Amatoxin Antibody-drug Conjugates And Uses Thereof

Abstract

Amatoxins, as well as antibody-drug conjugates (ADCs) comprising an amatoxin are provided, as well as compositions and methods of using the same. The compositions and methods provided herein can also be used to prepare a patient for hematopoietic stem cell transplant therapy and to improve the engraftment of hematopoietic stem cell transplants by selectively depleting endogenous hematopoietic stem cells prior to the transplant procedure. Methods and compositions for the treatment of various hematopoietic diseases, metabolic disorders, cancers, and autoimmune diseases, as well as prevention of graft-versus-host-disease (GVHD), are provided.

Description

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/838,290, filed on Apr. 24, 2019. The contents of the priority application are hereby incorporated by reference herein.

FIELD

[0002] The present invention relates to amatoxins, Antibody-Drug Conjugates (ADCs) comprising an amatoxin, compositions comprising such ADCs, and methods for using the same.

BACKGROUND

[0003] Monoclonal antibodies (mAb) can be conjugated to a therapeutic agent to form an antibody drug conjugate (ADC). ADCs can exhibit increased efficacy, as compared to an unconjugated antibody. The linkage of the antibody to the drug can be direct, or indirect via a linker. An important aspect of successful therapeutic ADCs is that the ADC be not only effective but well-tolerated. Often the cytotoxin impacts both efficacy and tolerability.

[0004] ADCs have been proposed as a therapeutic regimen for preparing patients for transplant and stem cell therapy. By conditioning a patient with a cell-specific ADC, stem cells or immune cells can be selectively depleted while leaving the patient's remaining immune system largely intact. For example, Palchaudhuri et al. (2016) Nat. Biotechnol. 34, 738-745 describes the use of a single dose of an anti-CD45 ADC where an anti-CD45 antibody was conjugated to saporin, and its ability to enable engraftment of donor cells and for treatment in a sickle-cell anemia model. Unlike irradiation, the CD45-SAP ADC was reported to have avoided neutropenia and anemia, and provided for rapid recovery of T and B cells with minimal overall toxicity. There remains a need for toxins that can be used for non-genotoxic targeted ADC-conditioning where the toxin is potent to the target cells while minimizing patient side effects.

SUMMARY

[0005] The present invention provides an amatoxin that can be used in an antibody drug conjugate (ADC), e.g., for delivery of the amatoxin to a target cell.

[0006] Presented herein is an antibody-drug conjugate (ADC) comprising an antibody, or an antigen-binding fragment thereof, conjugated to an amatoxin via a linker, wherein the ADC has the structure of formula (I):

##STR00001##

[0007] or a stereoisomer thereof;

[0008] wherein: [0009] Q is S; [0010] L is a non-cleavable linker; [0011] Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody, or antigen-binding fragment thereof; and [0012] Ab is the antibody, or the antigen binding fragment thereof.

[0013] In certain embodiments, an ADC disclosed herein has the structure of formula (Ia):

##STR00002##

[0014] In other embodiments, an ADC disclosed herein has the structure of formula (b):

##STR00003##

[0015] In certain embodiments, L comprises one or more of a bond, --(C.dbd.O)--, a --C(O)NH-- group, an --OC(O)NH-- group, C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group; wherein each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro; or each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0016] In some embodiments, the solubility enhancing group has the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein: [0017] a is 0 or 1; and [0018] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

[0019] In some embodiments, L comprises a --(CH.sub.2).sub.n-- unit, where n is an integer from 2-6, e.g., n is 6.

[0020] In some embodiments, wherein Ab, Z, and L, taken together as Ab-Z-L, is represented by the formula:

##STR00004##

wherein S is the sulfur atom of a cysteine residue present in the antibody, or the antigen-binding fragment thereof.

[0021] Also disclosed herein is an antibody-drug conjugate (ADC) comprising an antibody, or an antigen-binding fragment thereof, conjugated to an amatoxin via a linker, the ADC having the structure of formula (I):

##STR00005##

[0022] or a stereoisomer thereof;

[0023] wherein: [0024] Q is S; [0025] L is a cleavable linker; [0026] Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody, or antigen-binding fragment thereof; and [0027] Ab is the antibody, or the antigen binding fragment thereof.

[0028] In one embodiment, the ADC has a structure of formula (Ia):

##STR00006##

[0029] In another embodiment, the ADC has the structure of formula (b):

##STR00007##

[0030] In one embodiment, L comprises one or more of a hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-immolative group, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a --(C.dbd.O)-- group, a --C(O)NH-- group, an --OC(O)NH-- group, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group; wherein each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro; or each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0031] In one embodiment, the solubility enhancing group has the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein: [0032] a is 0 or 1; and [0033] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

[0034] In certain embodiments, L comprises a peptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg.

[0035] In certain embodiments, an ADC described herein further comprises a PAB group.

[0036] In one embodiment, L is represented by the formula:

##STR00008##

[0037] Also disclosed herein is an ADC comprising an antibody conjugated to an amatoxin, the ADC having a structure according to formula (II):

##STR00009## [0038] or a stereoisomer thereof, wherein Ab is an antibody, or an antigen binding fragment thereof.

[0039] In one embodiment, the ADC has the structure of formula (IIa):

##STR00010##

[0040] In another embodiment, the ADC has the structure of formula (Ib):

##STR00011##

[0041] In certain embodiments, an antibody, or antigen-binding fragment of an antibody, used in the ADCs described herein, has binding regions disclosed in the Sequence Table,

[0042] In one embodiment, the antibody, or the antigen binding fragment thereof, comprises either an Fc region comprising at least one mutation selected from the group consisting of D265C, H435A, L234A, or L235A (according to EU index); or an Fc region comprising D265C, H435A, L234A, or L235A (according to EU index) mutations.

[0043] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117.

[0044] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD45.

[0045] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD137.

[0046] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD5.

[0047] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD2.

[0048] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; and a light chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the light chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249;

[0049] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO: 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243; and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO: 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244.

[0050] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID No: 11, 12, and 13, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 14, 15, and 16, respectively.

[0051] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 245, 246, and 247, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 248, 249, and 250, respectively.

[0052] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10.

[0053] In one embodiment, the antibody, or the antigen binding fragment thereof, specifically binds to human CD117 and comprises a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 243, and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 244.

[0054] Also disclosed herein is a method of depleting a population of cells in a human subject, said method comprising administering an ADC disclosed herein to the subject, wherein the ADC comprises an antibody, or an antigen-binding fragment thereof, that specifically binds to an extracellular antigen expressed by cells in the population of cells.

[0055] Also provided is a method of conditioning a human subject for cell transplantation, said method comprising administering an ADC disclosed herein, to the human subject such that the endogenous stem or endogenous immune cells in the human subject are depleted, wherein the ADC specifically binds to an extracellular antigen expressed by the endogenous stem or endogenous immune cells.

[0056] In one embodiment, the method further comprises administering to the human subject allogenic stem cells or allogeneic immune cells.

[0057] Also provided is a pharmaceutical composition comprising an ADC disclosed herein, and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF FIGURES

[0058] FIG. 1 depicts the structures of formulae IV (FIG. 1A), VI (FIG. 1B), and IIa (FIG. 1C). "Ab" in FIGS. 1A to 1C represents an antibody. FIGS. 1A, 1B, and 1C represent Conjugates A, B, and C, respectively, referred to in the examples. Conjugates A, B, and C are also referred to as ADC A, ADC B, and ADC C.

[0059] FIG. 2 graphically depicts results from in vitro cytoxicity assays using Kasumi-1 cells in the presence of ADC with pre-incubation of ADC in media (A) or 50% human serum (B) to evaluate serum stability of conjugates.

[0060] FIG. 3 graphically depicts results from in vitro cytoxicity assays using Kasumi-1 cells in the presence of ADC with iteration on the time of incubation with titrated ADC samples to evaluate differences in the kinetics of cytotoxicity between cleavable and non-cleavable conjugates.

[0061] FIG. 4 graphically depicts results from two in vitro cell killing assays using Kasumi-1 cells (4A) and CD34+ cells (4B). The ADC tested was anti-CD117 ADC C.

[0062] FIG. 5 graphically depicts the ability of anti-CD117 ADC C to potently deplete human CD34+ in the bone marrow of humanized NSG mice.

[0063] FIG. 6 are Kaplan Meier plots reflecting the survival of Kasumi-1 implanted humanized NSG mice treated with the indicated doses of conjugates or controls.

[0064] FIG. 7 graphically depicts the efficacy of Conjugate C as evaluated in male cynomolgus monkeys. 2.0 mg/kg dose (LALA) 30.2867 batch issues may have resulted in a decrease in HSC sensitivity

[0065] FIG. 8 graphically depicts tolerability of ADCs containing either Conjugate A or Conjugate C in male cynomolgus monkeys.

[0066] FIG. 9 graphically depicts pharmacokinetic analysis of conjugate A and conjugate C administered to male cynomolgus monkeys.

[0067] FIG. 10 graphically depicts that anti-CD2 and CD5 ADC C are able to deplete T cells.

[0068] FIG. 11 graphically depicts that while anti-CD2 ADCs A and C are saturated by Day 5, some cells still express CD5.

[0069] FIGS. 12A and 12B graphically depict results showing anti-CD45 ADCs A or C (FIG. 14A) or anti-CD45 ADCs A or B (FIG. 14B) in in vitro cell killing assays.

[0070] FIG. 13 graphically depicts results showing anti-CD45 ADCs A or C in in vitro cell killing assays.

[0071] FIG. 14 graphically depicts results of anti-CD45 ADCs A or C in in vivo cell depletion experiments.

[0072] FIG. 15 graphically depicts results from administration of anti-CD45 ADCs A or C to mice at a number of dose amounts. Levels of peripheral lymphocytes, HSCs, and lymphocytes are shown. All ADCs were administered at 1 mg/kg.

[0073] FIG. 16 graphically depicts results showing anti-CD137 ADCs A and C in a T cell killing assay.

[0074] FIG. 17 graphically depicts cell line serum stability of anti-CD137 ADCs A and C over 48 hours.

DETAILED DESCRIPTION

[0075] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into the subsections which follow.

Definitions

[0076] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings.

[0077] The term "acyl" as used herein refers to --C(.dbd.O)R, wherein R is hydrogen ("aldehyde"), C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, C.sub.3-C.sub.7 carbocyclyl, C.sub.6-C.sub.20 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryloyl.

[0078] The term "C.sub.1-C.sub.12 alkyl" as used herein refers to a straight chain or branched, saturated hydrocarbon having from 1 to 12 carbon atoms. Representative C.sub.1-C.sub.12 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while branched C.sub.1-C.sub.12 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl. A C.sub.1-C.sub.12 alkyl group can be unsubstituted or substituted.

[0079] The term "alkenyl" as used herein refers to C.sub.2-C.sub.12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp.sup.2 double bond. Examples include, but are not limited to: ethylene or vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, and the like. An alkenyl group can be unsubstituted or substituted.

[0080] "Alkynyl" as used herein refers to a C.sub.2-C.sub.12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to acetylenic and propargyl. An alkynyl group can be unsubstituted or substituted.

[0081] "Aryl" as used herein refers to a C.sub.6-C.sub.20 carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and anthracenyl. An aryl group can be unsubstituted or substituted.

[0082] "Arylalkyl" as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms. An alkaryl group can be unsubstituted or substituted.

[0083] "Cycloalkyl" as used herein refers to a saturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkyl groups include a ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be unsubstituted or substituted.

[0084] "Cycloalkenyl" as used herein refers to an unsaturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkenyl groups include a ring having 3 to 6 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl. A cycloalkenyl group can be unsubstituted or substituted.

[0085] "Heteroaralkyl" as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp.sup.3 carbon atom, is replaced with a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like. The heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0086] "Heteroaryl" and "heterocycloalkyl" as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur. The heteroaryl or heterocycloalkyl radical comprises 2 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. A heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heteroaryl and heterocycloalkyl can be unsubstituted or substituted.

[0087] Heteroaryl and heterocycloalkyl groups are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

[0088] Examples of heteroaryl groups include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isatinoyl.

[0089] Examples of heterocycloalkyls include by way of example and not limitation dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.

[0090] By way of example and not limitation, carbon bonded heteroaryls and heterocycloalkyls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0091] By way of example and not limitation, nitrogen bonded heteroaryls and heterocycloalkyls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or beta-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0092] "Substituted" as used herein and as applied to any of the above alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, and the like, means that one or more hydrogen atoms are each independently replaced with a substituent. Unless otherwise constrained by the definition of the individual substituent, the foregoing chemical moieties, such as "alkyl", "alkylene", "heteroalkyl", "heteroalkylene", "alkenyl", "alkenylene", "heteroalkenyl", "heteroalkenylene", "alkynyl", "alkynylene", "heteroalkynyl", "heteroalkynylene", "cycloalkyl", "cycloalkylene", "heterocycloalkyl", heterocycloalkylene", "aryl," "arylene", "heteroaryl", and "heteroarylene" groups can optionally be substituted. Typical substituents include, but are not limited to, --X, --R, --OH, --OR, --SH, --SR, NH.sub.2, --NHR, --N(R).sub.2, --N.sup.+(R).sub.3, --CX.sub.3, --CN, --OCN, --SCN, --NCO, --NCS, --NO, --NO.sub.2, --N.sub.3, --NC(.dbd.O)H, --NC(.dbd.O)R, --C(.dbd.O)H, --C(.dbd.O)R, --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(R).sub.2, --SO.sub.3--, --SO.sub.3H, --S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR, --S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2N(R).sub.2, --S(.dbd.O)R, --OP(.dbd.O)(OH).sub.2, --OP(.dbd.O)(OR).sub.2, --P(.dbd.O)(OR).sub.2, --PO.sub.3, --PO.sub.3H.sub.2, --C(.dbd.O)X, --C(.dbd.S)R, --CO.sub.2H, --CO.sub.2R, --CO.sub.2--, --C(.dbd.S)OR, --C(.dbd.O)SR, --C(.dbd.S)SR, --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(R).sub.2, --C(.dbd.S)NH.sub.2, --C(.dbd.S)N(R).sub.2, --C(.dbd.NH)NH.sub.2, and --C(.dbd.NR)N(R).sub.2; wherein each X is independently selected for each occasion from F, C, Br, and I; and each R is independently selected for each occasion from C.sub.1-C.sub.12 alkyl, C.sub.6-C.sub.20 aryl, C.sub.3-C.sub.14 heterocycloalkyl or heteroaryl, protecting group and prodrug moiety. Wherever a group is described as "optionally substituted," that group can be substituted with one or more of the above substituents, independently for each occasion.

[0093] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene," "alkenylene," "arylene," "heterocycloalkylene," and the like.

[0094] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.

[0095] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers," or sometimes "optical isomers."

[0096] A carbon atom bonded to four non-identical substituents is termed a "chiral center." "Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0097] The compounds disclosed in this description and in the claims may comprise one or more asymmetric centers, and different diastereomers and/or enantiomers of each of the compounds may exist. The description of any compound in this description and in the claims is meant to include all enantiomers, diastereomers, and mixtures thereof, unless stated otherwise. In addition, the description of any compound in this description and in the claims is meant to include both the individual enantiomers, as well as any mixture, racemic or otherwise, of the enantiomers, unless stated otherwise. When the structure of a compound is depicted as a specific enantiomer, it is to be understood that the invention of the present application is not limited to that specific enantiomer. Accordingly, enantiomers, optical isomers, and diastereomers of each of the structural formulae of the present disclosure are contemplated herein. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. The compounds may occur in different tautomeric forms. The compounds according to the disclosure are meant to include all tautomeric forms, unless stated otherwise. When the structure of a compound is depicted as a specific tautomer, it is to be understood that the invention of the present application is not limited to that specific tautomer.

[0098] The compounds of any formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound of the disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of the disclosure. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. The compounds of the disclosure also include those salts containing quaternary nitrogen atoms.

[0099] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0100] Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. "Solvate" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H.sub.2O. A hydrate refers to, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

[0101] In addition, a crystal polymorphism may be present for the compounds or salts thereof represented by the formulae disclosed herein. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof, is included in the scope of the present disclosure.

[0102] As used herein, the term "about" refers to a value that is within 10% above or below the value being described. For example, the term "about 5 nM" indicates a range of from 4.5 nM to 5.5 nM.

[0103] As used herein, the term "amatoxin" refers to a member of the amatoxin family of peptides produced by Amanita phalloides mushrooms, or a variant or derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity. Suitable amatoxins and derivatives thereof are further described herein below. As described herein, amatoxins may be conjugated to an antibody, or antigen-binding fragment thereof, for instance, by way of a linker moiety (L) (thus forming a conjugate (i.e., ADC)). Exemplary methods of amatoxin conjugation and linkers useful for such processes are described below.

[0104] As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes monoclonal, genetically engineered, and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen binding fragments of antibodies, including, for example, Fab', F(ab').sub.2, Fab, Fv, rIgG, and scFv fragments. Unless otherwise indicated, the term "monoclonal antibody" (mAb) is meant to include both intact molecules, as well as antibody fragments (including, for example, Fab and F(ab').sub.2 fragments) that are capable of specifically binding to a target protein. As used herein, the Fab and F(ab').sub.2 fragments refer to antibody fragments that lack the Fc fragment of an intact antibody. Examples of these antibody fragments are described herein.

[0105] As used herein, the term "monoclonal antibody" refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

[0106] The antibodies of the present invention are generally isolated or recombinant. "Isolated," when used herein refers to a polypeptide, e.g., an antibody, that has been separated and/or recovered from a cell or cell culture from which it was expressed. Thus, an "isolated antibody," refers to an antibody which is substantially free of other antibodies having different antigenic specificities. For instance, an isolated antibody that specifically binds to CD117 is substantially free of antibodies that specifically bind antigens other than CD117.

[0107] The term "antigen-binding fragment," as used herein, refers a fragment of an antibody that retains the ability to specifically bind to a target antigen. The antigen-binding function of an antibody can be performed by fragments of a full-length antibody. The antibody fragment can be, for example, a Fab, F(ab').sub.2, scFv, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody. Examples of binding fragments encompassed of the term "antigen-binding fragment" of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the V.sub.L, V.sub.H, C.sub.L, and C.sub.H1 domains; (ii) a F(ab').sub.2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V.sub.H and C.sub.H1 domains; (iv) a Fv fragment consisting of the V.sub.L and V.sub.H domains of a single arm of an antibody, (v) a dAb including V.sub.H and V.sub.L domains; (vi) a dAb fragment that consists of a V.sub.H domain (see, e.g., Ward et al., Nature 341:544-546, 1989); (vii) a dAb which consists of a V.sub.H or a V.sub.L domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more (e.g., two, three, four, five, or six) isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, V.sub.L and V.sub.H, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the V.sub.L and V.sub.H regions pair to form monovalent molecules (known as single chain Fv (scFv); see, for example, Bird et al., Science 242:423-426, 1988 and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). Antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in certain cases, by chemical peptide synthesis procedures known in the art.

[0108] As used herein, the term "anti-CD117 antibody" or "an antibody that binds to CD117" refers to an antibody that is capable of binding CD117, e.g., human CD117, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD117. The amino acid sequences of the two main isoforms of human CD117 are provided in SEQ ID NO: 145 (isoform 1) and SEQ ID NO: 146 (isoform 2). An "anti-CD117 ADC" refers to an ADC wherein the antibody is an anti-CD117 antibody.

[0109] As used herein, the term "anti-CD45 antibody" or "an antibody that binds to CD45" refers to an antibody that is capable of binding CD45, e.g., human CD117, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD45. An "anti-CD45 ADC" refers to an ADC wherein the antibody is an anti-CD45 antibody.

[0110] As used herein, the term "anti-CD137 antibody" or "an antibody that binds to CD137" refers to an antibody that is capable of binding CD137, e.g., human CD137, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD137. An "anti-CD137 ADC" refers to an ADC wherein the antibody is an anti-CD137 antibody.

[0111] As used herein, the term "anti-CD2 antibody" or "an antibody that binds to CD2" refers to an antibody that is capable of binding CD2, e.g., human CD2, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD2. An "anti-CD2 ADC" refers to an ADC wherein the antibody is an anti-CD2 antibody.

[0112] As used herein, the term "anti-CD5 antibody" or "an antibody that binds to CD5" refers to an antibody that is capable of binding CD5, e.g., human CD5, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD5. An "anti-CD5 ADC" refers to an ADC wherein the antibody is an anti-CD5 antibody.

[0113] As used herein, the term "bispecific antibody" refers to, for example, a monoclonal, often a human or humanized antibody that is capable of binding at least two different antigens or at; least two different epitopes that may be on the same antigen or different antigens. For instance, one of the binding specificities can be directed towards a hematopoietic stem cell surface antigen, CD117 (e.g., GNNK+ CD117), and the other can specifically bind a different hematopoietic stem cell surface antigen or another cell surface protein, such as a receptor or receptor subunit involved in a signal transduction pathway that potentiates cell growth, among others.

[0114] As used herein, the term "complementarity determining region" (CDR) refers to a hypervariable region found both in the light chain and the heavy chain variable domains of an antibody. The more highly conserved portions of variable domains are referred to as framework regions (FRs). The amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. The antibodies described herein may contain modifications in these hybrid hypervariable positions. The variable domains of native heavy and light chains each contain four framework regions that primarily adopt a .beta.-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the .beta.-sheet structure. The CDRs in each chain are held together in close proximity by the framework regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, Md., 1987). In certain embodiments, numbering of immunoglobulin amino acid residues is performed according to the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise indicated (although any antibody numbering scheme, including, but not limited to IMGT and Chothia, can be utilized).

[0115] As used herein, the terms "condition" and "conditioning" refer to processes by which a patient is prepared for receipt of a transplant, e.g., a transplant containing hematopoietic stem cells. Such procedures promote the engraftment of a hematopoietic stem cell transplant (for instance, as inferred from a sustained increase in the quantity of viable hematopoietic stem cells within a blood sample isolated from a patient following a conditioning procedure and subsequent hematopoietic stem cell transplantation. According to the methods described herein, a patient may be conditioned for hematopoietic stem cell transplant therapy by administration to the patient of an ADC capable of binding an antigen expressed by hematopoietic stem cells, such as CD117 (e.g., GNNK+ CD117). Administration of an ADC capable of binding an HSC antigen to a patient in need of hematopoietic stem cell transplant therapy can promote the engraftment of a hematopoietic stem cell graft, for example, by selectively depleting endogenous hematopoietic stem cells, thereby creating a vacancy filled by an exogenous hematopoietic stem cell transplant.

[0116] As used herein, the term "conjugate" refers to a compound formed by the chemical bonding of a reactive functional group of one molecule, such as an antibody or antigen-binding fragment thereof, with an appropriately reactive functional group of another molecule, such as a cytotoxin described herein. Conjugates may include a linker between the two molecules bound to one another. Examples of linkers that can be used for the formation of a conjugate include peptide-containing linkers, such as those that contain naturally occurring or non-naturally occurring amino acids, such as D-amino acids. Linkers can be prepared using a variety of strategies described herein and known in the art. Depending on the reactive components therein, a linker may be cleaved, for example, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012). Notably, the term "conjugate" (when referring to a compound) is also referred to interchangeably herein as a "drug conjugate", "antibody drug conjugate" or "ADC".

[0117] As used herein, the term "coupling reaction" refers to a chemical reaction in which two or more substituents suitable for reaction with one another react so as to form a chemical moiety that joins (e.g., covalently) the molecular fragments bound to each substituent. Coupling reactions include those in which a reactive substituent bound to a fragment that is a cytotoxin, such as a cytotoxin known in the art or described herein, reacts with a suitably reactive substituent bound to a fragment that is an antibody, or antigen-binding fragment thereof, such as an antibody, antigen-binding fragment thereof, or specific anti-CD117 antibody that binds CD117 (such as GNNK+ CD117) known in the art or described herein. Examples of suitably reactive substituents include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thio/.alpha.,.beta.-unsaturated carbonyl pair, among others), a diene/dienophile pair (e.g., an azide/alkyne pair, among others), and the like. Coupling reactions include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine condensation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein.

[0118] As used herein, "CRU (competitive repopulating unit)" refers to a unit of measure of long-term engrafting stem cells, which can be detected after in-vivo transplantation.

[0119] As used herein, the term "donor" refers to a human or animal from which one or more cells are isolated prior to administration of the cells, or progeny thereof, into a recipient. The one or more cells may be, for example, a population of hematopoietic stem cells.

[0120] As used herein, the term "diabody" refers to a bivalent antibody containing two polypeptide chains, in which each polypeptide chain includes V.sub.H and V.sub.L domains joined by a linker that is too short (e.g., a linker composed of five amino acids) to allow for intramolecular association of V.sub.H and V.sub.L domains on the same peptide chain. This configuration forces each domain to pair with a complementary domain on another polypeptide chain so as to form a homodimeric structure. Accordingly, the term "triabody" refers to trivalent antibodies containing three peptide chains, each of which contains one V.sub.H domain and one V.sub.L domain joined by a linker that is exceedingly short (e.g., a linker composed of 1-2 amino acids) to permit intramolecular association of V.sub.H and V.sub.L domains within the same peptide chain. In order to fold into their native structures, peptides configured in this way typically trimerize so as to position the V.sub.H and V.sub.L domains of neighboring peptide chains spatially proximal to one another (see, for example, Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-48, 1993).

[0121] As used herein, "drug-to-antibody ratio" or "DAR" refers to the number of drugs, e.g., amatoxin, attached to the antibody of a conjugate. The DAR of an ADC can range from 1 to 8, although higher loads are also possible depending on the number of linkage sites on an antibody. In certain embodiments, the conjugate has a DAR of 1, 2, 3, 4, 5, 6, 7, or 8.

[0122] As used herein, the term "endogenous" describes a substance, such as a molecule, cell, tissue, or organ (e.g., a hematopoietic stem cell or a cell of hematopoietic lineage, such as a megakaryocyte, thrombocyte, platelet, erythrocyte, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T-lymphocyte, or B-lymphocyte) that is found naturally in a particular organism, such as a human patient.

[0123] As used herein, the term "engraftment potential" is used to refer to the ability of hematopoietic stem and progenitor cells to repopulate a tissue, whether such cells are naturally circulating or are provided by transplantation. The term encompasses all events surrounding or leading up to engraftment, such as tissue homing of cells and colonization of cells within the tissue of interest. The engraftment efficiency or rate of engraftment can be evaluated or quantified using any clinically acceptable parameter as known to those of skill in the art and can include, for example, assessment of competitive repopulating units (CRU); incorporation or expression of a marker in tissue(s) into which stem cells have homed, colonized, or become engrafted; or by evaluation of the progress of a subject through disease progression, survival of hematopoietic stem and progenitor cells, or survival of a recipient. Engraftment can also be determined by measuring white blood cell counts in peripheral blood during a post-transplant period. Engraftment can also be assessed by measuring recovery of marrow cells by donor cells in a bone marrow aspirate sample.

[0124] As used herein, the term "exogenous" describes a substance, such as a molecule, cell, tissue, or organ (e.g., a hematopoietic stem cell or a cell of hematopoietic lineage, such as a megakaryocyte, thrombocyte, platelet, erythrocyte, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T-lymphocyte, or B-lymphocyte) that is not found naturally in a particular organism, such as a human patient. Exogenous substances include those that are provided from an external source to an organism or to cultured matter extracted therefrom.

[0125] The terms "Fc", "Fc region," and "Fc domain," as used herein refer to the portion of an IgG antibody that correlates to a crystallizable fragment obtained by papain digestion of an IgG molecule. The Fc region comprises the C-terminal half of two heavy chains of an IgG molecule that are linked by disulfide bonds. It has no antigen binding activity but contains the carbohydrate moiety and binding sites for complement and Fc receptors, including the FcRn receptor. An Fc region contains the second constant domain CH2 (e.g., residues at EU positions 231-340 of IgG1) and the third constant domain CH3 (e.g., residues at EU positions 341-447 of human IgG1). As used herein, the Fc region includes the "lower hinge region" (e.g., residues at EU positions 233-239 of IgG1). Fc can refer to this region in isolation, or this region in the context of an antibody, antibody fragment, or Fc fusion protein. Polymorphisms have been observed at a number of positions in Fc domains, including but not limited to EU positions 270, 272, 312, 315, 356, and 358, and thus slight differences between the sequences presented in the instant application and sequences known in the art can exist. Thus, a "wild type IgG Fc domain" or "WT IgG Fc domain" refers to any naturally occurring IgG Fc region (i.e., any allele). The sequences of the heavy chains of human IgG1, IgG2, IgG3 and IgG4 can be found in a number of sequence databases, for example, at the Uniprot database (www.uniprot.org) under accession numbers P01857 (IGHG1_HUMAN), P01859 (IGHG2_HUMAN), P01860 (IGHG3_HUMAN), and P01861 (IGHG1_HUMAN), respectively. An example of a "WT" Fc region is provided in SEQ ID NO: 122 (which provides a heavy chain constant region containing an Fc region).

[0126] The terms "modified Fc region" or "variant Fc region" as used herein refers to an IgG Fc domain comprising one or more amino acid substitutions, deletions, insertions or modifications introduced at any position within the Fc region.

[0127] The terms "full length antibody" and "intact antibody" are used herein interchangeably to refer to an antibody in its substantially intact form, and not an antibody fragment as defined herein. In one embodiment, an ADC described herein comprises an intact antibody. Thus, for an IgG antibody, an intact antibody comprises two heavy chains each comprising a variable region, a constant region and an Fc region, and two light chains each comprising a variable region and a constant region. More specifically, an intact IgG comprises two light chains each comprising a light chain variable region (VL) and alight chain constant region (CL), and comprises two heavy chains each comprising a heavy chain variable region (VH) and three heavy chain constant regions (CH1, CH2, and CH3). CH2 and CH3 represent the Fc region of the heavy chain.

[0128] As used herein, the term "framework region" or "FW region" includes amino acid residues that are adjacent to the CDRs of an antibody or antigen-binding fragment thereof. FW region residues may be present in, for example, human antibodies, humanized antibodies, monoclonal antibodies, antibody fragments, Fab fragments, single chain antibody fragments, scFv fragments, antibody domains, and bispecific antibodies, among others.

[0129] As used herein, the term "hematopoietic stem cells" ("HSCs") refers to immature blood cells having the capacity to self-renew and to differentiate into mature blood cells containing diverse lineages including but not limited to granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells). Such cells may include CD34.sup.+ cells. CD34.sup.+ cells are immature cells that express the CD34 cell surface marker. In humans, CD34+ cells are believed to include a subpopulation of cells with the stem cell properties defined above, whereas in mice, HSCs are CD34-. In addition, HSCs also refer to long term repopulating HSCs (LT-HSC) and short term repopulating HSCs (ST-HSC). LT-HSCs and ST-HSCs are differentiated, based on functional potential and on cell surface marker expression. For example, human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin- (negative for mature lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, CD235A). In mice, bone marrow LT-HSCs are CD34-, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, CD48-, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr, CD3, CD4, CD8, B220, IL7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr, CD3, CD4, CD8, B220, IL7ra). In addition, ST-HSCs are less quiescent and more proliferative than LT-HSCs under homeostatic conditions. However, LT-HSC have greater self-renewal potential (i.e., they survive throughout adulthood, and can be serially transplanted through successive recipients), whereas ST-HSCs have limited self-renewal (i.e., they survive for only a limited period of time, and do not possess serial transplantation potential). Any of these HSCs can be used in the methods described herein. ST-HSCs are particularly useful because they are highly proliferative and thus, can more quickly give rise to differentiated progeny.

[0130] As used herein, the term "hematopoietic stem cell functional potential" refers to the functional properties of hematopoietic stem cells which include 1) multi-potency (which refers to the ability to differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells), 2) self-renewal (which refers to the ability of hematopoietic stem cells to give rise to daughter cells that have equivalent potential as the mother cell, and further that this ability can repeatedly occur throughout the lifetime of an individual without exhaustion), and 3) the ability of hematopoietic stem cells or progeny thereof to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis.

[0131] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. A human antibody may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or during gene rearrangement or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. A human antibody can be produced in a human cell (for example, by recombinant expression) or by a non-human animal or a prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (such as heavy chain and/or light chain) genes. When a human antibody is a single chain antibody, it can include a linker peptide that is not found in native human antibodies. For example, an Fv can contain a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes (see, for example, PCT Publication Nos. WO 1998/24893; WO 1992/01047; WO 1996/34096; WO 1996/33735; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598).

[0132] A "humanized" antibody refers to an antibody that contains minimal sequences derived from non-human immunoglobulin. Thus, "humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. All or substantially all of the FW regions may also be those of a human immunoglobulin sequence. The humanized antibody can also contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art and have been described, for example, in Riechmann et al., Nature 332:323-7, 1988; U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,761; 5,693,762; and 6,180,370.

[0133] As used herein, patients that are "in need of" a hematopoietic stem cell transplant include patients that exhibit a defect or deficiency in one or more blood cell types, as well as patients having a stem cell disorder, autoimmune disease, cancer, or other pathology described herein. Hematopoietic stem cells generally exhibit 1) multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells), 2) self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and 3) the ability to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. Hematopoietic stem cells can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo. For example, the patient may be suffering from cancer, and the deficiency may be caused by administration of a chemotherapeutic agent or other medicament that depletes, either selectively or non-specifically, the cancerous cell population. Additionally or alternatively, the patient may be suffering from a hemoglobinopathy (e.g., a non-malignant hemoglobinopathy), such as sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome. The subject may be one that is suffering from adenosine deaminase severe combined immunodeficiency (ADA SCID), HIV/AIDS, metachromatic leukodystrophy, Diamond-Blackfan anemia, and Schwachman-Diamond syndrome. The subject may have or be affected by an inherited blood disorder (e.g., sickle cell anemia) or an autoimmune disorder. Additionally or alternatively, the subject may have or be affected by a malignancy, such as neuroblastoma or a hematologic cancer. For instance, the subject may have a leukemia, lymphoma, or myeloma. In some embodiments, the subject has acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the subject has myelodysplastic syndrome. In some embodiments, the subject has an autoimmune disease, such as scleroderma, multiple sclerosis, ulcerative colitis, Crohn's disease, Type 1 diabetes, or another autoimmune pathology described herein. In some embodiments, the subject is in need of chimeric antigen receptor T-cell (CART) therapy. In some embodiments, the subject has or is otherwise affected by a metabolic storage disorder. The subject may suffer or otherwise be affected by a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, metachromatic leukodystrophy, or any other diseases or disorders which may benefit from the treatments and therapies disclosed herein and including, without limitation, severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper immunoglobulin M (IgM) syndrome, Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis, osteogenesis imperfecta, storage diseases, thalassemia major, sickle cell disease, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoid arthritis and those diseases, or disorders described in "Bone Marrow Transplantation for Non-Malignant Disease," ASH Education Book, 1:319-338 (2000), the disclosure of which is incorporated herein by reference in its entirety as it pertains to pathologies that may be treated by administration of hematopoietic stem cell transplant therapy. Additionally or alternatively, a patient "in need of" a hematopoietic stem cell transplant may one that is or is not suffering from one of the foregoing pathologies, but nonetheless exhibits a reduced level (e.g., as compared to that of an otherwise healthy subject) of one or more endogenous cell types within the hematopoietic lineage, such as megakaryocytes, thrombocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, microglia, granulocytes, monocytes, osteoclasts, antigen-presenting cells, macrophages, dendritic cells, natural killer cells, T-lymphocytes, and B-lymphocytes. One of skill in the art can readily determine whether one's level of one or more of the foregoing cell types, or other blood cell type, is reduced with respect to an otherwise healthy subject, for instance, by way of flow cytometry and fluorescence activated cell sorting (FACS) methods, among other procedures, known in the art.

[0134] As used herein a "neutral antibody" refers to an antibody, or an antigen binding fragment thereof, that is not capable of significantly neutralizing, blocking, inhibiting, abrogating, reducing or interfering with the activities of a particular or specified target (e.g., CD117), including the binding of receptors to ligands or the interactions of enzymes with substrates. In one embodiment, a neutral anti-CD117 antibody, or fragment thereof, is an anti-CD117 antibody that does not substantially inhibit SCF-dependent cell proliferation and does not cross block SCF binding to CD117. An example of a neutral antibody is Ab67 (or an antibody having the binding regions of Ab67). In contrast, an "antagonist" anti-CD117 antibody inhibits SCF-dependent proliferation and is able to cross block SCF binding to CD117. An example of an antagonist antibody is Ab55 (or an antibody having the binding regions of Ab55).

[0135] As used herein, the term "recipient" refers to a patient that receives a transplant, such as a transplant containing a population of hematopoietic stem cells. The transplanted cells administered to a recipient may be, e.g., autologous, syngeneic, or allogeneic cells.

[0136] As used herein, the term "sample" refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells) taken from a subject.

