectious disease, or a cancer in a subject in need thereof comprising administering to the subject an effective amount of a stradobody that comprises an Fab domain, one or more Fc domains, and one or more multimerization domains, wherein the one or more multimerization domains is capable of multimerizing said stradobody. In a further embodiment, the subject has cancer. In a still further embodiment, the cancer is selected from the group consisting of colorectal cancer, head and neck cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic disease, heavy chain disease, neuroendocrine tumors, and Schwanoma.

[0041] In another embodiment, the subject has an autoimmune or inflammatory disease. In a further embodiment, the autoimmune or inflammatory disease is selected from the group consisting of Idiopathic Thrombocytopenic Purpura, alloimmune/autoimmune thrombocytopenia, Acquired immune thrombocytopenia, Autoimmune neutropenia, Autoimmune hemolytic anemia, Parvovirus B19-associated red cell aplasia, Acquired antifactor VIII autoimmunity, acquired von Willebrand disease, Multiple Myeloma and Monoclonal Gammopathy of Unknown Significance, Alzheimer's Disease, Sepsis, Aplastic anemia, pure red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of the newborn, Immune-mediated neutropenia, refractoriness to platelet transfusion, neonatal, post-transfusion purpura, hemolytic uremic syndrome, systemic Vasculitis, Thrombotic thrombocytopenic purpura, Evan's syndrome, Guillain-Barre syndrome, Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Paraproteinemic IgM demyelinating Polyneuropathy, Lambert-Eaton myasthenic syndrome, Myasthenia gravis, Multifocal Motor Neuropathy, Lower Motor Neuron Syndrome associated with anti-/GM1, Demyelination, Multiple Sclerosis, optic neuritis, Stiff Man Syndrome, Paraneoplastic cerebellar degeneration with anti-Yo antibodies, paraneoplastic encephalomyelitis, sensory neuropathy with anti-Hu antibodies, epilepsy, Encephalitis, Myelitis, Myelopathy especially associated with Human T-cell lymphotropic virus-1, Autoimmune Diabetic Neuropathy, Acute Idiopathic Dysautonomic Neuropathy, Kawasaki's disease, Rheumatoid arthritis, Felty's syndrome, ANCA-positive Vasculitis, Spontaneous Polymyositis, Dermatomyositis, Antiphospholipid syndromes, Recurrent spontaneous abortions, Systemic Lupus Erythematosus, Juvenile idiopathic arthritis, Raynaud's, CREST syndrome, Uveitis, Toxic Epidermal Necrolysis, Gangrene, Granuloma, Autoimmune skin blistering diseases including Pemphigus vulgaris, Bullous Pemphigoid, and Pemphigus foliaceus, Vitiligo, Streptococcal toxic shock syndrome, Scleroderma, systemic sclerosis including diffuse and limited cutaneous systemic sclerosis, Atopic dermatitis (especially steroid dependent), Inclusion Body Myositis, Necrotizing fasciitis, Inflammatory Myopathies, Myositis, Anti-Decorin (BJ antigen) Myopathy, Paraneoplastic Necrotic Myopathy, X-linked Vacuolated Myopathy, Penacillamine-induced Polymyositis, Atherosclerosis, Coronary Artery Disease, Cardiomyopathy, pernicious anemia, autoimmune chronic active hepatitis, primary biliary cirrhosis, Celiac disease, dermatitis herpetiformis, cryptogenic cirrhosis, Reactive arthritis, Crohn's disease, Whipple's disease, ulcerative colitis, sclerosing cholangitis, Graft Versus Host Disease, Antibody-mediated rejection of the graft, Post-bone marrow transplant rejection, Post-infectious disease inflammation, Lymphoma, Leukemia, Neoplasia, Asthma, Type 1 Diabetes mellitus with anti-beta cell antibodies, Sjogren's syndrome, Mixed Connective Tissue Disease, Addison's disease, Vogt-Koyanagi-Harada Syndrome, Membranoproliferative glomerulonephritis, Goodpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, micropolyarterits, Churg-Strauss syndrome, Polyarteritis nodosa, and Multisystem organ failure.

[0042] The present invention further comprises methods and compositions effective for the treatment of infectious disease, including but not limited to those caused by bacterial, mycological, parasitic, and viral agents. Examples of such infectious agents include the following: staphylococcus, streptococcaceae, neisseriaaceae, cocci, enterobacteriaceae, pseudomonadaceae, vibrionaceae, campylobacter, pasteurellaceae, bordetella, francisella, brucella, legionellaceae, bacteroidaceae, clostridium, corynebacterium, propionibacterium, gram-positive bacilli, anthrax, actinomyces, nocardia, mycobacterium, treponema, borrelia, leptospira, mycoplasma, ureaplasma, rickettsia, chlamydiae, other gram-positive bacilli, other gram-negative bacilli, systemic mycoses, other opportunistic mycoses, protozoa, nematodes, trematodes, cestodes, adenoviruses, herpesviruses (including, for example, herpes simplex virus and Epstein Barr virus, and herpes zoster virus), poxviruses, papovaviruses, hepatitis viruses, papilloma viruses, orthomyxoviruses (including, for example, influenza A, influenza B, and influenza C), paramyxoviruses, coronaviruses, picornaviruses, reoviruses, togaviruses, flaviviruses, bunyaviridae, rhabdoviruses, respiratory syncitial virus, human immunodeficiency virus and retroviruses. Exemplary infectious diseases include but are not limited to candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, gram negative sepsis, tuberculosis, mononucleosis, influenza, respiratory illness caused by Respiratory Syncytial Virus, malaria, schistosomiasis, and trypanosomiasis.

[0043] In a further embodiment the stradobody is administered intravenously, subcutaneously, orally, nasally, intraperitoneally, sublingually, bucally, transdermally, by subcutaneous or subdermal implantation, intraduodenally, or intramuscularly. In one embodiment, the stradobody is administered intravenously. Because of the enhanced efficacy of the stradobodies of the current invention, in some embodiments the stradobodies may be administered at a lower dose intravenously compared with monoclonal antibodies specific for the same antigen. In one embodiment, the stradobody is administered intravenously at a dose of about 0.01 mg/Kg to about 1000 mg/Kg IV. In a further embodiment, the stradobody is administered at about 0.1 mg/Kg to about 100 mg/Kg IV. In yet a further embodiment, the stradobody is administered at about 0.5 mg/Kg to about 50 mg/Kg IV. In still a further embodiment, the stradobody is administered at about 1 mg/Kg to about 25 mg/Kg IV. In still a further embodiment, the stradobody is administered at about 5 mg/Kg to about 15 mg/Kg IV. In one embodiment, the stradobody is administered subcutaneously. Because of the enhanced efficacy of the stradobodies of the current invention, in some embodiments the stradobody may be administered at a lower dose subcutaneously compared with monoclonal antibodies specific for the same antigen. In one embodiment, the stradobody is administered subcutaneously at a dose of about 0.01 mg/Kg to about 1000 mg/Kg SQ. In a further embodiment, the stradobody is administered at about 0.2 mg/Kg to about 150 mg/Kg SQ. In yet a further embodiment, the stradobody is administered at about 0.5 mg/Kg to about 80 mg/Kg SQ. In still a further embodiment, the stradobody is administered at about 2 mg/Kg to about 50 mg/Kg SQ. In still a further embodiment, the stradobody is administered at about 5 mg/Kg to about 30 mg/Kg SQ. In still a further embodiment, the stradobody is administered before, concurrently, or after a monoclonal antibody. In still a further embodiment, the stradobody administered before, concurrently, or after a monoclonal antibody has an Fab directed against the same antigen as the monoclonal antibody. In still a further embodiment, the stradobody administered before, concurrently, or after a monoclonal antibody has an Fab directed against a different antigen from the monoclonal antibody.

[0044] In a further embodiment, the stradobody is administered before, during or after administration of one or more additional pharmaceutical and/or therapeutic agents. In a further embodiment the additional pharmaceutically active agent comprises a steroid; a biologic anti-autoimmune drug such as a monoclonal antibody, a fusion protein, or an anti-cytokine; a non-biologic anti-autoimmune drug; an immunosuppressant; an antibiotic; and anti-viral agent; a cytokine; or an agent otherwise capable of acting as an immune-modulator. In still a further embodiment, the steroid is prednisone, prednisolone, cortisone, dexamethasone, mometesone testosterone, estrogen, oxandrolone, fluticasone, budesonide, beclamethasone, albuterol, or levalbuterol. In still a further embodiment, the stradobody is administered before, during or after administration of a chemotherapeutic agent. In still a further embodiment, the stradobody and the additional therapeutic agent display therapeutic synergy when administered together. In one embodiment, the stradobody is administered prior to the administration of the additional therapeutic agent. In another embodiment, the stradobody is administered at the same time as the administration of the additional therapeutic agent. In still another embodiment, the stradobody is administered after the administration with the additional therapeutic agent. In one embodiment, the stradobody is administered prior to the administration of a danger signal. In another embodiment, the stradobody is administered at the same time as the administration of a danger signal. In still another embodiment, the stradobody is administered after the administration of a danger signal.

[0045] In another embodiment, the stradobody is administered to treat humans, non-human primates (e.g., monkeys, baboons, and chimpanzees), mice, rats, bovines, horses, cats, dogs, pigs, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, birds (e.g., chickens, turkeys, and ducks), fish and reptiles with species-specific or chimeric stradobody molecules. In yet another embodiment, the human is an adult or a child. In still another embodiment, the stradobody is administered to prevent autoimmune disease. In a further embodiment the stradobody is administered to prevent vaccine-associated autoimmune conditions in companion animals and livestock.

[0046] In one embodiment, the current invention relates to a stradobody wherein the stradobody displays enhanced cell killing compared to a monoclonal antibody specific for the same antigen. In one embodiment, the enhanced cell killing is mediated by ADCC. In a further embodiment, the stradobody displays ADCC that is at least 2 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays ADCC that is at least 5 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays ADCC that is at least 10 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays ADCC that is at least 20 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the enhanced cell killing is mediated by CDC. In a further embodiment, the stradobody displays CDC that is at least 2 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays CDC that is at least 5 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays CDC that is at least 10 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays CDC that is at least 20 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the enhanced cell killing is mediated by DC. In a further embodiment, the stradobody displays DC that is at least 2 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays DC that is at least 5 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays DC that is at least 10 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays DC that is at least 20 times higher compared to a monoclonal antibody specific for the same antigen.

[0047] In one embodiment, the stradobody contains two or more multimerization domains, and displays enhanced cell killing compared to a stradobody containing one multimerization domain. In one embodiment, the cell killing is mediated by ADCC. In a further embodiment, stradobody with two or more multimerization domains displays ADCC that is at least 2 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays ADCC that is at least 5 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays ADCC that is at least 10 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays ADCC that is at least 20 times higher compared to a stradobody containing one multimerization domain. In another embodiment, the enhanced cell killing is mediated by CDC. In a further embodiment, stradobody with two or more multimerization domains displays CDC that is at least 2 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays CDC that is at least 5 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays CDC that is at least 10 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays CDC that is at least 20 times higher compared to a stradobody containing one multimerization domain. In another embodiment, the enhanced cell killing is mediated by DC. In a further embodiment, stradobody with two or more multimerization domains displays DC that is at least 2 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays DC that is at least 5 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays DC that is at least 10 times higher compared to a stradobody containing one multimerization domain. In another embodiment, stradobody with two or more multimerization domains displays DC that is at least 20 times higher compared to a stradobody containing one multimerization domain.

[0048] In another embodiment, the current invention relates to a stradobody wherein the stradobody displays enhanced inhibition of cellular proliferation compared to a monoclonal antibody specific for the same antigen. In one embodiment, the stradobody inhibits cellular proliferation by at least 10% more compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody inhibits cellular proliferation by at least 20% more compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody inhibits cellular proliferation by at least 50% more compared to a monoclonal antibody specific for the same antigen. In another embodiment, the current invention relates to a stradobody that contains two or more multimerization domains, and displays enhanced inhibition of cellular proliferation compared to a stradobody containing one multimerization domain. In one embodiment, the stradobody inhibits cellular proliferation by at least 10% more compared to a stradobody containing one multimerization domain. In another embodiment, the stradobody inhibits cellular proliferation by at least 20% more compared to a stradobody containing one multimerization domain. In another embodiment, the stradobody inhibits cellular proliferation by at least 50% more compared to a stradobody containing one multimerization domain.

[0049] In one embodiment, the current invention relates to a stradobody wherein the stradobody displays enhanced complement binding compared to a monoclonal antibody specific for the same antigen. In a further embodiment, the stradobody displays enhanced complement binding compared to a monoclonal antibody specific for the same antigen. In one embodiment, the enhanced complement binding is binding to C1q. In one embodiment, the stradobody displays enhanced complement binding that is at least 2 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays enhanced complement binding that is at least 5 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays enhanced complement binding that is at least 10 times higher compared to a monoclonal antibody specific for the same antigen. In another embodiment, the stradobody displays enhanced complement binding that is at least 20 times higher compared to a monoclonal antibody specific for the same antigen. In one embodiment, the enhanced complement binding is measured by the EC50 value. In one embodiment, the EC50 value for complement binding is at least 5 times lower for the stradobody compared to the monoclonal antibody specific for the same antigen. In another embodiment, the EC50 value for complement binding is at least 10 times lower for the stradobody compared to the monoclonal antibody specific for the same antigen. In a further embodiment, the EC50 value for complement binding is at least 20 times lower for the stradobody compared to the monoclonal antibody specific for the same antigen. In one embodiment, a multimerizing stradobody demonstrates increased complement binding relative to a non-multimerizing stradobody specific for the same antigen. In another embodiment, a multimerizing stradobody demonstrates a lower EC50 value for complement binding relative to a non-multimerizing stradobody specific for the same antigen. In a further embodiment, the EC50 value for the multimerizing stradobody is at least 2 times lower for the multimerizing stradobody compared to the non-multimerizing stradobody. In a further embodiment, the EC50 value for the multimerizing stradobody is at least 5 times lower for the multimerizing stradobody compared to the non-multimerizing stradobody.

[0050] In one embodiment, the level of complement binding exhibited by a stradobody varies depending on the Fab. Thus, in one embodiment, two stradobodies having the identical multimerizing domains and identical Fc regions but different Fab exhibit a different level of complement binding. In one embodiment, a multimerizing stradobody having an anti-CD20 Fab exhibits dramatically higher complement binding compared to a multimerizing stradobody having the identical multimerizing domains and identical Fc regions as the anti-CD20 Fab, but having an anti-TNF or an anti-HER2/neu Fab.

[0051] In one embodiment, the current invention relates to compositions comprising multimerized stradobodies. In a further embodiment, the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more stradobodies.

BRIEF DESCRIPTION OF THE FIGURES

[0052] FIG. 1 is a schematic depiction of multimerized serial and multimerized C-terminal stradobodies and the building blocks that make up stradobodies.

[0053] FIG. 2 is a schematic depiction of general structures of serial stradobodies.

[0054] FIG. 3 is a schematic depiction of the structures of several serial stradobodies illustrating constructs with one or more of the indicated multimerization or linkage domains.

[0055] FIG. 4 is an illustration of serial stradobody constructs.

[0056] FIG. 5 is a schematic depiction of the structures of several multimerized C-terminal stradobodies illustrating constructs with one or more of the indicated multimerization domains.

[0057] FIG. 6 is an illustration of multimerized C-terminal stradobody constructs.

[0058] FIG. 7 is a schematic depiction of the structure of a preferred stradobody of the current invention, comprising two IgG1 Fc domains separated by an isoleucine zipper and an IgG2 hinge.

[0059] FIG. 8 is a non-reducing SDS-PAGE gel showing the formation of multimers of the indicated C-terminal multimerized stradobodies, in comparison to the unaltered antibody GB2500.

[0060] FIG. 9 is a non-reducing SDS-PAGE gel showing the formation of multimers of the indicated serial stradobodies, in comparison to the unaltered antibody GB2500.

[0061] FIG. 10 shows the ADCC of the indicated stradobodies in comparison to the unaltered HER2/neu antibody GB2500, as measured by percent killing of target cells at a range of effector to target cell ratios.

[0062] FIG. 11 shows the ADCC dose response of the indicated stradobodies in comparison to the unaltered HER2/neu antibody GB2500, as measured by percent killing of target cells at a range of stradobody concentrations.

[0063] FIG. 12 shows representative plasmon resonance (Biacore) data indicating binding to and dissociation from Fc.gamma.RIIIa for each indicated stradobody or unaltered antibody GB2500.

[0064] FIG. 13 shows the Fc.gamma.RIIIa binding data for all of the tested stradobodies or unaltered antibody GB2500.

[0065] FIG. 14 depicts the correlation between Biacore binding (RU) and ADCC activity of the indicated stradobodies. ADCC activity is presented as mean of fold difference relative to GB2500 for each stradobody.

[0066] FIG. 15 shows the results of the purification of a stradobody construct by ion exchange chromatography on a Mono Q column. Lane SB is the unfractionated stradobody; peaks 1, 2, and 3 on the elution chromatogram (right panel) were analyzed by non-denaturing gel (left panel).

[0067] FIG. 16 shows a non-reducing (top panel) and a reducing (bottom panel) SDS-PAGE gel showing the formation of multimers of the indicated serial stradobodies, in comparison to the unaltered antibody GB2500.

[0068] FIG. 17A-FIG. 17D show the binding of the parent antibody GB2500 or the indicated serial stradobody to Fc.gamma.RIIIa. GB2500 (grown in HEK or CHO cells; FIG. 17A) was tested at concentrations ranging from 3333-208 nM. Serial stradobodies GB2524 (FIG. 17A, GB2538 (FIG. 17B), GB2540 (FIG. 17B, GB2542 (FIG. 17C), GB2554 (FIG. 17C), and GB2555 (FIG. 17D) were tested at concentrations ranging from 200-12.5 nM.

[0069] FIG. 18 is a schematic diagram of the experimental flow chart for studies involving human PBMC-SCID (hu-PBMC SCID) mice treated with tradobodies or their corresponding monoclonal antibodies.

[0070] FIG. 19 shows the serum levels of human IgM over time in hu-PMBC SCID mice treated with PBS, GB4500, GB4563, or GB4542.

[0071] FIG. 20 shows the number of human B cells in the peripheral blood over time in hu-PBMC SCID mice treated with PBS, GB4500, GB4563, or GB4542.

[0072] FIG. 21 shows the number of human B cells in the spleens of hu-PBMC SCID mice treated with PBS, GB4500, GB4563, or GB4542.

[0073] FIG. 22 shows the percent inhibition of cell proliferation mediated by GB4500 or GB4542 at the indicated concentrations of antibody or stradobody, in .mu.g/mL. Statistical significance of GB4500 versus GB4542 was calculated using T-test; * p<0.05, **P<0.005.

[0074] FIG. 23 shows the percent inhibition of cell proliferation mediated by GB4500 or GB4542 at the indicated pmol/mL of antibody or stradobody.

[0075] FIG. 24 shows the percent complement-dependent cytoxicity mediated by GB4500, GB4596, or GB4542 at the indicated concentration of antibody or stradobody, in g/mL.

[0076] FIG. 25 shows the percent complement-dependent cytoxicity mediated by GB4500 or GB4542 at the indicated pmol/mL of antibody or stradobody.

[0077] FIG. 26 shows the mean tumor volume over time following intratumoral injection of PBS, GB4500, or GB4542, with or without CpG, in a mouse Raji-SCID lymphoma model.

[0078] FIG. 27 shows the median tumor volume over time following intratumoral injection of PBS, GB4500, or GB4542, with or without CpG, in a mouse Raji-SCID lymphoma model.

[0079] FIG. 28 shows complement C1q binding with antibody GB2500, stradobody GB2542, antibody GB7500, stradobody GB7542, antibody GB4500, and stradobody GB4542, as measured by absorbance (450 nm) at the indicated stradobody or antibody concentration.

[0080] FIG. 29 shows the EC50 values for binding to complement C1q for antibody GB2500, stradobody GB2542, antibody GB7500, stradobody GB7542, antibody GB4500, and stradobody GB4542.

[0081] FIG. 30 shows complement C1q binding with antibody GB2500, and stradobodies GB2542, GB2554, and GB2555. GB2542 is a multimerizing stradobody, and GB2554 and GB2555 are linear stradobodies that do not contain any multimerization domains.

[0082] FIG. 31 shows the EC50 values for binding to complement C1q for antibody GB2500, multimerizing stradobody GB2542, and non-multimerizing stradobodies GB2554 and GB2555.

[0083] FIG. 32 shows the compiled ADCC data on all 12 anti-HER2/neu stradobodies and GB2500. Each row in the table of FIG. 32 represents a purified and tested stradobody batch. Data are presented as percent killing by NK cells isolated from the indicated donor, at the indicated ratio of effector to target cell.

DETAILED DESCRIPTION OF THE INVENTION

[0084] The approach to rational molecular design for antigen-binding compounds with FcR binding capacity described herein includes recombinant and/or biochemical creation of immunologically active biomimetic(s) which are surprisingly more efficient at inducing cytotoxicity including antibody-mediated cell cytoxicity, complement-dependent cell cytoxicity, direct cell cytoxicity, and other mechanisms of cellular toxicity compared to mAbs with specificity for the same antigen. The compounds have utility for treating, for example, cancer, autoimmune and inflammatory diseases, and infectious diseases. Each embodiment is described in detail below along with specific exemplary embodiments.