[0137] As used herein, the term "scFv" refers to a single chain Fv antibody in which the variable domains of the heavy chain and the light chain from an antibody have been joined to form one chain. scFv fragments contain a single polypeptide chain that includes the variable region of an antibody light chain (V.sub.L) (e.g., CDR-L1, CDR-L2, and/or CDR-L3) and the variable region of an antibody heavy chain (V.sub.H) (e.g., CDR-H1, CDR-H2, and/or CDR-H3) separated by a linker. The linker that joins the V.sub.L and V.sub.H regions of a scFv fragment can be a peptide linker composed of proteinogenic amino acids. Alternative linkers can be used to so as to increase the resistance of the scFv fragment to proteolytic degradation (for example, linkers containing D-amino acids), in order to enhance the solubility of the scFv fragment (for example, hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (for example, a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to attenuate the immunogenicity of the scFv fragment (for example, linkers containing glycosylation sites). It will also be understood by one of ordinary skill in the art that the variable regions of the scFv molecules described herein can be modified such that they vary in amino acid sequence from the antibody molecule from which they were derived. For example, nucleotide or amino acid substitutions leading to conservative substitutions or changes at amino acid residues can be made (e.g., in CDR and/or framework residues) so as to preserve or enhance the ability of the scFv to bind to the antigen recognized by the corresponding antibody.

[0138] The terms "specific binding" or "specifically binding", as used herein, refers to the ability of an antibody to recognize and bind to a specific protein structure (epitope) rather than to proteins generally. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A" and the antibody, will reduce the amount of labeled A bound to the antibody. By way of example, an antibody "binds specifically" to a target if the antibody, when labeled, can be competed away from its target by the corresponding non-labeled antibody. In one embodiment, an antibody specifically binds to a target, e.g., CD117, CD45, CD2, CD5, CD137, CD134, or CD252, if the antibody has a K.sub.D for the target of at least about 10.sup.-4 M, 10.sup.-5 M, 10.sup.-6 M, 10.sup.-7 M, 10.sup.-8 M, 10.sup.-9 M, 10.sup.-10 M, 10.sup.-11 M, 10.sup.-12 M, or less (less meaning a number that is less than 10.sup.-12, e.g. 10.sup.-13). In one embodiment, the term "specific binding to CD117" or "specifically binds to CD117," as used herein, refers to an antibody or that binds to CD117 and has a dissociation constant (K.sub.D) of 1.0.times.10.sup.-7 M or less, as determined by surface plasmon resonance. In one embodiment, K.sub.D (M) is determined according to standard bio-layer interferometery (BLI). In one embodiment, K.sub.off (1/s) is determined according to standard bio-layer interferometery (BLI). It shall be understood, however, that the antibody may be capable of specifically binding to two or more antigens which are related in sequence. For example, in one embodiment, an antibody can specifically bind to both human and a non-human (e.g., mouse or non-human primate) orthologs of CD117, CD45, CD2, CD5, CD137, CD134, or CD252.

[0139] As used herein, the terms "subject" and "patient" refer to an organism, such as a human, that receives treatment for a particular disease or condition as described herein. For instance, a patient, such as a human patient, may receive treatment prior to hematopoietic stem cell transplant therapy in order to promote the engraftment of exogenous hematopoietic stem cells.

[0140] As used herein, the phrase "substantially cleared from the blood" refers to a point in time following administration of a therapeutic agent, e.g., an ADC comprising an amatoxin, to a patient when the concentration of the therapeutic agent in a blood sample isolated from the patient is such that the therapeutic agent is not detectable by conventional means (for instance, such that the therapeutic agent is not detectable above the noise threshold of the device or assay used to detect the therapeutic agent). A variety of techniques known in the art can be used to detect antibodies, or antibody fragments, such as ELISA-based detection assays known in the art or described herein. Additional assays that can be used to detect antibodies, or antibody fragments, include immunoprecipitation techniques and immunoblot assays, among others known in the art.

[0141] As used herein, the phrase "stem cell disorder" broadly refers to any disease, disorder, or condition that may be treated or cured by conditioning a subject's target tissues, and/or by ablating an endogenous stem cell population in a target tissue (e.g., ablating an endogenous hematopoietic stem or progenitor cell population from a subject's bone marrow tissue) and/or by engrafting or transplanting stem cells in a subject's target tissues. For example, Type I diabetes has been shown to be cured by hematopoietic stem cell transplant and may benefit from conditioning in accordance with the compositions and methods described herein. Additional disorders that can be treated using the compositions and methods described herein include, without limitation, sickle cell anemia, thalassemias, Fanconi anemia, aplastic anemia, Wiskott-Aldrich syndrome, ADA SCID, HIV/AIDS, metachromatic leukodystrophy, Diamond-Blackfan anemia, and Schwachman-Diamond syndrome. Additional diseases that may be treated using the patient conditioning and/or hematopoietic stem cell transplant methods described herein include inherited blood disorders (e.g., sickle cell anemia) and autoimmune disorders, such as scleroderma, multiple sclerosis, ulcerative colitis, and Crohn's disease. Additional diseases that may be treated using the conditioning and/or transplantation methods described herein include a malignancy, such as a neuroblastoma or a hematologic cancer, such as leukemia, lymphoma, and myeloma. For instance, the cancer may be acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. Additional diseases treatable using the conditioning and/or transplantation methods described herein include myelodysplastic syndrome. In some embodiments, the subject has or is otherwise affected by a metabolic storage disorder. For example, the subject may suffer or otherwise be affected by a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, metachromatic leukodystrophy, or any other diseases or disorders which may benefit from the treatments and therapies disclosed herein and including, without limitation, severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper immunoglobulin M (IgM) syndrome, Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis, osteogenesis imperfecta, storage diseases, thalassemia major, sickle cell disease, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoid arthritis and those diseases, or disorders described in "Bone Marrow Transplantation for Non-Malignant Disease," ASH Education Book, 1:319-338 (2000), the disclosure of which is incorporated herein by reference in its entirety as it pertains to pathologies that may be treated by administration of hematopoietic stem cell transplant therapy.

[0142] As used herein, the term "transfection" refers to any of a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, such as electroporation, lipofection, calcium-phosphate precipitation, DEAE-dextran transfection and the like.

[0143] As used herein, the terms "treat" or "treatment" refers to reducing the severity and/or frequency of disease symptoms, eliminating disease symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of disease symptoms and/or their underlying cause, and improving or remediating damage caused, directly or indirectly, by disease. Beneficial or desired clinical results include, but are not limited to, promoting the engraftment of exogenous hematopoietic cells in a patient following antibody conditioning therapy as described herein and subsequent hematopoietic stem cell transplant therapy. Additional beneficial results include an increase in the cell count or relative concentration of hematopoietic stem cells in a patient in need of a hematopoietic stem cell transplant following conditioning therapy and subsequent administration of an exogenous hematopoietic stem cell graft to the patient. Beneficial results of therapy described herein may also include an increase in the cell count or relative concentration of one or more cells of hematopoietic lineage, such as a megakaryocyte, thrombocyte, platelet, erythrocyte, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T-lymphocyte, or B-lymphocyte, following conditioning therapy and subsequent hematopoietic stem cell transplant therapy. Additional beneficial results may include the reduction in quantity of a disease-causing cell population, such as a population of cancer cells (e.g., CD117+ leukemic cells) or autoimmune cells (e.g., CD117+ autoimmune lymphocytes, such as a CD117+ T-cell that expresses a T-cell receptor that cross-reacts with a self-antigen). Insofar as the methods of the present invention are directed to preventing disorders, it is understood that the term "prevent" does not require that the disease state be completely thwarted. Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to disorders, such that administration of the compounds of the present invention may occur prior to onset of a disease. The term does not imply that the disease state is completely avoided.

[0144] As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.

[0145] As used herein, the term "vector" includes a nucleic acid vector, such as a plasmid, a DNA vector, a plasmid, a RNA vector, virus, or other suitable replicon. Expression vectors described herein may contain a polynucleotide sequence as well as, for example, additional sequence elements used for the expression of proteins and/or the integration of these polynucleotide sequences into the genome of a mammalian cell. Certain vectors that can be used for the expression of antibodies and antibody fragments of the invention include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of antibodies and antibody fragments contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements may include, for example, 5' and 3' untranslated regions and a polyadenylation signal site in order to direct efficient transcription of the gene carried on the expression vector. The expression vectors described herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker include genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, and nourseothricin.

Antibody-Drug Conjugates (ADCs)

[0146] Antibodies, and antigen-binding fragments thereof, as described herein can be conjugated (linked) to a cytotoxic molecule (i.e., a cytotoxin), thus forming an antibody-drug conjugate (ADC). As used herein, the terms "cytotoxin", "cytotoxic moiety", and "drug" are used interchangeably.

[0147] In particular, the ADCs as disclosed herein include an antibody (including an antigen-binding fragment thereof) conjugated to an amatoxin, e.g., amatoxin set forth in Formula (V), wherein the cytotoxic moiety, when not conjugated to an antibody, has a cytotoxic or cytostatic effect. In various embodiments, the cytotoxic moiety exhibits reduced or no cytotoxicity when bound in a conjugate, but resumes cytotoxicity after cleavage from the linker. In various embodiments, the cytotoxic moiety maintains cytotoxicity without cleavage from the linker. In some embodiments, the cytotoxic molecule is conjugated to a cell internalizing antibody, or antigen-binding fragment thereof as disclosed herein, such that following the cellular uptake of the antibody, or fragment thereof, the cytotoxin may access its intracellular target and, e.g., mediate hematopoietic cell death. ADCs of the present disclosure therefore may be of the general formula

Ab-(Z-L-Cy).sub.n,

wherein an antibody or antigen-binding fragment thereof (Ab) is conjugated (covalently linked) to linker (L), through a chemical moiety (Z), to a cytotoxic moiety (Cy).

[0148] Accordingly, the antibody or antigen-binding fragment thereof may be conjugated to a number of drug moieties as indicated by integer n, which represents the average number of cytotoxins per antibody, which may range, e.g., from about 1 to about 20. Any number of cytotoxins can be conjugated to the antibody, e.g., 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is from 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. The average number of drug moieties per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as mass spectroscopy, ELISA assay, and HPLC. The quantitative distribution of ADC in terms of n may also be determined. In some instances, separation, purification, and characterization of homogeneous ADC where n is a certain value from ADC with other drug loadings may be achieved by means such as reverse phase HPLC or electrophoresis.

[0149] For some antibody-drug conjugates, n may be limited by the number of attachment sites on the antibody. For example, where the attachment is a cysteine thiol, an antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached. Generally, antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug moiety; primarily, cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, an antibody may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups.

[0150] In certain embodiments, fewer than the theoretical maximum of drug moieties are conjugated to an antibody during a conjugation reaction. An antibody may contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below. Only the most reactive lysine groups may react with an amine-reactive linker reagent. In certain embodiments, an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine.

[0151] The loading (drug/antibody ratio) of an ADC may be controlled in different ways, e.g., by: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number and/or position of linker-drug attachments.

Cytotoxins

[0152] The cytotoxin of the antibody-drug conjugates described herein is an amatoxin or derivative thereof. Amatoxins are potent and selective inhibitors of RNA polymerase II and thereby also inhibit the transcription and protein biosynthesis of the affected cells. As used herein, the term "amatoxin" refers to a member of the amatoxin family of peptides produced by Amanita phalloides mushrooms, or a variant or derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity. Amatoxins are rigid bicyclic octapeptides having the basic sequence Ile-Trp-Gly-Ile-Gly-Cys-Asn(or Asp)-Pro, crosslinked by an attachment between the Cys sulfur and position 2 of the Trp indole ring, forming a tryptathionine. Depending on the particular amatoxin, certain amino acid substituents are varied by post-translational modification (i.e. Pro to Hyp; Ile to DHIle; and Trp to 5-OH Trp).

[0153] Amatoxins may be isolated from a variety of mushroom species (e.g., Amanita phalloides, Galerina marginata, Lepiota brunneo-incarnata) or may be prepared semi-synthetically or synthetically. Different mushroom species contain varying amounts of different amatoxin family members. A member of this family, .alpha.-amanitin, is known to be an extremely potent inhibitor of eukaryotic RNA polymerase II and to a lesser degree, RNA polymerase Ill, thereby inhibiting transcription and protein biosynthesis. Wieland, Int. J. Pept. Protein Res. 1983, 22(3):257-276.

[0154] Structures of the various naturally occurring amatoxins are represented by formula (III) and accompanying Table 1, and are disclosed in, e.g., Zanotti et al., Int. J. Peptide Protein Res. 30, 1987, 450-459, which is incorporated by reference herein in its entirety.

##STR00012##

TABLE-US-00001 TABLE 1 Amatoxin structures Name R.sub.1 R.sub.2 R.sub.3, R.sub.4 R.sub.5 R.sub.6, R.sub.7 R.sub.8 R.sub.9 .alpha.-amanitin OH OH H OH H NH.sub.2 OH .beta.-amanitin OH OH H OH H OH OH .gamma.-amanitin OH H H OH H NH.sub.2 OH .epsilon.-amanitin OH H H OH H OH OH Amanin OH OH H H H OH OH Amaninamide OH OH H H H NH.sub.2 OH Amanullin H H H OH H NH.sub.2 OH Amanullinic acid H H H OH H OH OH Proamanullin H H H OH H NH.sub.2 H

[0155] Antibodies, or antigen-binding fragments thereof, that recognize and bind to an antigen expressed on the cell surface of a human stem cell or a T cell can be conjugated to an amatoxin, such as an .alpha.-amanitin or a derivative thereof, as described in, for example, U.S. Pat. Nos. 9,233,173 and 9,399,681 and US Patent Application Publication Nos. 2016/0089450, 2016/0002298, 2015/0218220, 2014/0294865, the disclosure of each of which is incorporated herein by reference as it pertains, for example, to amatoxins, such as .alpha.-amanitin, as well as covalent linkers that can be used for covalent conjugation. Exemplary methods of amatoxin conjugation and linkers useful for such processes are described herein. Exemplary linker-containing amatoxins useful for conjugation to an antibody, or antigen-binding fragment, in accordance with the compositions and methods are also described herein.

[0156] As used herein, the term "amatoxin derivative" or "amanitin derivative" refers to an amatoxin that has been chemically modified at one or more positions relative to a naturally occurring amatoxin, such as .alpha.-amanitin, .beta.-amanitin, .gamma.-amanitin, .epsilon.-amanitin, amanin, amaninamide, amanullin, amanullinic acid, or proamanullin. In each instance, the derivative may be obtained by chemical modification of a naturally occurring compound ("semi-synthetic"), or may be obtained from an entirely synthetic source. Synthetic routes to various amatoxin derivatives are disclosed in, for example, U.S. Pat. No. 9,676,702 and in Perrin et al., J. Am. Chem. Soc. 2018, 140, p. 6513-6517, each of which is incorporated by reference herein in their entirety with respect to synthetic methods for preparing and derivatizing amatoxins.

[0157] In some embodiments, the amatoxin or derivative thereof is represented by formula (V):

##STR00013##

or an enantiomer or diastereomer thereof.

[0158] In some embodiments, Q is S.

[0159] In one embodiment, the amatoxin or derivative thereof is represented by formula (Va):

##STR00014##

[0160] In some embodiments, Q is S.

[0161] In this particular embodiment, the amatoxin or derivative thereof is represented by formula (Vb):

##STR00015##

[0162] In some embodiments, Q is S.

[0163] Additional amatoxins that may be used for conjugation to an antibody, or antigen-binding fragment thereof, in accordance with the compositions and methods described herein are described, for example, in WO 2016/142049; WO 2016/071856; WO 2017/149077; WO 2018/115466; and WO 2017/046658, the disclosures of which are incorporated herein by reference in their entirety.

Linkers

[0164] The term "Linker" as used herein means a divalent chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody or fragment thereof (Ab) to an amatoxin as described herein, e.g., an amatoxin of formulae (IV), (IVa), (IVb), (V), (Va), or (Vb), to form an antibody-drug conjugate (ADC).

[0165] Covalent attachment of the antibody and the amatoxin requires the linker to have two reactive functional groups, i.e. bivalency in a reactive sense. Bivalent linker reagents which are useful to attach two or more functional or biologically active moieties, such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups are known, and methods have been described their resulting conjugates (Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p. 234-242).

[0166] Accordingly, present linkers have two reactive termini, one for conjugation to an antibody and the other for conjugation to an amatoxin. The antibody conjugation reactive terminus of the linker (reactive moiety, defined herein as Z') is typically a chemical moiety that is capable of conjugation to the antibody through, e.g., a cysteine thiol or lysine amine group on the antibody, and so is typically a thiol-reactive group such as a Michael acceptor (as in maleimide), a leaving group, such as a chloro, bromo, iodo, or an R-sulfanyl group, or an amine-reactive group such as a carboxyl group. Conjugation of the linker to the antibody is described more fully herein below.

[0167] The amatoxin conjugation reactive terminus of the linker is typically a chemical moiety that is capable of conjugation to the amatoxin through formation of a bond with a reactive substituent within the amatoxin molecule. Non-limiting examples include, for example, formation of an amide bond with a basic amine or carboxyl group on the amatoxin, via a carboxyl or basic amine group on the linker, respectively, or formation of an ether or the like, via alkylation of an OH group on the amatoxin via e.g., a leaving group on the linker.

[0168] When the term "linker" is used in describing the linker in conjugated form, one or both of the reactive termini will be absent (such as reactive moiety Z', having been converted to chemical moiety Z, as described herein below) or incomplete (such as being only the carbonyl of the carboxylic acid) because of the formation of the bonds between the linker and/or the amatoxin, and between the linker and/or the antibody or antigen-binding fragment thereof. Such conjugation reactions are described further herein below.

[0169] A variety of linkers can be used to conjugate the antibodies, antigen-binding fragments, and ligands described to a cytotoxic molecule. Generally, linkers suitable for the present disclosure may be substantially stable in circulation, but allow for release of the amatoxin within or in close proximity to the target cells. In some embodiments, certain linkers suitable for the present disclosure may be categorized as "cleavable" or "non-cleavable". Generally, cleavable linkers contain one or more functional groups that is cleaved in response to a physiological environment. For example, a cleavable linker may contain an enzymatic substrate (e.g., valine-alanine) that degrades in the presence of an intracellular enzyme (e.g., cathepsin B), an acid-cleavable group (e.g., a hydrozone) that degrades in the acidic environment of a cellular compartment, or a reducible group (e.g., a disulfide) that degrades in an intracellular reducing environment. By contrast, generally, non-cleavable linkers are released from the ADC during degradation (e.g., lysosomal degradation) of the antibody moiety of the ADC inside the target cell.

Non-Cleavable Linkers

[0170] Non-cleavable linkers suitable for use herein further may include one or more groups selected from a bond, --(C.dbd.O)--, C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, and combinations thereof, each of which may be optionally substituted, and/or may include one or more heteroatoms (e.g., S, N, or O) in place of one or more carbon atoms. Non-limiting examples of such groups include (CH.sub.2).sub.p, (C.dbd.O)(CH.sub.2).sub.p, and polyethyleneglycol (PEG; (CH.sub.2CH.sub.2O).sub.p), units, wherein p is an integer from 1-6, independently selected for each occasion.

[0171] In some embodiments, the linker L comprises one or more of a bond, --(C.dbd.O)--, a --C(O)NH-- group, an --OC(O)NH-- group, C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group;

[0172] wherein each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro;

[0173] In some embodiments, each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0174] In some embodiments, each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N and may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro.

[0175] In some embodiments, the linker L comprises a solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--N(R.sup.1)--, wherein:

[0176] a is 0 or 1;

[0177] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl. Such solubility enhancing groups are described in, for example, U.S. Pat. No. 9,636,421 and U.S. Patent Application Publication No. 2017/0298145, the disclosures of each of which are incorporated herein by reference in their entirety.

[0178] In some embodiments, the solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--N(R')-- further comprises a C.sub.1-C.sub.6 alkylene or a --(CH.sub.2CH.sub.2O).sub.p-- group, where p is an integer from 1-6. Non-limiting examples of such solubility enhancing groups include those depicted in Table 2, above.

TABLE-US-00002 TABLE 2 Exemplary solubility enhancing groups ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## m = 1-6 ##STR00021## ##STR00022##

[0179] In some embodiments, the non-cleavable linker comprises a --(CH.sub.2).sub.n-- unit, where n is an integer from, 2-12, e.g., 2-6. In some embodiments, the non-cleavable linker comprises a --(CH.sub.2).sub.n-- where n is 1, 2, 3, 4, 5, or 6. In some embodiments, the non-cleavable linker is --(CH.sub.2).sub.n-- where n is 6, represented by the formula:

##STR00023##

Cleavable Linkers

[0180] In some embodiments, the linker conjugating the antibody or antigen binding fragment thereof and the amatoxin is cleavable under intracellular conditions, such that cleavage of the linker releases the drug unit from the antibody in the intracellular environment. Cleavable linkers are designed to exploit the differences in local environments, e.g., extracellular and intracellular environments, including, for example, pH, reduction potential or enzyme concentration, to trigger the release of the amatoxin in the target cell. Generally, cleavable linkers are relatively stable in circulation, but are particularly susceptible to cleavage in the intracellular environment through one or more mechanisms (e.g., including, but not limited to, activity of proteases, peptidases, and glucuronidases). Cleavable linkers used herein are substantially stable in circulating plasma and/or outside the target cell and may be cleaved at some efficacious rate inside the target cell or in close proximity to the target cell.

[0181] Suitable cleavable linkers include those that may be cleaved, for instance, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012, the disclosure of which is incorporated herein by reference as it pertains to linkers suitable for covalent conjugation). Suitable cleavable linkers may include, for example, chemical moieties such as a hydrazine, a disulfide, a thioether or a dipeptide.

[0182] Linkers hydrolyzable under acidic conditions include, for example, hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, or the like. (See, e.g., U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome.

[0183] Linkers cleavable under reducing conditions include, for example, a disulfide. A variety of disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene)- , SPDB and SMPT (See, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel ed., Oxford U. Press, 1987. See also U.S. Pat. No. 4,880,935, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation.

[0184] Linkers susceptible to enzymatic hydrolysis can be, e.g., a peptide-containing linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. One advantage of using intracellular proteolytic release of the therapeutic agent is that the agent is typically attenuated when conjugated and the serum stabilities of the conjugates are typically high. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Exemplary amino acid linkers include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. Examples of suitable peptides include those containing amino acids such as Valine, Alanine, Citrulline (Cit), Phenylalanine, Lysine, Leucine, and Glycine. Amino acid residues which comprise an amino acid linker component include those occurring naturally, as well as minor amino acids and non-naturally occurring amino acid analogs, such as citrulline. Exemplary dipeptides include valine-citrulline (vc or val-cit) and alanine-phenylalanine (af or ala-phe). Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). In some embodiments, the linker includes a dipeptide such as Val-Cit, Ala-Val, or Phe-Lys, Val-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit. Linkers containing dipeptides such as Val-Cit or Phe-Lys are disclosed in, for example, U.S. Pat. No. 6,214,345, the disclosure of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. In some embodiments, the linker comprises a dipeptide selected from Val-Ala and Val-Cit.

[0185] Linkers suitable for conjugating the antibodies, antigen-binding fragments, described herein to a cytotoxic molecule include those capable of releasing an amatoxin by a 1,6-elimination process. Chemical moieties capable of this elimination process include the p-aminobenzyl (PAB) group, 6-maleimidohexanoic acid, pH-sensitive carbonates, and other reagents as described in Jain et al., Pharm. Res. 32:3526-3540, 2015, the disclosure of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation.

[0186] In some embodiments, the linker includes a "self-immolative" group such as the afore-mentioned PAB or PABC (para-aminobenzyloxycarbonyl), which are disclosed in, for example, Carl et al., J. Med. Chem. (1981) 24:479-480; Chakravarty et al (1983) J. Med. Chem. 26:638-644; U.S. Pat. No. 6,214,345; US20030130189; US20030096743; U.S. Pat. No. 6,759,509; US20040052793; U.S. Pat. Nos. 6,218,519; 6,835,807; 6,268,488; US20040018194; WO98/13059; US20040052793; U.S. Pat. Nos. 6,677,435; 5,621,002; US20040121940; WO2004/032828). Other such chemical moieties capable of this process ("self-immolative linkers") include methylene carbamates and heteroaryl groups such as aminothiazoles, aminoimidazoles, aminopyrimidines, and the like. Linkers containing such heterocyclic self-immolative groups are disclosed in, for example, U.S. Patent Publication Nos. 20160303254 and 20150079114, and U.S. Pat. No. 7,754,681; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237; US 2005/0256030; de Groot et al (2001) J. Org. Chem. 66:8815-8830; and U.S. Pat. No. 7,223,837. In some embodiments, a dipeptide is used in combination with a self-immolative linker.

[0187] In some embodiments, the linker L comprises one or more of a hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-immolative group, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a --(C.dbd.O)-- group, a --C(O)NH-- group, an --OC(O)NH-- group, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group;

[0188] wherein each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro.

[0189] In some embodiments, each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0190] In some embodiments, each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N and may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro.

[0191] One of skill in the art will recognize that one or more of the groups listed may be present in the form of a bivalent (diradical) species, e.g., C.sub.1-C.sub.6 alkylene and the like.

[0192] In some embodiments, the linker L comprises a solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--N(R.sup.1)--, wherein:

[0193] a is 0 or 1;

[0194] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl. Such solubility enhancing groups are described in, for example, U.S. Pat. No. 9,636,421 and U.S. Patent Application Publication No. 2017/0298145, the disclosures of each of which are incorporated herein by reference in their entirety.

[0195] In some embodiments, the solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--N(R.sup.1)-- further comprises a C.sub.1-C.sub.6 alkylene or a --(CH.sub.2CH.sub.2O).sub.p-- group, where p is an integer from 1-6. Non-limiting examples of such solubility enhancing groups include those depicted in Table 2, above.

[0196] In some embodiments, the linker includes a p-aminobenzyl group (PAB). In one embodiment, the p-aminobenzyl group is disposed between the cytotoxic drug and a protease cleavage site in the linker. In one embodiment, the p-aminobenzyl group is part of a p-aminobenzyloxycarbonyl unit. In one embodiment, the p-aminobenzyl group is part of a p-aminobenzylamido unit.

[0197] In some embodiments, the linker comprises a dipeptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg. In some embodiments, the linker comprises one or more of PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB.

[0198] In some embodiments, the linker comprises a combination of one or more of a peptide, oligosaccharide, --(CH.sub.2).sub.p--, --(CH.sub.2CH.sub.2O).sub.p--, PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB.

[0199] In some embodiments, the linker comprises a --(C.dbd.O)(CH.sub.2).sub.p-- unit, wherein p is an integer from 1-6.

[0200] In some embodiments, the linker comprises PAB-Ala-Val-propionyl, represented by the formula:

##STR00024##

[0201] In some embodiments, the linker comprises PAB-Cit-Val-propionyl, represented by the formula:

##STR00025##

[0202] Such PAB-dipeptide-propionyl linkers are disclosed in, e.g., International Patent Application Publication No. WO2017/149077, which is incorporated by reference herein in its entirety. Further, the cytotoxins disclosed in WO2017/149077 are incorporated by reference herein.

[0203] It will be recognized by one of skill in the art that any one or more of the chemical groups, moieties and features disclosed herein may be combined in multiple ways to form linkers useful for conjugation of the antibodies and amatoxins as disclosed herein. Further linkers useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No. 2015/0218220, the disclosure of which is incorporated herein by reference in its entirety.

Linker-Amatoxin and Linker-Antibody Conjugation

[0204] In certain embodiments, the linker is reacted with an amatoxin or derivative thereof according to any of formulae (V), (Va), or (Vb) under appropriate conditions to form a linker-amatoxin conjugate. In certain embodiments, reactive groups are used on the amatoxin or linker to form a covalent attachment.

[0205] The amatoxin-linker conjugate is subsequently reacted with the antibody, derivatized antibody, or antigen-binding fragment thereof, under appropriate conditions to form the ADC. Alternatively, the linker may first be reacted with the antibody, derivatized antibody or antigen-binding fragment thereof, to form a linker-antibody conjugate, and then reacted with the amatoxin to form the ADC. Such conjugation reactions will now be described more fully.

[0206] A number of different reactions are available for covalent attachment of linkers or amatoxin-linker conjugates to the antibody or antigen-binding fragment thereof. Suitable attachment points on the antibody molecule include, but are not limited to, the amine groups of lysine, the free carboxylic acid groups of glutamic acid and aspartic acid, the sulfhydryl groups of cysteine, and the various moieties of aromatic amino acids. For instance, non-specific covalent attachment may be undertaken using a carbodiimide reaction to link a carboxy (or amino) group on a linker to an amino (or carboxy) group on an antibody moiety. Additionally, bifunctional agents such as dialdehydes or imidoesters may also be used to link the amino group on a linker to an amino group on an antibody moiety. Also available for attachment of amatoxins to antibody moieties is the Schiff base reaction. This method involves the periodate oxidation of a glycol or hydroxy group on either the antibody or linker, thus forming an aldehyde which is then reacted with the linker or antibody, respectively. Covalent bond formation occurs via formation of a Schiff base between the aldehyde and an amino group. Isothiocyanates may also be used as coupling agents for covalently attaching amatoxins or antibody moieties to linkers. Other techniques are known to the skilled artisan and within the scope of the present disclosure.

[0207] Linkers useful in for conjugation to the antibodies or antigen-binding fragments as described herein include, without limitation, linkers containing a chemical moiety Z, formed by a coupling reaction between the antibody and a reactive chemical moiety (referred to herein as a reactive substituent, Z') on the linker as depicted in Table 3, below. Wavy lines designate points of attachment to the antibody or antigen-binding fragment, and the cytotoxic molecule, respectively.

TABLE-US-00003 TABLE 3 Exemplary chemical moieties Z formed by coupling reactions in the formation of antibody-drug conjugates. Exemplary Coupling Reactions Chemical Moiety Z Formed by Coupling Reactions [3 + 2] Cycloaddition ##STR00026## [3 + 2] Cycloaddition ##STR00027## [3 + 2] Cycloaddition, Esterification ##STR00028## [3 + 2] Cycloaddition, Esterification ##STR00029## [3 + 2] Cycloaddition, Esterification ##STR00030## [3 + 2] Cycloaddition, Esterification ##STR00031## [3 + 2] Cycloaddition, Esterification ##STR00032## [3 + 2] Cycloaddition, Esterification ##STR00033## [3 + 2] Cycloaddition, Esterification ##STR00034## [3 + 2] Cycloaddition, Esterification ##STR00035## [3 + 2] Cycloaddition, Esterification ##STR00036## [3 + 2] Cycloaddition, Esterification ##STR00037## [3 + 2] Cycloaddition, Esterification ##STR00038## [3 + 2] Cycloaddition, Etherification ##STR00039## [3 + 2] Cycloaddition ##STR00040## Michael addition ##STR00041## Michael addition ##STR00042## Imine condensation, Amidation ##STR00043## Imine condensation ##STR00044## Disulfide formation ##STR00045## Thiol alkylation ##STR00046## Condensation, Michael addition ##STR00047##

[0208] One of skill in the art will recognize that a reactive substituent Z' attached to the linker and a reactive substituent on the antibody or antigen-binding fragment thereof, are engaged in the covalent coupling reaction to produce the chemical moiety Z, and will recognize the reactive substituent Z'. Therefore, antibody-drug conjugates useful in conjunction with the methods described herein may be formed by the reaction of an antibody, or antigen-binding fragment thereof, with a linker or amatoxin-linker conjugate, as described herein, the linker or amatoxin-linker conjugate including a reactive substituent Z', suitable for reaction with a reactive substituent on the antibody, or antigen-binding fragment thereof, to form the chemical moiety Z.

[0209] As depicted in Table 3, examples of suitably reactive substituents Z' on the linker and reactive substituents on the antibody or antigen-binding fragment thereof include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/.alpha.,.beta.-unsaturated carbonyl pair, and the like), a diene/dienophile pair (e.g., an azide/alkyne pair, or a diene/.alpha.,.beta.-unsaturated carbonyl pair, among others), and the like. Coupling reactions between the reactive substitutents to form the chemical moiety Z include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine or hydroxylamine condensation, hydrazine formation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein. In some embodiments, the reactive substituent Z' is an electrophilic functional group suitable for reaction with a nucleophilic functional group on the antibody, or antigen-binding fragment thereof.

[0210] Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, nucleophilic groups such as (i)N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of non-naturally occurring amino acids. In some embodiments, the reactive substituents present within an antibody, or antigen-binding fragment thereof as disclosed herein include, are amine or thiol moieties. Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges. Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol). Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol. Reactive thiol groups may be introduced into the antibody (or fragment thereof) by introducing one, two, three, four, or more cysteine residues (e.g., preparing mutant antibodies comprising one or more non-native cysteine amino acid residues). U.S. Pat. No. 7,521,541 teaches engineering antibodies by introduction of reactive cysteine amino acids.

[0211] In some embodiments, the reactive substituent Z' attached to the linker is a nucleophilic group which is reactive with an electrophilic group present on an antibody. Useful electrophilic groups on an antibody include, but are not limited to, aldehyde and ketone carbonyl groups. A nucleophilic group (e.g., a) heteroatom of can react with an electrophilic group on an antibody and form a covalent bond to the antibody. Useful nucleophilic groups include, but are not limited to, hydrazide, oxime, amino, hydroxyl, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.

[0212] In some embodiments, chemical moiety Z is the product of a reaction between reactive nucleophilic substituents present within the antibodies, or antigen-binding fragments thereof, such as amine and thiol moieties, and a reactive electrophilic substituent Z' attached to the linker. For instance, Z' may be a Michael acceptor (e.g., maleimide), activated ester, electron-deficient carbonyl compound, or an aldehyde, among others.

[0213] Several representative and non-limiting examples of reactive substituents Z' and the resulting chemical moieties Z are provided in Table 4.

TABLE-US-00004 TABLE 4 Complementary reactive substituents and chemical moieties Functional Group on Antibody Z' group Z group Naturally Occurring ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## Synthetically Introduced ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## R = H or alkyl (Y = O or NH)

[0214] For instance, linkers suitable for the synthesis of linker-antibody conjugates and ADCs include, without limitation, reactive substituents Z' attached to the linker, such as a maleimide or haloalkyl group. These may be attached to the linker by, for example, reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-L-carboxylate (SMCC), N-succinimidyl iodoacetate (SIA), sulfo-SMCC, m-maleimidobenzoyl-N-hydroxysuccinimidyl ester (MBS), sulfo-MBS, and succinimidyl iodoacetate, among others described, in for instance, Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation.

[0215] In some embodiments, the reactive substituent Z' attached to linker L is a maleimide, azide, or alkyne. An example of a maleimide-containing linker is the non-cleavable maleimidocaproyl-based linker, which is particularly useful for the conjugation of microtubule-disrupting agents such as auristatins. Such linkers are described by Doronina et al., Bioconjugate Chem. 17:14-24, 2006, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation.

[0216] In some embodiments, the reactive substituent Z' is --(C.dbd.O)-- or --NH(C.dbd.O)--, such that the linker may be joined to the antibody, or antigen-binding fragment thereof, by an amide or urea moiety, respectively, resulting from reaction of the --(C.dbd.O)-- or --NH(C.dbd.O)-- group with an amino group of the antibody or antigen-binding fragment thereof.

[0217] In some embodiments, the reactive substituent Z' is an N-maleimidyl group, halogenated N-alkylamido group, sulfonyloxy N-alkylamido group, carbonate group, sulfonyl halide group, thiol group or derivative thereof, alkynyl group comprising an internal carbon-carbon triple bond, (hetero)cycloalkynyl group, bicyclo[6.1.0]non-4-yn-9-yl group, alkenyl group comprising an internal carbon-carbon double bond, cycloalkenyl group, tetrazinyl group, azido group, phosphine group, nitrile oxide group, nitrone group, nitrile imine group, diazo group, ketone group, (O-alkyl)hydroxylamino group, hydrazine group, halogenated N-maleimidyl group, 1,1-bis (sulfonylmethyl)methylcarbonyl group or elimination derivatives thereof, carbonyl halide group, or an allenamide group, each of which may be optionally substituted. In some embodiments, the reactive substituent comprises a cycloalkene group, a cycloalkyne group, or an optionally substituted (hetero)cycloalkynyl group.

[0218] In some embodiments, the chemical moiety Z is selected from Table 3 or Table 4. In some embodiments, the chemical moiety Z is:

##STR00063##

where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, that specifically binds to an antigen expressed on the cell surface of a human stem cell or a T cell (e.g., from the --SH group of a cysteine residue).

[0219] In some embodiments, the linker-reactive substituent group, taken together as L-Z', prior to conjugation with the antibody or antigen binding fragment thereof, has the structure:

##STR00064##

where the wavy line indicates the point of attachment to a substituent on the amatoxin. This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta-maleimidopropyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB). The wavy line at the linker terminus indicates the point of attachment to the amatoxin. In some embodiments, the linker L and the chemical moiety Z, after conjugation to the antibody, taken together as L-Z-Ab, has the structure:

##STR00065##

where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, that specifically binds to an antigen expressed on the cell surface of a human stem cell or a T cell (e.g., from the --SH group of a cysteine residue. The wavy line at the linker terminus indicates the point of attachment to the amatoxin.

[0220] In some embodiments, the linker-reactive substituent group, taken together as L-Z', prior to conjugation with the antibody or antigen binding fragment thereof, has the structure:

##STR00066##

This linker-reactive substituent group may alternatively be referred to as 1-n-hexyl-maleimide, which is a non-cleavable linker. The wavy line at the linker terminus indicates the point of attachment to the amatoxin. In some embodiments, the linker L and the chemical moiety Z, after conjugation to the antibody, taken together as L-Z-Ab, has the structure:

##STR00067##

where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, that specifically binds to an antigen expressed on the cell surface of a human stem cell or a T cell (e.g., from the --SH group of a cysteine residue). The wavy line at the linker terminus indicates the point of attachment to the amatoxin. One of skill in the art will recognize that in this embodiment, the linker-reactive substituent group structure L-Z', prior to conjugation with the antibody or antigen binding fragment thereof, includes a maleimide as the group Z'. The foregoing linker moieties and amatoxin-linker conjugates, among others useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No. 2015/0218220 and Patent Application Publication No. WO2017/149077, the disclosure of each of which is incorporated herein by reference in its entirety.

[0221] In one aspect, the cytotoxin of the ADC as disclosed herein is an amatoxin or derivative thereof as represented by any of formulae (V), (Va), or (Vb). One of skill in the art will recognize that such amatoxins present multiple possibilities for attachment points to the linker.

[0222] In some embodiments, the amatoxin has the structure of formula (V), and the linker is attached by an ether bond to the OH group of the hydroxyl tryptophan residue. In such embodiments, the ADC may be represented by formula (I):

##STR00068##

or a stereoisomer thereof; wherein:

[0223] Q is S;

[0224] L is a linker;

[0225] Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within an antibody, or antigen-binding fragment thereof; and

[0226] Ab is an antibody,

[0227] each as disclosed herein.

[0228] In some embodiments, the amatoxin has the structure of formula (Va), and the linker is attached by an ether bond to the OH group of the hydroxyl tryptophan residue. In such embodiments, the ADC may be represented by formula (Ia):

##STR00069##

[0229] In some embodiments, the amatoxin has the structure of formula (Vb), and the linker is attached by an ether bond to the OH group of the hydroxyl tryptophan residue. In such embodiments, the ADC may be represented by formula (Ib):

##STR00070##

[0230] In some embodiments, the linker L of the ADC of formula (I), (Ia), or (Ib) is a non-cleavable linker. In some embodiments, the non-cleavable linker L comprises one or more of a bond, --(C.dbd.O)--, a --C(O)NH-- group, an --OC(O)NH-- group, C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group;

[0231] wherein each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro; or

[0232] each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0233] In some embodiments, the non-cleavable linker L comprises a solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein:

[0234] a is 0 or 1; and

[0235] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted, optionally interrupted, or both, by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

[0236] In some embodiments, the non-cleavable linker L comprises a --(CH.sub.2).sub.n-- unit, where n is an integer from 2-6. In some embodiments, the non-cleavable linker L is --(CH.sub.2).sub.n--, where n is 6.

[0237] In some embodiments, Ab, Z, and the non-cleavable linker L, taken together as Ab-Z-L, is represented by the formula:

##STR00071##

where S is a sulfur atom which represents the reactive substituent present within the antibody, or antigen-binding fragment thereof, that specifically binds to an antigen expressed on a cell, e.g., surface of a human stem cell or a T cell (e.g., from the --SH group of a cysteine residue). The wavy line at the linker terminus indicates the point of attachment to the amatoxin.

[0238] In some embodiments, the ADC according to formula (I) is represented by formula (II):

##STR00072##

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the ADC according to formula (II) is represented by formula (IIa):

##STR00073##

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the ADC according to formula (II) is represented by formula (Ib):

##STR00074##

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0241] Surprisingly, according to the present disclosure, it has been found that ADCs comprising an amatoxin and a non-cleavable linker conjugating the amatoxin to the antibody moiety of the ADC have improved tolerability as compared to an ADC comprising an amatoxin and a cleavable linker. For example, in some embodiments, the improved tolerability may be increased therapeutic index. In some embodiments, the improved tolerability may be a smaller elevation, or absence of elevation, of one or more blood liver enzyme levels (e.g., AST, ALT, ADH, or total bilirubin) at a particular dose of the ADC comprising a non-cleavable linker as compared to an ADC comprising a cleavable linker.

[0242] In some embodiments, the linker L of the ADC of formula (I), (Ia), or (Ib) is a cleavable linker. In some embodiments, the cleavable linker L comprises one or more of a hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-immolative group, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a --(C.dbd.O)-- group, a --C(O)NH-- group, an --OC(O)NH-- group, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group;

[0243] wherein each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro;

[0244] or each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

[0245] In some embodiments, the cleavable linker L comprises a solubility enhancing group of the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein:

[0246] a is 0 or 1; and

[0247] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

[0248] In some embodiments, the cleavable linker L comprises a peptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg.

[0249] In some embodiments, the cleavable linker L further comprises a PAB group.

[0250] In some embodiments, the cleavable linker L is represented by the formula:

##STR00075##

Preparation of Antibody-Drug Conjugates

[0251] In the ADCs of formula Ab-(Z-L-Cy), as disclosed herein, such as an ADC of any of formulae (I), (Ia), or (Ib), (II), (IIa), or (IIb), an antibody or antigen binding fragment thereof (Ab) is conjugated to one or more cytotoxic drug moieties (Cy; e.g., an amatoxin), for example, from about 1 to about 20 cytotoxic moieties per antibody, through a linker L and a chemical moiety Z, each as disclosed herein. In some embodiments, n is 1. In some embodiments, n is about 1 to about 5, about 1 to about 4, about 1 to about 3, or about 3 to about 5. In some embodiments, n is about 1, about 2, about 3, or about 4.

[0252] The ADCs of the present disclosure may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a reactive substituent of an antibody or antigen binding fragment thereof with a bivalent linker reagent to form Ab-Z-L as described herein above, followed by reaction with a cytotoxic moiety Cy; or (2) reaction of a reactive substituent of a cytotoxic moiety with a bivalent linker reagent to form Cy-L-Z', followed by reaction with a reactive substituent of an antibody or antigen binding fragment thereof as described herein above, to form an ADC of formula Ab-(Z-L-Cy).sub.n. Additional methods for preparing ADC are described herein.

[0253] In one embodiment, the antibody or antigen binding fragment thereof can have one or more carbohydrate groups that can be chemically modified to have one or more sulfhydryl groups. The ADC is then formed by conjugation through the sulfhydryl group's sulfur atom as described herein above.

[0254] In another embodiment, the antibody can have one or more carbohydrate groups that can be oxidized to provide an aldehyde (--CHO) group (see, for e.g., Laguzza, et al., J. Med. Chem. 1989, 32(3), 548-55). The ADC is then formed by conjugation through the corresponding aldehyde as described herein above. Other protocols for the modification of proteins for the attachment or association of cytotoxins are described in Coligan et al., Current Protocols in Protein Science, vol. 2, John Wiley & Sons (2002), incorporated herein by reference.

[0255] Methods for the conjugation of linker-drug moieties to cell-targeted proteins such as antibodies, immunoglobulins or fragments thereof are found, for example, in U.S. Pat. Nos. 5,208,020; 6,441,163; WO2005037992; WO2005081711; and WO2006/034488, all of which are hereby expressly incorporated by reference in their entirety.

[0256] Alternatively, a fusion protein comprising the antibody and cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.

[0257] In some embodiments, the ADC of formula (IIa) may be prepared by conjugation of a thiol group on the antibody to the amatoxin-linker conjugate Cy-L-Z', represented by the structure:

##STR00076##

This amatoxin-linker conjugate may be prepared according to Schemes 1 to 3, starting from commercially available 6-hydroxytryptophan (1). Compound 1 may be protected with tert-butyloxycarbonyl anhydride ((BOC).sub.2O). Hexahydropyrroloindole 3 may be produced as a mixture of cis and trans isomers upon irradiation of protected hydroxytryptophan 2 in the presence of oxygen and a sensitizer (Rose Bengal). Preparation of compound 3 (as well as procedure for preparation of compounds 2 to Va) are provided in International Patent Application Publication No. WO2019/030173, the disclosure of which is incorporated by reference herein in its entirety. Commercial 9-fluorenylmethoxycarbonyl (FMOC) protected 4-hydroxyproline (4) may be alkylated with allyl bromide and subsequently attached to tetrahydropyranyl (THP) polystyrene resin under mild acidic conditions (pyridinium para-toluenesulfonate; PPTS) to give the resin bound allyl ester 5, which may be deprotected with palladium tetrakistriphenylphosphine palladium and dimethyl barbituric acid to give intermediate 6. Protected amino acid 7 may be prepared according to the method reported in International Patent Application Publication No. WO2014/009025, the disclosure of which is incorporated herein in its entirety. Protected amine 7 may then be coupled to resin bound hydroxyproline 6 to afford peptide 8.

##STR00077## ##STR00078##

[0258] Peptide 8 may then be subjected to multiple coupling and deprotection reactions to provide monocyclic intermediate 9 (Scheme 2). Amino acids FmocAsn(Trt)OH, FmocCys(OTrt)OH, FmocGlyOH, FmocIleOH, FmocGlyOH, and hexahydropyrroloindole 3 may be utilized in sequential solid phase coupling reactions to yield intermediate 9. Each amino acid may be coupled using PyBOP/HOBT in dichloromethane and dimethylformamide (DMF) in the presence of diisopropylethylamine (DIEA). Deprotection may be performed with 20% piperidine in DMF.

##STR00079## ##STR00080##

[0259] Following the final coupling reaction, intermediate 9 may be cleaved from the solid phase support resin with trifluoroacetic acid in the presence of triisopropylsilane to give peptide 10. Treatment of 10 with diphenylphosphorylazide (DPPA) and DIEA induced macrocyclization, and deprotection with ammoniacal methanol provided the amatoxin derivative 11 (i.e., formula Va, where Q=S).

[0260] The maleimidohexyl amatoxin conjugate 14 may be prepared from compound 11 according to Scheme 3. Diels-Alder adduct 12 may be prepared from maleimide and 2,5-dimethylfuran and then alkylated with 1,6-dibromohexane to give protected linker 13. Compound 11 may be alkylated with compound 13 in dimethyl sulfoxide (DMSO) in the presence of sodium hydroxide, followed by heating to 100.degree. C. in DMSO to afford the amatoxin-linker conjugate 14. Procedures for preparing compounds 12 and 13, as well as O-alkylation of a related amatoxin (.alpha.-amanitin) have been previously reported in U.S. Patent Application Publication No. 2018/0043033, the disclosure of which is incorporated by reference herein in its entirety.

##STR00081##

Antibodies

[0261] The ADC compositions and methods disclosed herein comprise an agent to facilitate the selective delivery of such ADCs to a population of cells in the target tissues (e.g., hematopoietic stem cells of the bone marrow stem cell niche). The cell target specificity of the ADC is determined by an antigen binding protein such as an antibody, or antigen binding portion thereof.

[0262] In one embodiment, the invention includes ADCs comprising antibodies, and antigen-binding fragments thereof, that specifically bind to human CD45, CD49d (VLA-4), CD49f(VLA-6), CD51, CD84, CD90, CD117, CD133, CD134, CD184 (CXCR4), HLA-DR, CD11a, CD18, CD34, CD41/61, CD43, CD58, CD71, CD97, CD162, CD166, CD205 and CD361, CD13, CD33, CD34, CD44, CD4, CD59, CD84/CD150, CD90/Thy1, CD93, CD105/Endoglin, CD123/IL-3R, CD126/IL-6R, CD133, CD135/Flt3 receptor, CD166/ALCAM, Prominin 2, Erythropoietin R, Endothelial Cell-Selective Adhesion Molecule, CD244, Tie1, Tie2, MPL, G-CSFR, CSF3R, IL-1R, gp130, Leukemia inhibitory factor Receptor, oncostatin M receptor, Embigin and IL-18R. Other examples of antigens that can be bound by the ADCs disclosed herein include, but are not limited to, CD7, CDw12, CD13, CD15, CD19, CD21, CD22, CD29, CD30, CD33, CD34, CD36, CD38, CD40, CD41, CD42a, CD42b, CD42c, CD42d, CD43, CD45RA, CD45RB, CD45RC, CD45RO, CD48, CD49b, CD49d, CD49e, CD49f, CD50, CD53, CD55, CD64a, CD68, CD71, CD72, CD73, CD81, CD82, CD85A, CD85K, CD90, CD99, CD104, CD105, CD109, CD110, CD111, CD112, CD114, CD115, CD123, CD124, CD126, CD127, CD130, CD131, CD133, CD135, CD138, CD151, CD157, CD162, CD164, CD168, CD172a, CD173, CD174, CD175, CD175s, CD176, CD183, CD191, CD200, CD201, CD205, CD217, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD235a, CD235b, CD236, CD236R, CD238, CD240, CD242, CD243, CD277, CD292, CDw293, CD295, CD298, CD309, CD318, CD324, CD325, CD338, CD344, CD349 or CD350. Other examples of antigens that can be bound by the ADCs disclosed herein include, but are not limited to, CD11a, CD18, CD37, CD47, CD52, CD58, CD62L, CD69, CD74, CD97, CD103, CD132, CD156a, CD179a, CD79b, CD184, CD232, CD244, CD252, CD302, CD305, CD317 and CD361.

[0263] In certain embodiments, an antibody, or antigen binding fragment thereof, in an ADC described herein has a certain dissociation rate which is particularly advantageous when used as a part of a conjugate. For example, an anti-CD117 antibody has, in certain embodiments, an off rate constant (Koff) for human CD117 and/or rhesus CD117 of 1.times.10.sup.-2 to 1.times.10.sup.-3, 1.times.10.sup.-3 to 1.times.10.sup.-4, 1.times.10.sup.-5 to 1.times.10.sup.-6, 1.times.10.sup.-6 to 1.times.10.sup.-7 or 1.times.10.sup.-7 to 1.times.10.sup.-8, as measured by bio-layer interferometry (BLI). In some embodiments, the antibody or antigen-binding fragment thereof binds a cell surface antigen (e.g., human CD117 and/or rhesus CD117) with a K.sub.D of about 100 nM or less, about 90 nM or less, about 80 nM or less, about 70 nM or less, about 60 nM or less, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 8 nM or less, about 6 nM or less, about 4 nM or less, about 2 nM or less, about 1 nM or less as determined by a Bio-Layer Interferometry (BLI) assay.

Anti-CD117 Antibodies

[0264] In one embodiment, the present invention includes ADCs comprising antibodies, and antigen-binding fragments thereof, that specifically bind to CD117, such as GNNK+ CD117. Such ADCs may be used as therapeutic agents to, for example, (i) treat cancers and autoimmune diseases characterized by CD117+ cells and (ii) promote the engraftment of transplanted hematopoietic stem cells in a patient in need of transplant therapy. These therapeutic activities can be caused, for instance, by the binding of isolated anti-CD117 antibodies, antigen-binding fragments thereof, that bind to CD117 (e.g., GNNK+ CD117) expressed on the surface of a cell, such as a cancer cell, autoimmune cell, or hematopoietic stem cell and subsequently inducing cell death. The depletion of endogenous hematopoietic stem cells can provide a niche toward which transplanted hematopoietic stem cells can home, and subsequently establish productive hematopoiesis. In this way, transplanted hematopoietic stem cells may successfully engraft in a patient, such as human patient suffering from a stem cell disorder described herein.

[0265] Antibodies and antigen-binding fragments capable of binding human CD117 (also referred to as c-Kit, mRNA NCBI Reference Sequence: NM_000222.2, Protein NCBI Reference Sequence: NP_000213.1), including those capable of binding GNNK+ CD117, can be used in conjunction with the compositions and methods described herein in order to condition a patient for hematopoietic stem cell transplant therapy. Polymorphisms affecting the coding region or extracellular domain of CD117 in a significant percentage of the population are not currently well-known in non-oncology indications. There are at least four isoforms of CD117 that have been identified, with the potential of additional isoforms expressed in tumor cells. Two of the CD117 isoforms are located on the intracellular domain of the protein, and two are present in the external juxtamembrane region. The two extracellular isoforms, GNNK+ and GNNK-, differ in the presence (GNNK+) or absence (GNNK-) of a 4 amino acid sequence. These isoforms are reported to have the same affinity for the ligand (SCF), but ligand binding to the GNNK- isoform was reported to increase internalization and degradation. The GNNK+ isoform can be used as an immunogen in order to generate antibodies capable of binding CD117, as antibodies generated against this isoform will be inclusive of the GNNK+ and GNNK- proteins. The amino acid sequences of human CD117 isoforms 1 and 2 are described in SEQ ID Nos: 145 and 146, respectively. In certain embodiments, anti-human CD117 (hCD117) antibodies disclosed herein are able to bind to both isoform 1 and isoform 2 of human CD117.

[0266] As described below, a yeast library screen of human antibodies was performed to identify novel anti-CD117 antibodies, and fragments thereof, having diagnostic and therapeutic use. Antibody 54 (Ab54), Antibody 55 (Ab55), Antibody 56 (Ab56), Antibody 57 (Ab57), Antibody 58 (Ab58), Antibody 61 (Ab61), Antibody 66 (Ab66), Antibody 67 (Ab67), Antibody 68 (Ab68), and Antibody 69 (Ab69) were human antibodies that were identified in this screen. These antibodies cross react with human CD117 and rhesus CD117. Further, these antibodies disclosed herein are able to bind to both isoforms of human CD117, i.e., isoform 1 (SEQ ID NO: 145) and isoform 2 (SEQ ID NO: 146).

[0267] The amino acid sequences for the various binding regions of anti-CD117 antibodies, including Ab54, Ab55, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, and Ab69 are described in the Sequence Table below. Included in the invention are ADCs comprising human anti-CD117 antibodies comprising the CDRs as set forth in the Sequence Table below, as well as human anti-CD117 antibodies comprising the variable regions set forth in the Sequence Table below.

[0268] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 55. The heavy chain variable region (VH) amino acid sequence of Antibody 55 (i.e., Ab55) is set forth in SEQ ID NO: 19 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 55 are set forth in SEQ ID NO: 21 (VH CDR1); SEQ ID NO: 22 (VH CDR2), and SEQ ID NO: 23 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 55 is described in SEQ ID NO: 20 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 55 are set forth in SEQ ID NO: 24 (VL CDR1); SEQ ID NO: 25 (VL CDR2), and SEQ ID NO: 26 (VL CDR3). The heavy chain constant region of Antibody 55 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 55 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 21, 22, and 23, and a light chain variable region CDR set as set forth in SEQ ID Nos: 24, 25, and 26. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 20, and a heavy chain variable region as set forth in SEQ ID NO: 19.

[0269] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 54. The heavy chain variable region (VH) amino acid sequence of Antibody 54 (i.e., Ab54) is set forth in SEQ ID NO: 29 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 54 are set forth in SEQ ID NO: 31 (VH CDR1); SEQ ID NO: 32 (VH CDR2), and SEQ ID NO: 33 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 54 is described in SEQ ID NO: 30 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 54 are set forth in SEQ ID NO: 34 (VL CDR1); SEQ ID NO: 35 (VL CDR2), and SEQ ID NO: 36 (VL CDR3). The heavy chain constant region of Antibody 54 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 54 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 31, 32, and 33, and a light chain variable region CDR set as set forth in SEQ ID Nos: 34, 35, and 36. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 30, and a heavy chain variable region as set forth in SEQ ID NO: 29.

[0270] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 56. The heavy chain variable region (VH) amino acid sequence of Antibody 56 (i.e., Ab56) is set forth in SEQ ID NO: 39 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 56 are set forth in SEQ ID NO: 41 (VH CDR1); SEQ ID NO: 42 (VH CDR2), and SEQ ID NO: 43 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 56 is described in SEQ ID NO: 40 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 56 are set forth in SEQ ID NO: 44 (VL CDR1); SEQ ID NO: 45 (VL CDR2), and SEQ ID NO: 46 (VL CDR3). The heavy chain constant region of Antibody 56 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 56 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 41, 42, and 43, and a light chain variable region CDR set as set forth in SEQ ID Nos: 44, 45, and 46. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 40, and a heavy chain variable region as set forth in SEQ ID NO: 39.

[0271] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 57. The heavy chain variable region (VH) amino acid sequence of Antibody 57 (i.e., Ab57) is set forth in SEQ ID NO: 49 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 57 are set forth in SEQ ID NO: 51 (VH CDR1); SEQ ID NO: 52 (VH CDR2), and SEQ ID NO: 53 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 57 is described in SEQ ID NO: 50 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 57 are set forth in SEQ ID NO: 54 (VL CDR1); SEQ ID NO: 55 (VL CDR2), and SEQ ID NO: 56 (VL CDR3). The heavy chain constant region of Antibody 57 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 57 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 51, 52, and 53, and a light chain variable region CDR set as set forth in SEQ ID Nos: 54, 55, and 56. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 50, and a heavy chain variable region as set forth in SEQ ID NO: 49.

[0272] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 58. The heavy chain variable region (VH) amino acid sequence of Antibody 58 (i.e., Ab58) is set forth in SEQ ID NO: 59 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 58 are set forth in SEQ ID NO: 61 (VH CDR1); SEQ ID NO: 62 (VH CDR2), and SEQ ID NO: 63 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 58 is described in SEQ ID NO: 60 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 58 are set forth in SEQ ID NO: 64 (VL CDR1); SEQ ID NO: 65 (VL CDR2), and SEQ ID NO: 66 (VL CDR3). The heavy chain constant region of Antibody 58 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 58 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 61, 62, and 63, and a light chain variable region CDR set as set forth in SEQ ID Nos: 64, 65, and 66. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 60, and a heavy chain variable region as set forth in SEQ ID NO: 59.

[0273] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 61. The heavy chain variable region (VH) amino acid sequence of Antibody 61 (i.e., Ab61) is set forth in SEQ ID NO: 69 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 61 are set forth in SEQ ID NO: 71 (VH CDR1); SEQ ID NO: 72 (VH CDR2), and SEQ ID NO: 73 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 61 is described in SEQ ID NO: 70 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 61 are set forth in SEQ ID NO: 74 (VL CDR1); SEQ ID NO: 75 (VL CDR2), and SEQ ID NO: 76 (VL CDR3). The heavy chain constant region of Antibody 61 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 61 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 71, 72, and 73, and a light chain variable region CDR set as set forth in SEQ ID Nos: 74, 75, and 76. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 70, and a heavy chain variable region as set forth in SEQ ID NO: 69.

[0274] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 66. The heavy chain variable region (VH) amino acid sequence of Antibody 66 (i.e., Ab66) is set forth in SEQ ID NO: 79 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 66 are set forth in SEQ ID NO: 81 (VH CDR1); SEQ ID NO: 82 (VH CDR2), and SEQ ID NO: 83 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 66 is described in SEQ ID NO: 80 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 66 are set forth in SEQ ID NO: 84 (VL CDR1); SEQ ID NO: 85 (VL CDR2), and SEQ ID NO: 86 (VL CDR3). The heavy chain constant region of Antibody 66 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 66 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 81, 82, and 83, and a light chain variable region CDR set as set forth in SEQ ID Nos: 84, 85, and 86. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 80, and a heavy chain variable region as set forth in SEQ ID NO: 79.

[0275] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 67. The heavy chain variable region (VH) amino acid sequence of Antibody 67 is set forth in SEQ ID NO: 9 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 67 are set forth in SEQ ID NO 11 (VH CDR1); SEQ ID NO: 12 (VH CDR2), and SEQ ID NO: 13 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 67 is described in SEQ ID NO: 10 (see Table 2). The VL CDR domain amino acid sequences of Antibody 67 are set forth in SEQ ID NO 14 (VL CDR1); SEQ ID NO: 15 (VL CDR2), and SEQ ID NO: 16 (VL CDR3). The full length heavy chain (HC) of Antibody 67 is set forth in SEQ ID NO: 110, and the full length heavy chain constant region of Antibody 67 is set forth in SEQ ID NO: 122. The light chain (LC) of Antibody 67 is set forth in SEQ ID NO: 109. The light chain constant region of Antibody 67 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 11, 12, and 13, and alight chain variable region CDR set as set forth in SEQ ID Nos: 14, 15, and 16. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain comprising the amino acid residues set forth in SEQ ID NO: 9, and a heavy chain variable region as set forth in SEQ ID NO: 10. In further embodiments, an anti-CD117 antibody comprises a heavy chain comprising SEQ ID NO: 110 and a light chain comprising SEQ ID NO: 109.

[0276] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 68. The heavy chain variable region (VH) amino acid sequence of Antibody 68 (i.e., Ab68) is set forth in SEQ ID NO: 89 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 68 are set forth in SEQ ID NO: 91 (VH CDR1); SEQ ID NO: 92 (VH CDR2), and SEQ ID NO: 93 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 68 is described in SEQ ID NO: 90 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 68 are set forth in SEQ ID NO: 94 (VL CDR1); SEQ ID NO: 95 (VL CDR2), and SEQ ID NO: 96 (VL CDR3). The heavy chain constant region of Antibody 68 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 68 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 91, 92, and 93, and a light chain variable region CDR set as set forth in SEQ ID Nos: 94, 95, and 96. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 90, and a heavy chain variable region as set forth in SEQ ID NO: 89.

[0277] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 69. The heavy chain variable region (VH) amino acid sequence of Antibody 69 (i.e., Ab69) is set forth in SEQ ID NO: 99 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 69 are set forth in SEQ ID NO: 101 (VH CDR1); SEQ ID NO: 102 (VH CDR2), and SEQ ID NO: 103 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 69 is described in SEQ ID NO: 100 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 69 are set forth in SEQ ID NO: 104 (VL CDR1); SEQ ID NO: 105 (VL CDR2), and SEQ ID NO: 106 (VL CDR3). The heavy chain constant region of Antibody 69 is set forth in SEQ ID NO: 122. The light chain constant region of Antibody 69 is set forth in SEQ ID NO: 121. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 101, 102, and 103, and a light chain variable region CDR set as set forth in SEQ ID Nos: 104, 105, and 106. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 100, and a heavy chain variable region as set forth in SEQ ID NO: 99.

[0278] Further, the amino acid sequences for the various binding regions of the anti-CD117 antibodies Ab77, Ab79, Ab81, Ab85, Ab86, Ab87, Ab88, and Ab89 are described in the Sequence Table provided below. Anti-CD117 antibodies having these sequences can also be used in the ADCs described herein.

[0279] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 77. The heavy chain variable region (VH) amino acid sequence of Antibody 77 (i.e., Ab77) is set forth in SEQ ID NO: 147 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 77 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 77 is described in SEQ ID NO: 231 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 77 are set forth in SEQ ID NO: 264 (VL CDR1); SEQ ID NO: 265 (VL CDR2), and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of Antibody 77 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 77 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 263, 2, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 264, 265, and 266. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 231, and a heavy chain variable region as set forth in SEQ ID NO: 147.

[0280] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 79. The heavy chain variable region (VH) amino acid sequence of Antibody 79 (i.e., Ab79) is set forth in SEQ ID NO: 147 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 79 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 79 is described in SEQ ID NO: 233 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 79 are set forth in SEQ ID NO: 267 (VL CDR1); SEQ ID NO: 265 (VL CDR2), and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of Antibody 79 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 79 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 263, 2, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 267, 265, and 266. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 233, and a heavy chain variable region as set forth in SEQ ID NO: 147.

[0281] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 81. The heavy chain variable region (VH) amino acid sequence of Antibody 81 (i.e., Ab81) is set forth in SEQ ID NO: 147 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 81 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 81 is described in SEQ ID NO: 235 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 81 are set forth in SEQ ID NO: 264 (VL CDR1); SEQ ID NO: 268 (VL CDR2), and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of Antibody 81 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 81 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 263, 2, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 264, 268, and 266. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 235, and a heavy chain variable region as set forth in SEQ ID NO: 147.

[0282] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 85. The heavy chain variable region (VH) amino acid sequence of Antibody 85 (i.e., Ab86) is set forth in SEQ ID NO: 243 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 85 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 246 (VH CDR2), and SEQ ID NO: 247 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 85 is described in SEQ ID NO: 242 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 85 are set forth in SEQ ID NO: 248 (VL CDR1); SEQ ID NO: 249 (VL CDR2), and SEQ ID NO: 250 (VL CDR3). The heavy chain constant region of Antibody 85 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 85 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 245, 246, and 247, and a light chain variable region CDR set as set forth in SEQ ID Nos: 248, 249, and 250. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 244, and a heavy chain variable region as set forth in SEQ ID NO: 243.

[0283] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 86. The heavy chain variable region (VH) amino acid sequence of Antibody 86 (i.e., Ab86) is set forth in SEQ ID NO: 251 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 86 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 253 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 86 is described in SEQ ID NO: 252 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 86 are set forth in SEQ ID NO: 254 (VL CDR1); SEQ ID NO: 249 (VL CDR2), and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of Antibody 86 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 86 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 245, 253, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 254, 249, and 255. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 252, and a heavy chain variable region as set forth in SEQ ID NO: 251.

[0284] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 87. The heavy chain variable region (VH) amino acid sequence of Antibody 87 (i.e., Ab87) is set forth in SEQ ID NO: 243 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 87 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 246 (VH CDR2), and SEQ ID NO: 247 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 87 is described in SEQ ID NO: 256 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 87 are set forth in SEQ ID NO: 257 (VL CDR1); SEQ ID NO: 5 (VL CDR2), and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of Antibody 87 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 87 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 245, 246, and 247, and alight chain variable region CDR set as set forth in SEQ ID Nos: 257, 5, and 255. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 256, and a heavy chain variable region as set forth in SEQ ID NO: 243.

[0285] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 88. The heavy chain variable region (VH) amino acid sequence of Antibody 88 (i.e., Ab88) is set forth in SEQ ID NO: 258 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 88 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 259 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 88 is described in SEQ ID NO: 256 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 88 are set forth in SEQ ID NO: 257 (VL CDR1); SEQ ID NO: 5 (VL CDR2), and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of Antibody 88 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 88 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 245, 259, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 257, 5, and 255. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 256, and a heavy chain variable region as set forth in SEQ ID NO: 258.

[0286] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 89. The heavy chain variable region (VH) amino acid sequence of Antibody 89 (i.e., Ab89) is set forth in SEQ ID NO: 260 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 89 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 2 (VH CDR2), and SEQ ID NO: 3 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 89 is described in SEQ ID NO: 252 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 89 are set forth in SEQ ID NO: 254 (VL CDR1); SEQ ID NO: 249 (VL CDR2), and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of Antibody 89 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 89 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 245, 2, and 3, and a light chain variable region CDR set as set forth in SEQ ID Nos: 254, 249, and 255. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 252, and a heavy chain variable region as set forth in SEQ ID NO: 260.

[0287] In one embodiment, the invention provides an ADC comprising an anti-CD117 antibody, or antigen-binding fragment thereof, comprising binding regions, e.g., CDRs, variable regions, corresponding to those of Antibody 249. The heavy chain variable region (VH) amino acid sequence of Antibody 249 (i.e., Ab249) is set forth in SEQ ID NO: 238 (see Sequence Table). The VH CDR domain amino acid sequences of Antibody 249 are set forth in SEQ ID NO: 286 (VH CDR1); SEQ ID NO: 2 (VH CDR2), and SEQ ID NO: 287 (VH CDR3). The light chain variable region (VL) amino acid sequence of Antibody 249 is described in SEQ ID NO: 242 (see Sequence Table). The VL CDR domain amino acid sequences of Antibody 249 are set forth in SEQ ID NO: 288 (VL CDR1); SEQ ID NO: 249 (VL CDR2), and SEQ ID NO: 289 (VL CDR3). The heavy chain constant region of Antibody 249 is set forth in SEQ ID NO: 269. The light chain constant region of Antibody 249 is set forth in SEQ ID NO: 283. Thus, in certain embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable heavy chain CDR set (CDR1, CDR2, and CDR3) as set forth in SEQ ID Nos: 286, 2, and 287, and a light chain variable region CDR set as set forth in SEQ ID Nos: 288, 249, and 289. In other embodiments, an anti-CD117 antibody, or antigen-binding portion thereof, comprises a variable light chain comprising the amino acid residues set forth in SEQ ID NO: 242, and a heavy chain variable region as set forth in SEQ ID NO: 238.

Further, included in the disclosure is anti-CD117 antibody drug conjugates (ADCs) comprising binding regions (heavy and light chain CDRs or variable regions) as set forth in SEQ ID Nos: 147 to 168. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 148. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 149. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 150. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 151. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 152. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 153. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 154. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 155. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 156. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 157. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 158. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 159. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 160. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 161. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 162. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 163. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 164, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 165. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 166, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 167. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 168, and alight chain variable region as set forth in the amino acid sequence of SEQ ID NO: 169. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 170, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 171. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 172, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 173. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 174, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 175. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 176, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 177. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 178, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 179. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 180, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 181. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 172, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 182. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 183, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 184. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 185, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 186. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 187, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 188. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 189, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 190. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 191, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 192. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 193, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 194. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 195, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 196. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 197, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 198. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 199, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 200. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 201, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 190. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 202, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 203. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 204, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 205. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 206, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 207. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 208, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 209. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 210, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 211. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 212, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 213. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 214, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 215. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 216, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 217. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 218, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 219. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 220, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 221. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 222, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 223. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 224, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 225. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 226, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 227. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 228. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 229. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 230. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 231. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 232. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 233. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 234. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 235. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 236.

[0289] In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, of an ADC described herein comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 237. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 243, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 244. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 251, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 252. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 243, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 256. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 258, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 256. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 260, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 252. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 238, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 239. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 239. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 240. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 238, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 241. In one embodiment, the anti-CD117 antibody, or antigen binding portion thereof, comprises a heavy chain variable region as set forth in the amino acid sequence of SEQ ID NO: 238, and a light chain variable region as set forth in the amino acid sequence of SEQ ID NO: 242.

[0290] Certain of the anti-CD117 antibodies described herein are neutral antibodies, in that the antibodies do not substantially inhibit CD117 activity on a CD117 expressing cell. Neutral antibodies can be identified using, for example, an in in vitro stem cell factor (SCF)-dependent cell proliferation assay. In an SCF dependent cell proliferation assay, a neutral CD117 antibody will not kill CD34+ cells that are dependent on SCF to divide, as a neutral antibody will not block SCF from binding to CD117 such as to inhibit CD117 activity.

[0291] Neutral antibodies can be used for diagnostic purposes, given their ability to specifically bind to human CD117, but are also effective for killing CD117 expressing cells when conjugated to a cytotoxin, such as those described herein. Typically, antibodies used in conjugates have agonistic or antagonistic activity that is unique to the antibody. Described herein, however, is a unique approach to conjugates, especially in the context wherein the conjugate is being used as a conditioning agent prior to a stem cell transplantation. While antagonistic antibodies alone or in combination with a cytotoxin as a conjugate can be effective given the killing ability of the antibody alone in addition to the cytotoxin, conditioning with a conjugate comprising a neutral anti-CD117 antibody presents an alternative strategy where the activity of the antibody is secondary to the effect of the cytotoxin, but the internalizing and affinity characteristics, e.g., dissociation rate, of the antibody are important for effective delivery of the cytotoxin.

[0292] Examples of neutral anti-CD117 antibodies include Ab58, Ab61, Ab66, Ab67, Ab68, and Ab69. A comparison of the amino acid sequences of the CDRs of neutral, anti-CD117 antibody CDRs reveals consensus sequences among two groups of neutral antibodies identified. Ab58 and Ab61 share the same light chain CDRs and HC CDR3, with slight variations in the HC CDR1 and HC CDR2. Consensus sequences for the HC CDR1 and CDR2 are described in SEQ ID Nos: 133 and 134. Ab66, Ab67, Ab68, and Ab69 are also neutral antibodies. While Ab66, Ab67, Ab68, and Ab69 share the same light chain CDRs and the same HC CDR3, these antibodies have variability within their HC CDR1 and HC CDR2 regions. Consensus sequences for these antibodies in the HC CDR1 and HC CDR2 regions are provided in SEQ ID Nos: 139 and 140, respectively.

[0293] Antagonist antibodies are also provided herein, including Ab54, Ab55, Ab56, and Ab57. While Ab54, Ab55, Ab56, and Ab57 share the same light chain CDRs and the same HC CDR3, these antibodies have variability within their HC CDR1 and HC CDR2 regions. Consensus sequences for these antibodies in the HC CDR1 and HC CDR2 regions are provided in SEQ ID Nos: 127 and 128, respectively.

[0294] Anti-CD117 antibodies that may be used in the compositions and methods disclosed herein are also described in US 2019-0153114 and US 2019-0144558, the antibody sequences of which are hereby incorporated by reference.

[0295] In one embodiment, the anti-CD117 antibody, or antigen binding fragment thereof, comprises variable regions having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein. Alternatively, the anti-CD117 antibody, or antigen binding fragment thereof, comprises CDRs comprising the SEQ ID Nos disclosed herein with framework regions of the variable regions described herein having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein.