[0085] As used herein, the use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0086] As used herein, the terms "biomimetic", "biomimetic molecule", "biomimetic compound", and related terms, refer to a human made compound that imitates the function of another compound, such as pooled human Intravenous Immunoglobulin ("hIVIG"), a monoclonal antibody or the Fc or Fab fragment of an antibody. "Biologically active" biomimetics are compounds which possess biological activities that are the same as or similar to their naturally occurring counterparts. By "naturally occurring" is meant a molecule or portion thereof that is normally found in an organism. By naturally occurring is also meant substantially naturally occurring. "Immunologically active" biomimetics are biomimetics which exhibit immunological activity the same as or similar to naturally occurring immunologically active molecules, such as antibodies, cytokines, interleukins and other immunological molecules known in the art. In preferred embodiments, the biomimetics of the present invention are stradobodies, as defined herein.

[0087] By "homologous" is meant identity over the entire sequence of a given nucleic acid or amino acid sequence. For example, by "80% homologous" is meant that a given sequence shares about 80% identity with the claimed sequence and can include insertions, deletions, substitutions, and frame shifts. One of ordinary skill in the art will understand that sequence alignments can be done to take into account insertions and deletions to determine identity over the entire length of a sequence.

[0088] The immunologically active biomimetics of the present invention are capable of binding to one or more antigens. In some embodiments, the immunologically active biomimetics of the present invention are capable of binding to two different antigens, similar to bispecific antibodies. In other embodiments, the immunologically active biomimetics of the present invention are capable of binding to more than two different antigens. The biomimetics of the present invention also possess one or more immune modulating activities of the IgG Fc domain and have at least a first Fc domain capable of binding FcRn, DC-SIGN, SIGN-RI and/or an Fc.gamma.R including Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII and Fc.gamma.RIV. In some embodiments, the biomimetics of the present invention possess a second Fc domain capable of binding FcRn, DC-SIGN, SIGN-RI and/or an Fc.gamma.R including Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII and Fc.gamma.RIV. Thus, when multimerized, the immunologically active biomimetics contain at least two dimeric structures, each possessing the ability to bind to one or more antigens, and the ability to bind to one or more of FcRn, DC-SIGN, SIGN-RI and/or and FC.gamma.R.

[0089] The following paragraphs define the building blocks of the biomimetics of the present invention, both structurally and functionally, and then define the biomimetics themselves. However, it is first helpful to note that, as indicated above, each of the biomimetics of the present invention has at least two Fc domains, and at least one Fab domain. At a minimum, an Fc domain is a dimeric polypeptide (or a dimeric region of a larger polypeptide) that comprises two peptide chains or arms (monomers) that associate to form a functional Fc.gamma. receptor binding site. Therefore, the functional form of the individual Fc fragments and Fc domains discussed herein generally exist in a dimeric (or multimeric) form. The monomers of the individual fragments and domains discussed herein are the single chains or arms that must associate with a second chain or arm to form a functional dimeric structure.

Fc Regions and Fab Regions

[0090] "Fc fragment" is a term of art that is used to describe the protein region or protein folded structure that is routinely found at the carboxy terminus of immunoglobulins. The Fc fragment consists of the carboxy terminal portions of the antibody heavy chains. Each of the chains in an Fc fragment is between about 220-265 amino acids in length and the chains are often linked via a disulfide bond. The Fc fragment often contains one or more independent structural folds or functional subdomains. In particular, the Fc fragment encompasses an Fc domain, defined herein as the minimum structure that binds an Fc.gamma. receptor. An isolated Fc fragment is comprised of two Fc fragment monomers (e.g., the two carboxy terminal portions of the antibody heavy chains; further defined herein) that are dimerized. When two Fc fragment monomers associate, the resulting Fc fragment has Fc.gamma. receptor binding activity.

[0091] "Fab fragment" is a term of art that is used to describe the protein region or protein folded structure that contains the antigen binding domain of an antibody. Fab fragments are comprised of both a heavy chain and a light chain, and are between about 200-250 amino acids in length. In some embodiments, the Fab fragment is comprised of the variable region and the CH1 region of the parent antibody. The Fab fragment can be isolated from the Fc fragment of a monoclonal antibody through the use of enzymatic digestion, for example papain digestion, which is an incomplete and imperfect process (see Mihaesco C and Seligmann M. Papain Digestion Fragments Of Human IgM Globulins. Journal of Experimental Medicine, Vol 127, 431-453 (1968)). The Fab fragment and the Fc fragment together constitutes the holo-antibody, meaning here the complete antibody.

[0092] An "Fc partial fragment" is a domain comprising less than the entire Fc fragment of an antibody, yet which retains sufficient structure to have the same activity as the Fc fragment, including Fc.gamma. receptor binding activity. An Fc partial fragment may therefore lack part or all of a hinge region, part or all of a CH2 domain, part or all of a CH3 domain, and/or part or all of a CH4 domain, depending on the isotype of the antibody from which the Fc partial domain is derived. An example of a Fc partial fragment includes a molecule comprising the upper, core and lower hinge regions plus the CH2 domain of IgG3 (Tan, L K, Shopes, R J, Oi, V T and Morrison, S L, Influence of the hinge region on complement activation, CIq binding, and segmental flexibility in chimeric human immunoglobulins, Proc Natl Acad Sci USA. 1990 January; 87(1): 162-166). Thus, in this example the Fc partial fragment lacks the CH3 domain present in the Fc fragment of IgG3. Another example of an Fc partial fragment includes a molecule comprising the CH2 and CH3 domains of IgG1. In this example, the Fc partial fragment lacks the hinge domain present in IgG1. Fc partial fragments are comprised of two Fc partial fragment monomers. As further defined herein, when two such Fc partial fragment monomers associate, the resulting Fc partial fragment has Fc.gamma. receptor binding activity.

[0093] The term "Fab domain" describes the minimum region (in the context of a larger polypeptide) or smallest protein folded structure (in the context of an isolated protein) that can bind to an antigen. The Fab domain is the minimum binding region of an Fab fragment that allows binding of the molecule to an antigen. "Fab domain" is used interchangeably herein with "Fab".

[0094] As used herein, "Fc domain" describes the minimum region (in the context of a larger polypeptide) or smallest protein folded structure (in the context of an isolated protein) that can bind to or be bound by an Fc receptor (FcR). In both an Fc fragment and an Fc partial fragment, the Fc domain is the minimum binding region that allows binding of the molecule to an Fc receptor. While an Fc domain can be limited to a discrete homodimeric polypeptide that is bound by an Fc receptor, it will also be clear that an Fc domain can be a part or all of an Fc fragment, as well as part or all of an Fc partial fragment. When the term "Fc domains" is used in this invention it will be recognized by a skilled artisan as meaning more than one Fc domain. An Fc domain is comprised of two Fc domain monomers. As further defined herein, when two such Fc domain monomers associate, the resulting Fc domain has Fc receptor binding activity. Thus an Fc domain is a dimeric structure that can bind an Fc receptor.

[0095] As used herein, "Fc partial domain" describes a portion of an Fc domain. Fc partial domains include the individual heavy chain constant region domains (e.g., CH1, CH2, CH3 and CH4 domains) and hinge regions of the different immunoglobulin classes and subclasses. Thus, human Fc partial domains of the present invention include the CH1 domains of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE, the CH2 domains of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE, the CH3 domains of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE, the CH4 domains of IgM and IgE, and the hinge regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE. The corresponding Fc partial domains in other species will depend on the immunoglobulins present in that species and the naming thereof. In one preferred embodiment, the Fc partial domains of the current invention comprise CH1, CH2, and hinge domains of IgG. In another preferred embodiment, the Fc partial domains of the current invention comprise CH1, CH2 and hinge domains of IgG and the hinge domain of IgG2. The Fc partial domain of the present invention may further comprise a combination of more than one of these domains and hinges. However, the individual Fc partial domains of the present invention and combinations thereof lack the ability to bind an Fc.gamma.R. Therefore, the Fc partial domains and combinations thereof comprise less than an Fc domain. Fc partial domains may be linked together to form a peptide that has Fc.gamma. receptor binding activity, thus forming an Fc domain. In the present invention, Fc partial domains are used with Fc domains as the building blocks to create the biomimetics of the present invention, as defined herein. Each Fc partial domain is comprised of two Fc partial domain monomers. When two such Fc partial domain monomers associate, an Fc partial domain is formed.

[0096] As indicated above, each of Fc fragments, Fc partial fragments, Fc domains and Fc partial domains are dimeric proteins or domains. Thus, each of these molecules is comprised of two monomers that associate to form the dimeric protein or domain. While the characteristics and activity of the homodimeric forms was discussed above the monomeric peptides are discussed as follows.

[0097] As used herein, an "Fc fragment monomer" is a single chain protein that, when associated with another Fc fragment monomer, comprises an Fc fragment. The Fc fragment monomer is thus the carboxy terminal portion of one of the antibody heavy chains that make up the Fc fragment of a holo-antibody (e.g., the contiguous portion of the heavy chain that includes the hinge region, CH2 domain and CH3 domain of IgG). In one embodiment, the Fc fragment monomer comprises, at a minimum, one chain of a hinge region (a hinge monomer), one chain of a CH2 domain (a CH2 domain monomer) and one chain of a CH3 domain (a CH3 domain monomer), contiguously linked to form a peptide. In another embodiment, the Fc fragment monomer comprises at least one chain of a hinge region, one chain of a CH2 domain, one chain of a CH3 domain, and one chain of a CH4 domain (a CH4 domain monomer) contiguously linked to form a peptide. In one embodiment, the CH2, CH3 and hinge domains are from different isotypes. In a particular embodiment, the Fc fragment monomer contains an IgG2 hinge domain and IgG CH2 and CH3 domains.

[0098] As used herein, "Fc domain monomer" describes the single chain protein that, when associated with another Fc domain monomer, comprises an Fc domain that can bind to an Fc.gamma. receptor. The association of two Fc domain monomers creates one Fc domain. An Fc domain monomer alone, comprising only one side of an Fc domain, cannot bind an Fc.gamma. receptor.

[0099] As used herein, "Fc partial domain monomer" describes the single chain protein that, when associated with another Fc partial domain monomer, comprises an Fc partial domain. The association of two Fc partial domain monomers creates one Fc partial domain.

Stradomers

[0100] The stradobodies of the present invention are comprised of stradomers, and an Fab domain. In one embodiment, the stradobodies of the present invention are comprised of multimerizing stradomers and an Fab domain. Stradomers are biomimetic compounds capable of binding two or more Fc receptors, preferably two or more Fc.gamma. receptors, and more preferably demonstrating significantly improved binding relative to an Fc domain and most preferably demonstrating slow dissociation characteristic of avidity. In one embodiment, the stradobodies of the present invention are used to bind FcRn, DC-SIGN, SIGN-RI and/or Fc.gamma. receptors on effector cells such as NK cells and monocyte-derived cells such as immature dendritic cells and macrophages. In another embodiment, the stradobodies of the present invention are used to bind Fc.gamma.RIIb receptors on B cells. In one embodiment, the Fc.gamma. receptors are low affinity Fc.gamma. receptors such as Fc.gamma.IIIa. The physical stradomer conformations have been previously described in U.S. Patent Application Publication No. 2010/0239633, and PCT Publication No. WO 2012/016073, both of which are incorporated by reference herein in their entireties.

[0101] A "serial stradomer" is a dimeric polypeptide comprised of two linear stradomer monomers that, when associated, form two or more Fc domains capable of binding two or more Fc.gamma. receptors. Serial stradomers preferably have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more Fc domains, as well as Fc partial domains. The Fc domains and/or Fc partial domains may be linked by domain linkages, as further defined herein.

[0102] As will be evident, the Fc fragments, Fc partial fragments, Fc domains and Fc partial domains discussed above are used in the construction of the various stradomer conformations. It is the individual Fc domain monomers and Fc partial domain monomers, also discussed above, that self-associate to form the dimeric structures that are the stradomers that comprise the stradobodies described herein. Further, the stradomers are associated with an Fab domain to form the stradobodies of the present invention.

[0103] As used herein, the term "stradomer monomer" or "stradomer unit" refers to a single, contiguous peptide molecule that, when associated with at least a second stradomer monomer, forms a polypeptide comprising at least two Fc domains. Stradomer monomers may be associated to form stradomers by inter-stradomer monomer linkages or they may form stradomers through self-assembly via covalent and non-covalent bonds.

[0104] A stradomer monomer may have an amino acid sequence that will form one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more Fc domains when associated with another stradomer monomer to form a stradomer. A stradomer monomer may further have an amino acid sequence that will form one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more Fc partial domains when associated with another stradomer monomer to form a stradomer.

[0105] The regions of stradomer monomers that will form Fc domains and Fc partial domains in the context of a stradomer may simply be arranged from carboxy terminal to amino terminal of successive regions of the stradomer monomer molecule. The arrangement of the particular Fc domain monomers and Fc partial domain monomers permits formation of two functional Fc domains upon association of two stradomer monomers.

[0106] An Fc domain can be functionally defined by its ability to bind FcRn, DC-SIGN, SIGN-RI and/or an Fc.gamma. receptor. The compounds of the current invention bind to cognate canonical Fc receptors including Fc.gamma.RIIIa, Fc.gamma.RIIb and/or SIGN-RI with higher affinity and/or much higher avidity than human IgG1 Fc control. Alternatively, the compounds of the current invention bind preferentially to the neonatal receptor FcRn over the Fc canonical receptors as a result of a point mutation at position 297 of the IgG1 Fc. As a result, the particular amino acid sequence of an Fc domain will vary based on the Fc partial domains that comprise the Fc domain. However, in one embodiment of the present invention the Fc domain comprises the hinge region and a CH2 domain of an immunoglobulin molecule. In a further preferred embodiment the Fc domain comprises the hinge region, a CH2 domain and CH3 domain of an immunoglobulin molecule. In a further embodiment, the Fc domain comprises the hinge region, a CH2 domain, CH3 domain and CH4 domain of an immunoglobulin molecule. In yet another embodiment, the Fc domain comprises the hinge region, a CH2 domain and CH4 domain of an immunoglobulin molecule. In a further preferred embodiment, the Fc domain comprises a CH2 domain and CH3 domain. In a preferred embodiment, the Fc domain contains the hinge, CH2 and CH3 domain of IgG1 (SEQ ID NO:2). In another preferred embodiment, the Fc domain contains the CH2 and CH3 domains of IgG1 (SEQ ID NO: 19).

Domain Linkage

[0107] As indicated above, a "domain linkage" is a peptide linkage between Fc domain monomers and/or Fc partial domain monomers that comprise each of the individual stradomer monomers of the stradobodies of the present invention. The domain linkage may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more amino acids. A domain linkage does not occur between Fc partial domain monomers that are in their natural sequence. That is, where linked naturally contiguous portions of Fc domain monomers are used, such as the hinge region, CH2 domain and CH3 domain of IgG, these Fc partial domain monomers comprise a contiguous sequence and no domain linkage between these elements is required. In contrast, for example, when two or more Fc domain monomers or partial Fc domain monomers are linked in a manner that is not naturally occurring to form an individual stradomer monomer, domain linkages may be used. An example would be the linkage between two hinge/CH2/CH3 peptides, creating an individual stradomer monomer of a stradomer comprising: hinge/CH2/CH3/L/hinge/CH2/CH3, where "L" is the domain linkage. In the various cases described, the domain linkage may be one of the naturally occurring portions of the heavy chain that joins the hinge and CH domains in the Fc domain monomer of an antibody. Alternatively, the domain linkage may be any other amino acid sequence that provides needed spacing and flexibility between the Fc domain monomers and partial Fc domain monomers of an individual stradomer monomer and that allows the individual stradomer monomers to pair with each other to form the stradomers making up the stradobodies of the present invention. An exemplary domain linkage is a GS linker sequence. The GS linker sequence may comprise 1, 2, 3, 4, or more repeats of GGGGS. Preferably, a GS linker sequence comprises 3 (G3S) or 4 (G4S) repeats of GGGGS.

[0108] In some embodiments, each immunologically active biomimetic compound will preferably contain at least one domain linkage in each stradomer monomer of the stradobody which will function to maintain the Fc domains of the immunologically active biomimetic within a restricted spatial region and which will facilitate Fc.gamma.R activation activity, for example, by aggregating Fc.gamma.Rs through co-binding to the Fc domains within the immunologically active biomimetic. Preferably, the domain linkages will allow the same or a greater degree of conformational variability as is provided by the hinge domain of IgG molecules. All of the above linkages are well-known in the art.

Inter-Stradomer Monomer Linkage

[0109] A separate linkage found in the biomimetic compounds of the present invention is the "inter-stradomer monomer linkage" that occurs between two or more individual stradomer monomers that comprise the stradobodies of the present invention. While the domain linkages are short amino acid sequences that serve to link the Fc domain monomers and partial Fc domain monomers that comprise individual stradomer monomers of the biomimetic compounds to each other, the inter-stradomer monomer linkages serve to join two or more individual stradomer monomers that comprise the biomimetic compounds. The inter-stradomer monomer linkage may be any linkage capable of stably associating the individual stradomer monomers. In some embodiments, the inter-stradomer monomer linkage may be a covalent link between the stradomer monomers. Alternatively, the inter-stradomer monomer linkage between stradomer monomers may be by direct chemical cross-linking. In preferred embodiments, the stradomer monomer structures take advantage of the natural self-assembly properties between Fc domain monomers to create self-assembling stradomers comprising the stradobodies of the present invention. The skilled artisan will understand that the inter-stradomer monomer linkages permits two or more individual stradobody monomers to form the biomimetic compounds of the stradobody comprising the present multimerizing stradobody invention and that the resulting compounds have the ability to cross-link more than one Fc.gamma.R.

[0110] As discussed above, in a preferred embodiment, the inter-stradomer monomer linkage that forms a stradomer is a linkage that results from self-assembly of stradomer monomers. In one embodiment, the two stradomer monomers that comprise the stradomer are identical peptides, such that the two individual stradomer monomers that comprise the stradomer are identical in sequence. However, the skilled artisan will understand that other embodiments include stradomers where the stradomer monomers differ from each other in amino acid sequence.

[0111] Two stradomer monomers can form a stradomer by, for example, aligning in parallel such that pairing takes place between identical Fc partial domain monomers in the stradomer monomers. However, the present invention also includes embodiments where pairing occurs between non-identical Fc partial domain monomers, and embodiments where pairing occurs between identical Fc partial domain monomers in the stradomer monomers but where the alignment of the two stradomer monomers is offset.

Multimerization Domains

[0112] The multimerization domain may comprise a peptide sequence that causes dimeric proteins to further multimerize. "Multimerization," as used herein, refers to the linking or binding together of multiple (i.e., two or more) individual stradobody homodimers. For example, stradobodies are multimerized when at least one stradobody homodimer (i.e., at least one homodimeric polypeptide comprising one or more Fc domains and one or more Fab domains) is attached to at least one other stradobody homodimer via a multimerization domain. Examples of peptide multimerization domains include IgG2 hinge, isoleucine zipper, collagen Glycine-Proline-Proline repeat ("GPP") and zinc fingers. The influence of glycosylation on peptide multimerization is well described in the art (e.g., Role of Carbohydrate in Multimeric Structure of Factor VIII/V on Willebrand Factor Protein. Harvey R. Gralnick, Sybil B. Williams and Margaret E. Rick. Proceedings of the National Academy of Sciences of the United States of America, Vol. 80, No. 9, [Part 1: Biological Sciences] (May 1, 1983), pp. 2771-2774; Multimerization and collagen binding of vitronectin is modulated by its glycosylation. Kimie Asanuma, Fumio Arisaka and Haruko Ogawa. International Congress Series Volume 1223, December 2001, Pages 97-101).

[0113] In one preferred embodiment, the multimerization domain is an IgG2 hinge. As is known in the art, the hinge region of human IgG2 can form covalent dimers (Yoo, E. M. et al. J. Immunol. 170, 3134-3138 (2003); Salfeld Nature Biotech. 25, 1369-1372 (2007)). The dimer formation of IgG2 is potentially mediated through the IgG2 hinge structure by C--C bonds (Yoo et al 2003), suggesting that the hinge structure alone can mediate dimer formation. The amount of IgG2 dimers found in human serum, however, is limited. There is no quantitative evidence of the multimerization of IgG2 beyond the dimer of the homodimer. (Yoo et al. 2003). That is, native IgG2 has not been found to form higher order multimers in human serum.

[0114] The amino acid sequence of the human IgG2 hinge monomer is as follows: ERKCCVECPPCP (SEQ ID NO: 3). Mutation of any one of the 4 cysteines in SEQ ID NO: 3 may be associated with greatly diminished multimerization of the stradobody. There are two C-X-X-C portions of the IgG2 hinge monomer. Thus, stradobodies of the present invention may comprise either the complete 12 amino acid sequence of the IgG2 hinge monomer, or either or both of the four amino acid cores, along with Fc domain monomers. While the X-X of the core structures can be any amino acid, in a preferred embodiment the X-X sequence is V-E or P-P. The skilled artisan will understand that the IgG2 hinge monomer may be comprised of any portion of the hinge sequence in addition to the core four amino acid structure, including all of the IgG2 hinge sequence and some or all of the IgG2 CH2 and CH3 domain monomer sequences. Without being bound by theory, the IgG2 hinge multimerization domain of one stradobody homodimer may form multimers by interacting with any portion of another stradobody homodimer. That is, the IgG2 hinge of one stradobody homodimer may multimerize by binding the IgG2 hinge of another stradobody homodimer, thereby forming a dimer of the homodimer, or higher order multimers while retaining increased functional binding to Fc receptors relative to natural IgG1 Fc. Alternatively, the IgG2 hinge domain of one stradobody homodimer may bind the IgG1 hinge of another stradobody homodimer, thereby forming a dimer of the homodimer, or higher order multimers while retaining increased functional binding to Fc receptors relative to natural IgG1 Fc. It is also possible that the IgG2 hinge domain of one stradobody homodimer binds to another portion of the IgG1 Fc domain, i.e. the CH2 or CH3 domain of another stradobody homodimer to form the dimer of the homodimer, or higher order multimers while retaining increased functional binding to Fc receptors relative to natural IgG1 Fc.