[0296] The anti-CD117 antibodies described herein can be in the form of full-length antibodies, bispecific antibodies, dual variable domain antibodies, multiple chain or single chain antibodies, and/or binding fragments that specifically bind human CD117, including but not limited to Fab, Fab', (Fab')2, Fv), scFv (single chain Fv), surrobodies (including surrogate light chain construct), single domain antibodies, camelized antibodies and the like. They also can be of, or derived from, any isotype, including, for example, IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g. IgG1, IgG2, IgG3 or IgG4), or IgM. In some embodiments, the anti-CD117 antibody is an IgG (e.g. IgG1, IgG2, IgG3 or IgG4).

[0297] Antibodies for use in conjunction with the methods described herein include variants of those antibodies described above, such as antibody fragments that contain or lack an Fc domain, as well as humanized variants of non-human antibodies described herein and antibody-like protein scaffolds (e.g., .sup.10Fn3 domains) containing one or more, or all, of the CDRs or equivalent regions thereof of an antibody, or antibody fragment, described herein. Exemplary antigen-binding fragments of the foregoing antibodies include a dual-variable immunoglobulin domain, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab').sub.2 molecule, and a tandem di-scFv, among others.

[0298] In one embodiment, anti-CD117 antibodies comprising one or more radiolabeled amino acids are provided. A radiolabeled anti-CD117 antibody may be used for both diagnostic and therapeutic purposes (conjugation to radiolabeled molecules is another possible feature). Nonlimiting examples of labels for polypeptides include, but are not limited to 3H, 14C, 15N, 35S, 90Y, 99Tc, and 125I, 131I, and 186Re. Methods for preparing radiolabeled amino acids and related peptide derivatives are known in the art (see for instance Junghans et al., in Cancer Chemotherapy and Biotherapy 655-686 (2d edition, Chafner and Longo, eds., Lippincott Raven (1996)) and U.S. Pat. Nos. 4,681,581, 4,735,210, 5,101,827, U.S. Pat. No. 5,102,990 (U.S. RE35,500), U.S. Pat. No. 5,648,471 and U.S. Pat. No. 5,697,902. For example, a radioisotope may be conjugated by a chloramine T method.

Anti-CD45 Antibodies

[0299] In one embodiment, the present invention includes ADCs comprising antibodies, and antigen-binding fragments thereof, that specifically bind to a CD45 polypeptide, e.g., a human CD45 polypeptide, and uses thereof. In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, that specifically binds to a CD45 polypeptide comprises a heavy chain variable region and a light chain variable region.

[0300] CD45 is a hematopoietic cell-specific transmembrane protein tyrosine phosphatase essential for T and B cell antigen receptor-mediated signaling. CD45 includes a large extracellular domain, and a phosphatase containing cytosolic domain. CD45 may act as both a positive and negative regulator depending on the nature of the stimulus and the cell type involved. Although there are a large number of permutations possible in the CD45 gene, only six isoforms are traditionally identified in humans. The isoforms are RA, RO, RB, RAB, RBC and RABC (Hermiston et al. 2003 "CD45: a critical regulator of signaling thresholds in immune cells." Annu Rev Immunol. 2:107-137.). CD45RA is expressed on naive T cells, and CD45RO is expressed on activated and memory T cells, some B cell subsets, activated monocytes/macrophages, and granulocytes. CD45RB is expressed on peripheral B cells, naive T cells, thymocytes, weakly on macrophages, and dendritic cells.

[0301] In certain embodiments, the anti-CD45 antibody is selected from apamistamab (also known 90Y-BC8, lomab-B, BC8; as described in, e.g., US20170326259, WO2017155937, and Orozco et al. Blood. 127.3 (2016): 352-359.) or BC8-B10 (as described, e.g., in Li et al. PloS one 13.10 (2018): e0205135.), each of which is incorporated by reference. Other anti-CD45 antibodies have been described, for example, in WO2003048327, WO2016016442, US20170226209, US20160152733, U.S. Pat. No. 9,701,756; US20110076270, or U.S. Pat. No. 7,825,222, each of which is incorporated by reference.

Anti-CD137 Antibodies

[0302] The present invention includes ADCs comprising antibodies, and antigen-binding fragments thereof, that specifically bind to a CD137 polypeptide, e.g., a human CD137 polypeptide, and uses thereof. In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, that specifically binds to a CD137 polypeptide comprises a heavy chain variable region and a light chain variable region.

[0303] T cells have been shown to express CD137, as this antigen is a transmembrane TNF receptor superfamily of costimulatory molecules and is expressed on a variety of hematopoietic cells and promotes T cell activation and regulates proliferation and survival of T cells (see, e.g., Cannons et al., J. Immunol. 167:1313-1324, 2001, the disclosure of which is incorporated herein by reference as it pertains to the expression of CD137 by T cells). CD137 is alternatively named tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, or induced by lymphocyte activation (ILA).

[0304] In certain embodiments, the anti-CD137 antibody is selected from ADG106 (as described in, e.g., US20190055314, WO2019037711, WO2019036855); AGEN2373 (as described in, e.g., WO2018191502, US20180344870); ATOR-1017 (as described in, e.g., WO2018091740, US20180118841) PE0166 (as described in, e.g., Song et al. AACR 2019, Abstract 2397/21), urelumab (also known as BMS-663513; as described in, e.g., WO2004010947, WO2005035584, US20090068192, U.S. Pat. Nos. 7,659,384, 8,475,790, 8,137,667, US20100183621, U.S. Pat. No. 8,716,452, US20120141494, U.S. Pat. No. 9,382,328, US20140193422, WO2016029073, US20160368998, WO2017181034, US20190062445, Chin et al. Nature communications. 9.1 (2018): 4679.; Segal et al. Clinical Cancer Research. 23.8 (2017): 1929-1936.); and utomilumab (also known as PF-05082566, MOR-7480.; as described in, e.g., WO2012032433, US20120237498, US20140178368, WO2012145183, WO2015119923, WO2015179236, US20160152722, US20190031765, WO2017130076, Chin et al. Nature communications. 9.1 (2018): 4679.; Segal et al. Clinical Cancer Research. 24.8 (2018): 1816-1823; Fisher et al. Cancer Immunology, Immunotherapy. 61.10 (2012): 1721-1733), each of which is incorporated by reference.

[0305] Other anti-CD137 antibodies have been described, for example, in WO2018134787, WO2019020774, WO2017077085, US20180327504, US20190099488, US2019006045, US20190015508, WO2019014328, US20190071510, WO2018127787, US20180258177, U.S. Ser. No. 10/174,122, WO2016110584, WO2018017761, WO2018098370, US20130149301, WO2019027754, WO2018156740, US20160244528, WO2016134358, U.S. Ser. No. 10/233,251, US20170226215, US20160083474, WO2017049452, US20180282422, WO2015188047, WO2010132389, US20120076722, US20110177104, WO2011031063, US20080305113, US20080008716, U.S. Pat. No. 7,829,088, US20090041763, WO2006126835, Soderstrom et al. Circulation J. 81.12 (2017): 1945-1952; Makkouk, et al. Annals of Oncology 28.2 (2016): 415-420; Martinez-Forero et al. J. of Immunology. 190.12 (2013): 6694-6706; Dubrot et al. Cancer immunology, immunotherapy. 59.8 (2010): 1223-1233; each of which is incorporated by reference.

[0306] In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to an anti-CD137 antibody herein, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to an anti-CD137 antibody herein. In certain embodiments, an antibody comprises a modified heavy chain (HC) variable region comprising an HC variable domain of an anti-CD137 antibody herein, or a variant thereof, which variant (i) differs from the anti-CD137 antibody in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from the anti-CD137 antibody in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from the anti-CD137 antibody in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the anti-CD137 antibody, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region can have an enhanced biological activity relative to the heavy chain variable region of the anti-CD137 antibody, while retaining the CD137 binding specificity of the antibody.

[0307] In one embodiment, an anti-CD137 antibody that may be used in the methods and compositions (including ADCs) described herein is the murine anti-CD137 antibody BBK2 (Thermo Fisher; MS621PABX) or an anti-CD137 antibody comprising antigen binding regions corresponding to the BBK2 antibody. The BBK2 antibody (which may also be referred to as a BBK-2 antibody or an anti-4-1BB antibody), is a mouse monoclonal antibody (IgG1, kappa) that binds to the ectodomain of human 4-1BB recombinant protein (4-1BB is also known as CD137). In certain embodiments, the methods and compositions of the disclosure include an anti-CD137 antibody comprising the binding regions (e.g., the CDRs) of the BBK2 antibody. In another embodiment, the methods and compositions of the disclosure comprise an antibody that competitively inhibits the binding of the BBK2 antibody to its epitope on CD137. In certain embodiments, the anti-CD137 antibody is humanized BBK2 or chimeric BBK2.

[0308] In one embodiment, the methods and compositions described herein include a chimeric anti-CD137 (ch-BBK2) antibody comprising the variable heavy and light chain regions of BBK2. In certain embodiments, the chimeric BBK2 antibody is an IgG1 antibody comprising human constant regions. The heavy chain amino acid sequence of ch-BBK2 is described in SEQ ID NO: 290, and the light chain amino acid sequence of ch-BBK2 is described in SEQ ID NO: 291. The CDR regions (CDR1, CDR2, and CDR3) of each of the heavy and light chain sequences are described in bold below. The CDR regions of BBK2 can be defined according to Kabat numbering. CDRs as defined by Kabat numbering are described below for each of the heavy and light chain sequences (described in bold below). The variable regions of BBK2 are italicized.

TABLE-US-00005 (ch-BBK2 heavy chain; SEQ ID NO: 290) QVQLQQPGAELVRPGASVKLSCKASGYTFT WVKQRPGQGLEWIG KATLTVDKSSNTVYMQLNSPTSEDSAVYYCTR WGQGTSVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (ch-BBK2 light chain; SEQ ID NO: 291) DIQMTQTTSALSASLGDRVTIGC WYQQKPDGTVKLLIY GVPSRFSGSG SGTDYSLTIRNLEQEDVATYFC FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC

[0309] Thus, in one embodiment, the VH CDR amino acid sequences of anti-CD137 antibody BBK2 (including ch-BBK2) are as follows: SYWIN (VH CDR1; SEQ ID NO: 292); NIYPSDSYTNYNQKFKD (VH CDR2; SEQ ID NO: 293) and NGVEGYPHYYAMEY (VH CDR3; SEQ ID NO: 294), and the VL CDR amino acid sequences of anti-CD137 antibody BBK2 (including ch-BBK2) are as follows: RASQDLSNHLY (VL CDR1; SEQ ID NO: 295); YTSRLHS (VL CDR2; SEQ ID NO: 296) and QQGYTLPYT (VL CDR3; SEQ ID NO: 297).

[0310] The heavy chain variable region of BBK2 is set forth in SEQ ID NO: 298 as QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFK DKATLTVDKSSNTVYMQLNSPTSEDSAVYYCTRNGVEGYPHYYAMEYWGQGTSVTVSS. The light chain variable region of BBK2 is set forth in SEQ ID NO: 299 as DIQMTQTTSALSASLGDRVTIGCRASQDLSNHLYWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSG SGTDYSLTIRNLEQEDVATYFCQQGYTLPYTFGGGTKLEIK. Anti-CD137 antibodies (including anti-CD137 ADCs) can comprise the heavy and light chain variable region amino acid sequences as set forth in SEQ ID Nos: 298 and 299, respectively.

[0311] In one embodiment, the anti-CD137 antibody, e.g., a chimeric (ch-BBK2) antibody or a humanized BBK2 antibody, comprises a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 292, a CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 294; and comprises a light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 295, a CDR2 comprising the amino acid sequence of SEQ ID NO: 296, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 297.

[0312] In one embodiment, the anti-CD137 antibody, e.g., a chimeric (ch-BBK2) antibody or a humanized BBK2 antibody, comprises a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 292, a CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 294; and comprises a light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 295, a CDR2 comprising the amino acid sequence of SEQ ID NO: 296, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 297.

[0313] Thus, BBK2, humanized BBK2, or chimeric BBK2 antibodies can be used in the anti-CD137 ADCs and methods described herein. Each of these antibodies can be conjugated to any of the cytotoxin described below using methods known in the art and those described herein.

Anti-CD5 Antibodies

[0314] In certain embodiments, compositions and methods described herein include an ADC comprising an antibody, or fragment thereof, that specifically binds to human CD5. Human CD5 is also referred to as LEU or T1. Human CD5 is a type-I transmembrane glycoprotein found on the surface of thymocytes, T lymphocytes and a subset of B lymphocytes. Two isoforms of human CD5 have been identified. Isoform 1 contains 438 amino acids and is described in Jones. et al. (1988) Nature 323 (6086), 346-349 and below (NCBI Reference Sequence: NP_001333385.1):

TABLE-US-00006 (SEQ ID NO: 363) MVCSQSWGRS SKQWEDPSQASKVCQRLNCG VPLSLGPFLV TYTPQSSIICYGQL GSFSNCSHSRNDMCHS LGLTCLEPQKTTPPTTRPPPTTTPEPTAPP RLQLVAQSGG QHCAGVVEFYSGSLGGTISY EAQDKTQDLE NFLCNNLQCG SFLKHLPETE AGRAQDPGEP REHQPLPIQWKIQNSSCTSL EHCFRKIKPQ KSGRVLALLC SGFQPKVQSR LVGGSSICEG TVEVRQGAQWAALCDSSSAR SSLRWEEVCR EQQCGSVNSY RVLDAGDPTS RGLFCPHQKL SQCHELWERNSYCKKVFVTCQDPNPAGLAAGTVASIILAL VLLVVLLVVC GPLAYKKLVK KFRQKKQRQWIGPTGMNQNM SFHRNHTATV RSHAENPTAS HVDNEYSQPP RNSHLSAYPA LEGALHRSSMQPDNSSDSDY DLHGAQRL

[0315] T cells have been shown to express CD5, which is a cell adhesion molecule and has been implicated both in the proliferative response of activated T cells and in T cell helper function. It has also been shown to function as a receptor, delivering co-stimulatory signals to T cells by interacting with CD72, a cell surface protein exclusive to B cells. Antibodies, or antigen-binding fragments thereof, that bind CD5 may suppress T cell activation and T cell-mediated immune responses against hematopoietic stem cell grafts, for example, by inhibiting the interaction between CD5 and CD72. Antibodies, and antigen-binding fragments thereof, that bind CD5 can also be used to kill CD5+ T cells directly, for instance, by conjugating the antibody, or antigen-binding fragment thereof, to a cytotoxin (such as a cytotoxin described herein or known in the art) or by using an unconjugated antibody, or antigen-binding fragment thereof, capable of recruiting complement proteins to the T cell.

[0316] Additionally, subsets of activated B cells have been shown to express CD5, and this expression pattern is particularly common among autoreactive B cells (Werner-Favre et al., European Journal of Immunology 19:1209-1231 (1989), the disclosure of which is incorporated herein by reference in its entirety). CD5 has also been shown to be expressed by subsets of NK cells; particularly among patients that have multiple myeloma have been shown to harbor populations of low density CD5+ (CD5LOW+) NK cells, and this surface antigen has been implicated in NK cell activation (Ishiyama et al., Anticancer Research 14:725-730 (1994), the disclosure of which is incorporated herein by reference in its entirety). Antibodies, or antigen-binding fragments thereof, that specifically bind CD5 can thus be used to attenuate the activation of B cells and NK cells. Antibodies, or antigen-binding fragments thereof, that bind CD5 can also be used to kill CD5+ B cells and NK cells directly, for instance, by conjugating the antibody, or antigen-binding fragment thereof, to a cytotoxin (such as a cytotoxin described herein or known in the art) or by using an unconjugated antibody, or antigen-binding fragment thereof, capable of recruiting complement proteins to the B cell or NK cell.

[0317] The present invention encompasses ADCs comprising antibodies, and antigen-binding fragments thereof, that specifically bind to a CD5 polypeptide, e.g., a human CD5 polypeptide, and uses thereof. In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, that specifically binds to a CD5 polypeptide comprises a heavy chain variable region and a light chain variable region.

[0318] In one embodiment, an ADC comprises an antibody comprising the heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 341. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 342. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 341, SEQ ID NO: 342, and SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 341, SEQ ID NO: 342, and SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 341, a VH CDR2 comprising SEQ ID NO: 342, and a VH CDR3 comprising SEQ ID NO: 343.

[0319] In one embodiment, an ADC comprises an antibody comprising the light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 344. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 345. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 346. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 344, SEQ ID NO: 345, and SEQ ID NO: 346. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 344, SEQ ID NO: 345, and SEQ ID NO: 346. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 344, a VL CDR2 comprising SEQ ID NO: 345, and a VL CDR3 comprising SEQ ID NO: 346.

[0320] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 341, a VH CDR2 comprising SEQ ID NO: 342, and a VH CDR3 comprising SEQ ID NO: 343, and alight chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 344, a VL CDR2 comprising SEQ ID NO: 345, and a VL CDR3 comprising SEQ ID NO: 346.

[0321] In certain embodiments, one or more of the CDRs (i.e., one or more heavy chain CDRs having SEQ ID NOs: 341-343, and/or one or more light chain CDRs having SEQ ID NOs: 344-346) can comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while retaining the CD5 specificity of the antibody (i.e., specificity similar to an antibody, or antigen-binding fragment thereof, comprising heavy chain CDRs of SEQ ID NOs: 341 to 343, and light chain CDRs of SEQ ID NOs: 344 to 346).

[0322] In certain embodiments, the anti-CD5 antibody, or antigen binding fragment thereof, is murine antibody 5D7, or a humanized version thereof. Murine antibody 5D7 binds to human CD5 and is described in US Patent Publication No. 20008/0245027, the contents of which relating to the antibody sequences disclosed therein are incorporated by reference herein. SEQ ID Nos: 353 to 358 described in the sequence summary table correspond to the CDRs of murine anti-CD5 antibody 5D7. A humanized version of anti-CD5 antibody 5D7 is described in SEQ ID NO: 359 (humanized heavy chain variable region) and SEQ ID NO: 360 (humanized light chain variable region). In one embodiment, the ADCs and uses thereof described herein include an antibody comprising the CDRs set forth in SEQ ID Nos: 353 to 358. In one embodiment, the ADCs and uses thereof described herein include an antibody comprising the heavy and light chain variable regions as set forth in SEQ ID Nos: 359 and 360, respectively.

[0323] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 359. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 359, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 359. In certain embodiments, an antibody comprises a modified heavy chain (HC) variable region comprising an HC variable domain comprising SEQ ID NO: 359, or a variant of SEQ ID NO: 359, which variant (i) differs from SEQ ID NO: 359 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 359 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 359 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 359, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region can have an enhanced biological activity relative to the heavy chain variable region of SEQ ID NO: 359, while retaining the CD5 binding specificity of the antibody, i.e. has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO: 359.

[0324] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 360. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 360, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 360. In certain embodiments, an antibody comprises a modified light chain (LC) variable region comprising an LC variable domain comprising SEQ ID NO: 360, or a variant of SEQ ID NO: 360, which variant (i) differs from SEQ ID NO: 360 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 360 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 360 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 360, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region can have an enhanced biological activity relative to the light chain variable region of SEQ ID NO: 360, while retaining the CD5 binding specificity of the antibody, i.e., has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO: 360.

[0325] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 359, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 359, and a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 360, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 360. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises SEQ ID NO: 359, and a light chain variable region that comprises SEQ ID NO: 360.

[0326] In another embodiment, the anti-CD5 antibody, or antigen-binding fragment thereof, can contain a heavy chain variable region that comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 353. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 354. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 355. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 353, SEQ ID NO: 354, and SEQ ID NO: 355. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 353, SEQ ID NO: 354, and SEQ ID NO: 355. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 353, a VH CDR2 comprising SEQ ID NO: 354, and a VH CDR3 comprising SEQ ID NO: 355.

[0327] In one embodiment, the light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 356. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 357. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 358. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 356, a VL CDR2 comprising SEQ ID NO: 357, and a VL CDR3 comprising SEQ ID NO: 358.

[0328] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 353, a VH CDR2 comprising SEQ ID NO: 354, and a VH CDR3 comprising SEQ ID NO: 355, and alight chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 356, a VL CDR2 comprising SEQ ID NO: 357, and a VL CDR3 comprising SEQ ID NO: 358.

[0329] In certain embodiments, one or more of the CDRs (i.e., one or more heavy chain CDRs having SEQ ID NOs: 353-355, and/or one or more light chain CDRs having SEQ ID NOs: 356-358) can comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while retaining the CD5 specificity of the antibody (i.e., specificity similar to an antibody, or antigen-binding fragment thereof, comprising heavy chain CDRs of SEQ ID NOs: 353 to 355, and light chain CDRs of SEQ ID NOs:356 to 358).

[0330] Antibodies and antigen-binding fragments thereof capable of binding CD5 antigen can be identified using techniques known in the art and described herein, such as by immunization, computational modeling techniques, and in vitro selection methods, such as the phage display and cell-based display platforms described below.

[0331] Anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or both of the following variable regions, or an amino acid sequence having at least 85% sequence identity thereto (e.g., an amino acid sequence having 85%, 90%, 95%, 97%, 98%, 99%, or more, sequence identity thereto):

TABLE-US-00007 a V.sub.L having the amino acid sequence (SEQ ID NO: 325) DIQMTQSPSSMSASLGDRVTITCRASQDINSYLSWFQQKPGKSPKTLIYR ANRLVDGVPSRFSGSGSGTDYTLTISSLQYEDFGIYYCQQYDESPWTFGG GTKLEIK; and a V.sub.H having the amino acid sequence (SEQ ID NO: 326) QIQLVQSGPGLKKPGGSVRISCAASGYTFTNYGMNWVKQAPGKGLRWMGW INTHTGEPTYADDFKGRFTFSLDTSKSTAYLQINSLRAEDTATYFCTRRG YDWYFDVWGQGTTVTVSS.

[0332] Antibodies and antigen-binding fragments thereof containing the foregoing V.sub.L and V.sub.H sequences are described, e.g., in U.S. Pat. No. 5,869,619, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof, such as the he1 antibody. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the V.sub.L and V.sub.H chains of SEQ ID NO: 325 and SEQ ID NO: 326. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the CDRs contained in the V.sub.L and V.sub.H chains of SEQ ID NO: 325 and SEQ ID NO: 326. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the CDRs contained in the V.sub.L and V.sub.H chains of SEQ ID NO: 325 and SEQ ID NO: 326 and the remainder of the V.sub.L and V.sub.H sequences have at least 85% sequence identity (e.g., 85%, 90%, 95%, 97%, 98%, 99%, or greater sequence identity) to the V.sub.L and V.sub.H sequences of SEQ ID NO: 325 and SEQ ID NO: 326.

[0333] In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the following CDRs: [0334] a CDR-H1 having the amino acid sequence GYTFTNY (SEQ ID NO: 327); [0335] a CDR-H2 having the amino acid sequence NTHTGE (SEQ ID NO: 328); [0336] a CDR-H3 having the amino acid sequence RGYDWYFDV (SEQ ID NO: 329); [0337] a CDR-L1 having the amino acid sequence RASQDINSYLS (SEQ ID NO: 330); [0338] a CDR-L2 having the amino acid sequence RANRLVD (SEQ ID NO: 331); and [0339] a CDR-L3 having the amino acid sequence QQYDESPWT (SEQ ID NO: 332).

[0340] Additional anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or both of the following variable regions, or an amino acid sequence having at least 85% sequence identity thereto (e.g., an amino acid sequence having 85%, 90%, 95%, 97%, 98%, 99%, or more, sequence identity thereto):

TABLE-US-00008 a V.sub.L having the amino acid sequence (SEQ ID NO: 333) DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIY RANRLESGVPSRFSGSGSGTDYTLTISSLQYEDFGIYYCQQYDESPWTF GGGTKLEIK; and a V.sub.H having the amino acid sequence (SEQ ID NO: 334) EIQLVQSGGGLVKPGGSVRISCAASGYTFTNYGMNWVRQAPGKGLEWMGW INTHYGEPTYADSFKGTRTFSLDDSKNTAYLQINSLRAEDTAVYFCTRRG YDWYFDVWGQGGTTVTVSS.

[0341] Antibodies and antigen-binding fragments thereof containing the foregoing V.sub.L and V.sub.H sequences are described, e.g., in U.S. Pat. No. 5,869,619, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof, such as the he3 antibody. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the CDRs contained in the V.sub.L and V.sub.H chains of the antibody that includes the V.sub.L and V.sub.H chains of SEQ ID NO:327 and SEQ ID NO: 328. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the CDRs contained in the V.sub.L and V.sub.H chains of SEQ ID NO:327 and SEQ ID NO: 328 and the remainder of the V.sub.L and V.sub.H sequences have at least 85% sequence identity (e.g., 85%, 90%, 95%, 97%, 98%, 99%, or greater sequence identity) to the V.sub.L and V.sub.H sequences of SEQ ID NO:327 and SEQ ID NO: 328.

[0342] In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof includes the following CDRs: [0343] a CDR-H1 having the amino acid sequence GYTFTNY (SEQ ID NO: 335); [0344] a CDR-H2 having the amino acid sequence NTHYGE (SEQ ID NO: 336); [0345] a CDR-H3 having the amino acid sequence RRGYDWYFDV (SEQ ID NO: 337); [0346] a CDR-L1 having the amino acid sequence RASQDINSYLS (SEQ ID NO: 338); [0347] a CDR-L2 having the amino acid sequence RANRLES (SEQ ID NO: 339); and [0348] a CDR-L3 having the amino acid sequence QQYDESPWT (SEQ ID NO: 340).

[0349] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences are described, e.g., in U.S. Pat. No. 5,869,619, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof.

[0350] Other anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD5 antibodies that are described in U.S. Pat. Nos. 5,821,123; 5,766,886; 5,770,196; 7,153,932; 5,621,083; 6,649,742; 6,146,631; 5,756,699; 5,744,580; 6,376,217; 5,837,491; and 6,146,850, the disclosures of each of which are incorporated herein by reference as they pertain to anti-CD5 antibodies and antigen-binding fragments thereof.

[0351] Other anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, those produced by the hybridoma cell line deposited as ATCC CRL 8000 (anti-CD5 murine antibody OKT1). Such antibodies are described in U.S. Pat. Nos. 4,515,894; 4,657,760; and 4,363,799, the disclosures of each of which are incorporated herein by reference as they pertains to anti-CD5 antibodies and antigen-binding fragments thereof.

[0352] Anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or more, or all, of the following CDRs: [0353] a CDR-H1 having the amino acid sequence GYSITSGYY (SEQ ID NO: 341); [0354] a CDR-H2 having the amino acid sequence ISYSGFT (SEQ ID NO: 342); [0355] a CDR-H3 having the amino acid sequence AGDRTGSWFAY (SEQ ID NO: 343); [0356] a CDR-L1 having the amino acid sequence QDISNY (SEQ ID NO: 344); [0357] a CDR-L2 having the amino acid sequence ATS (SEQ ID NO: 345); and [0358] a CDR-L3 having the amino acid sequence LQYASYPFT (SEQ ID NO: 346).

[0359] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences are described, e.g., in U.S. Pat. No. 8,679,500, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof.

[0360] Anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or more, or all, of the following CDRs: [0361] a CDR-H1 having the amino acid sequence GYIFTNYG (SEQ ID NO: 347); [0362] a CDR-H2 having the amino acid sequence INTYNGEP (SEQ ID NO: 348); [0363] a CDR-H3 having the amino acid sequence ARGDYYGYEDY (SEQ ID NO: 349); [0364] a CDR-L1 having the amino acid sequence QGISNY (SEQ ID NO: 350); [0365] a CDR-L2 having the amino acid sequence YTS (SEQ ID NO: 351); and [0366] a CDR-L3 having the amino acid sequence QQYSKLPWT (SEQ ID NO: 352).

[0367] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences are described, e.g., in U.S. Pat. No. 8,679,500.

[0368] Anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or more, or all, of the following CDRs: [0369] a CDR-H1 having the amino acid sequence FSLSTSGMG (SEQ ID NO: 353); [0370] a CDR-H2 having the amino acid sequence WWDDD (SEQ ID NO: 354); [0371] a CDR-H3 having the amino acid sequence RRATGTGFDY (SEQ ID NO: 355); [0372] a CDR-L1 having the amino acid sequence QDVGTA (SEQ ID NO: 356); [0373] a CDR-L2 having the amino acid sequence WTSTRHT (SEQ ID NO: 357); and [0374] a CDR-L3 having the amino acid sequence YNSYNT (SEQ ID NO: 358).

[0375] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences are described, e.g., in US Patent Application Publication No. 2008/0254027, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof.

[0376] Other anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD5 antibodies that are described in PCT Application Publication No. WO1992/014491, such as the anti-CD5 antibodies produced by hybridoma cell line deposited at the Institut Pasteur under No. 1-1025 on Jan. 10, 1991. The disclosure of PCT Application Publication No. WO1992/014491 is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen-binding fragments thereof.

[0377] Other anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD5 antibodies that are described in U.S. Pat. Nos. 6,010,902 and 7,192,736, US Patent Application Publication Nos. 2011/0250203 and 2017/0129128, and PCT Application Publication Nos. WO2016/172606; WO1994/023747; and WO1996/041608; the disclosures of each of which are incorporated herein by reference as they pertain to anti-CD5 antibodies and antigen binding fragments thereof.

[0378] In some embodiments, the anti-CD5 antibodies that can be used in conjunction with the compositions and methods described herein include those that contain a combination of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 regions set forth in the table below.

TABLE-US-00009 TABLE CD5 antibody sequences Ab No. Name CDRH1 CDRH2 CDRH3 1 1D8 SGYSFTGYTM LINPYNGGTT CARDYYGSSPDFDYW 2 3I21 SGYSFTDYTM LINPYNGGTM CARDNYGSSPDFDYW 3 4H10 SGYSFTGYTM LINPYNGGTM CARDNYGSSPYFDYW 4 8J23 SGYSFTGYTM LINPYNGGTM CARDNYGSSPYFDYW 5 5O4 SGYSFTGYTM LINPYNGGTT CARDYYGSSPDFDYW 6 4H2 SGFTFSNYAM SISSGGNTF CVRYYYGVTYWYFDVW 7 5G2 SGFTFSSYAM SISSGGSTY CVRYYYGIRYWYFDVW 8 8G8 SGYSFTAYNI SIDPYYGDTK CARRMITMGDWYFDVW 9 6M4 SGYSFTAYSM SIDPYYGDTK CARRMITTGDWYFDVW 10 2E3 SGYTFTNFAI LISSNSGDVS CARHYGAHNYFDYW 11 4E24 SGYTFTNFAI LISTSSGDVS CARHYGANNYFDYW 12 4F10 SGYTFTNFAI LISSNSGDVS CARHYGAHNYFDYW 13 7J9 SGYTFTNFAI LISSNSGDVS CARHYGAHNYFDYW 14 7P9 SGFNIKDTYM RIDPANGNTK CAREENYYGTYYFDYW 15 8E24 SGYSFTSYWM MIHPSDSETR CARWGDHDDAMDFW 16 6L18 SGFSLTNYDV VIWSGGNTD CARNHGDGYFNWYFDVW 17 7H7 SGFSLTNYDV VIWSGGNTD CARNHGDGYYNWYFDVW 18 1E7 SGFTFSNYGM AINSNGDITY CARGTAWFTYW 19 8J21 SGYSFTGYTM LINPYNGGTR CARDGDDGWDIDVW 20 7I11 SGYIFANYGM WINTYTGEPT CARRGTYWHFDVW 21 8M9 SGYNFTNYGM WINTYTGEPT CARRGSYWHFDVW 22 1P21 SGYTFTNYGM WINTYTGEPT CARRSTLVFDYW 23 2H11 SGYTFTDYYI WIYPGGGNTR CARNGYWYFDVW 24 3M22 SGYTFTDYYI WIYPGGGNTR CARNGYWYFDVW 25 5M6 SGNTFTNFYL CIYPGNVKTK CAKEGDYDGTAYFDYW 26 5H8 SGYTFTNYGM WINTYTGEPT CARRRDGNFDYW 27 7I19 SEFTFSNYAM TISSGGSYTY CVRHGYFDVW 28 1A20 SGYTFTSYRM RIDPYDSGTH CAFYDGAYW 29 8E15 SGFNIKDTYM RIDPANGNTK CASYDPDYW 30 8C10 SGYSFTDYTM LINPYNGGTR CARDTTATYYFDYW 31 3P16 SGYMFTNHGM WINTYTGEPT CARRVATYFDVW 32 4F3 SGYMFTNYGM WINTYTGEPT CTRRSHITLDYW 33 5M24 SGYIFTNYGM WINTYTGEPT CARRRTTAFDYW 34 5O24 SGFNIKDYYI WIDPENGRTE CNNGNYVRHYYFDYW 35 7B16 SGYTFINYGM WINTYTGEPT CTRRREITFDYW 36 1E8 SGYTFTDYFI EIYPGSSNTY CARSGISPFTYW 37 2H16 SGYIFTGYNI AVYPGNGDTS CAKYDRFFASW

[0379] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences of the table above are described, e.g., in US Patent Application Publication No. 2011/0250203, the disclosure of which is incorporated herein by reference as it pertains to anti-CD5 antibodies and antigen binding fragments thereof.

Anti-CD2 Antibodies

[0380] Compositions and methods described herein include, in certain embodiments, an antibody, or fragment thereof, that specifically binds to human CD2. Human CD2 is also referred to as T-cell Surface Antigen T11/Leu-5, T11, CD2 antigen (p50), and Sheep Red Blood Cell Receptor (SRBC). CD2 is expressed on T cells. Two isoforms of human CD2 have been identified. Isoform 1 contains 351 amino acids is described in Seed, B. et al. (1987) 84: 3365-69 (see also Sewell et al. (1986) 83: 8718-22) and below (NCBI Reference Sequence: NP_001758.2):

TABLE-US-00010 (SEQ ID NO: 312) msfpckfvas fllifnvssk gavskeitna letwgalgqd inldipsfqm sddiddikwe ktsdkkkiaq frkeketfke kdtyklfkng tlkikhlktd dqdiykvsiy dtkgknvlek ifdlkiqerv skpkiswtci nttltcevmn gtdpelnlyq dgkhlklsqr vithkwttsl sakfkctagn kvskessvep vscpekgldi yliigicggg sllmvfvall vfyitkrkkq rsrrndeele trahrvatee rgrkphqipa stpqnpatsq hpppppghrs qapshrpppp ghrvqhqpqk rppapsgtqv hqqkgpplpr prvqpkpphg aaenslspss n

A second isoform of CD2 is 377 amino acids and is identified herein as NCBI Reference Sequence: NP_001315538.1.

[0381] T cells and NK cells have been shown to express CD2, which is a cell adhesion molecule and specific marker for such lymphocytes. For instance, CD2 interacts with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3/CD58), to potentiate T cell activation. Antibodies and antigen-binding fragments thereof capable of binding CD2 may suppress T cell activation and T cell-mediated immune responses against hematopoietic stem cell grafts, for example, by inhibiting the interaction between CD2 and LFA-3. Antibodies and antigen-binding fragments thereof that bind to this cell-surface antigen can be identified using techniques known in the art and described herein, including immunization, computational modeling techniques, and in vitro selection methods, such as the phage display and cell-based display platforms described below.

[0382] In certain embodiments, the present invention encompasses an ADC comprising an antibody, or antigen-binding fragment thereof, that specifically binds to a CD2 polypeptide, e.g., a human CD2 polypeptide, and uses thereof.

[0383] In one embodiment, an ADC comprises an anti-CD2 antibody comprising a heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:300. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO:301. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO:302. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO:300, SEQ ID NO:301, and SEQ ID NO:302. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO:300, SEQ ID NO:301, and SEQ ID NO:302.

[0384] In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO:300, a VH CDR2 comprising SEQ ID NO:301, and a VH CDR3 comprising SEQ ID NO:302.

[0385] In one embodiment, an ADC comprises an anti-CD2 antibody comprising light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO:303. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO:304. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO:305. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO:303, SEQ ID NO:304, and SEQ ID NO:305. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO:303, SEQ ID NO:304, and SEQ ID NO:305. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO:303, a VL CDR2 comprising SEQ ID NO:304, and a VL CDR3 comprising SEQ ID NO:305.

[0386] In an exemplary embodiment, the anti-CD2 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO:300, a VH CDR2 comprising SEQ ID NO:301, and a VH CDR3 comprising SEQ ID NO:302, and alight chain variable region that comprises a VL CDR1 comprising SEQ ID NO:303, a VL CDR2 comprising SEQ ID NO:304, and a VL CDR3 comprising SEQ ID NO:305.

[0387] In certain embodiments, one or more of the CDRs (i.e., one or more heavy chain CDRs having SEQ ID NOs: 300-302, and/or one or more light chain CDRs having SEQ ID NOs: 303-305) can comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while retaining the CD2 specificity of the antibody (i.e., specificity similar to an antibody, or antigen-binding fragment thereof, comprising heavy chain CDRs of SEQ ID NOs: 300 to 302, and light chain CDRs of SEQ ID NOs:303 to 305).

[0388] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 306. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 306, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 306. In certain embodiments, an antibody comprises a modified heavy chain (HC) variable region comprising an HC variable domain comprising SEQ ID NO: 306, or a variant of SEQ ID NO: 306, which variant (i) differs from SEQ ID NO: 306 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 306 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 306 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 306, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region can have an enhanced biological activity relative to the heavy chain variable region of SEQ ID NO: 306, while retaining the CD2 binding specificity of the antibody, i.e. has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO: 306. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that differs from the amino acid sequence set forth in SEQ ID NO: 306 at one, two, three or four amino acids. For example, the antibody, or antigen-binding fragment thereof, can comprise a heavy chain variable region that differs from the amino acid sequence set forth in SEQ ID NO: 306 at one, two, three, or four of positions 12, 13, 28, and/or 48. In one embodiment, the heavy chain variable region differs from the amino acid sequence set forth in SEQ ID NO:306 at positions 12, 13, 28, and 48. In one embodiment, the heavy chain variable region comprises one, two, three, or four of the following substitutions with respect to the sequence set forth in SEQ ID NO:306: K12Q; K13R; T28I; and M48V. In one embodiment, the heavy chain variable region comprises the substitutions K12Q; K13R; T28I; and M48V with respect to SEQ ID NO:306.

[0389] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO:307. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO:307, e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:307. In certain embodiments, an antibody comprises a modified light chain (LC) variable region comprising an LC variable domain comprising SEQ ID NO: 307, or a variant of SEQ ID NO: 307, which variant (i) differs from SEQ ID NO: 307 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 307 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 307 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 307, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region can have an enhanced biological activity relative to the light chain variable region of SEQ ID NO:307, while retaining the CD2 binding specificity of the antibody, i.e., has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO:307.

[0390] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 306, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 306, and alight chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO:307, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO:307. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises SEQ ID NO: 306, and a light chain variable region that comprises SEQ ID NO:307. In one embodiment, the antibody is an Ab1 antibody that comprises a heavy chain variable region comprising SEQ ID NO:306, and alight chain variable region comprising SEQ ID NO:307.

[0391] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO:308. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO:308, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO:308. In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO:308, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO:308, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO:309, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO:309. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises SEQ ID NO:308, and a light chain variable region that comprises SEQ ID NO:309. In one embodiment, the antibody is an Ab1a antibody that comprises a heavy chain variable region comprising SEQ ID NO:308, and a light chain variable region comprising SEQ ID NO:309.

[0392] In one embodiment, the heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:3131. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO:314. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO:315. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO:313, SEQ ID NO:314, and SEQ ID NO:315. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO:313, SEQ ID NO:314, and SEQ ID NO:315. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO:313, a VH CDR2 comprising SEQ ID NO:314, and a VH CDR3 comprising SEQ ID NO:315.

[0393] In one embodiment, the heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:313. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO:314. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO:316. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO:313, SEQ ID NO:314, and SEQ ID NO:316. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO:313, SEQ ID NO:314, and SEQ ID NO:316. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO:313, a VH CDR2 comprising SEQ ID NO:314, and a VH CDR3 comprising SEQ ID NO:316.

[0394] In one embodiment, the light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO:317. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO:318. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO:319. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO:317, a VL CDR2 comprising SEQ ID NO:318, and a VL CDR3 comprising SEQ ID NO:319.

[0395] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO:313, a VH CDR2 comprising SEQ ID NO:314, and a VH CDR3 comprising SEQ ID NO:315, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO:317, a VL CDR2 comprising SEQ ID NO:318, and a VL CDR3 comprising SEQ ID NO:319.

[0396] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO:313, a VH CDR2 comprising SEQ ID NO:314, and a VH CDR3 comprising SEQ ID NO:316, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO:317, a VL CDR2 comprising SEQ ID NO:318, and a VL CDR3 comprising SEQ ID NO:319.

[0397] In certain embodiments, one or more of the CDRs (i.e., one or more heavy chain CDRs having SEQ ID NOs: 313-316, and/or one or more light chain CDRs having SEQ ID NOs: 317-318) can comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while retaining the CD2 specificity of the antibody (i.e., specificity similar to an antibody, or antigen-binding fragment thereof, comprising heavy chain CDRs of SEQ ID NOs: 313 to 315, and light chain CDRs of SEQ ID NOs:18 to 20; or comprising heavy chain CDRs of SEQ ID NOs: 313, 314, 316, and light chain CDRs of SEQ ID NOs:317 to 319).

[0398] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 320. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 320, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 320. In certain embodiments, an antibody comprises a modified heavy chain (HC) variable region comprising an HC variable domain comprising SEQ ID NO: 320, or a variant of SEQ ID NO: 320, which variant (i) differs from SEQ ID NO: 320 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 320 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 320 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 320, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region can have an enhanced biological activity relative to the heavy chain variable region of SEQ ID NO: 320, while retaining the CD2 binding specificity of the antibody, i.e. has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO: 320.

[0399] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 321. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 321, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 321. In certain embodiments, an antibody comprises a modified heavy chain (HC) variable region comprising an HC variable domain comprising SEQ ID NO: 320, or a variant of SEQ ID NO: 321, which variant (i) differs from SEQ ID NO: 321 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 321 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 321 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 321, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region can have an enhanced biological activity relative to the heavy chain variable region of SEQ ID NO: 321, while retaining the CD2 binding specificity of the antibody, i.e. has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO: 321.

[0400] In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO:322. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO:322, e.g., at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO:322. In certain embodiments, an antibody comprises a modified light chain (LC) variable region comprising an LC variable domain comprising SEQ ID NO: 322, or a variant of SEQ ID NO: 322, which variant (i) differs from SEQ ID NO: 322 in 1, 2, 3, 4 or 5 amino acids substitutions, additions or deletions; (ii) differs from SEQ ID NO: 322 in at most 5, 4, 3, 2, or 1 amino acids substitutions, additions or deletions; (iii) differs from SEQ ID NO: 322 in 1-5, 1-3, 1-2, 2-5 or 3-5 amino acids substitutions, additions or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% identical to SEQ ID NO: 322, wherein in any of (i)-(iv), an amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region can have an enhanced biological activity relative to the light chain variable region of SEQ ID NO:322, while retaining the CD2 binding specificity of the antibody, i.e., has a binding specificity similar to an antibody, or antigen-binding fragment thereof, comprising SEQ ID NO:322.

[0401] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 320, e.g., at least about 95%, about 96%, about 97%, about 98% or about 99%, or 100% identity to SEQ ID NO: 320, and alight chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO:322, e.g., at least about 95%, about 96%, about 97%, about 98% or about 99%, or 100% identity to SEQ ID NO:322. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises SEQ ID NO: 320, and a light chain variable region that comprises SEQ ID NO:322.

[0402] In an exemplary embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 321, e.g., at least about 95%, about 96%, about 97%, about 98% or about 99%, or 100% identity to SEQ ID NO: 321, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO:322, e.g., at least about 95%, about 96%, about 97%, about 98% or about 99%, or 100% identity to SEQ ID NO:322. In one embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises SEQ ID NO: 321, and a light chain variable region that comprises SEQ ID NO:322.

[0403] Anti-CD2 antibodies that can be used in conjunction with the compositions and methods described herein include those that have one or more, or all, of the following CDRs: [0404] a. a CDR-H1 having the amino acid sequence EYYMY (SEQ ID NO: 300); [0405] b. a CDR-H2 having the amino acid sequence RIDPEDGSIDYVEKFKK (SEQ ID NO: 301); [0406] c. a CDR-H3 having the amino acid sequence GKFNYRFAY (SEQ ID NO: 302); [0407] d. a CDR-L1 having the amino acid sequence RSSQSLLHSSGNTYLN (SEQ ID NO: 303); [0408] e. a CDR-L2 having the amino acid sequence LVSKLES (SEQ ID NO: 304); and [0409] f. a CDR-L3 having the amino acid sequence MQFTHYPYT (SEQ ID NO: 305).

[0410] Antibodies and antigen-binding fragments thereof containing the foregoing CDR sequences are described, e.g., in U.S. Pat. No. 6,849,258, the disclosure of which is incorporated herein by reference as it pertains to anti-CD2 antibodies and antigen-binding fragments thereof.

[0411] The antibodies and fragments thereof disclosed in U.S. Pat. Nos. 5,730,979; 5,817,311; 5,951,983; and 7,592,006; such as LO-CD2a, BTI-322, and antibodies produced by the hybridoma cell line deposited as ATCC Deposit No. HB 11423 (e.g., antibodies or antigen-binding fragments thereof containing one or more, or all, of the CDR sequences of antibody LO-CD2a isolated from the hybridoma cell line deposited as ATCC Deposit No. HB 11423) can be used in conjunction with the compositions and methods disclosed herein. Exemplary antibodies that may be used in conjunction with the compositions and methods described herein include humanized antibodies containing one or more, or all, of the CDR sequences of an antibody isolated from the hybridoma cell line deposited as ATCC Deposit No. HB 11423, such as MEDI-507. MEDI-507 is a humanized anti-CD2 monoclonal antibody that contains the CDR-H and CDR-L sequences of (a) through (f) above, and is described in Branco et al., Transplantation 68:1588-1596 (1999). MEDI-507 is additionally described in WO99/03502A1 and WO1994/020619A1; U.S. Pat. Nos. U.S. Pat. Nos. 7,592,006, 6,849,258, 5,951,983, 5,817,311, and 5,730,979; and U.S. Patent Publication Nos. US2011/0280868, US2004/0265315 and 2011/0091453, the disclosures of each of which are incorporated herein by reference as they pertain to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody MEDI-507. In one embodiment, the anti-CD2 antibody is Siplizumab, or an antigen-binding fragment thereof.

[0412] Other anti-CD2 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD2 antibodies that are described in U.S. Pat. Nos. 6,541,611 and 7,250,167, the disclosures of each of which are incorporated herein by reference as they pertain to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody LO-CD2b and antibodies produced by the hybridoma cell line deposited as ATCC Deposit No. PTA-802. Exemplary antibodies that may be used in conjunction with the compositions and methods described herein include humanized antibodies containing one or more, or all, of the CDR sequences of an antibody isolated from the hybridoma cell line deposited as ATCC Deposit No. PTA-802.

[0413] Other anti-CD2 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD2 antibodies that are described in U.S. Pat. Nos. 5,795,572 and 5,807,734, the disclosures of each of which are incorporated herein by reference as they pertains to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody produced by hybridoma cell line deposited as ATCC Deposit No. HB 69277. For instance, anti-CD2 antibodies and antigen-binding fragments thereof that may be used in conjunction with the compositions and methods described herein include those that contain a hinge region having an amino acid sequence of EPKSSDKTHTSPPSP (SEQ ID NO: 316), such as scFv fragments containing a hinge region having the amino acid sequence of EPKSSDKTHTSPPSP (SEQ ID NO: 316). The incorporation of a hinge region having the amino acid sequence of SEQ ID NO: 316 can be beneficial, as this hinge motif has been mutated relative to wild-type hinge region sequences so as to eliminate potentially reactive cysteine residues that may promote undesirable oxidative dimerization of a single-chain antibody fragment, such as a scFv fragment.

[0414] Other anti-CD2 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD2 antibodies that are described in U.S. Pat. No. 6,764,688, such as the anti-CD2 antibody TS2/18 and antibodies produced by hybridoma cell line deposited as ATCC Deposit No. HB-195. The disclosure of U.S. Pat. No. 6,764,688 is incorporated herein by reference as it pertains to anti-CD2 antibodies and antigen-binding fragments thereof.

[0415] Other anti-CD2 antibodies that can be used in conjunction with the compositions and methods described herein include, for instance, anti-CD2 antibodies that are described in U.S. Pat. Nos. 6,162,432, 6,558,662, 7,408,039, 7,332,157, 7,638,121, 7,939,062, and 7,115,259, US Patent Application Publication No. 2006/0084107, 2014/0369974, 2002/0051784, and 2013/0183322, and PCT Publication No. WO1992/016563, the disclosures of each of which are incorporated herein by reference as they pertain to anti-CD2 antibodies and antigen binding fragments thereof.

Fc Mutations

[0416] The antibodies or binding fragments described herein may also include modifications and/or mutations that alter the properties of the antibodies and/or fragments, such as those that increase half-life, increase or decrease ADCC, etc., as is known in the art.

[0417] In one embodiment, an antibody, or binding fragment thereof, comprises a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, such that said molecule has an altered affinity for an FcgammaR. Certain amino acid positions within the Fc region are known through crystallography studies to make a direct contact with Fc.gamma.R. Specifically amino acids 234-239 (hinge region), amino acids 265-269 (B/C loop), amino acids 297-299 (C'/E loop), and amino acids 327-332 (F/G) loop. (see Sondermann et al., 2000 Nature, 406: 267-273). Thus, the antibodies (e.g., anti-CD117, CD45, CD137, CD2, CD5, CD262, or CD134) described herein may comprise variant Fc regions comprising modification of at least one residue that makes a direct contact with an Fc.gamma. R based on structural and crystallographic analysis. In one embodiment, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NH1, MD (1991), expressly incorporated herein by references. The "EU index as in Kabat" refers to the numbering of the human IgG1 EU antibody. The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference.) In one embodiment, the Fc region comprises a D265A mutation. In one embodiment, the Fc region comprises a D265C mutation. In some embodiments, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 234 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a L234A mutation. In some embodiments, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 235 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a L235A mutation. In yet another embodiment, the Fc region comprises a L234A and L235A mutation. In a further embodiment, the Fc region of the antibody of an ADC described herein comprises a D265C, L234A, and L235A mutation.

[0418] In certain aspects a variant IgG Fc domain comprises one or more amino acid substitutions resulting in decreased or ablated binding affinity for an Fc.gamma.R and/or C1q as compared to the wild type Fc domain not comprising the one or more amino acid substitutions. Fc binding interactions are essential for a variety of effector functions and downstream signaling events including, but not limited to, antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Accordingly, in certain aspects, an antibody comprising a modified Fc region (e.g., comprising a L234A, L235A, and a D265C mutation) has substantially reduced or abolished effector functions.

[0419] Affinity to an Fc region can be determined using a variety of techniques known in the art, for example but not limited to, equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA); KinExA, Rathanaswami et al. Analytical Biochemistry, Vol. 373:52-60, 2008; or radioimmunoassay (RIA)), or by a surface plasmon resonance assay or other mechanism of kinetics-based assay (e.g., BIACORE.TM.. analysis or Octet.TM. analysis (forteBIO)), and other methods such as indirect binding assays, competitive binding assays fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods may utilize a label on one or more of the components being examined and/or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound in the presence of increasing amounts of an unlabeled second antibody.

[0420] Antibodies may be further engineered to further modulate antibody half-life by introducing additional Fc mutations, such as those described for example in (Dall'Acqua et al. (2006) J Biol Chem 281: 23514-24), (Zalevsky et al. (2010) Nat Biotechnol 28: 157-9), (Hinton et al. (2004) J Biol Chem 279: 6213-6), (Hinton et al. (2006) J Immunol 176: 346-56), (Shields et al. (2001) J Biol Chem 276: 6591-604), (Petkova et al. (2006) Int Immunol 18: 1759-69), (Datta-Mannan et al. (2007) Drug Metab Dispos 35: 86-94), (Vaccaro et al. (2005) Nat Biotechnol 23: 1283-8), (Yeung et al. (2010) Cancer Res 70: 3269-77) and (Kim et al. (1999) Eur J Immunol 29: 2819-25), and include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434 and 435. Exemplary mutations that may be made singularly or in combination are T250Q, M252Y, 1253A,S254T,T256E, P2571, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R mutations.

[0421] Thus, in one embodiment, the Fc region comprises a mutation resulting in a decrease in half life. An antibody having a short half life may be advantageous in certain instances where the antibody is expected to function as a short-lived therapeutic, e.g., the conditioning step described herein where the antibody is administered followed by HSCs. Ideally, the antibody would be substantially cleared prior to delivery of the HSCs, which also generally express an antigen targeted by an ADC described herein, e.g., CD117, but are not the target of the ADC, unlike the endogenous stem cells. In one embodiment, the Fc regions comprise a mutation at position 435 (EU index according to Kabat). In one embodiment, the mutation is an H435A mutation.

[0422] In one embodiment, the antibody described herein has a half life of equal to or less than 24 hours, a half life of equal to or less than 22 hours, a half life of equal to or less than 20 hours, a half life of equal to or less than 18 hours, a half life of equal to or less than 16 hours, a half life of equal to or less than 14 hours, equal to or less than 13 hours, equal to or less than 12 hours, or equal to or less than 11 hours. In one embodiment, the half life of the antibody is 11 hours to 24 hours; 12 hours to 22 hours; 10 hours to 20 hours; 8 hours to 18 hours; or 14 hours to 24 hours.

[0423] In some aspects, the Fc region comprises two or more mutations that confer reduced half-life and greatly diminish or completely abolish an effector function of the antibody. In some embodiments, the Fc region comprises a mutation resulting in a decrease in half-life and a mutation of at least one residue that can make direct contact with an Fc.gamma.R (e.g., as based on structural and crystallographic analysis). In one embodiment, the Fc region comprises a H435A mutation, a L234A mutation, and a L235A mutation. In one embodiment, the Fc region comprises a H435A mutation and a D265C mutation. In one embodiment, the Fc region comprises a H435A mutation, a L234A mutation, a L235A mutation, and a D265C mutation.

[0424] In some embodiments, the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin (e.g., amatoxin) by way of a cysteine residue in the Fc domain of the antibody or antigen-binding fragment thereof. In some embodiments, the cysteine residue is introduced by way of a mutation in the Fc domain of the antibody or antigen-binding fragment thereof. For instance, the cysteine residue may be selected from the group consisting of Cys118, Cys239, and Cys265. In one embodiment, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a D265C mutation. In one embodiment, the Fc region comprises a D265C and H435A mutation. In one embodiment, the Fc region comprises a D265C, a L234A, and a L235A mutation. In one embodiment, the Fc region comprises a D265C, a L234A, a L235A, and a H435A mutation.

[0425] In some embodiments of these aspects, the cysteine residue is naturally occurring in the Fc domain of the antibody or antigen-binding fragment thereof. For instance, the Fc domain may be an IgG Fc domain, such as a human IgG1 Fc domain, and the cysteine residue may be selected from the group consisting of Cys261, Csy321, Cys367, and Cys425.

[0426] For example, in one embodiment, the Fc region of Antibody 67 is modified to comprise a D265C mutation (e.g., SEQ ID NO: 111). In another embodiment, the Fc region of Antibody 67 is modified to comprise a D265C, L234A, and L235A mutation (e.g., SEQ ID NO: 112). In yet another embodiment, the Fc region of Antibody 67 is modified to comprise a D265C and H435A mutation (e.g., SEQ ID NO: 113). In a further embodiment, the Fc region of Antibody 67 is modified to comprise a D265C, L234A, L235A, and H435A mutation (e.g., SEQ ID NO: 114).

[0427] In regard to Antibody 55, in one embodiment, the Fc region of Antibody 55 is modified to comprise a D265C mutation (e.g., SEQ ID NO: 117). In another embodiment, the Fc region of Antibody 55 is modified to comprise a D265C, L234A, and L235A mutation (e.g., SEQ ID NO: 118). In yet another embodiment, the Fc region of Antibody 55 is modified to comprise a D265C and H435A mutation (e.g., SEQ ID NO: 119). Ina further embodiment, the Fc region of Antibody 55 is modified to comprise a D265C, L234A, L235A, and H435A mutation (e.g., SEQ ID NO: 120).

[0428] The Fc regions of any one of Antibody 54, Antibody 55, Antibody 56, Antibody 57, Antibody 58, Antibody 61, Antibody 66, Antibody 67, Antibody 68, or Antibody 69 can be modified to comprise a D265C mutation (e.g., as in SEQ ID NO: 123); a D265C, L234A, and L235A mutation (e.g., as in SEQ ID NO: 124); a D265C and H435A mutation (e.g., as in SEQ ID NO: 125); or a D265C, L234A, L235A, and H435A mutation (e.g., as in SEQ ID NO: 126).

[0429] The variant Fc domains described herein are defined according to the amino acid modifications that compose them. For all amino acid substitutions discussed herein in regard to the Fc region, numbering is always according to the EU index. Thus, for example, D265C is an Fc variant with the aspartic acid (D) at EU position 265 substituted with cysteine (C) relative to the parent Fc domain. Likewise, e.g., D265C/L234A/L235A defines a variant Fc variant with substitutions at EU positions 265 (D to C), 234 (L to A), and 235 (L to A) relative to the parent Fc domain. A variant can also be designated according to its final amino acid composition in the mutated EU amino acid positions. For example, the L234A/L235A mutant can be referred to as LALA. It is noted that the order in which substitutions are provided is arbitrary.

[0430] In one embodiment, the antibody, or antigen binding fragment thereof, comprises variable regions having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein. Alternatively, the antibody, or antigen binding fragment thereof, comprises CDRs comprising the SEQ ID Nos disclosed herein with framework regions of the variable regions described herein having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein.

[0431] In one embodiment, the antibody, or antigen binding fragment thereof, comprises a heavy chain variable region and a heavy chain constant region having an amino acid sequence that is disclosed herein. In another embodiment, the antibody, or antigen binding fragment thereof, comprises alight chain variable region and a light chain constant region having an amino acid sequence that is disclosed herein. In yet another embodiment, the antibody, or antigen binding fragment thereof, comprises a heavy chain variable region, a light chain variable region, a heavy chain constant region and alight chain constant region having an amino acid sequence that is disclosed herein.

Methods of Identifying Antibodies

[0432] Provided herein are novel ADCs that may be used, for example, in conditioning methods for stem cell transplantation. In view of the disclosure herein, other antibodies can be identified that can be used in the ADCs and methods of the invention.

[0433] Methods for high throughput screening of antibody, or antibody fragment libraries for molecules capable of binding a cell surface antigen (e.g., CD117, CD45, CD2, CD5, CD134, CD252, CD137) can be used to identify and affinity mature antibodies useful for treating cancers, autoimmune diseases, and conditioning a patient (e.g., a human patient) in need of hematopoietic stem cell therapy as described herein. Such methods include in vitro display techniques known in the art, such as phage display, bacterial display, yeast display, mammalian cell display, ribosome display, mRNA display, and cDNA display, among others. The use of phage display to isolate ligands that bind biologically relevant molecules has been reviewed, for example, in Felici et al., Biotechnol. Annual Rev. 1:149-183, 1995; Katz, Annual Rev. Biophys. Biomol. Struct. 26:27-45, 1997; and Hoogenboom et al., Immunotechnology 4:1-20, 1998, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display techniques. Randomized combinatorial peptide libraries have been constructed to select for polypeptides that bind cell surface antigens as described in Kay, Perspect. Drug Discovery Des. 2:251-268, 1995 and Kay et al., Mol. Divers. 1:139-140, 1996, the disclosures of each of which are incorporated herein by reference as they pertain to the discovery of antigen-binding molecules. Proteins, such as multimeric proteins, have been successfully phage-displayed as functional molecules (see, for example, EP 0349578; EP 4527839; and EP 0589877, as well as Chiswell and McCafferty, Trends Biotechnol. 10:80-84 1992, the disclosures of each of which are incorporated herein by reference as they pertain to the use of in vitro display techniques for the discovery of antigen-binding molecules). In addition, functional antibody fragments, such as Fab and scFv fragments, have been expressed in in vitro display formats (see, for example, McCafferty et al., Nature 348:552-554, 1990; Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982, 1991; and Clackson et al., Nature 352:624-628, 1991, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display platforms for the discovery of antigen-binding molecules). These techniques, among others, can be used to identify and improve the affinity of antibodies that bind, e.g., CD117, CD45, CD2, CD5, CD134, CD252, CD137 (e.g., GNNK+ CD117) that can in turn be used to deplete endogenous hematopoietic stem cells in a patient (e.g., a human patient) in need of hematopoietic stem cell transplant therapy.

[0434] In addition to in vitro display techniques, computational modeling techniques can be used to design and identify antibodies, and antibody fragments, in silico that bind a cell surface antigen (e.g., CD117, CD45, CD2, CD5, CD134, CD252, CD137). For example, using computational modeling techniques, one of skill in the art can screen libraries of antibodies, and antibody fragments, in silico for molecules capable of binding specific epitopes, such as extracellular epitopes of this antigen. The antibodies, and antigen-binding fragments thereof, identified by these computational techniques can be used in conjunction with the therapeutic methods described herein, such as the cancer and autoimmune disease treatment methods described herein and the patient conditioning procedures described herein.

[0435] Additional techniques can be used to identify antibodies, and antigen-binding fragments thereof, that bind a cell surface antigen (e.g., CD117) on the surface of a cell (e.g., a cancer cell, autoimmune cell, or hematopoietic stem cell) and that are internalized by the cell, for instance, by receptor-mediated endocytosis. For example, the in vitro display techniques described above can be adapted to screen for antibodies, and antigen-binding fragments thereof, that bind a cell surface antigen (e.g., CD117) on the surface of a cancer cell, autoimmune cell, or hematopoietic stem cell and that are subsequently internalized. Phage display represents one such technique that can be used in conjunction with this screening paradigm. To identify antibodies, and fragments thereof, that bind a cell surface antigen (e.g., CD117) and are subsequently internalized by cancer cells, autoimmune cells, or hematopoietic stem cells, one of skill in the art can adapt the phage display techniques described, for example, in Williams et al., Leukemia 19:1432-1438, 2005, the disclosure of which is incorporated herein by reference in its entirety. For example, using mutagenesis methods known in the art, recombinant phage libraries can be produced that encode antibodies, antibody fragments, such as scFv fragments, Fab fragments, diabodies, triabodies, and .sup.10Fn3 domains, among others, or ligands that contain randomized amino acid cassettes (e.g., in one or more, or all, of the CDRs or equivalent regions thereof or an antibody or antibody fragment). The framework regions, hinge, Fc domain, and other regions of the antibodies or antibody fragments may be designed such that they are non-immunogenic in humans, for instance, by virtue of having human germline antibody sequences or sequences that exhibit only minor variations relative to human germline antibodies.

[0436] Using phage display techniques described herein or known in the art, phage libraries containing randomized antibodies, or antibody fragments, covalently bound to the phage particles can be incubated with a cell surface target antigen (e.g., CD117) antigen, for instance, by first incubating the phage library with blocking agents (such as, for instance, milk protein, bovine serum albumin, and/or IgG so as to remove phage encoding antibodies, or fragments thereof, that exhibit non-specific protein binding and phage that encode antibodies or fragments thereof that bind Fc domains, and then incubating the phage library with a population of hematopoietic stem cells. The phage library can be incubated with the target cells, such as cancer cells, autoimmune cells, or hematopoietic stem cells for a time sufficient to allow cell surface antigen specific antibodies, or antigen-binding fragments thereof, (e.g., CD117-specific antibodies, or antigen-binding fragments thereof) to bind cell-surface antigen (e.g., sell-surface CD117) antigen and to subsequently be internalized by the cancer cells, autoimmune cells, or hematopoietic stem cells (e.g., from 30 minutes to 6 hours at 4.degree. C., such as 1 hour at 4.degree. C.). Phage containing antibodies, or fragments thereof, that do not exhibit sufficient affinity for one or more of these antigens so as to permit binding to, and internalization by, cancer cells, autoimmune cells, or hematopoietic stem cells can subsequently be removed by washing the cells, for instance, with cold (4.degree. C.) 0.1 M glycine buffer at pH 2.8. Phage bound to antibodies, or fragments thereof, that have been internalized by the cancer cells, autoimmune cells, or hematopoietic stem cells can be identified, for instance, by lysing the cells and recovering internalized phage from the cell culture medium. The phage can then be amplified in bacterial cells, for example, by incubating bacterial cells with recovered phage in 2.times.YT medium using methods known in the art. Phage recovered from this medium can then be characterized, for instance, by determining the nucleic acid sequence of the gene(s) encoding the antibodies, or fragments thereof, inserted within the phage genome. The encoded antibodies, or fragments thereof, can subsequently be prepared de novo by chemical synthesis (for instance, of antibody fragments, such as scFv fragments) or by recombinant expression (for instance, of full-length antibodies).

[0437] An exemplary method for in vitro evolution of a cell surface antigen antibody (e.g., anti-CD117) antibodies for use with the compositions and methods described herein is phage display. Phage display libraries can be created by making a designed series of mutations or variations within a coding sequence for the CDRs of an antibody or the analogous regions of an antibody-like scaffold (e.g., the BC, CD, and DE loops of .sup.10Fn3 domains). The template antibody-encoding sequence into which these mutations are introduced may be, for example, a naive human germline sequence. These mutations can be performed using standard mutagenesis techniques known in the art. Each mutant sequence thus encodes an antibody corresponding to the template save for one or more amino acid variations. Retroviral and phage display vectors can be engineered using standard vector construction techniques known in the art. P3 phage display vectors along with compatible protein expression vectors can be used to generate phage display vectors for antibody diversification.

[0438] The mutated DNA provides sequence diversity, and each transformant phage displays one variant of the initial template amino acid sequence encoded by the DNA, leading to a phage population (library) displaying a vast number of different but structurally related amino acid sequences. Due to the well-defined structure of antibody hypervariable regions, the amino acid variations introduced in a phage display screen are expected to alter the binding properties of the binding peptide or domain without significantly altering its overall molecular structure.

[0439] In a typical screen, a phage library may be contacted with and allowed to bind one of the foregoing antigens or an epitope thereof. To facilitate separation of binders and non-binders, it is convenient to immobilize the target on a solid support. Phage bearing a cell surface-binding moiety can form a complex with the target on the solid support, whereas non-binding phage remain in solution and can be washed away with excess buffer. Bound phage can then liberated from the target by changing the buffer to an extreme pH (pH 2 or pH 10), changing the ionic strength of the buffer, adding denaturants, or other known means.

[0440] The recovered phage can then be amplified through infection of bacterial cells, and the screening process can be repeated with the new pool that is now depleted in non-binding antibodies and enriched for antibodies that bind a target antigen (e.g., CD117). The recovery of even a few binding phage is sufficient to amplify the phage for a subsequent iteration of screening. After a few rounds of selection, the gene sequences encoding the antibodies or antigen-binding fragments thereof derived from selected phage clones in the binding pool are determined by conventional methods, thus revealing the peptide sequence that imparts binding affinity of the phage to the target. During the panning process, the sequence diversity of the population diminishes with each round of selection until desirable peptide-binding antibodies remain. The sequences may converge on a small number of related antibodies or antigen-binding fragments thereof. An increase in the number of phage recovered at each round of selection is an indication that convergence of the library has occurred in a screen.

[0441] Another method for identifying antibodies includes using humanizing non-human antibodies that bind a cell surface target antigen (e.g., CD117), for instance, according to the following procedure. Consensus human antibody heavy chain and light chain sequences are known in the art (see e.g., the "VBASE" human germline sequence database; Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, 1991; Tomlinson et al., J. Mol. Biol. 227:776-798, 1992; and Cox et al. Eur. J. Immunol. 24:827-836, 1994, the disclosures of each of which are incorporated herein by reference as they pertain to consensus human antibody heavy chain and light chain sequences. Using established procedures, one of skill in the art can identify the variable domain framework residues and CDRs of a consensus antibody sequence (e.g., by sequence alignment). One can substitute one or more CDRs of the heavy chain and/or light chain variable domains of consensus human antibody with one or more corresponding CDRs of a non-human antibody that binds a cell surface antigen (e.g., CD117) as described herein in order to produce a humanized antibody. This CDR exchange can be performed using gene editing techniques described herein or known in the art.

[0442] To produce humanized antibodies, one can recombinantly express a polynucleotide encoding the above consensus sequence in which one or more variable region CDRs have been replaced with one or more variable region CDR sequences of a non-human antibody that binds a cell surface target antigen (e.g., CD117). As the affinity of the antibody for the hematopoietic stem cell antigen is determined primarily by the CDR sequences, the resulting humanized antibody is expected to exhibit an affinity for the hematopoietic stem cell antigen that is about the same as that of the non-human antibody from which the humanized antibody was derived. Methods of determining the affinity of an antibody for a target antigen include, for instance, ELISA-based techniques described herein and known in the art, as well as surface plasmon resonance, fluorescence anisotropy, and isothermal titration calorimetry, among others.

[0443] The internalizing capacity of an antibody, or fragment thereof, can be assessed, for instance, using radionuclide internalization assays known in the art. For example, antibodies, or fragments thereof, identified using in vitro display techniques described herein or known in the art can be functionalized by incorporation of a radioactive isotope, such as .sup.18F, .sup.75Br, .sup.77Br, .sup.122I, .sup.123I, .sup.124I, .sup.125I, .sup.129I, .sup.131I, .sup.211At, .sup.67Ga, .sup.111In, .sup.99Tc, .sup.169Yb, .sup.186Re, .sup.64Cu, .sup.67Cu, .sup.177Lu, .sup.77As, .sup.72As, .sup.86Y, .sup.90Y, .sup.89Zr, .sup.212Bi, .sup.213Bi, or .sup.225Ac. For instance, radioactive halogens, such as .sup.18F, .sup.75Br, .sup.77Br, .sup.122I, .sup.123I, .sup.124I, .sup.125I, .sup.129I, .sup.131I, .sup.211At, can be incorporated into antibodies, or fragments thereof, using beads, such as polystyrene beads, containing electrophilic halogen reagents (e.g., Iodination Beads, Thermo Fisher Scientific, Inc., Cambridge, Mass.). Radiolabeled antibodies, or fragments thereof, can be incubated with cancer cells, autoimmune cells, or hematopoietic stem cells for a time sufficient to permit internalization (e.g., from 30 minutes to 6 hours at 4.degree. C., such as 1 hour at 4.degree. C.). The cells can then be washed to remove non-internalized antibodies, or fragments thereof, (e.g., using cold (4.degree. C.) 0.1 M glycine buffer at pH 2.8). Internalized antibodies, or fragments thereof, can be identified by detecting the emitted radiation (e.g., .gamma.-radiation) of the resulting cancer cells, autoimmune cells, or hematopoietic stem cells in comparison with the emitted radiation (e.g., .gamma.-radiation) of the recovered wash buffer.

[0444] Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No. 4,816,567. In one embodiment, isolated nucleic acid encoding an antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making an anti-CLL-1 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0445] For recombinant production of an antibody, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0446] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0447] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).

Pharmaceutical Compositions

[0448] ADCs described herein can be administered to a patient (e.g., a human patient suffering from an immune disease or cancer) in a variety of dosage forms. For instance, ADCs described herein can be administered to a patient suffering from an immune disease or cancer in the form of an aqueous solution, such as an aqueous solution containing one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients for use with the compositions and methods described herein include viscosity-modifying agents. The aqueous solution may be sterilized using techniques known in the art.

[0449] Pharmaceutical formulations comprising ADCs as described herein are prepared by mixing such ADC with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG).

Methods of Use

[0450] ADCs described herein may be administered by a variety of routes, such as orally, transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intraocularly, or parenterally. The most suitable route for administration in any given case will depend on the particular antibody, or antigen-binding fragment, administered, the patient, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient's age, body weight, sex, severity of the diseases being treated, the patient's diet, and the patient's excretion rate.

[0451] The effective dose of an ADC, antibody, or antigen-binding fragment thereof, described herein can range, for example from about 0.001 to about 100 mg/kg of body weight per single (e.g., bolus) administration, multiple administrations, or continuous administration, or to achieve an optimal serum concentration (e.g., a serum concentration of 0.0001-5000 .mu.g/mL) of the antibody, antigen-binding fragment thereof. The dose may be administered one or more times (e.g., 2-10 times) per day, week, or month to a subject (e.g., a human) suffering from cancer, an autoimmune disease, or undergoing conditioning therapy in preparation for receipt of a hematopoietic stem cell transplant. In the case of a conditioning procedure prior to hematopoietic stem cell transplantation, the ADC, antibody, or antigen-binding fragment thereof, can be administered to the patient at a time that optimally promotes engraftment of the exogenous hematopoietic stem cells, for instance, from 1 hour to 1 week (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days) or more prior to administration of the exogenous hematopoietic stem cell transplant.

EXAMPLES

[0452] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

Example 1: Comparative Study of Amatoxins

[0453] Three different amanitins were tested in parallel to determine their kinetics and tolerability as toxins. FIG. 1 provides the structures of three amanitin/linker conjugates. FIG. 1A provides an amanitin/linker conjugate represented by Formula (IV) (also referred to as "Conjugate A" or "ADC A"), where the amanitin has a cleavable linker (BMP-Val-Ala-PAB) linker on AA1 (Asn). The amanitin in Formula (IV) is based on amatoxin having thiotryptophan moiety. FIG. 1B provides an amanitin/linker conjugate represented by Formula (VI) (also referred to as "Conjugate B" or "ADC B", where the amanitin is conjugated to a non-cleavable linker on indole 6' oxygen. The amanitin described in Formula (VI) is based on amatoxin having 6-hydroxy-tryptophan sulfoxide moiety. FIG. 1C provides an amanitin/linker conjugate described herein in Formula (IIa) (also referred to as "Conjugate C" or "ADC C", including a non-cleavable linker on indole 6' oxygen, where the amanitin is based on amatoxin having 6-hydroxy-thiotryptophan moiety.