[0115] In another preferred embodiment, leucine zippers may be used as multimerization domains. In another preferred embodiment, isoleucine zippers may be used as multimerization domains. Leucine and isoleucine zippers (coiled-coil domains) are known to facilitate formation of protein dimers, trimers and tetramers (Harbury et al. Science 262:1401-1407 (1993); O'Shea et al. Science 243:538 (1989)).

[0116] While the skilled artisan will understand that different types of leucine and isoleucine zippers may be used, in one embodiment the isoleucine zipper from the GCN4 transcriptional regulator modified as described (Morris et al., MoI. Immunol. 44:3112-3121 (2007); Harbury et al. Science 262:1401-1407 (1993)) is used: GGGSIKOIEDKIEEILSKIYHIENEIARIKKLIGERGHGGG (SEQ ID NO: 5). In another embodiment, the sequence of the isoleucine zipper used is: GGGSIKOIEDKIEEILSKIYHIENEIARIKKLIGERGHDI (SEQ ID NOs: 32). These isoleucine zipper sequences are only two of several possible sequences that can be used for multimerization of Fc domain monomers. While the entire sequence shown in SEQ ID NOs: 5 or 32 may be used, the underlined portion of the sequence represents the core sequence of the isoleucine zipper that may be used in the stradobodies of the present invention. Thus, stradomer monomers comprising the stradobodies of the present invention may comprise either the complete amino acid sequence of the isoleucine zipper, or the 28 amino acid core, along with one or more Fc domain monomers. The skilled artisan will also understand that the isoleucine zipper may be comprised of any portion of the zipper in addition to the core 28 amino acid structure, and thus may be comprised of more than 28 amino acids but less than the entire sequence of SEQ ID NOs: 5 or 32.

[0117] In another preferred embodiment, GPP repeats may be used as multimerization domains. GPP is an amino acid sequence found in human collagen that causes collagen protein: protein binding. While the skilled artisan will understand that different types of GPP repeats may be used as a Multimerization Domain, in a preferred embodiment the Glycine-Proline-Proline repeats as described (Fan et al FASEB Journal 3796 vol 22 2008) is used: (SEQ ID NO:26) This Glycine-Proline-Proline repeat sequence is only one of several possible sequences that can be used for multimerization of stradobodies. While the entire sequence shown in SEQ ID NO:26 may be used, repeats of different length may also possible be used to multimerize Fc domain monomers. Likewise, repeats containing different amino acids within the GPP repeats may also be substituted.

Stradobody

[0118] The present invention is directed to stradobodies and methods of making and using stradobodies. As used herein, "stradobody" refers to a molecule comprising two or more Fc domains, to which one or more Fab domains is attached. Thus, by virtue of such Fab domains and Fc domains, stradobodies have both antigen binding capacity and Fc.gamma. receptor binding activity. In some embodiments, the Fc.gamma. receptor activity may be due to an ability to bind and cross-link Fc.gamma.R equal to or greater than the Fc portion of a native structure holo-antibody. The Fab portion of the stradobody may comprise both a heavy and a light chain. The variable heavy chain and the light chain may be independently from any compatible immunoglobulin such as IgA1, IgA2, IgM, IgD, IgE, IgG, IgG2, IgG3, or IgG4, and may be from the same or different Ig isotype, but preferably are from the same Ig isotype. The light chains kappa or lambda may also be from different Ig isotypes. In some embodiments, stradobodies, like stradomers, can bind two or more Fc.gamma.Rs and modulate immune function. In one embodiment, the stradobodies of the current invention comprise a Fab domain, one or more Fc domains, and one or more multimerization domains, wherein at least one of the one or more multimerization domains separates two or more Fc domains, or is located at the carboxy end of the Fc region. The term "Fc region" is used herein to refer to the region of the stradobody that comprises Fc domains, domain linkages, and multimerization domains. Thus, the Fc region is the region of the stradobody that does not comprise the Fab domain. Multimerization domains are described above and are amino acid sequences known to cause protein multimerization in the proteins where they naturally occur. In one embodiment, the multimerization domains may be IgG hinges, isoleucine zippers, or a combination thereof. In a particular embodiment, the stradobody is comprised of an Fab, a first Fc domain, an isoleucine zipper, an IgG2 hinge, and a second Fc domain. The Fab comprises both a heavy chain and a light chain as found in native immunoglobulin structures.

[0119] The stradobodies of the current invention may be classified as either serial stradobodies or C-terminal stradobodies. The general structures of these stradobodies are shown in FIG. 1. The serial and C-terminal stradobodies of the current invention preferably comprise an Fab domain; one or more Fc domains; and one or more multimerization domains. For example, the serial and C-terminal stradobodies of the invention preferably comprise an Fab domain; 1, 2, 3, 4, or 5 Fc domains; and 1, 2, 3, 4, or 5 multimerization domains. In some embodiments, the serial and C-terminal stradobodies of the current invention further comprise one or more spacers or flexible linkers. Serial stradobodies preferably comprise 2 or more Fc domains. For example, serial stradobodies preferably comprise 2, 3, 4, 5, or 6 Fc domains.

[0120] Serial stradobodies were designed to simultaneously bind and cross-link multiple low-affinity Fc.gamma.Rs by incorporating two or more Fc domains in a chimeric heavy chain. The Fc domains are separated by one or more different or the same multimerization domains, spacers, and/or flexible linkers. Serial stradobodies may be either multimerizing serial stradobodies or non-multimerizing serial stradobodies. Multimerizing serial stradobodies comprise at least one multimerization domain are associated with the formation of multimers. Multimerization domains are described above and include IgG2 hinges, isoleucine zippers, collagen GPP, and zinc fingers. Non-multimerizing serial stradobodies may not comprise a multimerization domain, but may comprise one or more domain linkage, such as a G4S linker. In some embodiments, a multimerizing serial stradobody comprises both one or more multimerization domains and one or more domain linkages. General structures of serial stradobodies are shown in FIG. 2. More specific structures of exemplary serial stradobody constructs comprising one or more of the indicated multimerization domains and/or linker domains (ILZ refers to isoleucine zipper; 2H refers to IgG2 hinge; and G4S refers to an amino acid sequence Gly.sub.4Ser) are shown in FIG. 3. Serial stradobody constructs that comprise an Fab region specific for EGFR are shown below in Table 1. Serial stradobody constructs that comprise an Fab region specific for HER2/neu or an Fab region specific for CD20 are shown in FIG. 4 and below in Table 1.

[0121] C-terminal multimerized stradobodies were designed to simultaneously bind and cross-link multiple low-affinity Fc.gamma.Rs by incorporating one or more multimerization domains at the C-terminal end of the Fc region and thereby promote formation of stradobody complexes able to interact with multiple Fc receptors simultaneously. Exemplary structures of C-terminal stradobodies are shown in FIG. 5. C-terminal multimerized stradobodies that comprise an anti-EGFR Fab are shown in FIG. 6 and below in Table 1. C-terminal multimerized stradobody constructs that comprise an anti-CD20 Fab are also shown in FIG. 6 and below in Table 1. In the C-terminal stradobodies, the Fc region of the heavy chain has one or more different or the same multimerization domains, spacers, or flexible linkers on the C-terminal side. The C-terminal stradobodies shown also include a construct that contains a multimerization domain and a purification tag.

TABLE-US-00001 TABLE 1 Unaltered monoclonal antibody and stradobody constructs Construct Specificity Monoclonal antibodies GB2500 (Trastuzumab) HER2/neu GB3500 (Cetuximab) EGFR GB4500 (Rituximab) CD20 GB7500 (Adalimumab) TNF Multimerizing serial stradobodies GB2524 HER2/neu GB2538 HER2/neu GB2540 HER2/neu GB2542 HER2/neu GB3524 EGFR GB3538 EGFR GB3540 EGFR GB3542 EGFR GB4524 CD20 GB4538 CD20 GB4540 CD20 GB4542 CD20 GB7524 TNF GB7538 TNF GB7540 TNF GB7542 TNF Non-multimerizing serial stradobodies GB2554 HER2/neu GB2555 HER2/neu GB3554 EGFR GB3555 EGFR GB4554 CD20 GB4555 CD20 GB7554 TNF GB7555 TNF C-terminal multimerized stradobodies GB2534 HER2/neu GB2545 HER2/neu GB2546 HER2/neu GB2547 HER2/neu GB2549 HER2/neu GB2550 HER2/neu GB2560 HER2/neu GB2561 HER2/neu GB2562 HER2/neu GB2563 HER2/neu GB2589 HER2/neu GB2590 HER2/neu GB3534 EGFR GB3545 EGFR GB3546 EGFR GB3547 EGFR GB3549 EGFR GB3550 EGFR GB3560 EGFR GB3561 EGFR GB3562 EGFR GB3563 EGFR GB3589 EGFR GB3590 EGFR GB4534 CD20 GB4545 CD20 GB4546 CD20 GB4547 CD20 GB4549 CD20 GB4550 CD20 GB4560 CD20 GB4561 CD20 GB4562 CD20 GB4563 CD20 GB4589 CD20 GB4590 CD20 GB7534 TNF GB7545 TNF GB7546 TNF GB7547 TNF GB7549 TNF GB7550 TNF GB7560 TNF GB7561 TNF GB7562 TNF GB7563 TNF GB7589 TNF GB7590 TNF

[0122] The skilled artisan will recognize that the specific stradobodies described above are exemplary, and that serial stradobodies with various structures and combinations of stradomers and stradomer building blocks are possible, for example, serial multimerized C-terminal stradobodies comprising one or more multimerization domain and two or more Fc domains. Serial multimerized C-terminal stradobodies may comprise one or more multimerization domains between two Fc domains and one or more multimerization domains at the C-terminal end of the Fc region.

[0123] Stradobodies will possess the antigen binding properties of the Fab portion and the above described stradomer properties. Such a combination will serve to bind, cross-link, and activate Fc.gamma. receptors on effector cells at a higher rate than can be accomplished by an Fc backbone of a holo-antibody, particularly in the environment of low epitope expression (e.g. the 90% of breast cancer patients whose tumors are not classified as HER2/neu high expressors), inducing ADCC, CDC, and/or DC in a higher percentage of patients. As indicated above, one or more antigen-binding Fab domains can be added to the stradomers to form stradobodies.

[0124] We surprisingly found that stradobodies with one or more multimerization domains between two Fc domains (e.g. GB2542, GB3542, GB4542, and GB7542 corresponding to SEQ ID Nos 35, 33, 37 and 66, respectively), or located at the carboxy end of the Fc region (e.g. GB2547, GB3547, GB4547, and GB7547, corresponding to SEQ ID Nos 91, 70, 76 and 87, respectively), exhibited not only superior multimerization, but also superior binding and superior cytoxicity in comparison both to the parent mAb and to stradobodies without multimerization domains or with one or more multimerization domain located at the N-terminal end of the Fc region, including in ADCC, CDC, DC, and other mechanisms of cytoxicity. In particular, a stradobody comprising both an isoleucine zipper and an IgG2 hinge yielded particularly strong ADCC, CDC, and DC and particularly strong clq binding. Unexpectedly, when these two multimerization domains were located between two Fc domains, multimerization, binding to Fc.gamma.R, and ADCC, CDC, and DC results as well as clq binding were particularly robust.

[0125] We surprisingly found that the presence of an Fab can dramatically alter the ability of the resulting stradobody to multimerize relative to the isolated stradomer that comprises the stradobody. More specifically, stradomers with N-terminal multimerization domains can multimerize well and function well but a stradobody comprised of the same stradomer, as disclosed in WO 2008/151088, may multimerize poorly or not at all. Conversely, it is possible for serial stradobodies with one or more multimerization domains or stradobodies with one or more C-terminal multimerization domains to multimerize better than the stradomer that comprises such stradobody.

[0126] In some embodiments, the stradobody of the invention further comprises a danger signal or damage signal. In some embodiments, the stradobody of the invention is administered to patients concurrently with, or in the same treatment cycle as, a danger signal or damage signal. Pradeu and Cooper (Front Immunol. 3: Article 287, 1-9 (2012) have recently reviewed such danger signals or damage signals. In one embodiment, danger signals or damage signals that may be comprised within or administered with the stradobody of the invention include endogenous signals including CD40-L, TNF-.alpha., IL-1.beta., IFN.alpha., Intracellular nucleotides ATP or UTP, Long unmethylated CpG sequences, Heat Shock Proteins, reactive oxygen intermediates, Vasoactive Intestinal Peptide, metalloproteinase-9, degradation products of heparan sulfate, small breakdown products of hyaluronan, LDL-derived phospholipids, or LOX-1. In another embodiment, danger signals or damage signals that may be comprised within or administered with the stradobody of the invention include uric acid, high-mobility-group box 1, an inflammasome (a multiprotein complex that contains a pattern recognition receptor), IL-1 .alpha.; S100 proteins; hepatoma-derived growth factor, IL-1 .alpha.; high concentrations of adenosine 5'-triphosphatase, .beta.-D-glucopyranosylceramide, IL-33, nanoparticles such as gold nanoparticles, or F-actin. In an especially preferred embodiment, the stradobody of the invention comprises a peptide danger signal or damage signal at the carboxy end of the stradobody, including Vasoactive Intestinal Peptide, metalloproteinase-9, Heat Shock Protein, High Mobility group 1, S-100, IL-1a, hepatoma derived growth factor, peptides that share amino acid sequence similarity of at least 70% with these peptides, and peptides that are fragments of these peptides.

[0127] In some embodiments, the stradobody of the invention comprises an Fab that is specific for EGFR. In some embodiments, the EGFR-specific Fab is derived from the monoclonal antibody cetuximab. In some embodiments, the Fab is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO: 31.

[0128] In some embodiments, the stradobody of the invention comprises an Fab that is specific for HER2/neu. In other embodiments, the stradobody comprises an Fab that is derived from the anti-HER2/neu monoclonal antibody trastuzumab. In some embodiments, the Fab is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO 34.

[0129] In some embodiments, the stradobody of the invention comprises an Fab that is specific for CD20. In other embodiments, the stradobody comprises an Fab that is derived from the anti-CD20 monoclonal antibody rituximab. In some embodiments, the Fab is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO 36.

[0130] In some embodiments, the stradobody of the invention comprises an Fab that is specific for TNF. In other embodiments, the stradobody comprises an Fab that is derived from the anti-TNF monoclonal antibody adalimumab. In some embodiments, the Fab is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO 67.

[0131] In some embodiments, the stradobody of the invention comprises more than one Fab. In further embodiments, each of the more than one Fab is specific for a different antigen. For example, a stradobody may comprise Fabs specific for EGFR and HER2/neu; CD3 and CD19; CD3 and CD20; CD3 and carcinoembryonic antigen; CD3 and EGFR; and combinations thereof.

[0132] In certain embodiments, stradobodies comprise, from amino to carboxy terminus, an Fab domain, a first IgG1 CH2, a first IgG1 CH3, an isoleucine zipper, an IgG2 hinge, a second IgG1 CH2, and a second IgG1 CH3 (FIG. 7).

[0133] In a particular embodiment, the stradobody of the invention comprises a leader amino acid sequence according to SEQ ID NO: 1, an EGFR-specific variable region and CH2 region amino acid sequence according to SEQ ID NO: 31, an IgG1 Fc domain according to SEQ ID NO: 2, an isoleucine zipper according to SEQ ID NO: 32, and an IgG2 hinge according to SEQ ID NO: 3.

[0134] In another embodiment, the amino acid sequence of the whole stradobody is according to SEQ ID NO: 33 (construct GB3542 in Table 2). In one embodiment, the stradobody is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO: 33.

[0135] In another embodiment, the amino acid sequence of the whole stradobody is according to SEQ ID NO: 35 (construct GB2542 in Table 2). In one embodiment, the stradobody is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO: 35.

[0136] In another embodiment, the amino acid sequence of the whole stradobody is according to SEQ ID NO: 37 (construct GB4542 in Table 2). In one embodiment, the stradobody is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO: 37.

[0137] In another embodiment, the amino acid sequence of the whole stradobody is according to SEQ ID NO: 66 (construct GB7542 in Table 2). In one embodiment, the stradobody is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% homologous to SEQ ID NO: 66.

TABLE-US-00002 TABLE 2 Amino acid sequences of stradobody constructs GB2542, GB3542, GB4542, and GB7542, and components of constructs GB2542, GB3542 GB4542, and GB7542. Sequence Leader sequence METDTLLLWVLLLWVPGSTG (SEQ ID NO: 1) GB2542 Variable and EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQA CH1 regions (identical PGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAY to variable and CH1 LQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT regions of VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT trastuzumab/GB2500) VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ (SEQ ID NO: 34) TYICNVNHKPSNTKVDKKV GB3542 Variable and QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQS CH1 regions (identical PGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF to variable and CH1 KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA regions of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS cetuximab/GB3500) WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT (SEQ ID NO: 31) YICNVNHKPSNTKVDKRV GB4542 Variable and QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVK CH1 regions (identical QTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSST to variable and CH1 AYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTT regions of VTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP rituximab/GB4500) VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVVPSSSLG (SEQ ID NO: 36) TQTYICNVNHKPSNTKVDKKV GB 7542 Variable and EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQ CH1 regions (identical APGKGLEWVSAITWNSGHIDYADSVEGRFTISRDNAKNSL to variable and CH1 YLQMNSLRAEDTAVYYCAKVSYLSTASSLDYWGQGTLVT regions of VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT adalimumab/GB7500) VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ (SEQ ID NO: 67) TYICNVNHKPSNTKVDKKV IgG1 Fc EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP (SEQ ID NO: 2) EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Isoleucine Zipper GGGSIKQIEDKIEEILSKIYHIENEIARIKKLIGERGHDI (SEQ ID NO: 32 ) IgG2 Hinge ERKCCVECPPCP (SEQ ID NO: 3) GB2542 Construct METDTLLLWVLLLWVPGSTGEVQLVESGGGLVQPGGSLR (SEQ ID NO: 35) LSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTR YADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSR WGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSLEGG GSIKQIEDKIEEILSKIYHIENEIARIKKLIGERGHDIERKCCV ECPPCPRLEGPRFEEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK GB3542 Construct METDTLLLWVLLLWVPGSTGQVQLKQSGPGLVQPSQSLSI (SEQ ID NO: 33) TCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDY NTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALT YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGKSLEGGGSIKQI EDKIEEILSKIYHIENEIARIKKLIGERGHDIERKCCVECPPCP RLEGPRFEEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K GB4542 Construct METDTLLLWVLLLWVPGSTGQVQLQQPGAELVKPGASVK (SEQ ID NO: 37) MSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDT SYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCA RSTYYGGDWYFNVWGAGTTVTVSAASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSLEG GGSIKQIEDKIEEILSKIYHIENEIARIKKLIGERGHDIERKCC VECPPCPRLEGPRFEEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK GB7542 Construct METDTLLLWVLLLWVPGSTGEVQLVESGGGLVQPGRSLR (SEQ ID NO: 66) LSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWNSGHI DYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCA KVSYLSTASSLDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSLEGG GSIKQIEDKIEEILSKIYHIENEIARIKKLIGERGHDIERKCCV ECPPCPRLEGPRFEEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK

[0138] It is understood that the stradobodies disclosed herein can be derived from any of a variety of species. Indeed, Fc domains, or Fc partial domains, in any one biomimetic molecule of the present invention can be derived from immunoglobulin from more than one (e.g., from two, three, four, five, or more) species. However, they will more commonly be derived from a single species. In addition, it will be appreciated that any of the methods disclosed herein (e.g., methods of treatment) can be applied to any species. Generally, the components of a biomimetic applied to a species of interest will all be derived from that species. However, biomimetics in which all the components are of a different species or are from more than one species (including or not including the species to which the relevant method is applied) can also be used.

[0139] The specific CH1, CH2, CH3 and CH4 domains and hinge regions that comprise the Fc domains and Fc partial domains of the stradobodies of the present invention may be independently selected, both in terms of the immunoglobulin subclass, as well as in the organism, from which they are derived. Accordingly, the stradobodies disclosed herein may comprise Fc domains and partial Fc domains that independently come from various immunoglobulin types such as human IgG1, IgG2, IgG3, IgG4, IgA1, IgA1, IgD, IgE, and IgM, mouse IgG2a, or dog IgGa or IgGb. Preferably, for human therapeutics the Fc domains of the current invention are of the human IgG1 isotype. Similarly each Fc domain and partial Fc domain may be derived from various species, preferably a mammalian species, including non-human primates (e.g., monkeys, baboons, and chimpanzees), humans, murine, rattus, bovine, equine, feline, canine, porcine, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, birds (e.g., chickens, turkeys, and ducks), fish and reptiles to produce species-specific or chimeric stradobody molecules.

[0140] The Fab may be a chimeric structure comprised of human constant regions and non-human variable regions such as the variable region from a mouse, rat, rabbit, monkey, or goat antibody. One of ordinary skill in the art would be able to make a variety of Fab chimeric structures for incorporation into stradobodies using methodologies currently available and described in the scientific literature for such constructions. Individual Fab domains, Fc domains and partial Fc domains may also be humanized. Thus, "humanized" stradobodies may be designed analogous to "humanized" monoclonal antibodies.