[0454] Conjugates A, B and C were tested in parallel for their potency on CD117 expressing cells with or without a pre-incubation in human serum. ADC A, B, and C were either pre-incubated in cell culture media without human serum or 50% human serum at 37 C for 48 hours. The titrated ADC was then added to Kasumi-1 cells and incubated for 3 days at 37 C and cell killing was determined using CellTiter-Go. As described in FIG. 2, in the absence of serum incubation, cleavable Conjugate A and non-cleavable Conjugate C reached similar efficacy by day 3, with non-cleavable conjugate B demonstrating reduced maximum killing at higher concentrations. Each ADC conjugate demonstrated picomolar IC50 killing. When ADC was pre-incubated for 48 hours in the presence of human serum, potency was significantly decreased for non-cleavable conjugate B but was maintained for cleavable conjugate A and non-cleavable conjugate C. Thus, cleavable and non-cleavable conjugates A and C were serum stable while non-cleavable conjugate B was inactivated in the presence of human serum as measured by in vitro cytotoxicity.

[0455] To determine differences in the kinetics of ADC-mediated cytotoxicity, Kasumi-1 cells were incubated with titrations of cleavable conjugate A or non-cleavable conjugate C for 3-7 days at 37 C and cell viability was measured on day 3, 4, 5, 6, and 7 by CellTiter-Glo. As shown in FIG. 3, significant differences were observed in maximum cell killing at high concentrations for cleavable and non-cleavable ADC. When cells were incubated for a total of 6 days at 37 C with ADC, both cleavable conjugate A and non-cleavable conjugate C were able to achieve nearly complete cell killing at high concentrations. Killing of greater than 80% of Kasumi-1 cells in culture with 160 pM non-cleavable conjugate C could only be achieved after incubation of Kasumi-1 cells for 5 days or longer, while a similar threshold was achieved for cleavable conjugate A after 3 days or longer incubation.

[0456] In sum, the enzyme cleavable amanitin of FIG. 1A (Conjugate A) and the non-cleavable amanitin (conjugate C in FIG. 1C) showed long term stability in serum, while amanitin/linker B showed instability and inactivation in serum. Non-cleavable conjugate C demonstrated extended kinetics of cytotoxicity as measured in an in vitro assay compared to a similar cleavable amanitin conjugate (conjugate A).

Example 2: Anti-CD117 ADC Demonstrates Potent Killing of AML Cells and Human CD34+ Cells In Vitro, Selectively Depletes Human CD34+ Cells in Humanized Mice, and Demonstrates Anti-AML Activity in Xenograft Models

[0457] An anti-CD117 antibody (Ab85 having Fc modifications L234A, L235A, D265C, and H435A) was conjugated to Conjugate C forming anti-CD117 ADC C. Anti-CD117 ADC C was tested both in vitro and in vivo for its ability to target and kill cells expressing CD117 and human HSCs.

[0458] Two in vitro assays were performed using anti-CD117 ADC C. The first tested the ability of the ADC to kill Kasumi-1 cells (an AML cell line), which express human CD117. As described in FIG. 4A, Anti-CD117 ADC C (referred to as "Anti-CD117-AM" in FIG. 4A) was titrated and incubated with Kasumi-1 cells for 6 days at 37 C and viability was assessed by CellTiter-Glo. The control was a non-specific isotype matched ADC C. Non-cleavable conjugate C demonstrated potent killing of Kasumi-1 cells with an IC50 of 6.4 pM. In FIG. 4B, a similar cytotoxicity assay using Human CD34+ bone marrow cells collected was performed. Human CD34+ bone marrow cells were incubated with non-cleavable conjugate C or a corresponding isotype control ADC for 6 days. Cell killing was determined by flow cytometry. The non-cleavable conjugate C demonstrated potent killing of primary human CD34+ CD90+ cells with an IC50 of 5.1 pM.

[0459] An in vivo assay was also performed to test the ability of anti-CD117 ADC C to selectively deplete human CD34+ cells. A single dose of 0.1, 0.3, or 1.0 mg/kg of the anti-CD117 ADC C was administered to humanized NSG mice. Controls consisted of a 1 mg/kg dose of the unconjugated antibody that comprised part of non-cleavable conjugate C and vehicle (PBS) treatment. At Day 21, the number of human CD34+ cells were determined by flow cytometry analysis of bone marrow collected from the femur of treated humanized NSG mice. As described in FIG. 5, anti-CD117 ADC C was able to potently deplete human CD34+ cells, achieving greater than 95% depletion compared to PBS for both 0.3 and 1 mg/kg doses. The unconjugated antibody demonstrated no depletion as compared to vehicle control.

[0460] To assess in vivo anti-tumor activity of ADCs, humanized NSG mice were implanted with Kasumi-1 cells and then treated with vehicle, 30 mg/kg QD.times.5 cytarabine (ARA-C), cleavable conjugate A (1 mg/kg 1.times., 1 mg/kg QOD.times.2) or 10 mg/kg isotype conjugated to cleavable amanitin (FIG. 1A). In addition, Kasumi-1 implanted mice were treated with non-cleavable conjugate C (1 mg/kg 1.times., 3 mg/kg 1.times., 10 mg/kg 1.times.) or 10 mg/kg isotype conjugated to non-cleavable amanitin (FIG. 1C). Kaplan-Meier curves demonstrating survival of animals treated as indicated is depicted in FIG. 6. Kasumi-1 implanted mice treated with cleavable conjugate A demonstrate median survival above 50% at day 130 for groups treated with either 1 mg/kg or 1 mg/kg QOD.times.2 in comparison to isotype, ARA-C, or vehicle treated animals. Mice treated with either 3 mg/kg or 10 mg/kg non-cleavable conjugate C demonstrate full survival at day 130 in comparison to isotype, ARA-C, 1 mg/kg non-cleavable conjugate C, or vehicle treated animals.

[0461] In summary, non-cleavable conjugate C demonstrates potent in vitro cell killing of Kasumi-1 cells, an AML cell line, and primary human CD34+ CD90+ bone marrow cells. Conjugate C is capable of depleting more than 95% of human CD34+ cells from the bone marrow of humanized NSG mice. Both cleavable and non-cleavable conjugates demonstrated potent anti-tumor activity in vivo.

Example 3: Efficacy and Tolerability of ADC C in Non-Human Primates (NHPs)

[0462] To determine the efficacy of non-cleavable conjugate C in non-human primates, male cynomologus monkeys were treated with a single dose of non-cleavable conjugate C at 0.5, 1.0, and 2.0 mg/kg. The 0.5 and 1.0 mg/kg doses were with Ab85 with the following Fc modifications: D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (FIG. 1C). The 2.0 mg/kg dose comprised Ab85 with the following Fc modifications: L234A L235A D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (FIG. 1C). Bone marrow aspirates were collected from treated animals on day 7 and efficacy was assessed by quantitation of CD34+ CD90+ CD45RA- populations by flow cytometry. Significant depletion was observed at 0.5 and 1.0 mg/kg doses (FIG. 7). Peripheral blood samples were collected throughout the course of the 28 day study. Reticulocyte counts of animals treated at 0.5, 1.0, and 2.0 mg/kg decreased significantly beginning on day 2 with reticulocyte rebound occurring in a dose-dependent manner (FIG. 7). This is expected on-target pharmacology as reticulocytes are short-lived and progenitor populations in this hematopoietic lineage strongly express CD117. Neutrophil depletion was observed beginning on day 18 for all treatment groups (FIG. 7). This is also expected on-target pharmacology, as neutrophils are dependent on hematopoietic stem cell differentiation for regeneration.

[0463] In addition to efficacy, tolerability of ADCs containing either anti-CD117 ADC A or anti-CD117 ADC C were tested in NHPs. As described in FIG. 8, treatment of cynomologus monkeys with a 0.3 mg/kg dose of cleavable conjugate A conjugated to antibody CK6 (Fc modifications D265C and H435A) resulted in mild transient and reversible elevation of aspartate aminotransferase (AST) levels, with no elevation above normal range for alanine aminotransferase (ALT), lactate dehydrogenase (LDH), or total bilirubin (TBIL) over the course of the study. Treatment of animals with a 0.6 mg/kg dose of conjugate A resulted in more significant elevation of AST, ALT, LDH, and TBIL.

[0464] In cynomolgus monkeys treated with 0.5 and 1.0 mg/kg non-cleavable conjugate C, Ab85 with the following Fc modifications: D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (FIG. 1C), demonstrated mild transient and reversible elevation in AST with no elevation above normal range for ALT, LDH, and TBIL throughout the course of the study. In animals treated with 2.0 mg/kg non-cleavable conjugate C, Ab85 with the following Fc modifications: L234A L235A D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (FIG. 1C), more significant elevation was observed for AST and ALT. Results are described in FIG. 8.

[0465] Pharmacokinetic characteristics were also studied in anti-CD117 ADC A vs. C. As described in FIG. 9, well tolerated doses of ADC conjugate C achieved saturating explosures in NHPs compared to ADC Conjugate A. Pharmacokinetic data was also analyzed for ADC conjugate C with various Fc mutations. For both anti-CD117 ADC A and anti-CD117 ADC C, ex vivo cytotoxicity assays revealed that for boths ADCs there was a loss of efficacy at plasma concentrations below 100 ng/ml (data not shown).

[0466] In sum, anti-CD117 ADC C demonstrated efficacy at doses as low as 0.5 mg/kg and was tolerated at a single dose of 2.0 mg/kg in cynomologus monkeys while the cleavable conjugate A was efficacious at a dose as low as 0.3 mg/kg but not tolerated at a single dose of 0.6 mg/kg supporting the finding that non-cleavable amanitin (FIG. 1C) is better tolerated.

Example 4: Primary Human T-Cell Killing with Anti-CD2 ADC C and Anti-CD5 ADC C

[0467] A study was performed to determine if anti-CD2 and anti-CD5 D265C H435A antibodies used in an ADC C (as described above and in FIG. 1) was as efficacious as Conjugate A for killing primary T cells. Thus, an in vitro cell killing assay was used. The protocol of the study is provided below:

TABLE-US-00011 General Protocol T cell killing assay: 384 well format Coat plate with 0.5 mg/mL anti-CD3 incubate in 37 C. for 2 hours in TC treated low flange 384 well plate Wash plate Thaw primary T cells with AIM-V media Plate 2500 cells per well + 20 ng recombinant human IL-2 Titrate antibodies and add to cells in duplicate for 30 min on ice Culture for in 37.degree. C. for 5 days On day 5, stain cells for CD3, Live/Dead marker for 30 min, using Viaflo aspirate volume and add PBS Run cells on Celesta Readout: viability, CD2 and CD5 expression by flow

[0468] Anti-CD2 ADCs A and C included anti-CD2 antibody RPA with FC modifications D265C/H435A. Naked RPA was used as a control. Anti-CD5 ADCs A and C included anti-CD5 antibody 5D7 with Fc modifications D265/H435A. Naked 5D7 was used as a control. As described in FIG. 10, Conjugate C demonstrated T cell depletion comparable to Conjugate A. Effiicacy results are also provide in the table below.

TABLE-US-00012 IC50 % Label DAR (pM) Efficacy Ab85 D265C/H435A ADC A 1.9 -- 0.9 CD2 RPA naked -- -- 0.0 CD2 RPA2.10 D265C/H435A ADC A 2.1 54.0 85.7 CD2 RPA2.10 D265C/H435A ADC C 2.1 86.9 78.7 CD5 5D7 naked -- -- 0.0 CD5 5D7 D265C/H435A ADC A 2 22.1 89.4 CD5 5D7 D265C/H435A Ab ADC C 2.0 50.8 84.9

[0469] FIG. 11 provides results showing that CD2 is saturated by day 5, whereas some cells still express CD5.

[0470] The results above and in FIGS. 10 and 11 show that both anti-CD2 and anti-CD5 ADCs C (D265C H435A) were as efficacious as Conjugate A on primary human T-cells in vitro.

Example 5: Efficacy of Anti-CD45 ADC C

[0471] In addition to CD2, CD5, and CD117, Conjugate C was tested in comparison to Conjugate A in the context of anti-CD45 antibodies. A chimeric anti-CD45 antibody 3D6 was used in the below experiments (murine 3D6 variable regions and a human IgG1 framework with Fc modifications D265C and H435A).

[0472] An in vitro cell killing assay was performed comparing anti-CD45 ADC A and anti-CD45 ADC C. As described in FIG. 12A, both ADCs A and C were able to kill human bone marrow CD34+ cells, as well as PBMC. An isotype negative control was also tested. As described in the Table presented in FIG. 12A, both anti-CD45 ADCs A and C were effective at killing CD34+ bone marrow and PBMC cells. This assay was repeated with anti-CD45 ADC A and B, As described in FIG. 12B, anti-CD45 ADC A showed a higher efficiency for killing CD34+ bone marrow cells vs. anti-CD45 ADC B. Both molecules were effective in a similar manner at killing human and cyno PBMCs.

[0473] A second in vitro cell killing assay was also performed using anti-CD45 ADCs A and C looking at the ability of each ADC to kill cells expressing either SKNO-1 or REH. The results are provided in FIG. 13 (left panel are the number of live SKNO-1 cells following exposure to anti-CD45 ADC A or C; right panel are the number of live REH cells following exposure to anti-CD45 ADC A or C). The efficiency of each molecule in these assays is described in the table in FIG. 13.

[0474] Anti-CD45 ADCs A and C were further tested for the ability of each ADC to deplete CD45+ cells in vivo. Both ADC A (cleavable) and ADC C (non-cleavable) were able to deplete CD45+ cells efficiently in a humanized NSG mouse model. The results of the study are provided in FIG. 14. As described in FIG. 14, both ADCs were able to deplete peripheral CD45+ cells as well as bone marrow (BM) CD34+ cells. The maximum total dose in the mice for anti-CD45 ADC A was 3 mg/kg, whereas a much higher dose of ADC C was tolerated for anti-CD45 ADC C at more than 51 mg/kg. Thus, efficacy was observed for both anti-CD45 ADCs, but the ADC C was tolerated by the mice at higher doses.

[0475] Anti-CD45 ADCs A and C were also tested for their ability to deplete peripheral lymphocytes, bone marrow (BM) HSCs and lymphocytes in humanized NSG mice. Anti-CD45 ADCs A and C were each delivered at a dose of 1 mg/kg to the mice. The results from these studies are described in FIG. 15 and show that anti-CD45 ADCs A and C had comparable depletion of peripheral lymphocytes, HSCs, and BM lymphocytes at day 7 post injection at 1 mg/kg. Anti-CD45 ADC A showed mild, transient reversible liver enzyme elevation at 1 mg/kg, while little to no liver enzyme elevation was observed with anti-CD45 ADC C with the same 1 mg/kg dose.

Example 6: Anti-CD137 ADC A and C Characterization

[0476] Anti-CD137 ADC A and ADC C were tested for their ability to kill T cells, as well as for serum stability. Anti-CD137 antibody BBK2 was used in this example. An in vitro T cell killing assay was performed, where the results shown in FIG. 16 demonstrated both anti-CD137 ADC A and C were able to kill activated T cells in comparison to the isotype ADC A and C control. In addition, cell line serum stability was tested for both anti-CD137 ADC A and C over 48 hours, as described in FIG. 17.

Example 7: Synthesis of S-desoxy-5'-hydroxy-amaninamide

[0477] The ADCs of formula (IIa) as disclosed herein were prepared from the corresponding linker-amatoxin conjugates according to standard methods known to one of skill in the art. The penultimate amatoxin-linker conjugate to the ADCs of formula (IIa) (compound 14; Scheme 3) may be prepared from amatoxin derivative 11 following the general procedure for O-alkylation of the related amatoxin (.alpha.-amanitin) disclosed in U.S. Patent Application Publication No. 2018/0043033, the disclosure of which is incorporated by reference herein in its entirety. Amatoxin derivative 11 may be prepared according to the procedures disclosed in International Patent Application Publication No. WO2019/030173, the disclosure of which is incorporated by reference herein in its entirety. Compound 7 (Scheme 1) may be prepared according to the methods reported in International Patent Application Publication No. WO2014/009025, the disclosure of which is incorporated herein in its entirety.

TABLE-US-00013 SEQUENCE TABLE Sequence Identifier Description Sequence SEQ ID NO: 1 CK6 CDR-H1 SYWIG SEQ ID NO: 2 CK6 CDR-H2 IIYPGDSDTRYSPSFQG SEQ ID NO: 3 CK6 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: 4 CK6 CDR-L1 RASQGISSALA SEQ ID NO: 5 CK6 CDR-L2 DASSLES SEQ ID NO: 6 CK6 CDR-L3 CQQFNSYPLT SEQ ID NO: 7 Consensus human EVQLVESGGGLVQPGGSLRLSCAASGFTFSD Ab YAMSWVRQAPGKGLEWVAVISENGSDTYYA Heavy chain variable DSVKGRFTISRDDSKNTLYLQMNSLRAEDTAV domain YYCARDRGGAVSYFDVWGQGTLVTVSS SEQ ID NO: 8 Consensus human DIQMTQSPSSLSASVGDRVTITCRASQDVSSY Ab LAWYQQKPGKAPKLLIYAASSLESGVPSRFS Light chain variable GSGSGTDFTLTISSLQPEDFATYYCQQYNSLP domain YTFGQGTKVEIKRT SEQ ID NO: 9 Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSD variable region (e.g., ADMDWVRQAPGKGLEWVGRTRNKAGSYTTE as found in HC-67) YAASVKGRFTISRDDSKNSLYLQMNSLKTEDT (CDRs in bold) AVYYCAREPKYWIDFDLWGRGTLVTVSS SEQ ID NO: 10 Ab67 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-67) GSGTDFILTISSLOPEDFATYYCQQSYIAPYT (CDRs in bold) FGGGTKVEIK SEQ ID NO: 11 Ab67 CDR-H1 FTFSDADMD SEQ ID NO: 12 Ab67 CDR-H2 RTRNKAGSYTTEYAASVKG SEQ ID NO: 13 Ab67 CDR-H3 AREPKYWIDFDL SEQ ID NO: 14 Ab67 CDR-L1 RASQSISSYLN SEQ ID NO: 15 Ab67 CDR-L2 AASSLQS SEQ ID NO: 16 Ab67 CDR-L3 QQSYIAPYT SEQ ID NO: 17 Ab67 Heavy chain GAGGTGCAGCTGGTGGAGTCTGGGGGAGG variable region CTTGGTCCAGCCTGGAGGGTCCCTGAGACT (nucl) CTCCTGTGCAGCCTCTGGATTCACCTTCAGT GACGCCGACATGGACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTTGGCC GTACTAGAAACAAAGCAGGAAGTTACACCAC AGAATACGCCGCGTCTGTGAAAGGCAGATT CACCATCTCAAGAGATGATTCAAAGAACTCA CTGTATCTGCAAATGAACAGCCTGAAAACCG AGGACACGGCGGTGTACTACTGCGCCAGAG AGCCTAAATACTGGATCGACTTCGACCTATG GGGGAGAGGTACCTTGGTCACCGTCTCCTC A SEQ ID NO: 18 Ab67 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAGC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAAGC TACATCGCCCCTTACACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAA SEQ ID NO: 19 Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI variable region (e.g., YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ as found in HC-55) KFQGRVTITADESTSTAYMELSSLRSEDTAVY (CDRs in bold) YCARGGLDTDEFDLWGRGTLVTVSS SEQ ID NO: 20 Ab55 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSINSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-55) SGSGTDFTLTISSLQPEDFATYYCQQGVSDITF (CDRs in bold) GGGTKVEIK SEQ ID NO: 21 Ab55 CDR-H1 GTFRIYAIS SEQ ID NO: 22 Ab55 CDR-H2 GIIPDFGVANYAQKFQG SEQ ID NO: 23 Ab55 CDR-H3 ARGGLDTDEFDL SEQ ID NO: 24 Ab55 CDR-L1 RASQSINSYLN SEQ ID NO: 25 Ab55 CDR-L2 AASSLQS SEQ ID NO: 26 Ab55 CDR-L3 QQGVSDIT SEQ ID NO: 27 Ab55 Heavy chain CAGGTGCAGCTGGTGCAGTCTGGGGCTGA variable region GGTGAAGAAGCCTGGGTCCTCGGTGAAGGT (nucl) CTCCTGCAAGGCTTCTGGAGGCACCTTCCG AATCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCATCCCTGACTTCGGTGTAGCAAACTA CGCACAGAAGTTCCAGGGCAGAGTCACGAT TACCGCGGACGAATCCACGAGCACAGCCTA CATGGAGCTGAGCAGCCTGAGATCTGAGGA CACGGCGGTGTACTACTGCGCCAGAGGTGG ATTGGACACAGACGAGTTCGACCTATGGGG GAGAGGTACCTTGGTCACCGTCTCCTCA SEQ ID NO: 28 Ab55 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAAC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAGGA GTCAGTGACATCACTTTTGGCGGAGGGACC AAGGTTGAGATCAAA SEQ ID NO: 29 Ab54 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSS variable region (e.g., YAISWVRQAPGQGLEWMGGIIPIFGTANYAQK as found in HC-54) FQGRVTITADESTSTAYMELSSLRSEDTAVYY hIgG1 backbone CARGGLDTDEFDLWGRGTLVTVSS (CDRs in bold) SEQ ID NO: 30 Ab54 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSINSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-54) GSGTDFTLTISSLQPEDFATYYCQQGVSDITF (CDRs in bold) GGGTKVEIK SEQ ID NO: 31 Ab54 CDR-H1 GTFSSYAIS SEQ ID NO: 32 Ab54 CDR-H2 GIIPIFGTANYAQKFQG SEQ ID NO: 33 Ab54 CDR-H3 ARGGLDTDEFDL SEQ ID NO: 34 Ab54 CDR-L1 RASQSINSYLN SEQ ID NO: 35 Ab54 CDR-L2 AASSLQS SEQ ID NO: 36 Ab54 CDR-L3 QQGVSDIT SEQ ID NO: 37 Ab54 Heavy chain CAGGTGCAGCTGGTGCAGTCTGGGGCTGA variable region GGTGAAGAAGCCTGGGTCCTCGGTGAAGGT (nucl) CTCCTGCAAGGCTTCTGGAGGCACCTTCAG CAGCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCATCCCTATCTTTGGTACAGCAAACTA CGCACAGAAGTTCCAGGGCAGAGTCACGAT TACCGCGGACGAATCCACGAGCACAGCCTA CATGGAGCTGAGCAGCCTGAGATCTGAGGA CACGGCGGTGTACTACTGCGCCAGAGGTGG ATTGGACACAGACGAGTTCGACCTATGGGG GAGAGGTACCTTGGTCACCGTCTCCTCA SEQ ID NO: 38 Ab54 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAAC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAGGA GTCAGTGACATCACTTTTGGCGGAGGGACC AAGGTTGAGATCAAA SEQ ID NO: 39 Ab56 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSL variable region YAISWVRQAPGQGLEWMGGIIPAFGTANYAQ (e.g., as found in KFQGRVTITADESTSTAYMELSSLRSEDTAVY HC-56) YCARGGLDTDEFDLWGRGTLVTVSS (CDRs in bold) SEQ ID NO: 40 Ab56 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSINSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-56) GSGTDFTLTISSLQPEDFATYYCQQGVSDITF (CDRs in bold) GGGTKVEIK SEQ ID NO: 41 Ab56 CDR-H1 GTFSLYAIS SEQ ID NO: 42 Ab56 CDR-H2 GIIPAFGTANYAQKFQG SEQ ID NO: 43 Ab56 CDR-H3 ARGGLDTDEFDL SEQ ID NO: 44 Ab56 CDR-L1 RASQSINSYLN SEQ ID NO: 45 Ab56 CDR-L2 AASSLQS SEQ ID NO: 46 Ab56 CDR-L3 QQGVSDIT SEQ ID NO: 47 Ab56 Heavy chain CAGGTGCAGCTGGTGCAGTCTGGGGCTGA variable region GGTGAAGAAGCCTGGGTCCTCGGTGAAGGT (nucl) CTCCTGCAAGGCTTCTGGAGGCACCTTCAG CCTCTATGCTATCTCCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCATCCCTGCCTTCGGTACCGCAAACT ACGCACAGAAGTTCCAGGGCAGAGTCACGA TTACCGCGGACGAATCCACGAGCACAGCCT ACATGGAGCTGAGCAGCCTGAGATCTGAGG ACACGGCGGTGTACTACTGCGCCAGAGGTG GATTGGACACAGACGAGTTCGACCTATGGG GGAGAGGTACCTTGGTCACCGTCTCCTCA SEQ ID NO: 48 Ab56 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAAC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAGGA GTCAGTGACATCACTTTTGGCGGAGGGACC AAGGTTGAGATCAAA SEQ ID NO: 49 Ab57 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSL variable region (e.g., YAISWVRQAPGQGLEWMGGIIPHFGLANYAQ as found in HC-57) KFQGRVTITADESTSTAYMELSSLRSEDTAVY hIgG1 backbone YCARGGLDTDEFDLWGRGTLVTVSS (CDRs in bold) SEQ ID NO: 50 Ab57 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSINSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-57) SGSGTDFTLTISSLQPEDFATYYCQQGVSDITF hKappa backbone GGGTKVEIK (CDRs in bold) SEQ ID NO: 51 Ab57 CDR-H1 GTFSLYAIS SEQ ID NO: 52 Ab57 CDR-H2 GIIPHFGLANYAQKFQG SEQ ID NO: 53 Ab57 CDR-H3 ARGGLDTDEFDL SEQ ID NO: 54 Ab57 CDR-L1 RASQSINSYLN SEQ ID NO: 55 Ab57 CDR-L2 AASSLQS SEQ ID NO: 56 Ab57 CDR-L3 QQGVSDIT SEQ ID NO: 57 Ab57 Heavy chain CAGGTGCAGCTGGTGCAGTCTGGGGCTGA variable region GGTGAAGAAGCCTGGGTCCTCGGTGAAGGT (nucl) CTCCTGCAAGGCTTCTGGAGGCACCTTCTC CCTCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAG GGATCATCCCTCACTTCGGTCTCGCAAACTA CGCACAGAAGTTCCAGGGCAGAGTCACGAT TACCGCGGACGAATCCACGAGCACAGCCTA

CATGGAGCTGAGCAGCCTGAGATCTGAGGA CACGGCGGTGTACTACTGCGCCAGAGGTGG ATTGGACACAGACGAGTTCGACCTATGGGG GAGAGGTACCTTGGTCACCGTCTCCTCA SEQ ID NO: 58 Ab57 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAAC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAGGA GTCAGTGACATCACTTTTGGCGGAGGGACC AAGGTTGAGATCAAA SEQ ID NO: 59 Ab5. 8 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSN variable region (e.g., YAMSWVRQAPGKGLEWVSAISGSGGSTYYA as found in HC-58) DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV (CDRs in bold) YYCAKGPPTYHTNYYYMDVWGKGTTVTVSS SEQ ID NO: 60 Ab58 Light chain DIQMTQSPSSVSASVGDRVTITCRASQGISSW variable region (e.g., LAWYQQKPGKAPKLLIYAASSLQSGVPSRFS as found in LC-58) GSGSGTDFTLTISSLQPEDFATYYCQQTNSFP (CDRs in bold) YTFGGGTKVEIK SEQ ID NO: 61 Ab58 CDR-H1 FTFSNYAMS SEQ ID NO: 62 Ab58 CDR-H2 AISGSGGSTYYADSVKG SEQ ID NO: 63 Ab58 CDR-H3 AKGPPTYHTNYYYMDV SEQ ID NO: 64 Ab58 CDR-L1 RASQGISSWLA SEQ ID NO: 65 Ab58 CDR-L2 AASSLQS SEQ ID NO: 66 Ab58 CDR-L3 QQTNSFPYT SEQ ID NO: 67 Ab58 Heavy chain GAGGTGCAGCTGTTGGAGTCTGGGGGAGG variable region CTTGGTACAGCCTGGGGGGTCCCTGAGACT (nucl) CTCCTGTGCAGCCTCTGGATTCACCTTTAGC AATTATGCCATGAGCTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCAGC TATTAGTGGTAGTGGTGGTAGCACATACTAC GCAGACTCCGTGAAGGGCCGGTTCACCATC TCCAGAGACAATTCCAAGAACACGCTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACA CGGCGGTGTACTACTGCGCCAAGGGCCCTC CTACATACCACACAAACTACTACTACATGGA CGTATGGGGCAAGGGTACAACTGTCACCGT CTCCTCA SEQ ID NO: 68 Ab58 Light chain GACATCCAGATGACCCAGTCTCCATCTTCCG variable region TGTCTGCATCTGTAGGAGACAGAGTCACCAT (nucl) CACTTGTCGGGCGAGTCAGGGTATTAGCAG CTGGTTAGCCTGGTATCAGCAGAAACCAGG GAAAGCCCCTAAGCTCCTGATCTATGCTGCA TCCAGTTTGCAAAGTGGGGTCCCATCAAGG TTCAGCGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAA GATTTTGCAACTTATTACTGTCAGCAAACAA ATAGTTTCCCTTACACTTTTGGCGGAGGGAC CAAGGTTGAGATCAAA SEQ ID NO: 69 Ab61 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSS variable region (e.g., YVMIWVRQAPGKGLEWVSSISGDSVTTYVAD as found in HC-61) SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY hIgG1 backbone YCAKGPPTYHTNYYYMDVWGKGTIVIVSS (CDRs in bold) SEQ ID NO: 70 Ab61 Light chain DIQMTQSPSSVSASVGDRVTITCRASQGISSW variable region (e.g., LAWYQQKPGKAPKLLIYAASSLQSGVPSRFS as found in LC-61) GSGSGTDFTLTISSLQPEDFATYYCQQTNSFP (CDRs in bold) YTFGGGTKVEIK SEQ ID NO: 71 Ab61 CDR-H1 FTFSSYVMI SEQ ID NO: 72 Ab61 CDR-H2 SISGDSVTTYYADSVKG SEQ ID NO: 73 Ab61 CDR-H3 AKGPPTYHTNYYYMDV SEQ ID NO: 74 Ab61 CDR-L1 RASQGISSWLA SEQ ID NO: 75 Ab61 CDR-L2 AASSLQS SEQ ID NO: 76 Ab61 CDR-L3 QQTNSFPYT SEQ ID NO: 77 Ab61 Heavy chain GAGGTGCAGCTGTTGGAGTCTGGGGGAGG variable region CTTGGTACAGCCTGGGGGGTCCCTGAGACT (nucl) CTCCTGTGCAGCCTCTGGATTCACCTTTAGC AGCTATGTCATGATCTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCAAG CATTAGTGGTGACAGCGTAACAACATACTAC GCAGACTCCGTGAAGGGCCGGTTCACCATC TCCAGAGACAATTCCAAGAACACGCTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACA CGGCGGTGTACTACTGCGCCAAGGGCCCTC CTACATACCACACAAACTACTACTACATGGA CGTATGGGGCAAGGGTACAACTGTCACCGT CTCCTCA SEQ ID NO: 78 Ab61 Light chain GACATCCAGATGACCCAGTCTCCATCTTCCG variable region TGTCTGCATCTGTAGGAGACAGAGTCACCAT (nucl) CACTTGTCGGGCGAGTCAGGGTATTAGCAG CTGGTTAGCCTGGTATCAGCAGAAACCAGG GAAAGCCCCTAAGCTCCTGATCTATGCTGCA TCCAGTTTGCAAAGTGGGGTCCCATCAAGG TTCAGCGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAA GATTTTGCAACTTATTACTGTCAGCAAACAA ATAGTTTCCCTTACACTTTTGGCGGAGGGAC CAAGGTTGAGATCAAA SEQ ID NO: 79 Ab66 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSD variable region (e.g., HYMDWVRQAPGKGLEWVGRTRNKASSYTTE as found in HC-66) YAASVKGRFTISRDDSKNSLYLQMNSLKTEDT (CDRs in bold) AVYYCAREPKYWIDFDLWGRGTLVTVSS SEQ ID NO: 80 Ab66 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-66) SGSGTDFTLTISSLQPEDFATYYCQQSYIAPYT hKappa backbone FGGGTKVEIK (CDRs in bold) SEQ ID NO: 81 Ab66 CDR-H1 FTFSDHYMD SEQ ID NO: 82 Ab66 CDR-H2 RTRNKASSYTTEYAASVKG SEQ ID NO: 83 Ab66 CDR-H3 AREPKYWIDFDL SEQ ID NO: 84 Ab66 CDR-L1 RASQSISSYLN SEQ ID NO: 85 Ab66 CDR-L2 AASSLQS SEQ ID NO: 86 Ab66 CDR-L3 QQSYIAPYT SEQ ID NO: 87 Ab66 Heavy chain GAGGTGCAGCTGGTGGAGTCTGGGGGAGG variable region CTTGGTCCAGCCTGGAGGGTCCCTGAGACT (nucl) CTCCTGTGCAGCCTCTGGATTCACCTTCAGT GACCACTACATGGACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTTGGCCG TACTAGAAACAAAGCTAGTAGTTACACCACA GAATACGCCGCGTCTGTGAAAGGCAGATTC ACCATCTCAAGAGATGATTCAAAGAACTCAC TGTATCTGCAAATGAACAGCCTGAAAACCGA GGACACGGCGGTGTACTACTGCGCCAGAGA GCCTAAATACTGGATCGACTTCGACCTATGG GGGAGAGGTACCTTGGTCACCGTCTCCTCA SEQ ID NO: 88 Ab66 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAGC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAAGC TACATCGCCCCTTACACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAA SEQ ID NO: 89 Ab68 Heavy chain EVQLVESGGGLVQPGRSLRLSCTASGFTFSD variable region (e.g., HDMNWVRQAPGKGLEWVGRTRNAAGSYTTE as found in HC-68) YAASVKGRFTISRDDSKNSLYLQMNSLKTEDT (CDRs in bold) AVYYCAREPKYWIDFDLWGRGTLVTVSS SEQ ID NO: 90 Ab68 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-68) GSGTDFILTISSLQPEDFATYYCQQSYIAPYT (CDRs in bold) FGGGTKVEIK SEQ ID NO: 91 Ab68 CDR-H1 FTFSDHDMN SEQ ID NO: 92 Ab68 CDR-H2 RTRNAAGSYTTEYAASVKG SEQ ID NO: 93 Ab68 CDR-H3 AREPKYWIDFDL SEQ ID NO: 94 Ab68 CDR-L1 RASQSISSYLN SEQ ID NO: 95 Ab68 CDR-L2 AASSLQS SEQ ID NO: 96 Ab68 CDR-L3 QQSYIAPYT SEQ ID NO: 97 Ab68 Heavy chain GAGGTGCAGCTGGTGGAGTCTGGGGGAGG variable region CTTGGTACAGCCAGGGCGGTCCCTGAGACT (nucl) CTCCTGTACAGCTTCTGGATTCACCTTCAGT GACCACGACATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTTGGCCG TACTAGAAACGCCGCTGGAAGTTACACCAC AGAATACGCCGCGTCTGTGAAAGGCAGATT CACCATCTCAAGAGATGATTCAAAGAACTCA CTGTATCTGCAAATGAACAGCCTGAAAACCG AGGACACGGCGGTGTACTACTGCGCCAGAG AGCCTAAATACTGGATCGACTTCGACCTATG GGGGAGAGGTACCTTGGTCACCGTCTCCTC A SEQ ID NO: 98 Ab68 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAGC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAAGC TACATCGCCCCTTACACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAA SEQ ID NO: 99 Ab69 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFVD variable region (e.g., HDMDWVRQAPGKGLEWVGRTRNKLGSYTTE as found in HC-69) YAASVKGRFTISRDDSKNSLYLQMNSLKTEDT (CDRs in bold) AVYYCAREPKYWIDFDLWGRGTLVTVSS SEQ ID NO: Ab69 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL 100 variable region (e.g., NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG as found in LC-69) SGSGTDFTLTISSLQPEDFATYYCQQSYIAPYT (CDRs in bold) FGGGTKVEIK SEQ ID NO: Ab69 CDR-H1 FTFVDHDMD 101 SEQ ID NO: Ab69 CDR-H2 RTRNKLGSYTTEYAASVKG 102 SEQ ID NO: Ab69 CDR-H3 AREPKYWIDFDL 103 SEQ ID NO: Ab69 CDR-L1 RASQSISSYLN 104 SEQ ID NO: Ab69 CDR-L2 AASSLQS 105 SEQ ID NO: Ab69 CDR-L3 QQSYIAPYT 106 SEQ ID NO: Ab69 Heavy chain GAGGTGCAGCTGGTGGAGTCTGGGGGAGG 107 variable region CTTGGTCCAGCCTGGAGGGTCCCTGAGACT (nucl) CTCCTGTGCAGCCTCTGGATTCACCTTCGTA GACCACGACATGGACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTTGGCCG TACTAGAAACAAACTAGGAAGTTACACCACA GAATACGCCGCGTCTGTGAAAGGCAGATTC ACCATCTCAAGAGATGATTCAAAGAACTCAC TGTATCTGCAAATGAACAGCCTGAAAACCGA GGACACGGCGGTGTACTACTGCGCCAGAGA GCCTAAATACTGGATCGACTTCGACCTATGG GGGAGAGGTACCTTGGTCACCGTCTCCTCA