[0141] One of skill in the art will realize that different Fc domains and partial Fc domains will provide different types of functionalities. For example, Fc.gamma.Rs bind specifically to IgG immunoglobulins and not well other classes of immunoglobulins. Thus, one of skill in the art, intending to design a stradobody with multiple Fc.gamma. receptor binding capacity, would design stradomer Fc domains that at least incorporate the well characterized Fc.gamma. receptor binding sequences of IgG, including those in the lower IgG hinge region and/or the IgG CH2 & CH3 domains. One of ordinary skill in the art will also understand various deleterious consequences can be associated with the use of particular Ig domains, such as the anaphylaxis associated with IgA infusions. The biomimetics disclosed herein should generally be designed to avoid such effects, although in particular circumstances such effects may be desirable.

[0142] The present invention also encompasses stradobodies comprising Fc domains and Fc partial domains having amino acids that differ from the naturally-occurring amino acid sequences of the Fc domain or Fc partial domain. Preferred Fc domains for inclusion in the biomimetic compounds of the present invention have a measurable specific binding affinity to either a holo-Fc.gamma. receptor or a soluble extracellular domain portion of an Fc.gamma.R. Primary amino acid sequences and X-ray crystallography structures of numerous Fc domains and Fc domain monomers are available in the art. See, e.g., Woof J M, Burton D R. Human antibody-Fc receptor interactions illuminated by crystal structures. Nat Rev Immunol. 2004 February; 4(2):89-99. Representative Fc domains with Fc.gamma. receptor binding capacity include the Fc domains from human IgG (SEQ ID NO: 2). These native sequences have been subjected to extensive structure-function analysis including site directed mutagenesis mapping of functional sequences. Based on these prior structure-function studies and the available crystallography data, one of skill in the art may design functional Fc domain sequence variants while preserving the Fc domain's Fc.gamma.R receptor binding capacity. For example, cysteine residues may be added to enhance sulfide bonding between monomers or deleted to alter the interaction between stradomer homodimers that comprise the stradobody homodimer.

[0143] In addition, the present invention encompasses stradobodies comprising Fab domains having amino acids that differ from the amino acid sequence of the antibody from which the Fab domain is derived. Fab domains for inclusion in the biomimetic compounds of the present invention have a measurable specific binding affinity to a particular antigen. Preferably, the biomimetic compounds have a binding affinity that is greater than the binding affinity of corresponding unaltered antibodies.

[0144] The amino acid changes may decrease, increase, or leave unaltered the binding affinity of the stradobody to the Fc.gamma. receptor or the antigen. Preferably such amino acid changes will be conservative amino acid substitutions, however, such changes include deletions, additions and other substitutions. Conservative amino acid substitutions typically include changes within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine, glutamine, serine and threonine; lysine, histidine and arginine; and phenylalanine and tyrosine. Additionally, the amino acid change may enhance multimerization strength, for example by the addition of cysteine residues.

[0145] The amino acid changes may be naturally occurring or may be introduced, for example by site directed mutagenesis. The amino acid changes can occur anywhere within the Fc domain or Fab domain so long as the Fc domain retains its receptor binding function and biological activity, and the Fab domain retains its antigen binding function and biological activity. In a preferred embodiment, the polymorphism or mutation leads to enhanced receptor/antigen binding and/or enhanced multimerization or biological function. For Fc domains, the polymorphism/mutation preferably occurs at one or more of amino acid positions 233-435 according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5.sup.th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Specific polymorphisms/mutations in these amino acid positions are well known in the art and can be found, for example in Shields, et al. (2001) "High Resolution Mapping of the Binding Site on Human IgG1 for Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII and FcRn and Design of IgG Variants with Improved Binding to the Fc.gamma.R," J. Biol. Chem., 276(9):6591-6601, which is herein incorporated by reference in its entirety.

[0146] From the above, it will be appreciated that stradobodies of the present invention include stradobodies having: (a) only naturally occurring Fab and Fc domains; (b) a mixture of naturally occurring Fab and Fc domains and Fab and Fc domains with altered amino acid sequences; and (c) only Fab and Fc domains with altered amino acid sequences. All that is required is that stradobodies containing altered amino acid sequences have at least 25%; 30%; 40%; 50%; 60%; 70%; 80%; 90%; 95%; 96%; 97%; 98%; 99%; 99.5%; or 100% or even more of the ability of a corresponding stradobody comprising Fab and Fc domains with naturally-occurring sequences to bind to antigen and to Fc.gamma.R receptors.

[0147] The aforementioned Fc.gamma. receptor and antigen binding sites occurring in the stradobodies of the present invention may be altered in sequence through genetic engineering to predictably derive binding sites with altered binding capabilities and affinities relative to a native sequence. For example, specific residues may be altered that reduce Fc domain binding of the biomimetic compounds to Fc.gamma.RIIb while increasing binding to Fc.gamma.RIIIa or vice versa or that reduce Fc domain binding of the biomimetic compounds to Fc.gamma.RIIb while increasing binding to FcRn or vice versa. An example of an extensive mutagenesis based structure-function analysis for human IgG Fc.gamma. receptor binding sequences is Robert L. Shields, et al. High Resolution Mapping of the Binding Site on Human IgG1 for Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII, and FcRn and Design of IgG1 Variants with Improved Binding to the Fc.gamma.R. J. Biol. Chem., February 2001; 276: 6591-6604. Similar studies have been performed on murine IgG Fc (mIgG Fc). Based on the structural and primary sequence homologies of native IgG Fc domains across species, one of skill in the art may translate the extensive structure-function knowledge of human IgG Fc and mouse IgG Fc to rational mutagenesis of all native Fc.gamma. receptor binding site sequences in the biomimetic compounds of the present invention to design binding sites with particular Fc.gamma. receptor specificities and binding affinities.

[0148] In addition to the amino acid sequence composition, the carbohydrate content of the Fc domain is known to play an important role on Fc domain structure and binding interactions with Fc.gamma.R. See, e.g., Robert L. Shields, et al. Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human Fc.gamma.RIII and Antibody-dependent Cellular Toxicity. J. Biol. Chem., July 2002; 277: 26733-26740 (doi:10.1074/jbc.M202069200); Ann Wright and Sherie L. Morrison. Effect of C2-Associated Carbohydrate Structure on Ig Effector Function: Studies with Chimeric Mouse-Human IgG1 Antibodies in Glycosylation Mutants of Chinese Hamster Ovary Cells. J. Immunol, April 1998; 160: 3393-3402. Similarly, the extent of fucosylation of antibodies is known to play a role in antigen binding and ADCC. See, e.g., Yamane-Ohnuki and Satoh, Production of therapeutic antibodies with controlled fucosylation. Mabs. 2009 May-June; 1(3):230-236. Carbohydrate content may be controlled using, for example, particular protein expression systems including particular cell lines or in vitro enzymatic modification. In some embodiments, the stradobodies are defucosylated. Defucosylation is known to improve the affinity of IgG1 Fc for Fc.gamma.RIIIa. Thus, the present invention includes stradobodies with the native carbohydrate content of holo-antibody from which the domains were obtained, as well as those stradobody compounds with an altered carbohydrate content. In another embodiment, a modified cell line is used to generate a preferred glycosylation pattern. In another embodiment, chemoenzymatic glycosylation is used to generate a preferred glycosylation pattern including with non-natural sugars. In another embodiment, multimer components of the stradobody are characterized by a different glycosylation pattern compared with the homodimer component of the same stradobody. In a preferred embodiment, the stradobody is enriched for multimers comprising a glycosylation pattern that enhances Fc receptor binding.

[0149] The addition to the polypeptide chain of an Fc partial domain, a multimerization region, or glycosylation changes may create a conformational change in the Fc domain permitting enhanced binding of the Fc domain to an Fc.gamma. receptor. Thus, seemingly very minor changes to the polypeptide may also create a stradobody capable of enhanced binding of multiple Fc.gamma. receptors or FcRn receptors or a stradobody with decreased ability to bind multiple Fc.gamma. receptors or FcRn receptors.

[0150] The skilled artisan will further recognize that the Fc domains, and Fc partial domains used in the embodiments of the present invention need not be full-length versions. That is, the present invention encompasses the use of Fc domain monomers and Fc partial domain monomers lacking amino acids from the amino terminus, carboxy terminus or middle of the particular Fc domain monomers and Fc partial domain monomers that comprise the stradobodies of the present invention.

[0151] For example, the binding site on human IgG immunoglobulins for Fc.gamma. receptors has been described (e.g. Radaev, S., Sun, P., 2001. Recognition of Immunoglobulins by Fc.gamma. Receptors. Molecular Immunology 38, 1073-1083; Shields, R. L. et. al., 2001. High Resolution Mapping of the Binding Site on Human IgG1 for Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII, and FcRn and Design of IgG1 Variants with Improved Binding to the Fc.gamma.R. J. Biol. Chem. 276 (9), 6591-6604). Based on that knowledge, one may remove amino acids from the Fc domain of these immunoglobulins and determine the effects on the binding interaction between the Fc domain and the receptor. Thus, the present invention encompasses IgG Fc domains having at least about 90% of the amino acids encompassing positions 233 through 338 of the lower hinge and CH2 as defined in Radaev, S., Sun, P., 2001.

[0152] Fc partial domains of IgG immunoglobulins of the present invention may include all or part of the hinge region, all or part of the CH2 domain, and all or part of the CH3 domain.

[0153] The IgG Fc partial domains having only a part of the hinge region, part of the CH2 domain or part of the CH3 domain are constructed from Fc partial domain monomers. Thus, the present invention includes IgG hinge region monomers derived from the N-terminus of the hinge region or the C-terminus of the hinge region. They can thus contain, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62 (up to 15 for IgG1, up to 12 for IgG2, up to 62 for IgG3, up to 12 for IgG4) amino acids of the hinge region.

[0154] The present invention also includes IgG CH2 domain monomers derived from the N-terminus of the CH2 domain or the C-terminus of the CH2 domain. They can thus contain, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 (up to 110 for IgG1 and IgG3, up to 109 for IgG2 and IgG4) amino acids of the CH2 domain.

[0155] The present invention further includes IgG CH3 domain monomers derived from the N-terminus of the CH3 domain or the C-terminus of the CH3 domain. They can thus contain, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, or 107 (up to 106 for IgG1 and IgG3, up to 107 for IgG2 and IgG4) amino acids of the CH3 domain.

[0156] The term "isolated" polypeptide or peptide as used herein refers to a polypeptide or a peptide which either has no naturally-occurring counterpart or has been separated or purified from components which naturally accompany it, e.g., in tissues such as pancreas, liver, spleen, ovary, testis, muscle, joint tissue, neural tissue, gastrointestinal tissue, or breast tissue or tumor tissue (e.g., breast cancer tissue), or body fluids such as blood, serum, or urine. Typically, the polypeptide or peptide is considered "isolated" when it is at least 70%, by dry weight, free from the proteins and other naturally-occurring organic molecules with which it is naturally associated. Preferably, a preparation of a polypeptide (or peptide) of the invention is at least 80%, more preferably at least 90%, and most preferably at least 99%, by dry weight, the polypeptide (peptide), respectively, of the invention. Since a polypeptide or peptide that is chemically synthesized is, by its nature, separated from the components that naturally accompany it, the synthetic polypeptide or peptide is "isolated."

[0157] An isolated polypeptide (or peptide) of the invention can be obtained, for example, by extraction from a natural source (e.g., from tissues or bodily fluids); by expression of a recombinant nucleic acid encoding the polypeptide or peptide; or by chemical synthesis. A polypeptide or peptide that is produced in a cellular system different from the source from which it naturally originates is "isolated," because it will necessarily be free of components which naturally accompany it. The degree of isolation or purity can be measured by any appropriate method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.

Pharmaceutical Compositions

[0158] Administration of the stradobody compositions described herein will be via any common route, orally, parenterally, or topically. Exemplary routes include, but are not limited to oral, nasal, buccal, rectal, vaginal, ophthalmic, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intratumoral, spinal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, sublingual, oral mucosal, bronchial, lymphatic, intra-uterine, subcutaneous, intratumor, integrated on an implantable device such as a suture or in an implantable device such as an implantable polymer, intradural, intracortical, or dermal. Such compositions would normally be administered as pharmaceutically acceptable compositions as described herein. In a preferred embodiment the isolated stradobody is administered intravenously or subcutaneously.

[0159] The term "pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.

[0160] The stradobody compositions of the present invention may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

[0161] Sterile injectable solutions are prepared by incorporating the stradobody in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0162] Further, one embodiment is a stradobody composition suitable for oral administration and is provided in a pharmaceutically acceptable carrier with or without an inert diluent. The carrier should be assimilable or edible and includes liquid, semi-solid, i.e., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of a stradobody preparation contained therein, its use in an orally administrable a stradobody composition for use in practicing the methods of the present invention is appropriate. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof. The term "oral administration" as used herein includes oral, buccal, enteral or intragastric administration.

[0163] In one embodiment, the stradobody composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, microencapsulation, absorption and the like. Such procedures are routine for those skilled in the art.

[0164] In a specific embodiment, the stradobody composition in powder form is combined or mixed thoroughly with a semi-solid or solid carrier. The mixing can be carried out in any convenient manner such as grinding. Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity through, i.e., denaturation in the stomach. Examples of stabilizers for use in an orally administrable composition include buffers, antagonists to the secretion of stomach acids, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc., proteolytic enzyme inhibitors, and the like. More preferably, for an orally administered composition, the stabilizer can also include antagonists to the secretion of stomach acids.

[0165] Further, the stradobody composition for oral administration which is combined with a semi-solid or solid carrier can be further formulated into hard or soft shell gelatin capsules, tablets, or pills. More preferably, gelatin capsules, tablets, or pills are enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, i.e., U.S. Pat. No. 5,629,001. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the composition to be released to interact with intestinal cells, e.g., Peyer's patch M cells.

[0166] In another embodiment, the stradobody composition in powder form is combined or mixed thoroughly with materials that create a nanoparticle encapsulating the immunologically active biomimetic or to which the immunologically active biomimetic is attached. Each nanoparticle will have a size of less than or equal to 100 microns. The nanoparticle may have mucoadhesive properties that allow for gastrointestinal absorption of an immunologically active biomimetic that would otherwise not be orally bioavailable.

[0167] In another embodiment, a powdered composition is combined with a liquid carrier such as, i.e., water or a saline solution, with or without a stabilizing agent.

[0168] A specific stradobody formulation that may be used is a solution of immunologically active biomimetic protein in a hypotonic phosphate based buffer that is free of potassium where the composition of the buffer is as follows: 6 mM sodium phosphate monobasic monohydrate, 9 mM sodium phosphate dibasic heptahydrate, 50 mM sodium chloride, pH 7.0.+/-0.1. The concentration of immunologically active biomimetic protein in a hypotonic buffer may range from 10 microgram/ml to 100 milligram/ml. This formulation may be administered via any route of administration, for example, but not limited to, intravenous administration.

[0169] Further, a stradobody composition for topical administration which is combined with a semi-solid carrier can be further formulated into a cream or gel ointment. A preferred carrier for the formation of a gel ointment is a gel polymer. Preferred polymers that are used to manufacture a gel composition of the present invention include, but are not limited to carbopol, carboxymethyl-cellulose, and pluronic polymers. Specifically, a powdered stradobody composition is combined with an aqueous gel containing an polymerization agent such as Carbopol 980 at strengths between 0.5% and 5% wt/volume for application to the skin for treatment of disease on or beneath the skin. The term "topical administration" as used herein includes application to a dermal, epidermal, subcutaneous or mucosal surface.

[0170] Further, a stradobody composition can be formulated into a polymer for subcutaneous or subdermal implantation. A preferred formulation for the implantable drug-infused polymer is an agent Generally Regarded as Safe and may include, for example, cross-linked dextran (Samantha Hart, Master of Science Thesis, "Elution of Antibiotics from a Novel Cross-Linked Dextran Gel: Quantification" Virginia Polytechnic Institute and State University, Jun. 8, 2009) dextran-tyramine (Jin, et al. (2010) Tissue Eng. Part A. 16(8):2429-40), dextran-polyethylene glycol (Jukes, et al. (2010) Tissue Eng. Part A., 16(2):565-73), or dextran-gluteraldehyde (Brondsted, et al. (1998) J. Controlled Release, 53:7-13). One skilled in the art will know that many similar polymers and hydrogels can be formed incorporating the stradobody fixed within the polymer or hydrogel and controlling the pore size to the desired diameter.

[0171] Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective to result in an improvement or remediation of the symptoms. The formulations are easily administered in a variety of dosage forms such as ingestible solutions, drug release capsules and the like. Some variation in dosage can occur depending on the condition of the subject being treated. The person responsible for administration can, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations meet sterility, general safety and purity standards as required by FDA Center for Biologics Evaluation and Research standards.

[0172] The route of administration will vary, naturally, with the location and nature of the disease being treated, and may include, for example intradermal, transdermal, subdermal, parenteral, nasal, intravenous, intramuscular, subcutaneous, percutaneous, intratracheal, intraperitoneal, intratumoral, perfusion, lavage, direct injection, and oral administration.

[0173] The term "parenteral administration" as used herein includes any form of administration in which the compound is absorbed into the subject without involving absorption via the intestines. Exemplary parenteral administrations that are used in the present invention include, but are not limited to intramuscular, intravenous, intraperitoneal, intratumoral, intraocular, nasal or intraarticular administration.

[0174] In addition, the stradobody of the current invention may optionally be administered before, during or after another pharmaceutical agent.

[0175] Below are specific examples of various pharmaceutical formulation categories and preferred routes of administration, as indicated, for specific exemplary diseases:

[0176] Buccal or sub-lingual dissolvable tablet: angina, polyarteritis nodosa.

[0177] Intravenous: Idiopathic Thrombocytopenic Purpura, Inclusion Body Myositis, Paraproteinemic IgM demyelinating Polyneuropathy, Necrotizing fasciitis, Pemphigus, Gangrene, Dermatomyositis, Granuloma, Lymphoma, Sepsis, Aplastic anemia, Multisystem organ failure, Multiple Myeloma and Monoclonal Gammopathy of Unknown Significance, Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Inflammatory Myopathies, Thrombotic thrombocytopenic purpura, Myositis, Anemia, Neoplasia, Hemolytic anemia, Encephalitis, Myelitis, Myelopathy especially associated with Human T-cell lymphotropic virus-1, Leukemia, Multiple sclerosis and optic neuritis, Asthma, Epidermal necrolysis, Lambert-Eaton myasthenic syndrome, Myasthenia gravis, Neuropathy, Uveitis, Guillain-Barre syndrome, Graft Versus Host Disease, Stiff Man Syndrome, Paraneoplastic cerebellar degeneration with anti-Yo antibodies, paraneoplastic encephalomyelitis and sensory neuropathy with anti-Hu antibodies, systemic vasculitis, Systemic Lupus Erythematosus, autoimmune diabetic neuropathy, acute idiopathic dysautonomic neuropathy, Vogt-Koyanagi-Harada Syndrome, Multifocal Motor Neuropathy, Lower Motor Neuron Syndrome associated with anti-/GM1, Demyelination, Membranoproliferative glomerulonephritis, Cardiomyopathy, Kawasaki's disease, Rheumatoid arthritis, and Evan's syndrome IM-ITP, CIDP, MS, Dermatomyositis, Myasthenia Gravis, muscular dystrophy. The term "intravenous administration" as used herein includes all techniques to deliver a compound or composition of the present invention to the systemic circulation via an intravenous injection or infusion.

[0178] Dermal gel, lotion, cream or patch: vitiligo, Herpes zoster, acne, chelitis psoriasis.

[0179] Rectal suppository, gel, or infusion: ulcerative colitis, Crohn's disease, hemorrhoidal inflammation.

[0180] Oral as pill, troche, encapsulated, or with enteric coating: Crohn's disease, celiac sprue, irritable bowel syndrome, inflammatory liver disease, Barrett's esophagus.

[0181] Intra-cortical: epilepsy, Alzheimer's Disease, Multiple sclerosis, Parkinson's Disease, Huntingdon's Disease.

[0182] Intra-abdominal infusion or implant: endometriosis.

[0183] Intra-vaginal gel or suppository: bacterial, trichomonal, or fungal vaginitis.

[0184] Medical devices: coated on coronary artery stent, prosthetic joints.

[0185] The stradobodies described herein may be administered at least once daily, weekly, biweekly or monthly or potentially less frequently. A biphasic dosage regimen may be used wherein the first dosage phase comprises about 0.1% to about 300% of the second dosage phase. Because of the enhanced efficacy of the stradobodies of the current invention, in some embodiments the stradobodies may be administered at a lower dose intravenously compared with monoclonal antibodies specific for the same antigen. The effective stradobody dose is generally from about 1% to about 500% of the effective monoclonal antibody whose Fab is the same as the stradobody, more preferably, about 50% to about 100% of the effective monoclonal antibody dose. The effective monoclonal antibody dose in clinical cancer treatment varies. For the Her-2/neu monoclonal antibody, the dose is generally in the range of about 2 mg/Kg to about 4 mg/Kg administered every 7-21 days. For the EGFR monoclonal antibody the dose is generally in the range of about 250-400 mg/square meter which is about 5 mg/Kg-25 mg/Kg administered every 7-21 days.

[0186] In one embodiment, the stradobody is administered intravenously at a dose of about 0.01 mg/Kg to about 1000 mg/Kg IV. In a further embodiment, the stradobody is administered at about 0.1 mg/Kg to about 100 mg/Kg IV. In yet a further embodiment, the stradobody is administered at about 0.5 mg/Kg to about 50 mg/Kg IV. In still a further embodiment, the stradobody is administered at about 1 mg/Kg to about 25 mg/Kg IV. In still a further embodiment, the stradobody is administered at about 5 mg/Kg to about 15 mg/Kg IV. In one embodiment, the stradobody is administered subcutaneously. Because of the enhanced efficacy of the stradobodies of the current invention, in some embodiments the stradobody may be administered at a lower dose subcutaneously compared with monoclonal antibodies specific for the same antigen. In one embodiment, the stradobody is administered subcutaneously at a dose of about 0.01 mg/Kg to about 1000 mg/Kg SQ. In a further embodiment, the stradobody is administered at about 0.2 mg/Kg to about 150 mg/Kg SQ. In yet a further embodiment, the stradobody is administered at about 0.5 mg/Kg to about 80 mg/Kg SQ. In still a further embodiment, the stradobody is administered at about 2 mg/Kg to about 50 mg/Kg SQ. In still a further embodiment, the stradobody is administered at about 5 mg/Kg to about 30 mg/Kg SQ.

Therapeutic Applications of Stradobodies

[0187] Based on rational design and in vitro and in vivo validations, the stradobodies of the present invention will serve as important biopharmaceuticals for treating cancer and for modulating immune function in a variety of other contexts such as bioimmunotherapy for autoimmune diseases and inflammatory diseases and infections. Medical conditions suitable for treatment with the immunologically active biomimetics described herein include those cancers or inflammatory disease conditions in which a monoclonal antibody may be used or is already in clinical use.

[0188] In addition, exemplary medical conditions having an inflammatory component that will benefit from treatment with stradobodies include Amyotrophic Lateral Sclerosis, Huntington's Disease, Alzheimer's Disease, Parkinson's Disease, Atherogenesis, Myocardial Infarction, Stroke, Hepatitis B, Hepatitis C, Human Immunodeficiency Virus associated inflammation, adrenoleukodystrophy, and epileptic disorders especially those believed to be associated with postviral encephalitis including Rasmussen Syndrome, West Syndrome, and Lennox-Gastaut Syndrome.

[0189] The general approach to therapy using the isolated stradobodies described herein is to administer to a subject having a disease or condition, a therapeutically effective amount of the isolated immunologically active biomimetic to effect a treatment. In some embodiments, diseases or conditions may be broadly categorized as inflammatory diseases with an imbalance in cytokine networks, an autoimmune disorder mediated by pathogenic autoantibodies or autoaggressive T cells, or an acute or chronic phase of a chronic relapsing disease or process.

[0190] "Immune modulating activities," "modulating immune response," "modulating the immune system," and "immune modulation" mean altering immune systems by changing the activities, capacities, and relative numbers of one or more immune cells, including maturation of a cell type within its cell type or into other cell types. For example, immune modulation of immature monocytes may lead to greater populations of more mature monocytes, dendritic cells, macrophages, or osteoclasts, all of which are derived from immature monocytes. As another example, immune modulation of memory B cells may lead to selective apoptosis of certain memory B cells with concomitant decreases in production of particular antibodies. As another example, immune modulation of NK cells may lead to enhanced Antibody Dependent Cell Cytotoxicity. As another example, immune modulating activities may lead to increased populations of cells with phenotypes that may otherwise not be expressed at high levels, such as CD8 beta+/CD11c+cells. As another example, immune modulating activities may lead to decreases of proinflammatory cytokines or cytokines that are commonly elevated in autoimmune diseases such as IL-6 and IL-8. As another example, immune modulating activities may lead to activation of NKT cells with subsequent secretion and cleavage of TGF-beta. For example, immune cell receptors may be bound by immunologically active biomimetics and activate intracellular signaling to induce various immune cell changes, referred to separately as "activating immune modulation." Blockading immune cell receptors to prevent receptor activation is also encompassed within "immune modulation" and may be separately referred to as "inhibitory immune modulation."

[0191] The terms "treating" and "treatment" as used herein refer to administering to a subject a therapeutically effective amount of a stradobody of the present invention so that the subject has an improvement in a disease or condition, or a symptom of the disease or condition. The improvement is any improvement or remediation of the disease or condition, or symptom of the disease or condition. The improvement is an observable or measurable improvement, or may be an improvement in the general feeling of well-being of the subject. Thus, one of skill in the art realizes that a treatment may improve the disease condition, but may not be a complete cure for the disease. Specifically, improvements in subjects may include one or more of: decreased inflammation; decreased inflammatory laboratory markers such as C-reactive protein; decreased autoimmunity as evidenced by one or more of: improvements in autoimmune markers such as autoantibodies or in platelet count, white cell count, or red cell count, decreased rash or purpura, decrease in weakness, numbness, or tingling, increased glucose levels in patients with hyperglycemia, decreased joint pain, inflammation, swelling, or degradation, decrease in cramping and diarrhea frequency and volume, decreased angina, decreased tissue inflammation, or decrease in seizure frequency; decreases in cancer tumor burden, increased time to tumor progression, decreased cancer pain, increased survival or improvements in the quality of life; or delay of progression or improvement of osteoporosis.

[0192] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount that results in an improvement or remediation of the symptoms of the disease or condition.

[0193] As used herein, "prophylaxis" can mean complete prevention of the symptoms of a disease, a delay in onset of the symptoms of a disease, or a lessening in the severity of subsequently developed disease symptoms.

[0194] The term "subject" is used interchangeably with the term "patient" herein, and is taken to mean any mammalian subject to which stradobodies of the present invention are administered according to the methods described herein. In a specific embodiment, the methods of the present disclosure are employed to treat a human subject. The methods of the present disclosure may also be employed to treat non-human primates (e.g., monkeys, baboons, and chimpanzees), mice, rats, bovines, horses, cats, dogs, pigs, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, birds (e.g., chickens, turkeys, and ducks), fish and reptiles.

[0195] In particular, the stradobodies of the present invention may be used to treat conditions including but not limited to congestive heart failure (CHF), vasculitis, rosacea, acne, eczema, myocarditis and other conditions of the myocardium, systemic lupus erythematosus, diabetes, spondylopathies, synovial fibroblasts, and bone marrow stroma; bone loss; Paget's disease, osteoclastoma; multiple myeloma; breast cancer; disuse osteopenia; malnutrition, periodontal disease, Gaucher's disease, Langerhans' cell histiocytosis, spinal cord injury, acute septic arthritis, osteomalacia, Cushing's syndrome, monoostotic fibrous dysplasia, polyostotic fibrous dysplasia, periodontal reconstruction, and bone fractures; sarcoidosis; osteolytic bone cancers, lung cancer, kidney cancer and rectal cancer; bone metastasis, bone pain management, and humoral malignant hypercalcemia, ankylosing spondylitis and other spondyloarthropathies; transplantation rejection, viral infections, hematologic neoplasias and neoplastic-like conditions for example, Hodgkin's lymphoma; non-Hodgkin's lymphomas (Burkitt's lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, hairy cell leukemia and lymphoplasmacytic leukemia), tumors of lymphocyte precursor cells, including B-cell acute lymphoblastic leukemia/lymphoma, and T-cell acute lymphoblastic leukemia/lymphoma, thymoma, tumors of the mature T and NK cells, including peripheral T-cell leukemias, adult T-cell leukemia/T-cell lymphomas and large granular lymphocytic leukemia, Langerhans cell histiocytosis, myeloid neoplasias such as acute myelogenous leukemias, including AML with maturation, AML without differentiation, acute promyelocytic leukemia, acute myelomonocytic leukemia, and acute monocytic leukemias, myelodysplastic syndromes, and chronic myeloproliferative disorders, including chronic myelogenous leukemia, tumors of the central nervous system, e.g., brain tumors (glioma, neuroblastoma, astrocytoma, medulloblastoma, ependymoma, and retinoblastoma), solid tumors (nasopharyngeal cancer, basal cell carcinoma, pancreatic cancer, cancer of the bile duct, Kaposi's sarcoma, testicular cancer, uterine, vaginal or cervical cancers, ovarian cancer, primary liver cancer or endometrial cancer, tumors of the vascular system (angiosarcoma and hemangiopericytoma)) or other cancer.

[0196] The stradobodies of the present invention may be used to treat autoimmune diseases. The term "autoimmune disease" as used herein refers to a varied group of more than 80 diseases and conditions. In all of these diseases and conditions, the underlying problem is that the body's immune system attacks the body itself. Autoimmune diseases affect all major body systems including connective tissue, nerves, muscles, the endocrine system, skin, blood, and the respiratory and gastrointestinal systems. Autoimmune diseases include, for example, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and type 1 diabetes.

[0197] The disease or condition treatable using the compositions and methods of the present invention may be a hematoimmunological process, including but not limited to Idiopathic Thrombocytopenic Purpura, alloimmune/autoimmune thrombocytopenia, Acquired immune thrombocytopenia, Autoimmune neutropenia, Autoimmune hemolytic anemia, Parvovirus B19-associated red cell aplasia, Acquired antifactor VIII autoimmunity, acquired von Willebrand disease, Multiple Myeloma and Monoclonal Gammopathy of Unknown Significance, Sepsis, Aplastic anemia, pure red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of the newborn, Immune-mediated neutropenia, refractoriness to platelet transfusion, neonatal, post-transfusion purpura, hemolytic uremic syndrome, systemic Vasculitis, Thrombotic thrombocytopenic purpura, or Evan's syndrome.

[0198] The disease or condition may also be a neuroimmunological process, including but not limited to Guillain-Barre syndrome, Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Paraproteinemic IgM demyelinating Polyneuropathy, Lambert-Eaton myasthenic syndrome, Myasthenia gravis, Multifocal Motor Neuropathy, Lower Motor Neuron Syndrome associated with anti-/GM1, Demyelination, Multiple Sclerosis and optic neuritis, Stiff Man Syndrome, Paraneoplastic cerebellar degeneration with anti-Yo antibodies, paraneoplastic encephalomyelitis, sensory neuropathy with anti-Hu antibodies, epilepsy, Encephalitis, Myelitis, Myelopathy especially associated with Human T-cell lymphotropic virus-1, Autoimmune Diabetic Neuropathy, Alzheimer's disease, Parkinson's disease, Huntingdon's disease, or Acute Idiopathic Dysautonomic Neuropathy.

[0199] The disease or condition may also be a Rheumatic disease process, including but not limited to Kawasaki's disease, Rheumatoid arthritis, Felty's syndrome, ANCA-positive Vasculitis, Spontaneous Polymyositis, Dermatomyositis, Antiphospholipid syndromes, Recurrent spontaneous abortions, Systemic Lupus Erythematosus, Juvenile idiopathic arthritis, Raynaud's, CREST syndrome, or Uveitis.

[0200] The disease or condition may also be a dermatoimmunological disease process, including but not limited to Toxic Epidermal Necrolysis, Gangrene, Granuloma, Autoimmune skin blistering diseases including Pemphigus vulgaris, Bullous Pemphigoid, Pemphigus foliaceus, Vitiligo, Streptococcal toxic shock syndrome, Scleroderma, systemic sclerosis including diffuse and limited cutaneous systemic sclerosis, or Atopic dermatitis (especially steroid dependent).

[0201] The disease or condition may also be a musculoskeletal immunological disease process, including but not limited to Inclusion Body Myositis, Necrotizing fasciitis, Inflammatory Myopathies, Myositis, Anti-Decorin (BJ antigen) Myopathy, Paraneoplastic Necrotic Myopathy, X-linked Vacuolated Myopathy, Penacillamine-induced Polymyositis, Atherosclerosis, Coronary Artery Disease, or Cardiomyopathy.

[0202] The disease or condition may also be a gastrointestinal immunological disease process, including but not limited to pernicious anemia, autoimmune chronic active hepatitis, primary biliary cirrhosis, Celiac disease, dermatitis herpetiformis, cryptogenic cirrhosis, Reactive arthritis, Crohn's disease, Whipple's disease, ulcerative colitis, or sclerosing cholangitis.

[0203] The disease or condition may also be Graft Versus Host Disease, Antibody-mediated rejection of the graft, Post-bone marrow transplant rejection, Postinfectious disease inflammation, Lymphoma, Leukemia, Neoplasia, Asthma, Type 1 Diabetes mellitus with anti-beta cell antibodies, Sjogren's syndrome, Mixed Connective Tissue Disease, Addison's disease, Vogt-Koyanagi-Harada Syndrome, Membranoproliferative glomerulonephritis, Goodpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, micropolyarterits, Churg-Strauss syndrome, Polyarteritis nodosa or Multisystem organ failure.

[0204] In addition to having clinical utility for treating immunological disorders, stradobodies have therapeutic use in infectious disease, cancer, and inflammatory disease treatment. The stradobodies may be used essentially following known protocols for any corresponding therapeutic antibody. The stradobodies will generally be designed to enhance the effect demonstrated on an effector cell by a monoclonal antibody, such as ADCC in cancer or decreased monocyte and DC maturation with decreased cytokine release in autoimmune disease, and thereby potentiate the immune response against the cancer relative to that which would occur using, for example, a source monoclonal antibody for the Fab portion of the stradobody.

[0205] Infectious diseases, include, but are not limited to, those caused by bacterial, mycological, parasitic, and viral agents. Examples of such infectious agents include the following: staphylococcus, streptococcaceae, neisseriaaceae, cocci, enterobacteriaceae, pseudomonadaceae, vibrionaceae, campylobacter, pasteurellaceae, bordetella, francisella, brucella, legionellaceae, bacteroidaceae, clostridium, corynebacterium, propionibacterium, gram-positive bacilli, anthrax, actinomyces, nocardia, mycobacterium, treponema, borrelia, leptospira, mycoplasma, ureaplasma, rickettsia, chlamydiae, other gram-positive bacilli, other gram-negative bacilli, systemic mycoses, other opportunistic mycoses, protozoa, nematodes, trematodes, cestodes, adenoviruses, herpesviruses (including, for example, herpes simplex virus and Epstein Barr virus, and herpes zoster virus), poxviruses, papovaviruses, hepatitis viruses, papilloma viruses, orthomyxoviruses (including, for example, influenza A, influenza B, and influenza C), paramyxoviruses, coronaviruses, picornaviruses, reoviruses, togaviruses, flaviviruses, bunyaviridae, rhabdoviruses, respiratory syncitial virus, human immunodeficiency virus and retroviruses. Exemplary infectious diseases include but are not limited to candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, gram negative sepsis, tuberculosis, mononucleosis, influenza, respiratory illness caused by Respiratory Syncytial Virus, malaria, schistosomiasis, and trypanosomiasis.

[0206] "Cancer" herein refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to carcinoma, lymphoma, blastoma, sarcoma (including liposarcoma, osteogenic sarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, myxosarcoma, chondrosarcoma), osteoclastoma, neuroendocrine tumors, mesothelioma, chordoma, synovioma, schwanoma, meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, small cell lung carcinoma, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, tumors of the biliary tract, Ewing's tumor, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic disease, heavy chain disease, neuroendocrine tumors, Schwanoma, and other carcinomas, head and neck cancer, myeloid neoplasias such as acute myelogenous leukemias, including AML with maturation, AML without differentiation, acute promyelocytic leukemia, acute myelomonocytic leukemia, and acute monocytic leukemias, myelodysplastic syndromes, and chronic myeloproliferative disorders, including chronic myelogenous leukemia, tumors of the central nervous system, e.g., brain tumors (glioma, neuroblastoma, astrocytoma, medulloblastoma, ependymoma, and retinoblastoma), solid tumors (nasopharyngeal cancer, basal cell carcinoma, pancreatic cancer, cancer of the bile duct, Kaposi's sarcoma, testicular cancer, uterine, vaginal or cervical cancers, ovarian cancer, primary liver cancer or endometrial cancer, tumors of the vascular system (angiosarcoma and hemangiopericytoma), hematologic neoplasias and neoplastic-like conditions for example, Hodgkin's lymphoma; non-Hodgkin's lymphomas (Burkitt's lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, hairy cell leukemia and lymphoplasmacytic leukemia), tumors of lymphocyte precursor cells, including B-cell acute lymphoblastic leukemia/lymphoma, and T-cell acute lymphoblastic leukemia/lymphoma, thymoma, tumors of the mature T and NK cells, including peripheral T-cell leukemias, adult T-cell leukemia/T-cell lymphomas and large granular lymphocytic leukemia, osteolytic bone cancers, and bone metastasis.

[0207] Antibodies comprise Fab domains from which a stradobody may be designed. Exemplary monoclonal antibodies include but are not limited to 3F8, 8H9, abagovomab, abciximab, adalimumab, adecatumumab, afelimomab, afutuzumab, alacizumab pegol, ALD518, alemtuzumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anrukinzumab (IMA-638), apolizumab, arcitumomab, aselizumab, atinumab, atlizumab (tocilizumab), atorolimumab, bapineuzumab, basiliximab, bavituximab, bectumomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, biciromab, bivatuzumab mertansine, blinatumomab, blosozumab, brentuximab vedotin, briakinumab, brodalumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, capromab pendetide, carlumab, catumaxomab, CC49, cedelizumab, certolizumab pegol, cetuximab, Ch.14.18, citatuzumab bogatox, cixutumumab, clenoliximab, clivatuzumab tetraxetan, conatumumab, crenezumab, CR6261, dacetuzumab, daclizumab, dalotuzumab, daratumumab, denosumab, detumomab, dorlimomab aritox, drozitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, elotuzumab, elsilimomab, enavatuzumab, enlimomab pegol, enokizumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, FBTA05, felvizumab, fezakinumab, ficlatuzumab, figitumumab, flanvotumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab ozogamicin, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, GS6624, ibalizumab, ibritumomab tiuxetan, icrucumab, igovomab, imciromab, indatuximab ravtansine, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, iratumumab, itolizumab, ixekizumab, keliximab, labetuzumab, lebrikizumab, lemalesomab, lerdelimumab, lexatumumab, libivirumab, lintuzumab, lorvotuzumab mertansine, lucatumumab, lumiliximab, mapatumumab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, narnatumab, natalizumab, nebacumab, necitumumab, nerelimomab, nimotuzumab, nofetumomab merpentan, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, oportuzumab monatox, oregovomab, otelixizumab, oxelumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, panobacumab, pascolizumab, pateclizumab, pemtumomab, pertuzumab, pexelizumab, pintumomab, ponezumab, priliximab, pritumumab, PRO 140, racotumomab, radretumab, rafivirumab, ramucirumab, ranibizumab, raxibacumab, regavirumab, reslizumab, rilotumumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, samalizumab, sarilumab, satumomab pendetide, secukinumab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, siplizumab, sirukumab, solanezumab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, teprotumumab, TGN1412, ticilimumab (tremelimumab), tigatuzumab, TNX-650, tocilizumab (=atlizumab), toralizumab, tositumomab, tralokinumab, trastuzumab, TRBS07, tregalizumab, tremelimumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, urelumab, urtoxazumab, ustekinumab, vapaliximab, vatelizumba, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volociximab, votumumab, zalutumumab, zanolimumab, ziralimumab, and zolimomab aritox.

[0208] The stradobody of the present invention may be specific for a cytokine. For example, the stradobody of the present invention may be specific for an Interferon (such as, for example, IFN.gamma., IFN.alpha., or IFN.beta.), IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, or IL-23. In one embodiment, the stradobody of the current invention is specific for a cytokine, and is useful for treatment or prevention of one or more inflammatory diseases or autoimmune diseases. For example, in one embodiment, the stradobody is an anti-IL-2, anti-IL-8, or anti-IL-17 stradobody.

[0209] The term "autoimmune disease" as used herein refers to a varied group of more than 80 chronic illnesses. In all of these diseases, the underlying problem is that the body's immune system attacks the body itself. Autoimmune diseases affect all major body systems including connective tissue, nerves, muscles, the endocrine system, skin, blood, and the respiratory and gastrointestinal systems.

[0210] The autoimmune disease or condition may be a hematoimmunological process, including but not limited to Idiopathic Thrombocytopenic Purpura, alloimmune/autoimmune thrombocytopenia, Acquired immune thrombocytopenia, Autoimmune neutropenia, Autoimmune hemolytic anemia, Parvovirus B19-associated red cell aplasia, Acquired antifactor VIII autoimmunity, acquired von Willebrand disease, Multiple Myeloma and Monoclonal Gammopathy of Unknown Significance, Sepsis, Aplastic anemia, pure red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of the newborn, Immune-mediated neutropenia, refractoriness to platelet transfusion, neonatal, post-transfusion purpura, hemolytic uremic syndrome, systemic Vasculitis, Thrombotic thrombocytopenic purpura, or Evan's syndrome.

[0211] The autoimmune disease or condition may be a neuroimmunological process, including but not limited to Guillain-Barre syndrome, Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Paraproteinemic IgM demyelinating Polyneuropathy, Lambert-Eaton myasthenic syndrome, Myasthenia gravis, Multifocal Motor Neuropathy, Lower Motor Neuron Syndrome associated with anti-/GM1, Demyelination, Multiple Sclerosis and optic neuritis, Stiff Man Syndrome, Paraneoplastic cerebellar degeneration with anti-Yo antibodies, paraneoplastic encephalomyelitis, sensory neuropathy with anti-Hu antibodies, epilepsy, Encephalitis, Myelitis, Myelopathy especially associated with Human T-cell lymphotropic virus-1, Autoimmune Diabetic Neuropathy, or Acute Idiopathic Dysautonomic Neuropathy.

[0212] The autoimmune disease or condition may be a Rheumatic disease process, including but not limited to Kawasaki's disease, Rheumatoid arthritis, Felty's syndrome, ANCA-positive Vasculitis, Spontaneous Polymyositis, Dermatomyositis, Antiphospholipid syndromes, Recurrent spontaneous abortions, Systemic Lupus Erythematosus, Juvenile idiopathic arthritis, Raynaud's, CREST syndrome, or Uveitis.

[0213] The autoimmune disease or condition may be a dermatoimmunological disease process, including but not limited to Toxic Epidermal Necrolysis, Gangrene, Granuloma, Autoimmune skin blistering diseases including Pemphigus vulgaris, Bullous Pemphigoid, and Pemphigus foliaceus, Vitiligo, Streptococcal toxic shock syndrome, Scleroderma, systemic sclerosis including diffuse and limited cutaneous systemic sclerosis, or Atopic dermatitis (especially steroid dependent).

[0214] The autoimmune disease or condition may be a musculoskeletal immunological disease process, including but not limited to Inclusion Body Myositis, Necrotizing fasciitis, Inflammatory Myopathies, Myositis, Anti-Decorin (BJ antigen) Myopathy, Paraneoplastic Necrotic Myopathy, X-linked Vacuolated Myopathy, Penacillamine-induced Polymyositis, Atherosclerosis, Coronary Artery Disease, or Cardiomyopathy.

[0215] The autoimmune disease or condition may be a gastrointestinal immunological disease process, including but not limited to pernicious anemia, autoimmune chronic active hepatitis, primary biliary cirrhosis, Celiac disease, dermatitis herpetiformis, cryptogenic cirrhosis, Reactive arthritis, Crohn's disease, Whipple's disease, ulcerative colitis, or sclerosing cholangitis.

[0216] The autoimmune disease or condition may be Graft Versus Host Disease, Antibody-mediated rejection of the graft, Post-bone marrow transplant rejection, Post-infectious disease inflammation, Lymphoma, Leukemia, Neoplasia, Asthma, Type 1 Diabetes mellitus with anti-beta cell antibodies, Sjogren's syndrome, Mixed Connective Tissue Disease, Addison's disease, Vogt-Koyanagi-Harada Syndrome, Membranoproliferative glomerulonephritis, Goodpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, micropolyarterits, Churg-Strauss syndrome, Polyarteritis nodosa or Multisystem organ failure.

[0217] In another embodiment, the stradobodies herein described could be utilized in a priming system wherein blood is drawn from a patient and transiently contacted with the stradobodies for a period of time from about one half hour to about three hours prior to being introduced back into the patient. In this form of cell therapy, the patient's own effector cells are exposed to stradobodies that are fixed on a matrix ex vivo in order to modulate the effector cells through exposure of the effector cells to the stradobodies. The blood including the modulated effector cells are then infused back into the patient. Such a priming system could have numerous clinical and therapeutic applications.

[0218] The stradobodies disclosed herein may also be readily applied to alter immune system responses in a variety of contexts to affect specific changes in immune response profiles. Altering or modulating an immune response in a subject refers to increasing, decreasing or changing the ratio or components of an immune response. For example, cytokine production or secretion levels may be increased or decreased as desired by targeting the appropriate combination of Fc.gamma.Rs with a stradobody designed to interact with those receptors. Antibody production may also be increased or decreased; the ratio of two or more cytokines or immune cell receptors may be changed; or additional types of cytokines or antibodies may be caused to be produced. The immune response may also be an effector function of an immune cell expressing a Fc.gamma.R, including increased or decreased phagocytic potential of monocyte macrophage derived cells, increased or decreased osteoclast function, increased or decreased antigen presentation by antigen-presenting cells (e.g. Dendritic Cells), increased or decreased NK cell function, increased or decreased B-cell function, as compared to an immune response which is not modulated by an immunologically active biomimetic disclosed herein.

[0219] In a preferred embodiment, a subject with cancer or an autoimmune or inflammatory disease or infectious disease has their immune response altered comprising the step of administering a therapeutically effective amount of a stradobody described herein to a subject, wherein the therapeutically effective amount of the stradobody alters the immune response in the subject. Ideally this intervention treats the disease or condition in the subject. The altered immune response may be an increased or a decreased response and may involve altered cytokine levels including the levels of any of IL-6, IL-10, IL-8, IL-23, IL-7, IL-4, IL-12, IL-13, IL-17, TNF-alpha and IFN-alpha. In a preferred embodiment, 11-6 or IL-8 are decreased in response to therapy. In an especially preferred embodiment, IL-6 and IL-8 are decreased in a sustained response to therapy. The invention is however not limited by any particular mechanism of action of the described biomimetics. The altered immune response may be an altered autoantibody level in the subject. The altered immune response may be an altered autoaggressive T-cell level in the subject.

[0220] For example, reducing the amount of TNF-alpha production in autoimmune diseases can have therapeutic effects. A practical application of this is anti-TNF-alpha antibody therapy (e.g. Remicade.RTM.) which is clinically proven to treat Plaque Psoriasis, Rheumatoid Arthritis, Psoriatic Arthritis, Crohn's Disease, Ulcerative Colitis and Ankylosing Spondylitis. These autoimmune diseases have distinct etiologies but share key immunological components of the disease processes related to inflammation and immune cell activity. A stradobody designed to reduce TNF-alpha production will likewise be effective in these and many other autoimmune diseases. The altered immune response profile may also be direct or indirect modulation to effect a reduction in antibody production, for example autoantibodies targeting a subject's own tissues, or altered autoaggressive T-cell levels in the subject. For example, Multiple Sclerosis is an autoimmune disorder involving autoreactive T-cells which may be treated by interferon beta therapy. See, e.g., Zafranskaya M, et al., Interferon-beta therapy reduces CD4+ and CD8+ T-cell reactivity in multiple sclerosis, Immunology 2007 May; 121(1):29-39-Epub 2006 Dec. 18. A stradobody design to reduce autoreactive T-cell levels will likewise be effective in Multiple Sclerosis and may other autoimmune diseases involving autoreactive T-cells.

[0221] The stradobodies described herein may be used to modulate expression of co-stimulatory molecules from an immune cell, including a dendritic cell, a macrophage, an osteoclast, a monocyte, or an NK cell or to inhibit in these same immune cells differentiation, maturation, or cytokine secretion, including interleukin-12 (IL-12), or of increasing cytokine secretion, including interleukin-10 (IL-10), or interleukin-6 (IL-6). A skilled artisan may also validate the efficacy of an immunologically active biomimetic by exposing an immune cell to the immunologically active biomimetic and measuring modulation of the immune cell function, wherein the immune cell is a dendritic cell, a macrophage, an osteoclast, or a monocyte. In one embodiment the immune cell is exposed to the immunologically active biomimetic in vitro and further comprising the step of determining an amount of a cell surface receptor or of a cytokine production, wherein a change in the amount of the cell surface receptor or the cytokine production indicates a modulation of the immune cell function. In another embodiment the immune cell is exposed to the immunologically active biomimetic in vivo in a model animal for an autoimmune disease further comprising a step of assessing a degree of improvement in the autoimmune disease. The stradobodies described herein may be used to modulate expression of co-stimulatory molecules from a B cell.

[0222] The methods of the invention can be applied to any animal species and the IgG molecules from which the IgG-derived portions of Fc reagents are made can be from any animal species. Naturally, relevant animal species are those in which IgG or IgG-like molecules occur. Generally the species to which the methods are applied and the species from which the IgG-derived portions of the Fc reagents used in the methods are the same. However, they are not necessarily the same. Relevant animal species are preferably mammals and these include, without limitation, humans, non-human primates (e.g., monkeys, baboons, and chimpanzees), horses, bovine animals (e.g., bulls, cows, or oxen), pigs, goats, sheep, dogs, cats, rabbits, gerbils, hamsters, rats, and mice. Non-mammalian species include, for example, birds (e.g., chickens, turkeys, and ducks) and fish.

[0223] The stradobodies disclosed herein have a number of further applications and uses.

EXAMPLES

Example 1. Production and Purification of HER2/Neu-Specific Stradobodies

[0224] A synthetic DNA construct encoding the trastuzumab variable and CH1 region was obtained from Blue Heron Biotechnology (Bothell, Wash.) and fused by PCR to a corresponding Fc region containing the human IgG1 hinge, CH2 and CH3 regions to generate a reading frame encoding the full trastuzumab antibody heavy chain. cDNA was cloned into the expression vector pOptiVec (Invitrogen) for expression in mammalian cells. Simultaneously, a similar synthetic construct was obtained containing the trastuzumab light chain and cloned into the vector pcDNA3.3 (Invitrogen). Stradobody heavy chain constructs were generated by overlapping PCR using the trastuzumab heavy chain as a template with primers encoding the multimerization domains and linker regions. PCR products were cloned into the pOptiVec expression vector by TA cloning to generate the stradobody expression constructs. Following TA cloning, all constructs were confirmed by sequencing of the complete coding frame as well as surrounding sequences. For stradobody protein expression, large scale DNA plasmid isolation was performed by endotoxin-free plasmid purification kits (Macherey Nagel) and protein produced in 293-T HEK or CHO cells by transient protein expression. Stradobody protein was expressed by co-transfection of heavy-chain and light chain DNA constructs. Stradobody protein was purified by FPLC on an AKTAxpress using protein G affinity chromatography followed by desalting on a HiPrep desalting column (GE life sciences). Stradobody constructs are shown in FIG. 32.

[0225] To observe the formation of stradobody multimers, purified stradobodies were analyzed by non-reducing SDS-PAGE gel. Bands of higher molecular weight relative to the unaltered antibody GB2500 indicated multimer formation in several constructs. As shown in FIG. 8, several C-terminal stradobodies exhibited higher molecular weight bands relative to the unaltered protein. In particular, several high molecular weight bands were detected upon analysis of the construct GB2547. Serial stradobody constructs were also tested. As shown in FIG. 9, several serial stradobody constructs, particularly multimerizing serial stradobody GB2542, exhibited higher molecular weight bands relative to the unaltered antibody GB2500.

[0226] Other stradobodies directed against targets other than HER2/neu are produced, purified, and analyzed in an analogous manner. These other stradobodies include the GB3500 series directed against EGFR, the GB4500 series directed against CD20, and the GB7500 series directed against TNF.

Example 2. Cytoxicity and Binding Activity of HER2/Neu-Specific Stradobodies

[0227] Antibody-dependent cell cytotoxicity was determined for several stradobodies, in comparison to the unaltered antibody GB2500. The ADCC assay was performed on freshly isolated NK cells as effectors cells with the low HER2/neu expressing tumor cell line MDA-MB-231 as the target cell line. MDA-MB-231 cells were radioactively labeled with Cr-51, followed by a one hour incubation with one of the five following solutions: media only, media containing a non-binding human IgG1, media containing the monoclonal antibody GB2500, and media containing the stradobody to be tested. Cells were then plated out with freshly isolated human NK cells at varying NK to tumor cell ratios for four hours and the amount of killing was determined by the amount of Cr-51 released free into the media after the cells had been pelleted.

[0228] One to four independently expressed and purified protein batches from each of a total of 18 proteins, including GB2500, were tested. The effector to target cell ratios tested were 50:1, 25:1, 12.5:1 and 6.5:1. Where the NK yield permitted, a ratio of 100:1 was used. FIG. 10 shows a representative example of ADCC data, demonstrating the increased ADCC observed with GB2542 relative to GB2500 over the range of effector to target cells. FIG. 10 also demonstrates the variability of two different independently purified batches of GB2500.

[0229] The compiled ADCC data on all 12 anti-HER2/neu stradobodies and GB2500 are shown in FIG. 32. Each row in FIG. 32 represents a purified and tested stradobody batch (e.g., four batches of GB2542 were produced and tested). Data are presented as percent killing by NK cells isolated from the indicated donor, at the indicated ratio of effector to target cell.

[0230] The results of the study showed that surprisingly, even though the novel stradobodies and the trastuzumab antibody GB2500 share the identical Fab, several stradobodies were significantly more potent in ADCC response. GB2542 was particularly potent in ADCC assays. The rank order of the ADCC response in this particular experiment was as follows: GB2542 (multimerizing serial stradobody with two multimerization domains)>GB2547 (multimerizing C-terminal stradobody with two multimerization domains)>GB2550 (multimerizing C-terminal stradobody with one multimerization domain)>GB2500>human Isotope control and media control.

[0231] In addition to the effector to target cell ratio response ADCC, an analysis of the stradobody concentration response ADCC was conducted. The ADCC assay was performed with concentrations of stradobodies and HER2/neu antibody varying from 0.4 to 4000 ng/mL to assess the dose response of the stradobodies. The ratio of NK cells to MDA-MB-231 target cells was kept constant at 25:1 for these experiments. The results of the study are shown in FIG. 11. The concentration-dependent analysis confirmed the increased ADCC activity of stradobodies, particularly GB2542, relative to the trastuzumab antibody (GB2500). Based on this experiment, multimerizing serial stradobody GB2542 was estimated to be more than 2-log more potent in the ADCC assay than GB2500, despite the fact that the two molecules share the same Fab.

[0232] The binding strength of the stradobodies in comparison to GB2500 was assessed as measured by plasmon resonance, using a Biacore 3000 system. Recombinant human Fc.gamma.RIIIa was diluted to 3 ug/ml in 10 mM Sodium Acetate pH 5.0 and manually immobilized onto a flow cell of a CM5 chip. Stradobodies or GB2500 were diluted to 1 .mu.M with HBS-EP (0.01 M HEPES pH 7.4, 0.15M NaCl, 1 mM EDTA, 0.005% Surfactant P20) and perfused over the immobilized human Fc.gamma.RIIIa as follows. After activation of the flow cell, 3 ug/ml of the protein was injected in 1 .mu.l increments at a flow rate of 5 .mu.l/min until an RU (resonance unit) of 400 was reached. The flow cell was then blocked with 1M Ethanolamine. Another flow cell was used as a blank control. Typically, 20 .mu.l of the diluted samples were injected at a flow rate of 20 .mu.l/min. Regeneration of the flow cell was performed by an extended wash with running buffer HBS-EP at 20 .mu.L/min.

[0233] Examples of binding data are shown in FIG. 12. The binding curve for the parental antibody GB2500, the high binder/high ADCC stradobodies GB2542 (multimerizing serial) and GB2547 (multimerizing C-terminal), and the low binders/low ADCC stradobody GB2554 (non-multimerizing serial) are shown. As a comparison, a binding curve for the mouse Fc based antibody MB2500 is included as an example of a non/low binder. The rank order of binding strength is indicated in FIG. 13. Several of the stradobodies had a higher RU max than GB2500. In addition, GB2542 in this assay had the highest RU max and among the slowest rates of dissociation.

[0234] Next, the correlation between the ADCC activity and the binding measured by Biacore was evaluated. The ADCC activity was calculated as fold difference relative to the ADCC activity of the monoclonal antibody GB2500. When two GB2500 batches were measured in the same experiment for the same donor, the average ADCC was used to calculate the mean fold difference in ADCC. The binding was measured as RU max and the data presented in FIG. 14. For several of the stradobodies, there was an average fold increase in ADCC higher than the parental antibody (GB2500=1). While the data set was somewhat limited in quantity and some variance in the ADCC activity was observed, there seemed to be an overall correlation between binding and ADCC activity. Importantly, for several of the high ADCC/high binding stradobodies, including GB2542 (multimerizing serial with two multimerization domains), GB2524 (multimerizing serial with one multimerization domain and one linker), GB2547 (multimerizing C-terminal with two multimerization domains) and GB2540 (multimerizing serial with one multimerization domain), higher order forms were readily observable on the non-denaturing gels indicating a correlation between multimer formation, receptor binding, and ADCC activity.

[0235] Overall, the results of the study indicated that several of the stradobody constructs exhibited higher ADCC and stronger binding activity compared to the monoclonal antibody GB2500, which shares the same Fab as all of the stradobodies tested. The stradobody construct exhibiting the highest ADCC and strongest binding activity was GB2542, comprising an isoleucine zipper multimerization domain and an IgG2 hinge multimerization domain located between the two Fc domains. In addition, there was a significant degree of correlation between binding measured by plasmon resonance and ADCC activity.

[0236] Other stradobodies directed against targets other than HER2/neu are assessed for cytotoxicity and binding in an analogous manner. These other stradobodies include the GB3500 series directed against EGFR, the GB4500 series directed against CD20, and the GB7500 series directed against TNF.

Example 3. Further Purification of Stradobodies

[0237] In order to determine if stradobody multimers and monomers could be successfully separated, GB2054 was purified by ion exchange chromatography on a Mono Q column.

[0238] The results of the study, shown in FIG. 15, demonstrated that higher order multimers could be separated from monomers. Multimer peaks were not easily identified in the unfractionated peak (lane SB), but were readily detectable after ion exchange. Without wishing to be bound by theory, it is thought that purification of stradobody multimers will increase the potency of the compounds.

Example 4. Enhanced Multimerization and Fc.gamma.RIIIa Binding of Stradobodies with Multimerization Domains

[0239] In order to more stringently assess multimerization of the serial stradobody compounds, a sensitive SDS-PAGE gel method was used to compare multimerization of stradobody constructs to one another and to the HER2 monoclonal antibody construct GB2500. 4-12% gels were used for non-reduced SDS-PAGE, and 12% gels were used for reduced SDS-PAGE. All samples were loaded at 2 .mu.g and run at 150V for approximately 2.3 hours prior to Coomassie staining.

[0240] As shown in FIG. 16, the control mAb GB2500 (lane 1) and the non-multimerizing serial stradobody construct GB2555 (lane 7), which has a non-multimerizing linker between the two IgG1 Fc regions, did not multimerize. Similarly, non-multimerizing serial stradobody construct GB2554 (lane 6), which has a G4S linker domain between the two IgG1 Fc regions, exhibited little multimerization. Some multimerization was evident for multimerizing serial stradobody constructs GB2538 (lane 3) and GB2540 (lane 4), which have an isoleucine zipper or an IgG2 hinge multimerization domain, respectively, between the two IgG1 Fc regions. Multimerizing serial stradobody construct GB2524 (lane 2) has a G4S linker domain and an IgG2 hinge multimerization domain between the two IgG1 Fc regions, but multimerized poorly. In contrast to the lesser degree of multimerization of GB2538, GB2540, and GB2524, multimerizing serial stradobody construct GB2542, which has an isoleucine zipper and an IgG2 hinge between the two IgG1 Fc regions, exhibited a great deal of multimerization (lane 5).

[0241] To analyze the binding of the GB2500 parent antibody and each of the serial stradobody constructs to Fc.gamma.RIIIa, a binding analysis was performed in which purified Fc.gamma.RIIIa-His was loaded onto a ForteBio anti-penta-His sensor (Cat #18-5077) at 10 .mu.g/ml. GB2500 (produced in HEK cells), GB2524, GB2538, GB2540, GB2542, GB2554, or GB2555 were incubated with the receptor in 1.times. kinetics buffer (ForteBio Cat #18-5032) to measure on rate (Kon) and the sensor tip later transferred to binding buffer to measure off rate (Kdis). GB2500 antibodies were tested at concentrations ranging from 3333-208 nM, and the stradobodies were tested at concentrations ranging from 200-12.5 nM. KD was calculated from on and off rate using ForteBio analysis software. As shown in Table 3 and FIGS. 17A-D, multimerizing serial stradobodies GB2542 and GB2538 exhibited the lowest KD, and therefore the best binding capacity.

TABLE-US-00003 TABLE 3 Kinetics binding data summary KD Kon Kon+/- Kdis Kdis+/- Rmax R2 X2 GB2500 2.75E-07 6.74E+04 3.02E+03 1.85E-02 1.28E-03 1.335 0.984 0.2903 GB2524 3.94E-09 2.38E+05 4.08E+03 9.36E-04 2.54E-05 1.1079 0.997 0.1058 GB2538 1.23E-10 2.21E+05 8.04E+03 2.71E-05 4.37E-05 1.666 0.989 0.3945 GB2540 5.11E-09 1.79E+05 4.09E+03 9.16E-04 2.73E-05 1.127 0.997 0.1335 GB2542 1.49E-10 2.28E+05 8.77E+03 3.39E-05 4.65E-05 1.362 0.987 0.3185 GB2554 4.38E-09 3.99E+05 1.34E+04 1.74E-03 6.00E-05 0.6158 0.988 0.1848 GB2555 3.14E-09 1.95E-05 2.27E+03 6.12E-04 1.82E-05 0.793 0.998 0.0296 All compounds were generated in the same CHO transient transfection system.

[0242] Binding data from other stradobodies directed against targets other than Her2/neu are analogous. These other stradobodies include the GB3500 series directed against EGFR, the GB4500 series directed against CD20, and the GB7500 series directed against TNF.

[0243] The results of the study confirmed that GB2542 exhibited superior multimerization compared to the control mAb and all other serial stradobody constructs tested, as reported above. In addition, GB2542 and GB2538 exhibited the most robust binding to Fc.gamma.RIIIa. Together, the data showing superior multimerization and Fc.gamma.RIIIa binding capacity of GB2542 were supportive of the data presented above with regard to the superior ADCC observed with GB2542.

Example 5. Multimerizing Stradobodies Reduce Serum IgM and B Cells in the Peripheral Blood in an In Vivo Mouse Model

[0244] Severe Combined Immunodeficiency (SCID) mice were injected intraperitoneally with 5.times.10.sup.7 human peripheral blood mononuclear cells (PBMC) at week 0. At weeks 2 through 10, mice were injected intraperitoneally with PBS, GB4500 (10 nM weekly), GB4563 (1.7 nM weekly), or GB4542 (1.4 nM weekly). GB4500 was injected three times per week, while PBS, GB4563, and GB4542 were each injected one time per week. Therefore, stradobodies were administered not only less frequently relative to the monoclonal antibody, but were also given at a lower molar dose. Molarity was based on the molecular weights estimated from non-reduced SDS-PAGE. Blood samples were collected at weeks 1, 2, 3, 5, 7, 9, 10, 12, 16, and 20 relative to the adoptive transfer of human PBMC, and were evaluated for B cell numbers and serum human IgM. At the endpoint of the study (i.e., at week 21), mice were euthanized and spleens were harvested and evaluated for numbers of B cells. The experimental flow chart is shown schematically in FIG. 18.

[0245] Human IgM in the serum of mice treated with PBS, GB4500, GB4563, or GB4542 was evaluated by ELISA. The stradobodies GB4563 and GB4542 were as effective as the monoclonal antibody GB4500 in decreasing human IgM levels (FIG. 19).

[0246] The number of human B cells per mL of peripheral blood collected from mice treated with PBS, GB4500, GB4563, or GB4542 was evaluated by flow cytometry. The stradobodies GB4563 and GB4542 were at least as effective as the monoclonal antibody GB4500 in decreasing human B cells in the peripheral blood (FIG. 20).

[0247] At the end of the study, mice were euthanized and B cells in the spleen were enumerated by flow cytometry. Stradobody GB4563 was as effective as monoclonal antibody GB4500 in decreasing the number of human B cells present in the spleen. Stradobody GB4542, was more effective than the monoclonal antibody GB4500 in decreasing the number of human B cells present in the spleen (FIG. 21).

[0248] The results of the study showed that despite the fact that the stradobodies GB4563 and GB4542 were administered at lower doses compared to the monoclonal antibody GB4500, the stradobodies were at least as effective both in reducing serum human IgM levels and in reducing human B cell numbers. In addition, the anti-CD20 stradobody GB4542 induced B cell depletion better than the corresponding anti-CD20 monoclonal antibody GB4500.

Example 6. Multimerizing Stradobodies Inhibit Proliferation of B Cell Lymphoma Cell Lines

[0249] B cell lymphoma cells (Daudi, Ramos, 454B, and 924B cell lines) were cultured in the presence of various concentrations of human IgG (negative control), monoclonal antibody GB4500, or the stradobody GB4542 for 3 days. 0.5 .mu.ci 3H-TdR was added to the cultures, and incorporation of 3H-TdR was measured in corrected counts per minute (CCPM) 16 hours later. The inhibition of cell proliferation was calculated using the formula: (1--experimental condition CCPM/no treatment CCPM).times.100%. The results of the study are shown in FIGS. 22 and 23, which are representative of 3 independent experiments. GB4542 was at least as effective at direct inhibition of cell proliferation as GB4500 in all B lymphocyte cell lines at all concentrations as measured by .mu.g/mL (FIG. 22) or in moles (FIG. 23). GB4542 was significantly more effective at direct inhibition of Ramos cells, 454B cells, and 924B cells at a range of concentrations in .mu.g/mL and at a range of pmol/mL (FIGS. 22 and 23).

[0250] The results of the study showed that the anti-CD20 stradobody GB4542 mediated enhanced inhibition of proliferation of B cell lymphoma cell lines in comparison to the corresponding anti-CD20 monoclonal antibody GB4500.

Example 7. Multimerizing Stradobodies Mediate CDC of B Cell Lymphoma Cell Lines

[0251] B cell lymphoma cells (Daudi, Ramos, 454B, and 924B cell lines) were cultured in the presence of various concentrations of human IgG (negative control), monoclonal antibody GB4500, or stradobody GB4542 or GB4596, and in the presence or absence of rabbit complement for 1 hour. The extent of cytoxicity was measured by flow cytometric analysis of annexin V/7-AAD staining. The results of the study are shown in FIGS. 24 and 25, which are representative of 2 independent experiments. Stradobody GB4596 was as effective as monoclonal antibody GB4500 at CDC at all concentrations, as measured in .mu.g/mL (FIG. 24) or in moles (FIG. 25). Strikingly, stradobody GB4542 was more effective than monoclonal antibody GB4500 at all concentrations tested, as measured in .mu.g/mL (FIG. 24) or in moles (FIG. 25).

[0252] The results of the study indicated that B cell lymphoma cell lines exhibit increased susceptibility to CDC in the presence of the anti-CD20 stradobody GB4542, in comparison with its corresponding anti-CD20 monoclonal antibody, GB4500. These effects occur at stradobody concentrations that are at least one log order lower than traditional monoclonal antibody concentrations.

[0253] Together, the data showed that stradobodies induce equivalent or superior ADCC, CDC, DC, and inhibition of proliferation of B lymphoma cell lines when compared to the corresponding monoclonal antibody. The superior activity of stradobodies was present even when the stradobodies were tested at a lower concentration relative to the concentration of the monoclonal antibody. These results indicated that the stradobodies of the present invention offer a therapeutic benefit over traditional monoclonal antibodies or other antigen-binding molecules.

Example 8. Multimerizing Stradobodies Reduce Mean Tumor Volume in an In Vivo Mouse Model

[0254] Studies were conducted to assess the extent to which a CD20-specific stradobody exhibits tumor cell killing in vivo, relative to an anti-CD20 monoclonal antibody sharing the identical Fab. Severe Combined Immunodeficiency (SCID) mice were injected subcutaneously with 5.times.10.sup.7 Raji cells at day 0. At day 10, tumor volume reached 100 mm.sup.3, and CD20-specific stradobody (GB4542) or monoclonal antibody (GB4500) treatment was initiated. Equimolar GB4542 (13.5 mg/kg) or GB4500 (10 mg/kg) was administered 4 times daily by intratumoral injection with CpG (100 .mu.g per injection) or without CpG (PBS). Control mice received PBS alone or PBS with CpG. Tumor size was measured every 1-3 day. Tumor size was calculated as width.sup.2.times.length/2. When tumor volume reached 2000 m.sup.3, mice were euthanized.

[0255] The results of the study are shown in FIGS. 26 and 27. For both GB4542 with CpG and GB4500 with CpG groups, the mean (FIG. 26) and median (FIG. 27) tumor volume remained at or near baseline levels throughout the study (i.e., through at least day 23). Treatment with GB4500 in the absence of CpG resulted in about half the tumor volume of the PBS group at the last timepoint prior to euthanization that PBS groups were measured (day 18 of both FIGS. 26 and 27). Furthermore, treatment with GB4500 in the absence of CpG resulted in equal mean (FIG. 26) and median (FIG. 27) tumor volume compared to the PBS/CpG group at day 18, and only marginally lower mean tumor volume (FIG. 26) or approximately half of the median tumor volume (FIG. 27) relative to the PBS/CpG group at the final timepoint (day 23). In contrast, treatment with GB4542 in the absence of CpG resulted in a drastic reduction in mean as well as median tumor volume through day 23 relative to the tumor volume in mice treated with GB4500 alone (FIGS. 26 and 27, respectively). The results of the study therefore demonstrate that GB4542 exhibits superior results relative to the corresponding monoclonal antibody with respect to mean tumor volume in vivo.

Example 9. Stradobodies Reduce Inflammation in an In Vivo Mouse Model of Arthritis

[0256] A collagen-induced arthritis (CIA) mouse model is employed to determine the efficacy of stradobodies in inhibiting the inflammation, pannus formation, cartilage destruction, and bone resorption associated with type II collagen arthritis in mice.

[0257] Male mice are anesthetized with Isoflurane and intradermally administered 150 .mu.l of bovine Type II collagen in Freund's complete adjuvant (with supplemental M. tuberculosis, 4 mg/mL; Difco) on study days 0 and 21 of the study. In this model, onset of arthritis occurs on study days 18-35. Mice are monitored for clinical signs of disease using the following clinical scoring scale:

[0258] 0=normal

[0259] 1=1 hind or fore paw joint affected or minimal diffuse erythema and swelling

[0260] 2=2 hind or fore paw joints affected or mild diffuse erythema and swelling

[0261] 3=3 hind or fore paw joints affected or moderate diffuse erythema and swelling

[0262] 4=marked diffuse erythema and swelling, or 4 digit joints affected

[0263] 5=severe diffuse erythema and severe swelling of entire paw, unable to flex digits

[0264] One group of mice (n=4) is naive (i.e., is not administered collagen). All other groups of mice are randomized after collagen administration to receive intravenous injections of PBS, GB7500 (anti-TNF monoclonal antibody), GB7542 (anti-TNF multimerizing stradobody), GB4500 (anti-CD20 monoclonal antibody), or GB4542 (anti-CD20 multimerizing stradobody), at the doses indicated below in Table 4.

TABLE-US-00004 TABLE 4 Groups of mice in collagen-induced arthritis study Volume per Endotoxin Concentration Dose dose ml/ mg/ # of Level Cpm Mice mg/ml mg/kg .mu.l vial vial vials Route EU/mg PBS 10 400 4.8 9.6 5 IV <0.05 GB7500 10 0.75 15 400 4.8 3.6 5 IV <0.07 GB7542 10 1.00 20 400 4.8 4.8 5 IV <0.05 GB4500 10 0.75 15 400 4.8 3.6 5 IV <0.07 GB4542 10 1.00 20 400 4.8 4.8 5 IV <0.05

[0265] Mice are randomized into one of the five treatment groups after swelling is obviously established in at least one paw (i.e., clinical score of at least 1; the first day that the animal is graded at a clinical score of 1 is designated arthritis day 1).

[0266] Treatment with PBS, GB7500, GB7542, GB4500, or GB4542 is initiated after randomization and continued for 10 days. Body weight is determined on arthritis days 1, 3, 5, 7, 9, and 11; and paw score is determined on each of arthritis days 1 through 11. Plasma, serum, and whole blood are collected on various study days to measure pharmacokinetics and/or anti-collagen responses, for example using anti-collagen ELISA assays. Animals are necropsied on arthritis day 11. Tissues, including joints, are collected and analyzed histologically.

[0267] Clinical data for paw scores are analyzed by determining the area under the dosing curve (AUC) for arthritis days. For calculation of AUC, the daily mean scores for each mouse are entered into Microsoft Excel and the area between the treatment days after the onset of disease to the termination day is computed. Means for each group are determined and % inhibition from arthritis controls is calculated using the following formula:

% Inhibition=A-B/A.times.100

A=Mean Disease Control-Mean Normal

B=Mean Treated-Mean Normal

[0268] Data are analyzed using a Student's t-test or Mann-Whitney U test (non parametric). If appropriate, data are further analyzed across all groups, using a one-way analysis of variance (1-way ANOVA) or Kruskal-Wallis test (non-parametric), along with the appropriate multiple raw (untransformed) data only. Statistical tests make certain assumptions regarding the data's normality and homogeneity of variance, and further analysis may be required if testing resulted in violations of these assumptions. Significance for all tests will be set at p<0.05.

[0269] The results of the study will demonstrate that stradobodies provide superior treatment of CIA relative to monoclonal antibodies sharing the identical Fab as the stradobody. Specifically, the study will show that treatment with multimerizing anti-CD20 stradobodies and multimerizing anti-TNF stradobodies results in reduced development and/or progression of CIA relative to anti-CD20 monoclonal antibodies or anti-TNF monoclonal antibodies, respectively. The study will show that treatment of CIA with stradobodies is superior to the corresponding monoclonal antibody despite the fact that the stradobody and its corresponding monoclonal antibody share the identical Fab.

Example 10. Multimerizing Stradobodies Exhibit Superior C1q Complement Binding Relative to the Corresponding Monoclonal Antibody or to Non-Multimerizing Stradobodies Sharing the Same Fab

[0270] A complement binding assay was conducted to compare C1q binding of three multimerizing stradobodies relative to the corresponding monoclonal antibodies having the same Fabs as the multimerizing stradobodies.

[0271] ELISA plates were coated with 1 .mu.g/mL in PBS at 100 .mu.L volume of complement component C1q human serum (Sigma Cat#: C1740-0.5MG) overnight at 4.degree. C. The plates were washed 3 times with phosphate buffered saline (PBS) containing 0.05% Tween. Non-specific binding was blocked using PBS containing 1% BSA and 0.05% Tween solution for 2 h at room temperature. Coated wells were then incubated with experimental compounds at various concentrations for 2 hours at room temperature. Plates were washed 3 times with PBS containing 0.05% Tween and incubated with 1:5000 biotinylated mouse anti-human IgG1 (Cat#555869, BD Biosciences) and Strepdavidin-HRP (Cat#: 7100-05 SouthernBiotech) as detection reagent for 1 hour at room temperature. Wells were washed 3 times and detected with standard TMB ELISA detection method, and absorbance was read at 450 nm.

[0272] GB4542 and the corresponding mAb sharing the same Fab (GB4500), GB7542 and the corresponding mAb sharing the same Fab (GB7500) and GB2542 and the corresponding mAb sharing the same Fab (GB2500) were tested for complement C1q binding. Surprisingly, all three of the multimerizing antibodies tested (GB4542, GB7442, and GB2542) exhibited exponentially higher complement C1q binding relative to their corresponding mAbs (FIG. 28). In particular, GB4542 exhibited an extremely high level of complement C1q binding. GB4542, GB7542, and GB2542 each share the identical multimerization domains and Fc regions, and differ only in that each has a different Fab. Thus, unexpectedly, the Fab on the multimerizing stradobody affects the level of complement C1q binding.

[0273] The data were log transformed with a curve fit using GraphPad prism 5, a commercially available software, and the EC50 (in ug/ml) was calculated for each molecule tested. EC50 is the half-maximal effective concentration and refers to the concentration of a molecule that gives the half-maximal response. Strikingly, the EC50 for each stradobody was 10-20 times lower than the EC50 for the corresponding antibody (FIG. 29). Specifically, the EC50 for stradobody GB7542 was 8.69, whereas the EC50 for the corresponding mAb GB7500 was 202.0; the EC50 for stradobody GB4542 was 3.25, whereas the EC50 for the corresponding mAb GB4500 was 34.5; and the EC50 for stradobody GB2542 was 11.0, whereas the EC50 for the corresponding mAb GB2500 could not be determined due to the extremely low level of C1q binding exhibited by this molecule (FIG. 29). Thus, the concentration of stradobody required to give a half-maximal complement binding response was at least 10-20 times lower than that required for a monoclonal antibody having the same Fab to achieve a half-maximal complement binding response. In addition, the concentration of stradobody required to give a half-maximal complement binding response was influenced by the stradobody's Fab, and not just the multimerizing and Fc regions. Further complement binding assays were conducted to assess the complement C1q binding capacity of non-multimerizing stradobodies relative to their multimerizing counterpart or to the corresponding monoclonal antibody sharing the same Fab. In order to assess complement C1q binding, complement assays were conducted as described above using GB2500, GB2542, and the linear, non-multimerizing stradobodies GB2554 and GB2555, all four of which share the same anti Her2/neu Fab. The non-multimerizing stradobodies GB2554 and GB2555 each exhibited superior complement C1q binding relative to the monoclonal antibody GB2500 (FIG. 30); however, the multimerizing stradobody GB2542 exhibited far superior complement C1q binding compared to either of the non-multimerizing stradobodies (FIG. 30). Furthermore, the EC50 value for the multimerizing stradobody GB2542 was 2.5-7.0 times lower than the EC50 values for GB2554 and GB2555. Specifically, the EC50 value for complement C1q binding for GB2542 was 3.83, whereas the EC50 value for complement C1q binding for GB2554 and GB2555 were 26.4 and 9.45, respectively (FIG. 31).

[0274] The results of the study indicated that, unexpectedly, multimerizing stradobodies exhibited dramatically superior complement binding relative to the corresponding monoclonal antibody sharing the same Fab. The results also indicated that while non-multimerizing stradobodies exhibit superior complement binding relative to the corresponding monoclonal antibody sharing the same Fab, multimerizing stradobodies exhibit far superior complement binding relative to non-multimerizing stradobodies sharing the same Fab. Finally, the study showed that the Fab on the multimerizing stradobody dramatically affects the amount of C1q binding.

[0275] All, documents, patents, patent applications, publications, product descriptions, and protocols which are cited throughout this application are incorporated herein by reference in their entireties for all purposes.

[0276] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Modifications and variation of the above-described embodiments of the invention are possible without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Sequence CWU 1

1

91120PRTHomo sapiens 1Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 2232PRTHomo sapiens 2Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 165 170 175 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys 225 230 312PRTHomo sapiens 3Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 1 5 10 4264PRTHomo sapiens 4Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys 245 250 255 Cys Val Glu Cys Pro Pro Cys Pro 260 541PRTHomo sapiens 5Gly Gly Gly Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu 1 5 10 15 Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu 20 25 30 Ile Gly Glu Arg Gly His Gly Gly Gly 35 40 6245PRTHomo sapiens 6Asp Ala Ala Asp Ile Gln His Ser Gly Gly Arg Ser Ser Glu Pro Lys 1 5 10 15 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 20 25 30 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 35 40 45 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 50 55 60 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 65 70 75 80 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 85 90 95 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 100 105 110 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 115 120 125 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 130 135 140 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 145 150 155 160 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 165 170 175 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 180 185 190 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 195 200 205 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 210 215 220 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 225 230 235 240 Leu Ser Pro Gly Lys 245 7260PRTHomo sapiens 7Asp Ala Ala Asp Ile Gln His Ser Gly Gly Arg Ser Ser Glu Pro Lys 1 5 10 15 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 20 25 30 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 35 40 45 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 50 55 60 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 65 70 75 80 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 85 90 95 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 100 105 110 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 115 120 125 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 130 135 140 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 145 150 155 160 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 165 170 175 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 180 185 190 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 195 200 205 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 210 215 220 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 225 230 235 240 Leu Ser Pro Gly Lys Ser Leu Glu Glu Arg Lys Cys Cys Val Glu Cys 245 250 255 Pro Pro Cys Pro 260 8264PRTHomo sapiens 8Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 20 25 30 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 35 40 45 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 50 55 60 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 65 70 75 80 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 85 90 95 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 100 105 110 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 115 120 125 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 130 135 140 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 145 150 155 160 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 165 170 175 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 180 185 190 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 195 200 205 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 210 215 220 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 225 230 235 240 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 245 250 255 Ser Leu Ser Leu Ser Pro Gly Lys 260 9294PRTHomo sapiens 9Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gly Gly Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly His Gly Gly Gly Ser Ser Glu Pro 50 55 60 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 65 70 75 80 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 85 90 95 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 100 105 110 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 115 120 125 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 130 135 140 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 145 150 155 160 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 165 170 175 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 180 185 190 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 195 200 205 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 210 215 220 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 225 230 235 240 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 245 250 255 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 260 265 270 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 275 280 285 Ser Leu Ser Pro Gly Lys 290 10289PRTHomo sapiens 10Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Ser 245 250 255 Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr 260 265 270 His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg 275 280 285 Gly 11266PRTMus sp. 11Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Glu Arg 245 250 255 Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 260 265 12278PRTMus sp. 12Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ala Ala Asp Ile Gln His Ser Gly Gly Arg Ser 20 25 30 Arg Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys 35 40 45 Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro 50 55 60 Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys 65 70 75 80 Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp

85 90 95 Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg 100 105 110 Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln 115 120 125 His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn 130 135 140 Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly 145 150 155 160 Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu 165 170 175 Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met 180 185 190 Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu 195 200 205 Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe 210 215 220 Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn 225 230 235 240 Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr 245 250 255 Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Glu Arg Lys Cys Cys Val 260 265 270 Glu Cys Pro Pro Cys Pro 275 13265PRTMus sp. 13Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 20 25 30 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 35 40 45 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 50 55 60 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 65 70 75 80 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 85 90 95 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 100 105 110 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 115 120 125 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 130 135 140 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 145 150 155 160 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 165 170 175 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 180 185 190 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 195 200 205 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 210 215 220 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 225 230 235 240 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 245 250 255 Lys Ser Phe Ser Arg Thr Pro Gly Lys 260 265 14287PRTMus sp. 14Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile 20 25 30 Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys 35 40 45 Leu Ile Gly Glu Arg Gly Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 50 55 60 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 65 70 75 80 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 85 90 95 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 100 105 110 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 115 120 125 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 130 135 140 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 145 150 155 160 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 165 170 175 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 180 185 190 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 195 200 205 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 210 215 220 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 225 230 235 240 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 245 250 255 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 260 265 270 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 275 280 285 15291PRTMus sp. 15Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Gly Gly 245 250 255 Gly Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys 260 265 270 Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly 275 280 285 Glu Arg Gly 290 16299PRTMus sp. 16Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ala Ala Asp Ile Gln His Ser Gly Gly Arg Ser 20 25 30 Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile 35 40 45 Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu 50 55 60 Arg Gly Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys 65 70 75 80 Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro 85 90 95 Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr 100 105 110 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 115 120 125 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 130 135 140 Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile 145 150 155 160 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 165 170 175 Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys 180 185 190 Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu 195 200 205 Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe 210 215 220 Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu 225 230 235 240 Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr 245 250 255 Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg 260 265 270 Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His 275 280 285 Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 290 295 17753DNAHomo sapiens 17atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60gagcgcaaat gttgtgtgga gtgcccaccg tgcccagcac ctgaactcct ggggggaccg 120tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 180gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 240gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 300acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 360tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 420gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 480accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 540gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 600gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 660caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 720aagagcctct ccctgtcccc gggtaaatga taa 75318249PRTHomo sapiens 18Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 20 25 30 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 35 40 45 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 50 55 60 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 65 70 75 80 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 85 90 95 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 100 105 110 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 115 120 125 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 130 135 140 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 145 150 155 160 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 165 170 175 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 180 185 190 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 195 200 205 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 210 215 220 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 225 230 235 240 Lys Ser Leu Ser Leu Ser Pro Gly Lys 245 19217PRTHomo sapiens 19Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215 20264PRTHomo sapiens 20Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln Tyr Asn Ala Thr Tyr Arg Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys 245 250 255 Cys Val Glu Cys Pro Pro Cys Pro 260 21264PRTHomo sapiens 21Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln

Tyr Asn Ser Thr Tyr Ala Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys 245 250 255 Cys Val Glu Cys Pro Pro Cys Pro 260 22266PRTMus sp. 22Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ala Thr Leu Arg Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Glu Arg 245 250 255 Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 260 265 23266PRTMus sp. 23Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Ala Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Glu Arg 245 250 255 Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 260 265 24282PRTHomo sapiens 24Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln Tyr Asn Ala Thr Tyr Arg Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Pro Pro Gly 245 250 255 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro 260 265 270 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 275 280 25284PRTMus sp. 25Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ala Thr Leu Arg Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Gly Pro 245 250 255 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 260 265 270 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 275 280 2630PRTArtificial SequenceGPP multimerization domain 26Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 1 5 10 15 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 20 25 30 27282PRTHomo sapiens 27Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 20 25 30 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 35 40 45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 50 55 60 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 65 70 75 80 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 85 90 95 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 100 105 110 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 115 120 125 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 130 135 140 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 145 150 155 160 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 165 170 175 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 180 185 190 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 195 200 205 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 210 215 220 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 225 230 235 240 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Pro Pro Gly 245 250 255 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro 260 265 270 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 275 280 28282PRTHomo sapiens 28Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 20 25 30 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 35 40 45 Pro Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 50 55 60 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 65 70 75 80 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 85 90 95 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 100 105 110 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 115 120 125 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 130 135 140 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 145 150 155 160 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 165 170 175 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 180 185 190 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 195 200 205 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 210 215 220 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 225 230 235 240 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 245 250 255 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 260 265 270 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 275 280 29284PRTMus sp. 29Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 20 25 30 Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 35 40 45 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 50 55 60 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 65 70 75 80 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 85 90 95 Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala 100 105 110 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 115 120 125 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 130 135 140 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 145 150 155 160 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 165 170 175 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 180 185 190 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 195 200 205 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 210 215 220 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 225 230 235 240 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Gly Pro 245 250 255 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 260 265 270 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 275 280 30283PRTMus sp. 30Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 20 25 30 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 35 40 45 Pro Pro Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys 50 55 60 Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro 65 70 75 80 Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 100 105 110 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 115 120 125 Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu

Pro Ile 130 135 140 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 145 150 155 160 Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys 165 170 175 Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu 180 185 190 Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe 195 200 205 Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu 210 215 220 Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr 225 230 235 240 Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg 245 250 255 Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His 260 265 270 Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 275 280 31217PRTHomo sapiens 31Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val 210 215 3240PRTHomo sapiens 32Gly Gly Gly Ser Ile Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu 1 5 10 15 Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu 20 25 30 Ile Gly Glu Arg Gly His Asp Ile 35 40 33764PRTHomo sapiens 33Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Ser Leu Glu Gly Gly Gly Ser Ile Lys Gln Ile 465 470 475 480 Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn 485 490 495 Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Asp Ile 500 505 510 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Arg Leu Glu Gly 515 520 525 Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 530 535 540 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 545 550 555 560 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 565 570 575 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 580 585 590 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 595 600 605 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 610 615 620 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 625 630 635 640 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 645 650 655 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 660 665 670 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 675 680 685 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 690 695 700 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 725 730 735 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 740 745 750 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 755 760 34218PRTHomo sapiens 34Glu 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 210 215 35765PRTHomo sapiens 35Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys Gln 465 470 475 480 Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu 485 490 495 Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Asp 500 505 510 Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Arg Leu Glu 515 520 525 Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 530 535 540 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 545 550 555 560 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 565 570 575 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 580 585 590 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 595 600 605 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 610 615 620 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 625 630 635 640 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 645 650 655 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 660 665 670 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 675 680 685 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 690 695 700 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 705 710 715 720 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 725 730 735 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 740 745 750 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 755 760 765 36219PRTHomo sapiens 36Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130

135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 210 215 37766PRTHomo sapiens 37Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Asp Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Arg Leu 515 520 525 Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His Thr 530 535 540 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 545 550 555 560 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 565 570 575 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 580 585 590 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 595 600 605 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 610 615 620 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 625 630 635 640 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 645 650 655 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 660 665 670 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 675 680 685 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 690 695 700 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 705 710 715 720 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 725 730 735 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 740 745 750 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 755 760 765 38450PRTHomo sapiens 38Glu 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 Glu Glu Met 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 39214PRTHomo sapiens 39Asp 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 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 40470PRTHomo sapiens 40Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys 465 470 41234PRTHomo sapiens 41Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp 35 40 45 Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr 100 105 110 Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 42497PRTHomo sapiens 42Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65

70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Glu Pro Lys Ser Cys Asp Lys Thr His Thr 465 470 475 480 Cys Pro Pro Cys Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 485 490 495 Pro 43467PRTHomo sapiens 43Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Arg 225 230 235 240 Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 275 280 285 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Pro Gly Lys 465 44512PRTHomo sapiens 44Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 465 470 475 480 Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro 485 490 495 Pro Gly Pro Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 500 505 510 45512PRTHomo sapiens 45Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Gly Pro 225 230 235 240 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 245 250 255 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Glu Arg Lys Cys 260 265 270 Cys Val Glu Cys Pro Pro Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr 275 280 285 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 290 295 300 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 305 310 315 320 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 325 330 335 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 340 345 350 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 355 360 365 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 370 375 380 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 385 390 395 400 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 405 410 415 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 420 425 430 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 435 440 445 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 450 455 460 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 465 470 475 480 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 485 490 495 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 500 505 510 46729PRTHomo sapiens 46Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375

380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Gly Gly Gly Gly Ser Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 485 490 495 Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 565 570 575 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 47754PRTHomo sapiens 47Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Val Glu Gly Gly Gly Ser Ile Lys Gln 465 470 475 480 Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu 485 490 495 Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Gly 500 505 510 Gly Gly Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp 515 520 525 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 530 535 540 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 545 550 555 560 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 565 570 575 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 580 585 590 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 595 600 605 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 610 615 620 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 625 630 635 640 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 645 650 655 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 660 665 670 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 675 680 685 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 690 695 700 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 705 710 715 720 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 725 730 735 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 740 745 750 Gly Lys 48725PRTHomo sapiens 48Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Leu Glu Glu Arg Lys Cys Cys Val Glu 465 470 475 480 Cys Pro Pro Cys Pro Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys 485 490 495 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 500 505 510 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 515 520 525 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 530 535 540 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 545 550 555 560 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 565 570 575 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 580 585 590 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 595 600 605 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 610 615 620 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 625 630 635 640 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 645 650 655 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 660 665 670 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 675 680 685 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 690 695 700 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 705 710 715 720 Leu Ser Pro Gly Lys 725 49719PRTHomo sapiens 49Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465

470 475 480 Gly Gly Gly Gly Ser Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His 485 490 495 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 500 505 510 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 515 520 525 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 530 535 540 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 545 550 555 560 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 565 570 575 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 580 585 590 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 595 600 605 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 610 615 620 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 625 630 635 640 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 645 650 655 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 660 665 670 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 675 680 685 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 690 695 700 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 50710PRTHomo sapiens 50Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Pro Arg Phe Glu Glu Pro 465 470 475 480 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 485 490 495 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 500 505 510 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 515 520 525 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 530 535 540 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 545 550 555 560 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 565 570 575 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 580 585 590 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 595 600 605 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 610 615 620 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 625 630 635 640 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 645 650 655 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 660 665 670 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 675 680 685 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 690 695 700 Ser Leu Ser Pro Gly Lys 705 710 51471PRTMus sp. 51Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro 245 250 255 Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys 260 265 270 Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val 275 280 285 Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn 290 295 300 Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr 305 310 315 320 Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp 325 330 335 Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu 340 345 350 Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg 355 360 365 Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys 370 375 380 Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp 385 390 395 400 Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys 405 410 415 Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser 420 425 430 Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser 435 440 445 Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser 450 455 460 Phe Ser Arg Thr Pro Gly Lys 465 470 52467PRTMus sp. 52Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Arg 225 230 235 240 Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Asn Leu Leu Gly 245 250 255 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 260 265 270 Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 275 280 285 Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 290 295 300 His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 305 310 315 320 Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly 325 330 335 Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 340 345 350 Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 355 360 365 Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 370 375 380 Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 385 390 395 400 Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 420 425 430 Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 435 440 445 His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 450 455 460 Pro Gly Lys 465 53451PRTHomo sapiens 53Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 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 54213PRTHomo sapiens 54Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro 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 55471PRTHomo sapiens 55Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 56233PRTHomo sapiens 56Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser 20 25 30 Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser 35 40 45 Val Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys 50 55 60 Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg 65 70 75 80 Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg 85 90 95 Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser 100 105 110 Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr 115 120 125 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 130 135 140 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 145 150 155 160 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 165 170 175 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 180 185 190 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 195 200 205 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 210 215 220 Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 57468PRTHomo sapiens 57Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 245 250 255 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 260 265 270 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 275 280 285 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 290 295 300 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 305 310 315 320 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 325 330 335 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 340 345 350 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Gly Lys 465 58472PRTMus sp. 58Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala 245 250 255 Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile 260 265 270 Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val 275 280 285 Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val 290 295 300 Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp 305 310 315 320 Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln 325 330 335 Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp 340 345 350 Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val 355 360 365 Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr 370 375 380 Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu 385 390 395 400 Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr 405 410 415 Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr 420 425 430 Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr 435 440 445 Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys 450 455 460 Ser Phe Ser Arg Thr Pro Gly Lys 465 470 59468PRTMus sp. 59Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Asn Leu Leu 245 250 255 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 260 265 270 Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser 275 280 285 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 290 295 300 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 305 310 315 320 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 325 330 335 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro 340 345 350 Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln 355 360 365 Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val 370 375 380

Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val 385 390 395 400 Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 420 425 430 Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val 435 440 445 Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg 450 455 460 Thr Pro Gly Lys 465 60449PRTHomo sapiens 60Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 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 Ala Leu Pro Ala Pro 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 Glu Glu Met 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 61213PRTHomo sapiens 61Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 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 Ala 210 62469PRTHomo sapiens 62Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 63233PRTHomo sapiens 63Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser 20 25 30 Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser 35 40 45 Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro 50 55 60 Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn 85 90 95 Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn 100 105 110 Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Ala 225 230 64471PRTHomo sapiens 64Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 65234PRTHomo sapiens 65Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly 35 40 45 Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn 100 105 110 Arg Ala Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 66766PRTHomo sapiens 66Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr

Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Asp Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Arg Leu 515 520 525 Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His Thr 530 535 540 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 545 550 555 560 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 565 570 575 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 580 585 590 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 595 600 605 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 610 615 620 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 625 630 635 640 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 645 650 655 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 660 665 670 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 675 680 685 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 690 695 700 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 705 710 715 720 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 725 730 735 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 740 745 750 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 755 760 765 67219PRTHomo sapiens 67Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 210 215 68527PRTHomo sapiens 68Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 165 170 175 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile 225 230 235 240 Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His 245 250 255 Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly 260 265 270 His Asp Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Arg 275 280 285 Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys Thr His 290 295 300 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 305 310 315 320 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 325 330 335 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 340 345 350 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 355 360 365 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 370 375 380 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 385 390 395 400 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 405 410 415 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 420 425 430 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 435 440 445 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 450 455 460 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 465 470 475 480 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 485 490 495 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 500 505 510 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 515 520 525 69513PRTHomo sapiens 69Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 165 170 175 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys Ser Ile Lys Gln Ile Glu Asp Lys 225 230 235 240 Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala 245 250 255 Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Asp Ile Glu Arg Lys 260 265 270 Cys Cys Val Glu Cys Pro Pro Cys Pro 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 Glu Glu Met 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 70524PRTHomo sapiens 70Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Ser Leu Glu Gly Gly Gly Ser Ile Lys Gln Ile 465 470 475 480 Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn 485 490 495 Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Asp Ile 500 505 510 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 515 520 71496PRTHomo sapiens 71Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 465 470 475 480 Pro Pro Cys Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 485 490 495 72511PRTHomo sapiens 72Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro 465 470 475 480 Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro 485 490 495 Gly Pro Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 500 505 510 73728PRTHomo sapiens 73Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 465 470 475 480 Gly Gly Gly Ser Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 485 490 495 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 500 505 510 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 515 520 525 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 530 535 540 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 545 550 555 560 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 565 570 575 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 580 585 590 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 595 600 605 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 610 615 620 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 625 630 635 640 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 645 650 655 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 660 665 670 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 675 680 685 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 690 695 700 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 705 710 715 720 Ser Leu Ser Leu Ser Pro Gly Lys 725 74753PRTHomo sapiens 74Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Ser Val Glu Gly Gly Gly Ser Ile Lys Gln Ile 465 470 475 480 Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn 485 490 495 Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Gly Gly 500 505 510 Gly Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp Lys 515 520 525 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 530 535 540 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 545 550 555 560 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 565 570 575 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 580 585 590 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 595 600 605 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 610 615 620 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 625 630 635 640 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 645 650 655 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 660 665 670 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 675 680 685 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 690 695 700 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 705 710 715 720 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 725 730 735 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 740 745 750 Lys 75713PRTHomo sapiens 75Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val 20 25 30 Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser 35 40 45 Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly 50 55 60 Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn 65 70 75 80 Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser 85 90 95 Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile 100 105 110 Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 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 Arg 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 Glu Glu Met 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 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 465 470 475 480 Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 485 490 495 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 500 505 510 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 515 520 525 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 530 535 540 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 545 550 555 560 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 565 570 575 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 580 585 590 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 595 600 605 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 610 615 620 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 625 630 635 640 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 645 650 655 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 660 665 670 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 675 680 685 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 690 695 700 Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 76526PRTHomo sapiens 76Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Asp Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 515 520 525 77498PRTHomo sapiens 77Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Glu Pro Lys Ser Cys Asp Lys Thr His 465 470 475 480 Thr Cys Pro Pro Cys Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro 485 490 495 Cys Pro 78513PRTHomo sapiens 78Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro

Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Gly Pro Pro Gly Pro Pro Gly Pro Pro 465 470 475 480 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 485 490 495 Pro Pro Gly Pro Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 500 505 510 Pro 79730PRTHomo sapiens 79Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly 465 470 475 480 Ser Gly Gly Gly Gly Ser Glu Arg Lys Cys Cys Val Glu Cys Pro Pro 485 490 495 Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 500 505 510 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 515 520 525 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 530 535 540 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 545 550 555 560 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 565 570 575 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 580 585 590 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 595 600 605 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 610 615 620 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 625 630 635 640 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 645 650 655 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 660 665 670 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 675 680 685 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 690 695 700 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 705 710 715 720 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 730 80755PRTHomo sapiens 80Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Val Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Gly Gly Gly Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 660 665 670 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 81715PRTHomo sapiens 81Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val 20 25 30 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 35 40 45 Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly 50 55 60 Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr 65 70 75 80 Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 85 90 95 Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe 115 120 125 Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys Cys Val Glu Cys Pro 465 470 475 480 Pro Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 485 490 495 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 500 505 510 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 515 520 525 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 530 535 540 Trp Tyr Val Asp Gly

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 545 550 555 560 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 565 570 575 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 580 585 590 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 595 600 605 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 610 615 620 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 625 630 635 640 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 645 650 655 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 660 665 670 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 675 680 685 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 690 695 700 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 82498PRTHomo sapiens 82Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Glu Pro Lys Ser Cys Asp Lys Thr His 465 470 475 480 Thr Cys Pro Pro Cys Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro 485 490 495 Cys Pro 83513PRTHomo sapiens 83Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Gly Pro Pro Gly Pro Pro Gly Pro Pro 465 470 475 480 Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly 485 490 495 Pro Pro Gly Pro Pro Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 500 505 510 Pro 84730PRTHomo sapiens 84Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly 465 470 475 480 Ser Gly Gly Gly Gly Ser Glu Arg Lys Cys Cys Val Glu Cys Pro Pro 485 490 495 Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 500 505 510 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 515 520 525 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 530 535 540 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 545 550 555 560 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 565 570 575 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 580 585 590 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 595 600 605 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 610 615 620 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 625 630 635 640 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 645 650 655 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 660 665 670 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 675 680 685 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 690 695 700 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 705 710 715 720 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 730 85755PRTHomo sapiens 85Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Val Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Gly Gly Gly Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 660 665 670 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 86715PRTHomo sapiens 86Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys Cys Val Glu Cys Pro 465 470 475 480 Pro Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 485 490 495 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 500 505 510 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 515 520 525 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 530 535 540 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 545 550 555 560 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 565 570 575 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 580 585 590 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 595 600 605 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 610 615 620 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 625 630 635 640 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 645 650 655 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 660 665 670 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 675 680 685 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 690 695 700 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 715 87526PRTHomo sapiens 87Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr 65 70 75 80 Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 85 90 95 Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 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 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys 465 470 475 480 Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile 485 490 495 Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His 500 505 510 Asp Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 515 520 525 88729PRTHomo sapiens 88Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Gly Gly Gly Gly Ser Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 485 490 495 Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 565 570 575 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp

Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 89714PRTHomo sapiens 89Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Glu Arg Lys Cys Cys Val Glu Cys Pro Pro 465 470 475 480 Cys Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 485 490 495 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 500 505 510 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 515 520 525 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 530 535 540 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 545 550 555 560 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 565 570 575 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 580 585 590 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 595 600 605 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 610 615 620 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 625 630 635 640 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 645 650 655 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 660 665 670 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 675 680 685 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 690 695 700 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 705 710 90754PRTHomo sapiens 90Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Val Glu Gly Gly Gly Ser Ile Lys Gln 465 470 475 480 Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu 485 490 495 Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Gly 500 505 510 Gly Gly Arg Leu Glu Gly Pro Arg Phe Glu Glu Pro Lys Ser Cys Asp 515 520 525 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 530 535 540 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 545 550 555 560 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 565 570 575 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 580 585 590 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 595 600 605 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 610 615 620 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 625 630 635 640 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 645 650 655 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 660 665 670 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 675 680 685 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 690 695 700 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 705 710 715 720 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 725 730 735 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 740 745 750 Gly Lys 91525PRTHomo sapiens 91Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 35 40 45 Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys 85 90 95 Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210 215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330 335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys Ser Leu Glu Gly Gly Gly Ser Ile Lys Gln 465 470 475 480 Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile Glu 485 490 495 Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Arg Gly His Asp 500 505 510 Ile Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 515 520 525

Claims

1.-128. (canceled)

129. A method of modulating an immune response in a subject comprising administering to the subject an effective amount of a stradobody comprising an Fab domain; one or more Fc domains; and one or more multimerization domains, wherein the one or more multimerization domains separates two Fc domains or is located at the carboxy terminus of the one or more Fc domains, and wherein the one or more multimerization domains is capable of multimerizing said stradobody.

130. The method of claim 129, wherein the one or more multimerization domains are independently selected from the group consisting of an isoleucine zipper, an IgG2 hinge, and a GPP repeat.

131. The method of claim 129, wherein the stradobody comprises at least one IgG2 hinge domain, wherein the amino acid sequence of the IgG2 hinge domain is at least 80% homologous to SEQ ID NO: 3, and wherein the IgG2 hinge is capable of multimerizing the stradobody.

132. The method of claim 129, wherein the stradobody comprises at least one isoleucine zipper, wherein the amino acid sequence of the at least one isoleucine zipper is at least 80% homologous to SEQ ID NO: 32, and wherein the isoleucine zipper is capable of multimerizing the stradobody.

133. The method of claim 129, wherein the stradobody comprises two multimerization domains.

134. The method of claim 133, wherein the two multimerization domains are an isoleucine zipper and an IgG2 hinge.

135. The method of claim 134, wherein the two multimerization domains separate two Fc domains.

136. The method of claim 134, wherein the two multimerization domains are located at the carboxy end of the Fc region.

137. The method of claim 129, wherein the at least one Fc domain is an IgG1 Fc domain, and wherein the IgG1 Fc domain comprises an IgG1 CH2 and IgG1 CH3.

138. The method of claim 137, wherein the IgG1 Fc domain further comprises an IgG1 hinge.

139. The method of claim 137, wherein the amino acid sequence of at least one IgG1 Fc domain is at least 80% homologous to SEQ ID NO: 2.

140. The method of claim 129, wherein the Fab domain is specific for EGFR, Her2/neu, or CD20.

141. The method of claim 129, wherein the subject is a human.

142. The method of claim 129, wherein the stradobody is administered to the subject intravenously, subcutaneously, orally, nasally, intraperitoneally, sublingually, bucally, transdermally, by subcutaneous or subdermal implantation, or intramuscularly.

143. A method of treating an inflammatory disease, autoimmune disease, infectious disease, or cancer in a subject in need thereof, comprising administering to the subject an effective amount of a stradobody comprising an Fab domain; one or more Fc domains; and one or more multimerization domains, wherein the one or more multimerization domains separates two Fc domains or is located at the carboxy terminus of the one or more Fc domains, and wherein the one or more multimerization domains is capable of multimerizing said stradobody.

144. The method of claim 143, wherein the subject is a human.

145. The method of claim 143, wherein the stradobody is administered to the subject intravenously, subcutaneously, orally, nasally, intraperitoneally, sublingually, bucally, transdermally, by subcutaneous or subdermal implantation, or intramuscularly.

146. The method of claim 143, wherein the subject has cancer and the cancer is selected from the group consisting of colorectal cancer, head and neck cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic disease, heavy chain disease, neuroendocrine tumors, and Schwanoma.

147. The method of claim 143, wherein the subject has an autoimmune or inflammatory disease, and wherein the autoimmune or inflammatory disease is selected from the group consisting of idiopathic thrombocytopenic purpura, Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis, optic neuritis, Kawasaki's disease, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, atherosclerosis, coronary artery disease, cardiomyopathy, reactive arthritis, Crohn's disease, ulcerative colitis, graft versus host disease, and type 1 diabetes mellitus.

148. The method of claim 143, wherein the subject has an infectious disease, and wherein the infectious disease is selected from the group consisting of candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, gram negative sepsis, tuberculosis, mononucleosis, influenza, respiratory illness caused by respiratory syncytial virus, human immunodeficiency virus, Hepatitis B, Hepatitis C, malaria, schistosomiasis, methicillin-resistant Staph aureus, vancomycin-resistant Enterococcus, carbapenem-resistant and carbapenemase-producing Enterobacteriaceae, mycobacterial disease, and trypanosomiasis.