SEQ ID NO: Ab69 Light chain GACATCCAGATGACCCAGTCTCCATCCTCC 108 variable region CTGTCTGCATCTGTAGGAGACAGAGTCACC (nucl) ATCACTTGCCGGGCAAGTCAGAGCATTAGC AGCTATTTAAATTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTG CATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGTGGCAGTGGATCTGGGACAGATT TCACTCTCACCATCAGCAGTCTGCAACCTGA AGATTTTGCAACTTACTACTGTCAGCAAAGC TACATCGCCCCTTACACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAA SEQ ID NO: Ab67 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSIS 109 LC constant region SYLNWYQQKPGKAPKLLIYAASSLQSGVP underlined SRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYIAPYTFGGGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC SEQ ID NO: Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFT 110 HC constant region FSDADMDWVRQAPGKGLEWVGRTRNKA underlined GSYTTEYAASVKGRFTISRDDSKNSLYLQ MNSLKTEDTAVYYCAREPKYWIDFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFT 111 (D265C)* FSDADMDWVRQAPGKGLEWVGRTRNKA HC constant region GSYTTEYAASVKGRFTISRDDSKNSLYLQ underlined MNSLKTEDTAVYYCAREPKYWIDFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVCVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFT 112 (L234A/L235A/ FSDADMDWVRQAPGKGLEWVGRTRNKA D265C)* GSYTTEYAASVKGRFTISRDDSKNSLYLQ HC constant region MNSLKTEDTAVYYCAREPKYWIDFDLWG underlined RGTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFT 113 (D265C/H435A)* FSDADMDWVRQAPGKGLEWVGRTRNKA HC constant region GSYTTEYAASVKGRFTISRDDSKNSLYLQ underlined MNSLKTEDTAVYYCAREPKYWIDFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVCVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNAYTQKSLSLSPGK SEQ ID NO: Ab67 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFT 114 (L234A/L235A/ FSDADMDWVRQAPGKGLEWVGRTRNKA D265C/H435A)* GSYTTEYAASVKGRFTISRDDSKNSLYLQ HC constant region MNSLKTEDTAVYYCAREPKYWIDFDLWG underlined RGTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNAYTQKSLSLSPGK SEQ ID NO: Ab55 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSINSYL 115 LC constant region NWYQQKPGKAPKLLIYAASSLQSGVPSRFSG underlined SGSGTDFTLTISSLQPEDFATYYCQQGVSDITF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGE C SEQ ID NO: Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI 116 HC constant region YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ underlined KFQGRVTITADESTSTAYMELSSLRSEDTAVY YCARGGLDTDEFDLWGRGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI 117 (D265C)* YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ HC constant region KFQGRVTITADESTSTAYMELSSLRSEDTAVY underlined YCARGGLDTDEFDLWGRGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVCV SHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI 118 (L234A/L235A / YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ D265C)* KFQGRVTITADESTSTAYMELSSLRSEDTAVY HC constant region YCARGGLDTDEFDLWGRGTLVTVSSASTKG underlined PSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAG GPSVFLFPPKPKDTLMISRTPEVTCVVVC VSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK SEQ ID NO: Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI 119 (D265C/H435A)* YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ HC constant region KFQGRVTITADESTSTAYMELSSLRSEDTAVY underlined YCARGGLDTDEFDLWGRGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVCV SHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNAYT QKSLSLSPGK SEQ ID NO: Ab55 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFRI 120 (L234A/L235A/ YAISWVRQAPGQGLEWMGGIIPDFGVANYAQ D265C/H435A)* KFQGRVTITADESTSTAYMELSSLRSEDTAVY HC constant region YCARGGLDTDEFDLWGRGTLVTVSSASTKG underlined PSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAG GPSVFLFPPKPKDTLMISRTPEVTCVVVC VSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNAY TQKSLSLSPGK SEQ ID NO: Light chain constant RTVAAPSVFIFPPSDEQLKSGTASVVCLL 121 region of LC-54, NNFYPREAKVQWKVDNALQSGNSQESVT LC-55, LC-56, LC- EQDSKDSTYSLSSTLTLSKADYEKHKVYA 57, LC-58, LC-61, CEVTHQGLSSPVTKSFNRGEC LC-66, LC-67, LC- 68, LC-69 SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLV 122 constant region of KDYFPEPVTVSWNSGALTSGVHTFPAVL WT QSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLV 123 constant region KDYFPEPVTVSWNSGALTSGVHTFPAVL (D265C)* QSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVCVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLV 124 constant region KDYFPEPVTVSWNSGALTSGVHTFPAVL (L234A/L235A/ QSSGLYSLSSVVTVPSSSLGTQTYICNVN D265C)* HKPSNTKVDKKVEPKSCDKTHTCPPCPA PEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVCVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLV 125 constant region KDYFPEPVTVSWNSGALTSGVHTFPAVL (H435A/D265C)* QSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTC

VVVCVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNAYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLV 126 constant region KDYFPEPVTVSWNSGALTSGVHTFPAVL (L234A/L235A/ QSSGLYSLSSVVTVPSSSLGTQTYICNVN H435A/D265C)* HKPSNTKVDKKVEPKSCDKTHTCPPCPA PEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVCVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNAYTQKSLSLSPGK SEQ ID NO: Consensus GTF(S/R)(S/I/L)YAIS 127 sequence of variable heavy chain CDR1 (Abs 54-57) SEQ ID NO: Consensus GIIP(I/D/A/H)FG(T/V/L)ANYAQKFQG 128 sequence of variable heavy chain CDR2 (Abs 54-57) SEQ ID NO: Variable heavy chain ARGGLDTDEFDL 129 CDR3 (Abs 54-57) SEQ ID NO: Variable light chain RASQSINSYLN 130 CDR1 (Abs 54-57) SEQ ID NO: Variable light chain AASSLQS 131 CDR2 (Abs 54-57) SEQ ID NO: Variable light chain QQGVSDIT 132 CDR3 (Abs 54-57) SEQ ID NO: Consensus FTFS(N/S)Y(A/V)M(S/I) 133 sequence of variable heavy chain CDR1 (Abs 58, 61) SEQ ID NO: Consensus (A/S)ISG(S/D)(G/S)(G/V)(S/T) 134 sequence of variable TYYADSVKG heavy chain CDR2 (Abs 58, 61) SEQ ID NO: Variable heavy chain AKGPPTYHTNYYYMDV 135 CDR3 (Abs 58, 61) SEQ ID NO: Variable light chain RASQGISSWLA 136 CDR1 (Abs 58, 61) SEQ ID NO: Variable light chain AASSLQS 137 CDR2 (Abs 58, 61) SEQ ID NO: Variable light chain QQTNSFPYT 138 CDR3 (Abs 58, 61) SEQ ID NO: Consensus FTF(S/V)D(H/A)(Y/D)M(D/N) 139 sequence of variable heavy chain CDR1 (Abs 66-69) SEQ ID NO: Consensus RTRN(K/A)(A/L)(S/G)SYTTEYAASVKG 140 sequence of variable heavy chain CDR2 (Abs 66-69) SEQ ID NO: Variable heavy chain AREPKYWIDFDL 141 CDR3 (Abs 66-69) SEQ ID NO: Variable light chain RASQSISSYLN 142 CDR1 (Abs 66-69) SEQ ID NO: Variable light chain AASSLQS 143 CDR2 (Abs 66-69) SEQ ID NO: Variable light chain QQSYIAPYT 144 CDR3 (Abs 66-69) SEQ ID NO: Human CD117 MRGARGAWDFLCVLLLLLRVQTGSSQPS 145 (mast/stem cell VSPGEPSPPSIHPGKSDLIVRVGDEIRLLC growth factor TDPGFVKWTFEILDETNENKQNEWITEKA receptor Kit isoform EATNTGKYTCTNKHGLSNSIYVFVRDPAK 1 precursor) LFLVDRSLYGKEDNDTLVRCPLTDPEVTN Protein NCBI YSLKGCQGKPLPKDLRFIPDPKAGIMIKSV Reference KRAYHRLCLHCSVDQEGKSVLSEKFILKV Sequence: RPAFKAVPVVSVSKASYLLREGEEFTVTC NP_000213.1 TIKDVSSSVYSTWKRENSQTKLQEKYNS WHHGDFNYERQATLTISSARVNDSGVFM CYANNIFGSANVITTLEVVDKGFINIFPMI NTTVFVNDGENVDLIVEYEAFPKPEHQQ WIYMNRTFTDKWEDYPKSENESNIRYVSE LHLTRLKGTEGGTYTFLVSNSDVNAAIAF NVYVNTKPEILTYDRLVNGMLQCVAAGFP EPTIDWYFCPGTEQRCSASVLPVDVQTLN SSGPPFGKLVVQSSIDSSAFKHNGTVECK AYNDVGKTSAYFNFAFKGNNKEQIHPHTL FTPLLIGFVIVAGMMCIIVMILTYKYLQKPM YEVQWKVVEEINGNNYVYIDPTQLPYDHK WEFPRNRLSFGKTLGAGAFGKVVEATAY GLIKSDAAMTVAVKMLKPSAHLTEREALM SELKVLSYLGNHMNIVNLLGACTIGGPTLV ITEYCCYGDLLNFLRRKRDSFICSKQEDH AEAALYKNLLHSKESSCSDSTNEYMDMK PGVSYVVPTKADKRRSVRIGSYIERDVTP AIMEDDELALDLEDLLSFSYQVAKGMAFL ASKNCIHRDLAARNILLTHGRITKICDFGLA RDIKNDSNYVVKGNARLPVKWMAPESIFN CVYTFESDVWSYGIFLWELFSLGSSPYPG MPVDSKFYKMIKEGFRMLSPEHAPAEMY DIMKTCWDADPLKRPTFKQIVQLIEKQISE STNHIYSNLANCSPNRQKPVVDHSVRINS VGSTASSSQPLLVHDDV SEQ ID NO: Human CD117 MRGARGAWDFLCVLLLLLRVQTGSSQPS 146 (mast/stem cell VSPGEPSPPSIHPGKSDLIVRVGDEIRLLC growth factor TDPGFVKWTFEILDETNENKQNEWITEKA receptor Kit isoform EATNTGKYTCTNKHGLSNSIYVFVRDPAK 2 precursor) LFLVDRSLYGKEDNDTLVRCPLTDPEVTN Protein NCBI YSLKGCQGKPLPKDLRFIPDPKAGIMIKSV Reference KRAYHRLCLHCSVDQEGKSVLSEKFILKV Sequence: RPAFKAVPVVSVSKASYLLREGEEFTVTC NP_001087241.1 TIKDVSSSVYSTWKRENSQTKLQEKYNS WHHGDFNYERQATLTISSARVNDSGVFM CYANNTFGSANVITTLEVVDKGFINIFPMI NTTVFVNDGENVDLIVEYEAFPKPEHQQ WIYMNRTFTDKWEDYPKSENESNIRYVSE LHLTRLKGTEGGTYTFLVSNSDVNAAIAF NVYVNTKPEILTYDRLVNGMLQCVAAGFP EPTIDWYFCPGTEQRCSASVLPVDVQTLN SSGPPFGKLVVQSSIDSSAFKHNGTVECK AYNDVGKTSAYFNFAFKEQIHPHTLFTPLL IGFVIVAGMMCIIVMILTYKYLQKPMYEVQ WKVVEEINGNNYVYIDPTQLPYDHKWEFP RNRLSFGKTLGAGAFGKVVEATAYGLIKS DAAMTVAVKMLKPSAHLTEREALMSELKV LSYLGNHMNIVNLLGACTIGGPTLVITEYC CYGDLLNFLRRKRDSFICSKQEDHAEAAL YKNLLHSKESSCSDSTNEYMDMKPGVSY VVPTKADKRRSVRIGSYIERDVTPAIMEDD ELALDLEDLLSFSYQVAKGMAFLASKNCI HRDLAARNILLTHGRITKICDFGLARDIKN DSNYVVKGNARLPVKWMAPESIFNCVYT FESDVWSYGIFLWELFSLGSSPYPGMPV DSKFYKMIKEGFRMLSPEHAPAEMYDIMK TCWDADPLKRPTFKQIVQLIEKQISESTNH IYSNLANCSPNRQKPVVDHSVRINSVGST ASSSQPLLVHDDV SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-1 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQLTQSPSSLSASVGDRVTITCRASQGVSSAL 148 region of LC-1 AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-2 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGIRTDL 149 region of LC-2 GWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-3 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIRMTQSPSSLSASVGDRVTITCRASQGIRNDL 150 region of LC-3 AWYQQKPGKTPKLLIYDASSLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-4 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQMTQSPSSLSASVGDRVTITCRASQGIRND 151 region of LC-4 LGWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVDIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-5 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable NIQMTQSPSSLSASVGDRVTITCRASQAISDYL 152 region of LC-5 AWFQQKPGKAPKLLIYDASNLETGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQLNSYPLTF GGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-6 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIRMTQSPSSLSASVGDRVIIACRASQGIGGAL 153 region of LC-6 AWYQQKPGNAPKVLVYDASTLESGVPSRFSG GGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-7 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIAMTQSPPSLSAFVGDRVTITCRASQGIISSL 154 region of LC-7 AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTDFTLTIRSLQPEDFATYYCQQFNSYPLT FGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-8 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGISSAL 155 region of LC-8 AWYQQKAGKAPKVLISDASSLESGVPSRFSG SGSGTDFTLSISSLQPEDFATYYCQQFNGYPL TFGGGTKVDIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-9 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS amino acid FQGQVTISAGKSISTAYLQWSSLKASDTAMYY sequence CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIRMTQSPSSLSASVGDRVTITCQASQGIRND 156 region of LC-9 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTFTISSLQPEDIATYYCQQFNSYPLT FGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-10 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS

SEQ ID NO: Light chain variable NIQMTQSPSSLSTSVGDRVTITCRASQGIGTSL 157 region of LC-10 AWYQQKPGKPPKLLIYDASSLESGVPSRLSGS GSGTDFTLTISSLQPEDFATYYCQQSNSYPITF GQGTRLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-11 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQLTQSPSSLSASVGDRVTITCRASQSIGDYL 158 region of LC-11 TWYQQKPGKAPKVLIYGASSLQSGVPPRFSG SGSGTDFTLTVSSLQPEDFATYYCQQLNSYPL TFGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-12 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVRST 159 region of LC-12 LAWYQQKPGKAPKLLIYDASILESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNGYPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-13 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIVMTQSPSSLSASVGDRVTITCRASQGIRNDL 160 region of LC-13 GWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-14 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGISSFL 161 region of LC-14 AWYQQKPGKAPKLLIYDASTLQSGVPSRFSG SASGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-15 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQLTQSPSSLSASVGDRVTITCRASQGIGSAL 162 region of LC-15 AWYQQKPGIGPKLLIYDASTLESGVPARFSGS GSRTDFTLTITSLQPEDFATYYCQQFNGYPLT FGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-16 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQLTQSPSSLSASVGDRVTITCRASQGITSAL 163 region of LC-16 AWYQEKPGKAPNLLIYDASSLESGVPSRFSGS GYGTDFTLTISSLQPEDFATYYCQQLNSYPLTF GGGTKVDIK SEQ ID NO: Heavy chain variable QIQLVQSGPELRKPGESVKISCKASGYTFTDY 164 region of HC-17 AMYWVKQAPGKGLKWMGWINTYTGKPTYAD DFKGRFVFSLEASANTANLQISNLKNEDTATYF CARARGLVDDYVMDAWGQGTSVTVSS SEQ ID NO: Light chain variable SYELIQPPSASVTLGNTVSLTCVGDELSKRYA 165 region of LC-17 QWYQQKPDKTIVSVIYKDSERPSGISDRFSGS SSGTTATLTIHGTLAEDEADYYCLSTYSDDNLP VFGGGTKLTVL SEQ ID NO: Heavy chain variable EVQLQQYGAELGKPGTSVRLSCKVSGYNIRN 166 region of HC-18 TYIHWVNQRPGEGLEWIGRIDPTNGNTISAEK FKTKATLTADTSSHTAYLQFSQLKSDDTAIYFC ALNYEGYADYWGQGVMVTGSS SEQ ID NO: Light chain variable DIQMTQSPSFLSASVGDRVTINCKASQNINKYL 167 region of LC-18 NWYQQKVGEAPKRLIFKTNSLQTGIPSRFSGS GSGTDYTLTISSLQTEDVATYFCFQYNIGYTFG AGTKVELK SEQ ID NO: Heavy chain variable EVQLQESGPGLVKPSQSLSLTCSVTGYSISSN 168 region of HC-19 YRWNWIRKFPGNKVEWMGYINSAGSTNYNPS LKSRISMTRDTSKNQFFLQVNSVTTEDTATYY CARSLRGYITDYSGFFDYWGQGVMVTVSS SEQ ID NO: Light chain variable DIRMTQSPASLSASLGETVNIECLASEDIFSDL 169 region of LC-19 AWYQQKPGKSPQLLIYNANSLQNGVPSRFSG SGSGTRYSLKINSLQSEDVATYFCQQYKNYPL TFGSGTKLEIK SEQ ID NO: Heavy chain variable EVQLQQYGAELGKPGTSVRLSCKLSGYKIRNT 170 region of HC-20 YIHWVNQRPGKGLEWIGRIDPANGNTIYAEKF KSKVTLTADTSSNTAYMQLSQLKSDDTALYFC AMNYEGYEDYWGQGVMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSFLSASVGDSVTINCKASQNINKYL 171 region of LC-20 NWYQQKLGEAPKRLIHKTDSLQTGIPSRFSGS GSGTDYTLTISSLQPEDVATYFCFQYKSGFMF GAGTKLELK SEQ ID NO: Heavy chain variable QIQLVQSGPELKKPGESVKISCKASGYTFTDY 172 region of HC-21 AVYWVIQAPGKGLKWMGWINTYTGKPTYADD FKGRFVFSLETSASTANLQISNLKNEDTATYFC ARGAGMTKDYVMDAWGRGVLVTVS SEQ ID NO: Light chain variable SYELIQPPSASVTLGNTVSLTCVGDELSKRYA 173 region of LC-21 QWYQQKPDKTIVSVIYKDSERPSDISDRFSGS SSGTTATLTIHGTLAEDEADYYCLSTYSDDNLP VFGGGTKLTVL SEQ ID NO: Heavy chain variable QVQLKESGPGLVQPSQTLSLICTVSGFSLTSY 174 region of HC-22 LVHWVRQPPGKTLEWVGLMWNDGDTSYNSA LKSRLSISRDTSKSQVFLKMHSLQAEDTATYY CARESNLGFTYWGHGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPASLSASLEEIVTITCKASQGIDDDLS 175 region of LC-22 WYQQKPGKSPQLLIYDVTRLADGVPSRFSGS RSGTQYSLKISRPQVADSGIYYCLQSYSTPYT FGAGTKLELK SEQ ID NO: Heavy chain variable EVQLQQYGAELGKPGTSVRLSCKVSGYNIRN 176 region of HC-23 TYIHWVHQRPGEGLEWIGRIDPTNGNTISAEK FKSKATLTADTSSNTAYMQFSQLKSDDTAIYF CAMNYEGYADYWGQGVMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSFLSASVGDRLTINCKASQNINKYL 177 region of LC-23 NWYQQKLGEAPKRLIFKTNSLQTGIPSRFSGS GSGTDYTLTISSLQPEDVATYFCFQYNIGFTFG AGTKLELK SEQ ID NO: Heavy chain variable EVQLVESGGGLVQSGRSLKLSCAASGFTVSD 178 region of HC-24 YYMAWVRQAPTKGLEWVATINYDGSTTYHRD SVKGRFTISRDNAKSTLYLQMDSLRSEDTATY YCARHGDYGYHYGAYYFDYWGQGVMVTVSS SEQ ID NO: Light chain variable DIVLTQSPALAVSLGQRATISCRASQTVSLSGY 179 region of LC-24 NLIHWYQQRTGQQPKLLIYRASNLAPGIPARF SGSGSGTDFTLTISPVQSDDIATYYCQQSRES WTFGGGTNLEMK SEQ ID NO: Heavy chain variable QIQLVQSGPELKKPGESVKISCKASGYTFTDY 180 region of HC-25 AIHWVKQAPGQGLRWMAWINTETGKPTYADD FKGRFVFSLEASASTAHLQISNLKNEDTATFFC AGGSHWFAYWGQGTLVTVSS SEQ ID NO: Light chain variable SYELIQPPSASVTLENTVSITCSGDELSNKYAH 181 region of LC-25 WYQQKPDKTILEVIYNDSERPSGISDRFSGSS SGTTAILTIRDAQAEDEADYYCLSTFSDDDLPIF GGGTKLTVL SEQ ID NO: Heavy chain variable QIQLVQSGPELKKPGESVKISCKASGYTFTDY 172 region of HC-26 AVYWVIQAPGKGLKWMGWINTYTGKPTYADD FKGRFVFSLETSASTANLQISNLKNEDTATYFC ARGAGMTKDYVMDAWGRGVLVTVS SEQ ID NO: Light chain variable SYELIQPPSTSVTLGNTVSLTCVGNELPKRYAY 182 region of LC-26 WFQQKPDQSIVRLIYDDDRRPSGISDRFSGSS SGTTATLTIRDAQAEDEAYYYCHSTYTDDKVPI FGGGTKLTVL SEQ ID NO: Heavy chain variable EVQLVESGGGLVQPGRSMKLSCKASGFTFSN 183 region of HC-27 YDMAWVRQAPTRGLEWVASISYDGITAYYRD SVKGRFTISRENAKSTLYLQLVSLRSEDTATYY CTTEGGYVYSGPHYFDYWGQGVMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSMSVSLGDTVTITCRASQDVGIF 184 region of LC-27 VNWFQQKPGRSPRRMIYRATNLADGVPSRFS GSRSGSDYSLTISSLESEDVADYHCLQYDEFP RTFGGGTKLELK SEQ ID NO: Heavy chain variable EVQLQQYGAELGKPGTSVRLSCKVSGYKIRNT 185 region of HC-28 YIHWVNQRPGKGLEWIGRIDPANGNTIYAEKF KSKVTLTADTSSNTAYMQLSQLKSDDTALYFC AMNYEGYEDYWGQGVMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSFLSASVGDSVTINCKASQNINKYL 186 region of LC-28 NWYQQKLGEAPKRLIHKTNSLQPGFPSRFSG SGSGTDYTLTISSLQPEDVAAYFCFQYNSGFT FGAGTKLELK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTD 187 region of HC-29 YYIHWVRQAPGQGLEWMGWMNPHSGDTGY AQKFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYCARHGRGYNGYEGAFDIWGQGTLVTVS SAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGNE 188 region of LC-29 LGWYQQKPGKAPKLLIYAASNLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYDNLP LTFGQGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTG 189 region of HC-30 YYLHWVRQAPGQGLEWMGWINPNSGDTNYA QNFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARHGRGYNGYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 190 region of LC-30 LGWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTG 191 region of HC-31 YYLHWVRQAPGQGLEWMGWINPNSGGTNYA QKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARHGRGYEGYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 192 region of LC-31 LGWYQQKPGKAPKLLIYDASELETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTS 193 region of HC-32 YYIHWVRQAPGQGLEWMGWLNPSGGGTSYA QKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARHGRGYDGYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 194 region of LC-32 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFST 195 region of HC-33 YYMHWVRQAPGQGLEWMGIINPSGGSTSYA QKFQGRVTMTRDTSTSTVYMKLSSLRSEDTA VYYCARHGRGYEGYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRDD 196 region of LC-33 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQANGFPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTG 197 region of HC-34 YYIHWVRQAPGQGLEWMGIINPSGGNTNYAQ NFQGRVTMTRDTSTSTVYMELSSLRSEDTAV YYCARHGRGYNAYEGAFDIWGQGTLVTVSSA S SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 198 region of LC-34 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQVNGYPL TFGGGTKVEIK

SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGGTFSS 199 region of HC-35 YAISWVRQAPGQGLEWMGVINPTVGGANYAQ KFQGRVTMTRDTSTSTVYMELSSLRSEDTAV YYCARHGRGYNEYEGAFDIWGQGTLVTVSSA S SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCQASQDISDYL 200 region of LC-35 NWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQGNSFPL TFGGGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKLGASVKVSCKASGYTFSS 201 region of HC-36 YYMHWVRQAPGQGLEWMGVINPNGAGTNFA QKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARHGRGYEGYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 190 region of LC-36 LGWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTT 202 region of HC-37 YYMHWVRQAPGQGLEWMGWINPTGGGTNY AQNFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYCARHGRGYEGYEGAFDIWGQGTLVTVS SAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 203 region of LC-37 VSWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDATYYCQQLSGYPIT FGQGTKLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYTFTS 204 region of HC-38 YYIHWVRQAPGQGLEWMGMINPSGGSTNYA QKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARHGRGYNDYEGAFDIWGQGTLVTVSS AS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQSISDW 205 region of LC-38 LAWYQQKPGKAPKLLIYEASNLEGGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQANSFPY TFGQGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAEVKKPGASVKVSCKASGYIFSAY 206 region of HC-39 YIHWVRQAPGQGLEWMGIINPSGGSTRYAQK FQGRVTMTRDTSTSTVYMELSSLRSEDTAVY YCARHGRGYGGYEGAFDIWDQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGDY 207 region of LC-39 VAWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTRLEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFTSY 208 region of HC-40 WIGWVRQMPGKGLEWMGIIYPDDSDTRYSPS FQGQVTISVDKSNSTAYLQWSSLKASDTAMY YCARHGRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGISSYL 209 region of LC-40 AWYQQKPGKAPKLLIYDASNLETGVPSRFSGS GSGTYFTLTISSLQPEDFATYYCQQGASFPITF GQGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGSSFPNS 210 region of HC-41 WIAWVRQMPGKGLEWMGIIYPSDSDTRYSPS FQGQVTISADKSISTAYLQWSSLEASDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRNY 211 region of LC-41 LAWYQQKPGKAPKLLIYDASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFDSY 212 region of HC-42 WIGWVRQMPGKGLEWMGIMYPGDSDTRYSP SFQGQVTISADKSISTAYLQWSSLKASDTAMY YCARHGRGYNAYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQSINNW 213 region of LC-42 LAWYQQKPGKAPKLLIYDAFILQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCLQLNSYPLT FGPGTKVDIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTN 214 region of HC-43 WIAWVRQMPGKGLEWMGIIYPGDSETRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYYGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGISDN 215 region of LC-43 LNWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAISFPLT FGQGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYNFTSY 216 region of HC-44 WIGWVRQMPGKGLEWMGVIYPDDSETRYSP SFQGQVTISADKSISTAYLQWSSLKASDTAMY YCARHGRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASRDIRDDL 217 region of LC-44 GWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQANSFPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYTFNTY 218 region of HC-45 IGWVRQMPGKGLEWMGIIYPGDSGTRYSPSF QGQVTISADKAISTAYLQWSSLKASDTAMYYC ARHSRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGISNYL 219 region of LC-45 AWYQQKPGKAPKLLIYDASNLETGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQANSFPVT FGQGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYNFTTY 220 region of HC-46 WIGWVRQMPGKGLEWMGIIHPADSDTRYNPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRVSQGISSYL 221 region of LC-46 AWYQQKPGKAPKLLIYDASNLETGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQANSFPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFSNY 222 region of HC-47 WIAWVRQMPGKGLEWMGIIYPDNSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYDGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRSD 223 region of LC-47 LAWYQQKPGKAPKLLIYGASSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQANSFP LSFGQGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFASY 224 region of HC-48 WIGWVRQMPGKGLEWMGITYPGDSETRYNP SQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYGGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 225 region of LC-48 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQANSFPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTSY 226 region of HC-49 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSSAS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQSISNW 227 region of LC-49 LAWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQTNSFPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-74 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVISAL 228 region of LC-74 AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-75 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGIRSAL 229 region of LC-75 AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-76 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVGSA 230 region of LC-76 LAWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-77 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVISAL 231 region of LC-77 AWYQQKPGKAPKLLIYDASILESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-78 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGIRSAL 232 region of LC-78 AWYQQKPGKAPKLLIYDASILESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-79 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVGSA 233 region of LC-79 LAWYQQKPGKAPKLLIYDASILESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-80 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGISSAL 234 region of LC-80 AWYQQKPGKAPKLLIYDASILESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-81 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVISAL 235 region of LC-81 AWYQQKPGKAPKLLIYDASTLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-82 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGIRSAL 236 region of LC-82 AWYQQKPGKAPKLLIYDASTLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-83 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVGSA

237 region of LC-83 LAWYQQKPGKAPKLLIYDASTLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-84 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQLTQSPSSLSASVGDRVTITCRASQGVGSA 237 region of LC-84 LAWYQQKPGKAPKLLIYDASTLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPL TFGGGTKVEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 238 region of HC-245 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGLGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGSA 239 region of LC-245 LAWYQQKPGKAPKLLIYDASTLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNGYPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-246 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGSA 239 region of LC-246 LAWYQQKPGKAPKLLIYDASTLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNGYPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTTY 147 region of HC-247 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASRGISDYL 240 region of LC-247 AWYQQKPGKAPKLLIYDASNLETGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQANSFPITF GQGTRLEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 238 region of HC-248 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGLGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGSA 241 region of LC-248 LAWYQQKPGKAPKLLIYDASTLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 238 region of HC-249 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGLGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGSA 242 region of LC-249 LAWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGQGTRLEIK SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 243 region of Ab 85 WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYEGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRSSQGIRSD 244 region of Ab 85 LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQANGFPL TFGGGTKVEIK SEQ ID NO: Ab85 CDR-H1 NYWIG 245 SEQ ID NO: Ab85 CDR-H2 IINPRDSDTRYRPSFQG 246 SEQ ID NO: Ab85 CDR-H3 HGRGYEGYEGAFDI 247 SEQ ID NO: Ab85 CDR-L1 RSSQGIRSDLG 248 SEQ ID NO: Ab85 CDR-L2 DASNLET 249 Ab249 CDR-L2 SEQ ID NO: Ab85 CDR-L3 QQANGFPLT 250 SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 251 region of Ab 86 WIGWVRQMPGKGLEWMGIIYPGDSDIRYSPS LQGQVTISVDTSTSTAYLQWNSLKPSDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGDS 252 region of Ab 86 LAWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTKVEIK SEQ ID NO: Ab86 CDR-H1 NYWIG 245 SEQ ID NO: Ab86 CDR-H2 IIYPGDSDIRYSPSLQG 253 SEQ ID NO: 3 Ab86 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab86 CDR-L1 RASQGIGDSLA 254 SEQ ID NO: Ab86 CDR-L2 DASNLET 249 SEQ ID NO: Ab86 CDR-L3 QQLNGYPIT 255 SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 243 region of Ab 87 WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYEGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 256 region of Ab 87 LGWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTKVEIK SEQ ID NO: Ab87 CDR-H1 NYWIG 245 SEQ ID NO: Ab87 CDR-H2 IINPRDSDTRYRPSFQG 246 SEQ ID NO: Ab87 CDR-H3 HGRGYEGYEGAFDI 247 SEQ ID NO: Ab87 CDR-L1 RASQGIRNDLG 257 SEQ ID NO: 5 Ab87 CDR-L2 DASSLES SEQ ID NO: Ab87 CDR-L3 QQLNGYPIT 255 SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 258 region of Ab 88 WIGWVRQMPGKGLEWMGIIYPGDSLTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIRND 256 region of Ab 88 LGWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTKVEIK SEQ ID NO: Ab88 CDR-H1 NYWIG 245 SEQ ID NO: Ab88 CDR-H2 IIYPGDSLTRYSPSFQG 259 SEQ ID NO: 3 Ab88 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab88 CDR-L1 RASQGIRNDLG 257 SEQ ID NO: 5 Ab88 CDR-L2 DASSLES SEQ ID NO: Ab88 CDR-L3 QQLNGYPIT 255 SEQ ID NO: Heavy chain variable EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 260 region of Ab89 WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTLVTVSS SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGIGDS 252 region of Ab89 LAWYQQKPGKAPKLLIYDASNLETGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLNGYPIT FGQGTKVEIK SEQ ID NO: Ab89 CDR-H1 NYWIG 245 SEQ ID NO: 2 Ab89 CDR-H2 IIYPGDSDTRYSPSFQG SEQ ID NO: 3 Ab89 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab89 CDR-L1 RASQGIGDSLA 254 SEQ ID NO: Ab89 CDR-L2 DASNLET 249 SEQ ID NO: Ab89 CDR-L3 QQLNGYPIT 255 SEQ ID NO: Heavy chain variable QVQLVQSGAAVKKPGESLKISCKGSGYRFTSY 261 region amino acid WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS sequence of CK6 FQGQVTISAGKSISTAYLQWSSLKASDTAMYY CARHGRGYNGYEGAFDIWGQGTMVTVSS SEQ ID NO: Light chain variable AIQLTQSPSSLSASVGDRVTITCRASQGISSAL 262 region amino acid AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS sequence of CK6 GSGTDFTLTISSLQPEDFATYYCQQFNSYPLT FGGGTKVEIK SEQ ID NO: Ab77 CDR-H1 TYWIG 263 SEQ ID NO: 2 Ab77 CDR-H2 IIYPGDSDTRYSPSFQG SEQ ID NO: 3 Ab77 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab77 CDR-L1 RASQGVISALA 264 SEQ ID NO: Ab77 CDR-L2 DASILES 265 SEQ ID NO: Ab77 CDR-L3 QQFNSYPLT 266 SEQ ID NO: Ab79 CDR-H1 TYWIG 263 SEQ ID NO: 2 Ab79 CDR-H2 IIYPGDSDTRYSPSFQG SEQ ID NO: 3 Ab79 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab79 CDR-L1 RASQGVGSALA 267 SEQ ID NO: Ab79 CDR-L2 DASILES 265 SEQ ID NO: Ab79 CDR-L3 QQFNSYPLT 266 SEQ ID NO: Ab81 CDR-H1 TYWIG 263 SEQ ID NO: 2 Ab81 CDR-H2 IIYPGDSDTRYSPSFQG SEQ ID NO: 3 Ab81 CDR-H3 HGRGYNGYEGAFDI SEQ ID NO: Ab81 CDR-L1 RASQGVISALA 264 SEQ ID NO: Ab81 CDR-L2 DASTLES

268 SEQ ID NO: Ab81 CDR-L3 QQFNSYPLT 266 SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 269 constant region FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY (Wild type (WT)) SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 270 constant region with FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY L234A, L235A SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD (LALA) mutations KKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF (mutations in bold)* PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK SEQ ID NO: Heavy chain constant ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 271 region with D265C FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY mutation SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD (mutation in bold)* KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVCVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK SEQ ID NO: Heavy chain constant ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 272 region with H435A FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY mutation SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD (mutation in bold)* KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNAYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 273 constant region: FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY modified Fc region SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD with L234A, L235A, KKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF D265C mutations PPKPKDTLMISRTPEVTCVVVCVSHEDPEVKF (mutations in bold)* NWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK SEQ ID NO: Heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 274 constant region: FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY modified Fc region SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD with L234A, L235A, KKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF D265C, H435A PPKPKDTLMISRTPEVTCVVVCVSHEDPEVKF mutations (mutations NWYVDGVEVHNAKTKPREEQYNSTYRVVSVL in bold)* TVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNAYTQKSLSLSPGK SEQ ID NO: Ab85 full length EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 275 heavy chain WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined CARHGRGYEGYEGAFDIWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab85 full length EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 276 heavy chain WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined; CARHGRGYEGYEGAFDIWGQGTLVTVSSAST modified Fc region KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE with L234A, L235A PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS mutations (mutations VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE in bold)* PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab85 full length EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 277 heavy chain WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS sequence: constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined; CARHGRGYEGYEGAFDIWGQGTLVTVSSAST modified Fc region KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE with L234A, L235A, PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS D2650 mutations VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE (mutations in bold)* PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab85 full length EVQLVQSGAEVKKPGESLKISCKGSGYSFTNY 278 heavy chain WIGWVRQMPGKGLEWMAIINPRDSDTRYRPS sequence (LALA- FQGQVTISADKSISTAYLQWSSLKASDTAMYY D265C-H435A CARHGRGYEGYEGAFDIWGQGTLVTVSSAST mutant); constant KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE region underlined PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNAYT QKSLSLSPGK SEQ ID NO: Ab249 full length EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 279 heavy chain WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined CARHGLGYNGYEGAFDIWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab249 full length EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 280 heavy chain WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined CARHGLGYNGYEGAFDIWGQGTLVTVSSAST (LALA mutations)* KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab249 full length EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 281 heavy chain WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined CARHGLGYNGYEGAFDIWGQGTLVTVSSAST (LALA-D265C KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE mutations)* PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: Ab249 full length EVQLVQSGAEVKKPGESLKISCKGSGYRFTTS 282 heavy chain WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS sequence; constant FQGQVTISADKSISTAYLQWSSLKASDTAMYY region underlined; CARHGLGYNGYEGAFDIWGQGTLVTVSSAST (LALA-D265C- KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE H435A mutations)* PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVVVCVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNAYT QKSLSLSPGK SEQ ID NO: Light chain constant RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY 283 region PREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC SEQ ID NO: Ab85 full length light DIQMTQSPSSLSASVGDRVTITCRSSQGIRSD 284 chain; constant LGWYQQKPGKAPKLLIYDASNLETGVPSRFSG region underlined SGSGTDFTLTISSLQPEDFATYYCQQANGFPL TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: Ab249 light chain; DIQMTQSPSSLSASVGDRVTITCRASQGIGSA 285 constant region LAWYQQKPGKAPKLLIYDASNLETGVPSRFSG underlined SGSGTDFTLTISSLQPEDFATYYCQQLNGYPL TFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: Ab249 HC-CDR1 TSWIG 286 SEQ ID NO: Ab249 HC-CDR3 HGLGYNGYEGAFDI 287 SEQ ID NO: Ab249 LC-CDR1 RASQGIGSALA 288 SEQ ID NO: Ab249 LC-CDR3 CQQLNGYPLT 289 SEQ ID NO: ch-BBK2 Heavy Chain QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWI 290 (Variable region NWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKA italicized) TLTVDKSSNTVYMQLNSPTSEDSAVYYCTRNGVE GYPHYYAMEYWGQGTSVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP

GK SEQ ID NO: ch-BBK2 Light Chain DIQMTQTTSALSASLGDRVTIGCRASQDLSNHLYW 291 (Variable region YQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTD italicized) YSLTIRNLEQEDVATYFCQQGYTLPYTFGGGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC SEQ ID NO: ch-BBK2 VH CDR1 SYWIN 292 SEQ ID NO: ch-BBK2 VH CDR2 NIYPSDSYTNYNQKFKD 293 SEQ ID NO: ch-BBK2 VH CDR3 NGVEGYPHYYAMEY 294 SEQ ID NO: ch-BBK2 VL CDR1 RASQDLSNHLY 295 SEQ ID NO: ch-BBK2 VL CDR2 YTSRLHS 296 SEQ ID NO: ch-BBK2 VL CDR3 QQGYTLPYT 297 SEQ ID NO: ch-BBK2 Light Chain QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWI 298 Variable Region NWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKA TLTVDKSSNTVYMQLNSPTSEDSAVYYCTRNGVE GYPHYYAMEYWGQGTSVTVSS SEQ ID NO: ch-BBK2 Heavy Chain DIQMTQTTSALSASLGDRVTIGCRASQDLSNHLYW 299 Variable Region YQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTD YSLTIRNLEQEDVATYFCQQGYTLPYTFGGGTKLEI K. SEQ ID NO: Anti CD2 Ab1 CDR- EYYMY 300 H1 SEQ ID NO: Ab1 CDR-H2 RIDPEDGSIDYVEKFKK 301 SEQ ID NO: Ab1 CDR-H3 GKFNYRFAY 302 SEQ ID NO: Ab1 CDR-L1 RSSQSLLHSSGNTYLN 303 SEQ ID NO: Ab1 CDR-L2 LVSKLES 304 SEQ ID NO: Ab1 CDR-L3 MQFTHYPYT 305 SEQ ID NO: Ab1 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTE 306 variable region YYMYWVRQAPGQGLELMGRIDPEDGSIDYVE KFKKKVTLTADTSSSTAYMELSSLTSDDTAVY YCARGKFNYRFAYWGQGTLVTVSS SEQ ID NO: Ab1 Light chain DVVMTQSPPSLLVTLGQPASISCRSSQSLLHS 307 variable region SGNTYLNWLLQRPGQSPQPLIYLVSKLESGVP DRFSGSGSGTDFTLKISGVEAEDVGVYYCMQ FTHYPYTFGQGTKLEIK SEQ ID NO: Ab1a Heavy chain QVQLVQSGAEVQRPGASVKVSCKASGYIFTE 308 variable region YYMYWVRQAPGQGLELVGRIDPEDGSIDYVE KFKKKVTLTADTSSSTAYMELSSLTSDDTAVY YCARGKFNYRFAYWGQGTLVTVSS SEQ ID NO: Ab1a Light chain DVVMTQSPPSLLVTLGQPASISCRSSQSLLHS 309 variable region SGNTYLNWLLQRPGQSPQPLIYLVSKLESGVP DRFSGSGSGTDFTLKISGVEAEDVGVYYCMQ FTHYPYTFGQGTKLEIK SEQ ID NO: Consensus human EVQLVESGGGLVQPGGSLRLSCAASGFTFSD 310 Ab YAMSWVRQAPGKGLEWVAVISENGSDTYYA Heavy chain variable DSVKGRFTISRDDSKNTLYLQMNSLRAEDTAV domain YYCARDRGGAVSYFDVWGQGTLVTVSS SEQ ID NO: Consensus human DIQMTQSPSSLSASVGDRVTITCRASQDVSSY 311 Ab LAWYQQKPGKAPKLLIYAASSLESGVPSRFS Light chain variable GSGSGTDFTLTISSLQPEDFATYYCQQYNSLP domain YTFGQGTKVEIKRT SEQ ID NO: Human CD2 MSFPCKFVASFLLIFNVSSKGAVSKEITNALET 312 sequence WGALGQDINLDIPSFQMSDDIDDIKWEKTSDK KKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLK TDDQDIYKVSIYDTKGKNVLEKIFDLKIQERVSK PKISWTCINTTLTCEVMNGTDPELNLYQDGKH LKLSQRVITHKWTTSLSAKFKCTAGNKVSKES SVEPVSCPEKGLDIYLIIGICGGGSLLMVFVALL VFYITKRKKQRSRRNDEELETRAHRVATEERG RKPHQIPASTPQNPATSQHPPPPPGHRSQAP SHRPPPPGHRVQHQPQKRPPAPSGTQVHQQ KGPPLPRPRVQPKPPHGAAENSLSPSSN SEQ ID NO: RPA-2.10 CDR-H1 GFTFSSY 313 SEQ ID NO: Anti-CD2 RPA-2.10 SGGGF 314 CDR-H2 SEQ ID NO: RPA-2.10 CDR-H3 SSYGEIMDY 315 Variant 1 SEQ ID NO: RPA-2.10 CDR-H3 SSYGELMDY 316 Variant 2 SEQ ID NO: RPA-2.10 CDR-L1 RASQRIGTSIH 317 SEQ ID NO: RPA-2.10 CDR-L2 YASESIS 318 SEQ ID NO: RPA-2.10 CDR-L3 QQSHGWPFTF 319 SEQ ID NO: RPA-2.10 Heavy EVKLVESGGGLVKPGGSLKLSCAASGFTFSSY 320 chain variable DMSWVRQTPEKRLEWVASISGGGFLYYLDSV region KGRFTISRDNARNILYLHMTSLRSEDTAMYYC Variant 1 ARSSYGEIMDYWGQGTSVTVSS SEQ ID NO: RPA-2.10 Heavy EVKLVESGGGLVKPGGSLKLSCAASGFTFSSY 321 chain variable DMSWVRQTPEKRLEWVASISGGGFLYYLDSV region KGRFTISRDNARNILYLHMTSLRSEDTAMYYC Variant 2 ARSSYGELMDYWGQGTSVTVSS SEQ ID NO: RPA-2.10 Light chain DILLTQSPAILSVSPGERVSFSCRASQRIGTSIH 322 variable region WYQQRTTGSPRLLIKYASESISGIPSRFSGSG SGTDFTLSINSVESEDVADYYCQQSHGWPFT FGGGTKLEIE SEQ ID NO: RPA-2.10 Heavy AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGY 323 chain constant region FPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTL SSSVTVPSSTVVPSETVICNVAHPASSTKVDK KIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVL TITLTPKVTCVVVDISKDDPEVQFSWFVDDVEV HTAQTQPREEQFNSTFRSVSELPIMHQDWLN GKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQ VYTIPPPKEQMAKDKVSLTCMITDFFPEDITVE WQWNGQPAENYKNTQPIMDTDGSYFVYSKL NVQKSNWEAGNTFTCSVLHEGLHNHHTEKSL SHSPGK SEQ ID NO: RPA-2.10 Light chain RADAAPTVSIFPPSSEQLTSGGASVVCFLNNF 324 constant region YPKDINVKWKIDGSERQNGVLNSWTDQDSKD STYSMSSTLTLTKDEYERHNSYTCEATHKTST SPIVKSFNRNEC SEQ ID NO: Anti-CD5 antibody DIQMTQSPSSMSASLGDRVTITCRASQDINSY 325 Light chain variable LSWFQQKPGKSPKTLIYRANRLVDGVPSRFS region GSGSGTDYTLTISSLQYEDFGIYYCQQYDESP WTFGGGTKLEIK SEQ ID NO: Heavy chain variable QIQLVQSGPGLKKPGGSVRISCAASGYTFTNY 326 region GMNWVKQAPGKGLRWMGWINTHTGEPTYAD DFKGRFTFSLDTSKSTAYLQINSLRAEDTATYF CTRRGYDWYFDVWGQGTTVTVSS SEQ ID NO: CDR-H1 GYTFTNY 327 SEQ ID NO: CDR-H2 NTHTGE 328 SEQ ID NO: CDR-H3 RGYDWYFDV 329 SEQ ID NO: CDR-L1 RASQDINSYLS 330 SEQ ID NO: CDR-L2 RANRLVD 331 SEQ ID NO: CDR-L3 QQYDESPWT 332 SEQ ID NO: Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQDINSYL 333 region SWFQQKPGKAPKTLIYRANRLESGVPSRFSG SGSGTDYTLTISSLQYEDFGIYYCQQYDESPW TFGGGTKLEIK SEQ ID NO: Heavy chain variable EIQLVQSGGGLVKPGGSVRISCAASGYTFTNY 334 region GMNWVRQAPGKGLEWMGWINTHYGEPTYAD SFKGTRTFSLDDSKNTAYLQINSLRAEDTAVYF CTRRGYDWYFDVWGQGGTTVTVSS SEQ ID NO: CDR-H1 GYTFTNY 335 SEQ ID NO: CDR-H2 NTHYGE 336 SEQ ID NO: CDR-H3 RRGYDWYFDV 337 SEQ ID NO: CDR-L1 RASQDINSYLS 338 SEQ ID NO: CDR-L2 RANRLES 339 SEQ ID NO: CDR-L3 QQYDESPWT 340 SEQ ID NO: CDR-H1 GYSITSGYY 341 SEQ ID NO: CDR-H2 ISYSGFT 342 SEQ ID NO: CDR-H3 AGDRTGSWFAY 343 SEQ ID NO: CDR-L1 QDISNY 344 SEQ ID NO: CDR-L2 ATS 345 SEQ ID NO: CDR-L3 LQYASYPFT 346 SEQ ID NO: CDR-H1 GYIFTNYG 347 SEQ ID NO: CDR-H2 INTYNGEP 348 SEQ ID NO: CDR-H3 ARGDYYGYEDY 349 SEQ ID NO: CDR-L1 QGISNY 350 SEQ ID NO: CDR-L2 YTS 351 SEQ ID NO: CDR-L3 QQYSKLPWT 352 SEQ ID NO: 5D7 CDR-H1 FSLSTSGMG 353 SEQ ID NO: 5D7 CDR-H2 WWDDD 354 SEQ ID NO: 5D7 CDR-H3 RRATGTGFDY 355

SEQ ID NO: 5D7 CDR-L1 QDVGTA 356 SEQ ID NO: 5D7 CDR-L2 WTSTRHT 357 SEQ ID NO: 5D7 CDR-L3 YNSYNT 358 SEQ ID NO: Humanized 5D7 QVTLKESGPVLVKPTETLTLTCTFSGFSLSTSG 359 Heavy chain variable MGVGWIRQAPGKGLEWVAHIWWDDDVYYNP region (CDRs in SLKSRLTITKDASKDQVSLKLSSVTAADTAVYY bold) CVRRRATGTGFDYWGQGTLVTVSS SEQ ID NO: Humanized 5D7 Light NIVMTQSPSSLSASVGDRVTITCQASQDVGTA 360 chain variable region VAWYQQKPDQSPKLLIYWTSTRHTGVPDRFT (CDRs in bold) GSGSGTDFTLTISSLQPEDIATYFCHQYNSYNT FGSGTKLEIK SEQ ID NO: Consensus human EVQLVESGGGLVQPGGSLRLSCAASGFTFSD 361 Heavy chain variable YAMSWVRQAPGKGLEWVAVISENGSDTYYA domain (CDRs in DSVKGRFTISRDDSKNTLYLQMNSLRAEDTAV bold) YYCARDRGGAVSYFDVWGQGTLVTVSS SEQ ID NO: Consensus human DIQMTQSPSSLSASVGDRVTITCRASQDVSSY 362 Light chain variable LAWYQQKPGKAPKLLIYAASSLESGVPSRFS domain (CDRs in GSGSGTDFTLTISSLQPEDFATYYCQQYNSLP bold) YTFGQGTKVEIKRT SEQ ID NO: Human CD5 amino MVCSQSWGRS SKQWEDPSQA 363 acid sequence SKVCQRLNCG VPLSLGPFLV TYTPQSSIIC YGQLGSFSNCSHSRNDMCHS LGLTCLEPQK TTPPTTRPPP TTTPEPTAPP RLQLVAQSGG QHCAGVVEFYSGSLGGTISY EAQDKTQDLE NFLCNNLQCG SFLKHLPETE AGRAQDPGEP REHQPLPIQWKIQNSSCTSL EHCFRKIKPQ KSGRVLALLC SGFQPKVQSR LVGGSSICEG TVEVRQGAQWAALCDSSSAR SSLRWEEVCR EQQCGSVNSY RVLDAGDPTS RGLFCPHQKL SQCHELWERNSYCKKVFVTC QDPNPAGLAA GTVASIILAL VLLVVLLVVC GPLAYKKLVK KFRQKKQRQWIGPTGMNQNM SFHRNHTATV RSHAENPTAS HVDNEYSQPP RNSHLSAYPA LEGALHRSSMQPDNSSDSDY DLHGAQRL

Other Embodiments

[0478] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[0479] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0480] Other embodiments are within the claims.

Sequence CWU 1

1

44215PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 1Ser Tyr Trp Ile Gly1 5217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 2Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln1 5 10 15Gly314PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 3His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile1 5 10411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 4Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala1 5 1057PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 5Asp Ala Ser Ser Leu Glu Ser1 5610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 6Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr1 5 107120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 7Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 1208109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 8Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 100 1059121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 9Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser 115 12010107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 10Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105119PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 11Phe Thr Phe Ser Asp Ala Asp Met Asp1 51219PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 12Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly1312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 13Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu1 5 101411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 14Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 10157PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 15Ala Ala Ser Ser Leu Gln Ser1 5169PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 16Gln Gln Ser Tyr Ile Ala Pro Tyr Thr1 517363DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 17gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt gacgccgaca tggactgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt actagaaaca aagcaggaag ttacaccaca 180gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga 300gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc 360tca 36318321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 18gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 32119119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 19Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11520106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 20Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105219PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 21Gly Thr Phe Arg Ile Tyr Ala Ile Ser1 52217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 22Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly2312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 23Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu1 5 102411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 24Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn1 5 10257PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 25Ala Ala Ser Ser Leu Gln Ser1 5268PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 26Gln Gln Gly Val Ser Asp Ile Thr1 527357DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 27caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttccga atctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatccctg acttcggtgt agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga 300ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca 35728318DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 28gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg 300accaaggttg agatcaaa 31829119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 29Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11530106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 30Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105319PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 31Gly Thr Phe Ser Ser Tyr Ala Ile Ser1 53217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 32Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly3312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 33Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu1 5 103411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 34Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn1 5 10357PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 35Ala Ala Ser Ser Leu Gln Ser1 5368PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 36Gln Gln Gly Val Ser Asp Ile Thr1 537357DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 37caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga 300ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca 35738318DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 38gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg 300accaaggttg agatcaaa 31839119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 39Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Leu Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11540106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 40Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105419PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 41Gly Thr Phe Ser Leu Tyr Ala Ile Ser1 54217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 42Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly4312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 43Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu1 5 104411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 44Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn1 5 10457PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 45Ala Ala Ser Ser Leu Gln Ser1 5468PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 46Gln Gln Gly Val Ser Asp Ile Thr1 547357DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 47caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttcagc ctctatgcta tctcctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatccctg ccttcggtac cgcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga 300ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca 35748318DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 48gacatccaga tgacccagtc tccatcctcc

ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg 300accaaggttg agatcaaa 31849119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 49Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Leu Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro His Phe Gly Leu Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11550106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 50Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105519PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 51Gly Thr Phe Ser Leu Tyr Ala Ile Ser1 55217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 52Gly Ile Ile Pro His Phe Gly Leu Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly5312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 53Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu1 5 105411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 54Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn1 5 10557PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 55Ala Ala Ser Ser Leu Gln Ser1 5568PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 56Gln Gln Gly Val Ser Asp Ile Thr1 557357DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 57caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg caccttctcc ctctatgcta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggaggg atcatccctc acttcggtct cgcaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga 300ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca 35758318DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 58gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg 300accaaggttg agatcaaa 31859123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 59Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val 100 105 110Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 12060107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 60Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105619PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 61Phe Thr Phe Ser Asn Tyr Ala Met Ser1 56217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 62Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly6316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 63Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val1 5 10 156411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 64Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala1 5 10657PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 65Ala Ala Ser Ser Leu Gln Ser1 5669PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 66Gln Gln Thr Asn Ser Phe Pro Tyr Thr1 567369DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 67gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc aattatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggcggtgt actactgcgc caagggccct 300cctacatacc acacaaacta ctactacatg gacgtatggg gcaagggtac aactgtcacc 360gtctcctca 36968321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 68gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcagcaa acaaatagtt tcccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 32169123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 69Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Val Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Gly Asp Ser Val Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val 100 105 110Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 12070107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 70Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105719PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 71Phe Thr Phe Ser Ser Tyr Val Met Ile1 57217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 72Ser Ile Ser Gly Asp Ser Val Thr Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly7316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 73Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val1 5 10 157411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 74Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala1 5 10757PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 75Ala Ala Ser Ser Leu Gln Ser1 5769PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 76Gln Gln Thr Asn Ser Phe Pro Tyr Thr1 577369DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 77gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgtca tgatctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcaagc attagtggtg acagcgtaac aacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggcggtgt actactgcgc caagggccct 300cctacatacc acacaaacta ctactacatg gacgtatggg gcaagggtac aactgtcacc 360gtctcctca 36978321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 78gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcagcaa acaaatagtt tcccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 32179121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 79Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Ser Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser 115 12080107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 80Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105819PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 81Phe Thr Phe Ser Asp His Tyr Met Asp1 58219PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 82Arg Thr Arg Asn Lys Ala Ser Ser Tyr Thr Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly8312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 83Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu1 5 108411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 84Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 10857PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 85Ala Ala Ser Ser Leu Gln Ser1 5869PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 86Gln Gln Ser Tyr Ile Ala Pro Tyr Thr1 587363DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 87gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt gaccactaca tggactgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt actagaaaca aagctagtag ttacaccaca 180gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga 300gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc 360tca 36388321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 88gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 32189121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 89Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30Asp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Ala Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser 115 12090107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 90Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100

105919PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 91Phe Thr Phe Ser Asp His Asp Met Asn1 59219PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 92Arg Thr Arg Asn Ala Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly9312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 93Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu1 5 109411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 94Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 10957PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 95Ala Ala Ser Ser Leu Gln Ser1 5969PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 96Gln Gln Ser Tyr Ile Ala Pro Tyr Thr1 597363DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 97gaggtgcagc tggtggagtc tgggggaggc ttggtacagc cagggcggtc cctgagactc 60tcctgtacag cttctggatt caccttcagt gaccacgaca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt actagaaacg ccgctggaag ttacaccaca 180gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga 300gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc 360tca 36398321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 98gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 32199121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 99Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp His 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Leu Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser 115 120100107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 100Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1051019PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 101Phe Thr Phe Val Asp His Asp Met Asp1 510219PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 102Arg Thr Arg Asn Lys Leu Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly10312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 103Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu1 5 1010411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 104Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 101057PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 105Ala Ala Ser Ser Leu Gln Ser1 51069PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 106Gln Gln Ser Tyr Ile Ala Pro Tyr Thr1 5107363DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 107gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60tcctgtgcag cctctggatt caccttcgta gaccacgaca tggactgggt ccgccaggct 120ccagggaagg ggctggagtg ggttggccgt actagaaaca aactaggaag ttacaccaca 180gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca 240ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga 300gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc 360tca 363108321DNAArtificial SequenceDescription of Artificial Sequence Synthetic polynucleotide 108gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga 300gggaccaagg ttgagatcaa a 321109214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 109Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210110451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 110Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450111451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 111Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450112451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 112Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450113451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 113Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1

5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450114451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 114Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala 20 25 30Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly 100 105 110Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450115213PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 115Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210116449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 116Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys117449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 117Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys118449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 118Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys119449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 119Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys120449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 120Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys121107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 121Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105122330PRTHomo sapiens 122Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330123330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 123Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330124330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 124Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330125330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 125Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330126330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 126Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3301279PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(4)..(4)Ser or ArgMOD_RES(5)..(5)Ser, Ile or Leu 127Gly Thr Phe Xaa Xaa Tyr Ala Ile Ser1 512817PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(5)..(5)Ile, Asp, Ala or HisMOD_RES(8)..(8)Thr, Val or Leu 128Gly Ile Ile Pro Xaa Phe Gly Xaa Ala Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly12912PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 129Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu1 5 1013011PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 130Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn1 5 101317PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 131Ala Ala Ser Ser Leu Gln Ser1 51328PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 132Gln Gln Gly Val Ser Asp Ile Thr1 51339PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(5)..(5)Asn or SerMOD_RES(7)..(7)Ala or ValMOD_RES(9)..(9)Ser or Ile 133Phe Thr Phe Ser Xaa Tyr Xaa Met Xaa1 513417PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ala or SerMOD_RES(5)..(5)Ser or AspMOD_RES(6)..(6)Gly or SerMOD_RES(7)..(7)Gly or ValMOD_RES(8)..(8)Ser or Thr 134Xaa Ile Ser Gly Xaa Xaa Xaa Xaa Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly13516PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 135Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val1 5 10 1513611PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 136Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala1 5 101377PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 137Ala Ala Ser Ser Leu Gln Ser1 51389PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 138Gln Gln Thr Asn Ser Phe Pro Tyr Thr1 51399PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(4)..(4)Ser or ValMOD_RES(6)..(6)His or AlaMOD_RES(7)..(7)Tyr or AspMOD_RES(9)..(9)Asp or Asn 139Phe Thr Phe Xaa Asp Xaa Xaa Met Xaa1 514019PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(5)..(5)Lys or AlaMOD_RES(6)..(6)Ala or LeuMOD_RES(7)..(7)Ser or Gly 140Arg Thr Arg Asn Xaa Xaa Xaa Ser Tyr Thr Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly14112PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 141Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu1 5 1014211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 142Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 101437PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 143Ala Ala Ser Ser Leu Gln Ser1 51449PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 144Gln Gln Ser Tyr Ile Ala Pro Tyr Thr1 5145976PRTHomo sapiens 145Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu1 5 10 15Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly 20 25 30Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val 35 40 45Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val 50 55 60Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn65 70 75 80Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr 85 90 95Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg 100 105 110Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu 115 120 125Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr 130 135 140Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu145 150 155 160Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys 165 170 175Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly 180 185 190Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe 195 200 205Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg 210 215 220Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser225 230 235 240Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln 245 250 255Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln 260 265 270Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe 275 280 285Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr 290 295 300Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn305 310 315 320Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu 325 330 335Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn 340 345 350Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu 355 360 365Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly 370 375 380Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn385 390 395 400Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu 405 410 415Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly 420 425 430Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln 435 440 445Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser 450 455 460Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser465 470 475 480Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp 485 490 495Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Gly Asn Asn 500 505 510Lys Glu Gln Ile His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly 515 520 525Phe Val Ile Val Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr 530 535 540Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val545 550 555 560Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu 565 570 575Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly 580 585 590Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala 595 600 605Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met 610 615 620Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu625 630 635 640Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu 645 650 655Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr 660 665 670Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser 675 680 685Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys 690 695 700Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu705 710 715 720Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala 725 730 735Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val 740 745 750Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp 755 760 765Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala 770 775 780Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu785 790 795 800Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp 805 810 815Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro 820 825 830Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe 835 840 845Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser 850 855 860Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr865 870 875 880Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro 885 890 895Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu 900 905 910Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile 915 920 925Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro 930 935 940Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val945 950 955 960Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val 965 970 975146972PRTHomo sapiens 146Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu1 5 10 15Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly 20 25 30Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val 35 40 45Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val 50 55 60Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn65 70 75 80Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr 85 90 95Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg 100 105 110Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu 115 120 125Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr 130 135 140Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu145 150 155 160Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys 165 170 175Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly 180 185 190Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe 195 200 205Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg 210 215 220Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser225 230 235 240Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln 245 250 255Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln 260 265 270Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe 275 280 285Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr 290 295 300Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn305 310 315 320Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu 325 330 335Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn 340 345 350Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu 355 360 365Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly 370 375 380Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn385 390 395 400Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu 405 410 415Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly 420 425 430Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln 435 440 445Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser 450 455 460Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser465 470 475 480Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp 485 490 495Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Glu Gln Ile 500 505 510His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly Phe Val Ile Val 515 520 525Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr Tyr Lys Tyr Leu 530 535 540Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val Glu Glu Ile Asn545 550 555 560Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp His 565 570 575Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly 580 585 590Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile 595 600 605Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser 610 615 620Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu625 630 635 640Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu Leu Gly Ala Cys 645 650 655Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr Gly 660 665 670Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys Ser 675

680 685Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu His 690 695 700Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met705 710 715 720Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg 725 730 735Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile 740 745 750Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser Phe 755 760 765Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala Ser Lys Asn Cys 770 775 780Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly Arg785 790 795 800Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Lys Asn Asp 805 810 815Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp Met 820 825 830Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val 835 840 845Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser 850 855 860Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys865 870 875 880Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met Tyr 885 890 895Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro Thr 900 905 910Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile Ser Glu Ser Thr 915 920 925Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro Asn Arg Gln Lys 930 935 940Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val Gly Ser Thr Ala945 950 955 960Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val 965 970147123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 147Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Gly Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120148107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 148Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105149107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 149Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Thr Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105150107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 150Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105151107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 151Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105152107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 152Asn Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Ser Asp Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105153107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 153Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Ile Ile Ala Cys Arg Ala Ser Gln Gly Ile Gly Gly Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Lys Val Leu Val 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105154107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 154Asp Ile Ala Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Phe Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ile Ser Ser 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105155107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 155Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Ala Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Ser Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105156107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 156Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105157107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 157Asn Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Thr Ser 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Leu Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105158107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 158Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Asp Tyr 20 25 30Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Pro Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105159107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 159Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Arg Ser Thr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105160107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 160Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105161107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 161Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105162107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 162Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ile Gly Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105163107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 163Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Thr Ser Ala 20 25 30Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105164121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 164Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Arg Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ala Met Tyr Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Asn Thr Ala Asn65 70 75 80Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Ala Arg Gly Leu Val Asp Asp Tyr Val Met Asp Ala Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 120165108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 165Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Gly Asn1

5 10 15Thr Val Ser Leu Thr Cys Val Gly Asp Glu Leu Ser Lys Arg Tyr Ala 20 25 30Gln Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Val Ser Val Ile Tyr 35 40 45Lys Asp Ser Glu Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile His Gly Thr Leu Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Tyr Ser Asp Asp Asn Leu 85 90 95Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105166117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 166Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr1 5 10 15Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Asn Ile Arg Asn Thr 20 25 30Tyr Ile His Trp Val Asn Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Asp Pro Thr Asn Gly Asn Thr Ile Ser Ala Glu Lys Phe 50 55 60Lys Thr Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser His Thr Ala Tyr65 70 75 80Leu Gln Phe Ser Gln Leu Lys Ser Asp Asp Thr Ala Ile Tyr Phe Cys 85 90 95Ala Leu Asn Tyr Glu Gly Tyr Ala Asp Tyr Trp Gly Gln Gly Val Met 100 105 110Val Thr Gly Ser Ser 115167106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 167Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Arg Leu Ile 35 40 45Phe Lys Thr Asn Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Thr65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ile Gly Tyr Thr 85 90 95Phe Gly Ala Gly Thr Lys Val Glu Leu Lys 100 105168124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 168Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Ser Ser Asn 20 25 30Tyr Arg Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Val Glu Trp 35 40 45Met Gly Tyr Ile Asn Ser Ala Gly Ser Thr Asn Tyr Asn Pro Ser Leu 50 55 60Lys Ser Arg Ile Ser Met Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe65 70 75 80Leu Gln Val Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Ser Leu Arg Gly Tyr Ile Thr Asp Tyr Ser Gly Phe Phe Asp 100 105 110Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser 115 120169107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 169Asp Ile Arg Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly1 5 10 15Glu Thr Val Asn Ile Glu Cys Leu Ala Ser Glu Asp Ile Phe Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Asn Ala Asn Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Arg Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr Lys Asn Tyr Pro Leu 85 90 95Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105170117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 170Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr1 5 10 15Ser Val Arg Leu Ser Cys Lys Leu Ser Gly Tyr Lys Ile Arg Asn Thr 20 25 30Tyr Ile His Trp Val Asn Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Ile Tyr Ala Glu Lys Phe 50 55 60Lys Ser Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Met Gln Leu Ser Gln Leu Lys Ser Asp Asp Thr Ala Leu Tyr Phe Cys 85 90 95Ala Met Asn Tyr Glu Gly Tyr Glu Asp Tyr Trp Gly Gln Gly Val Met 100 105 110Val Thr Val Ser Ser 115171106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 171Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15Asp Ser Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile 35 40 45His Lys Thr Asp Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Lys Ser Gly Phe Met 85 90 95Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105172120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 172Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ala Val Tyr Trp Val Ile Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Asn65 70 75 80Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Gly Ala Gly Met Thr Lys Asp Tyr Val Met Asp Ala Trp Gly 100 105 110Arg Gly Val Leu Val Thr Val Ser 115 120173108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 173Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Gly Asn1 5 10 15Thr Val Ser Leu Thr Cys Val Gly Asp Glu Leu Ser Lys Arg Tyr Ala 20 25 30Gln Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Val Ser Val Ile Tyr 35 40 45Lys Asp Ser Glu Arg Pro Ser Asp Ile Ser Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile His Gly Thr Leu Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Tyr Ser Asp Asp Asn Leu 85 90 95Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105174116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 174Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30Leu Val His Trp Val Arg Gln Pro Pro Gly Lys Thr Leu Glu Trp Val 35 40 45Gly Leu Met Trp Asn Asp Gly Asp Thr Ser Tyr Asn Ser Ala Leu Lys 50 55 60Ser Arg Leu Ser Ile Ser Arg Asp Thr Ser Lys Ser Gln Val Phe Leu65 70 75 80Lys Met His Ser Leu Gln Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95Arg Glu Ser Asn Leu Gly Phe Thr Tyr Trp Gly His Gly Thr Leu Val 100 105 110Thr Val Ser Ser 115175107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 175Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Glu1 5 10 15Glu Ile Val Thr Ile Thr Cys Lys Ala Ser Gln Gly Ile Asp Asp Asp 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Asp Val Thr Arg Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Arg Pro Gln Val65 70 75 80Ala Asp Ser Gly Ile Tyr Tyr Cys Leu Gln Ser Tyr Ser Thr Pro Tyr 85 90 95Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105176117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 176Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr1 5 10 15Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Asn Ile Arg Asn Thr 20 25 30Tyr Ile His Trp Val His Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Asp Pro Thr Asn Gly Asn Thr Ile Ser Ala Glu Lys Phe 50 55 60Lys Ser Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Met Gln Phe Ser Gln Leu Lys Ser Asp Asp Thr Ala Ile Tyr Phe Cys 85 90 95Ala Met Asn Tyr Glu Gly Tyr Ala Asp Tyr Trp Gly Gln Gly Val Met 100 105 110Val Thr Val Ser Ser 115177106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 177Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Leu Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile 35 40 45Phe Lys Thr Asn Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ile Gly Phe Thr 85 90 95Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105178124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 178Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asp Tyr 20 25 30Tyr Met Ala Trp Val Arg Gln Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Thr Ile Asn Tyr Asp Gly Ser Thr Thr Tyr His Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg His Gly Asp Tyr Gly Tyr His Tyr Gly Ala Tyr Tyr Phe Asp 100 105 110Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser 115 120179109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 179Asp Ile Val Leu Thr Gln Ser Pro Ala Leu Ala Val Ser Leu Gly Gln1 5 10 15Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Thr Val Ser Leu Ser Gly 20 25 30Tyr Asn Leu Ile His Trp Tyr Gln Gln Arg Thr Gly Gln Gln Pro Lys 35 40 45Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Pro Gly Ile Pro Ala Arg 50 55 60Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Pro65 70 75 80Val Gln Ser Asp Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Ser Arg Glu 85 90 95Ser Trp Thr Phe Gly Gly Gly Thr Asn Leu Glu Met Lys 100 105180116PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 180Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ala Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Arg Trp Met 35 40 45Ala Trp Ile Asn Thr Glu Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala His65 70 75 80Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys 85 90 95Ala Gly Gly Ser His Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser 115181108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 181Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Glu Asn1 5 10 15Thr Val Ser Ile Thr Cys Ser Gly Asp Glu Leu Ser Asn Lys Tyr Ala 20 25 30His Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Leu Glu Val Ile Tyr 35 40 45Asn Asp Ser Glu Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Thr Thr Ala Ile Leu Thr Ile Arg Asp Ala Gln Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Phe Ser Asp Asp Asp Leu 85 90 95Pro Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105182108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 182Ser Tyr Glu Leu Ile Gln Pro Pro Ser Thr Ser Val Thr Leu Gly Asn1 5 10 15Thr Val Ser Leu Thr Cys Val Gly Asn Glu Leu Pro Lys Arg Tyr Ala 20 25 30Tyr Trp Phe Gln Gln Lys Pro Asp Gln Ser Ile Val Arg Leu Ile Tyr 35 40 45Asp Asp Asp Arg Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile Arg Asp Ala Gln Ala Glu65 70 75 80Asp Glu Ala Tyr Tyr Tyr Cys His Ser Thr Tyr Thr Asp Asp Lys Val 85 90 95Pro Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105183123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 183Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Met Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Asp Met Ala Trp Val Arg Gln Ala Pro Thr Arg Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Tyr Asp Gly Ile Thr Ala Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Ser Thr Leu Tyr65 70 75 80Leu Gln Leu Val Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Thr Thr Glu Gly Gly Tyr Val Tyr Ser Gly Pro His Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Val Met Val Thr Val Ser Ser 115 120184107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 184Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly1 5 10 15Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Gly Ile Phe 20 25 30Val Asn Trp Phe Gln Gln Lys Pro Gly Arg Ser Pro Arg Arg Met Ile 35 40 45Tyr Arg Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Val Ala Asp Tyr His Cys Leu Gln Tyr Asp Glu Phe Pro Arg 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 100 105185117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide

185Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr1 5 10 15Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Lys Ile Arg Asn Thr 20 25 30Tyr Ile His Trp Val Asn Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Ile Tyr Ala Glu Lys Phe 50 55 60Lys Ser Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Met Gln Leu Ser Gln Leu Lys Ser Asp Asp Thr Ala Leu Tyr Phe Cys 85 90 95Ala Met Asn Tyr Glu Gly Tyr Glu Asp Tyr Trp Gly Gln Gly Val Met 100 105 110Val Thr Val Ser Ser 115186106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 186Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15Asp Ser Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile 35 40 45His Lys Thr Asn Ser Leu Gln Pro Gly Phe Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Ala Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Phe Thr 85 90 95Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105187125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 187Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Met Asn Pro His Ser Gly Asp Thr Gly Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125188107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 188Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asn Glu 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105189125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 189Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Asp Thr Asn Tyr Ala Gln Asn Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125190107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 190Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105191125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 191Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125192107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 192Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Glu Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105193125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 193Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Leu Asn Pro Ser Gly Gly Gly Thr Ser Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asp Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125194107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 194Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105195125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 195Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Lys Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125196107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 196Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asp Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105197125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 197Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Ser Gly Gly Asn Thr Asn Tyr Ala Gln Asn Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Ala Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125198107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 198Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105199125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 199Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Val Ile Asn Pro Thr Val Gly Gly Ala Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Glu Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125200107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 200Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asp Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105201125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 201Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Leu Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Val Ile Asn Pro Asn Gly Ala Gly Thr Asn Phe Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125202125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 202Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Thr Gly Gly Gly Thr Asn Tyr Ala Gln Asn Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125203107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 203Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Ser Gly Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105204125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 204Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu

Glu Trp Met 35 40 45Gly Met Ile Asn Pro Ser Gly Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Asp Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125205107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 205Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asp Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Asn Leu Glu Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105206125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 206Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Ala Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Arg Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Gly Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125207107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 207Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Tyr 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105208125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 208Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Val Asp Lys Ser Asn Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125209107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 209Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ala Ser Phe Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105210125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 210Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Ser Ser Phe Pro Asn Ser 20 25 30Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Ser Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Glu Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125211107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 211Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105212125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 212Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Asp Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Met Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Ala Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125213107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 213Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Phe Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105214124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 214Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Trp 20 25 30Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly 35 40 45Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe Gln 50 55 60Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu65 70 75 80Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Arg His Gly Arg Gly Tyr Tyr Gly Tyr Glu Gly Ala Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120215107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 215Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asp Asn 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ile Ser Phe Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105216125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 216Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Val Ile Tyr Pro Asp Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125217107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 217Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Asp Ile Arg Asp Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105218124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 218Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Asn Thr Tyr 20 25 30Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly 35 40 45Ile Ile Tyr Pro Gly Asp Ser Gly Thr Arg Tyr Ser Pro Ser Phe Gln 50 55 60Gly Gln Val Thr Ile Ser Ala Asp Lys Ala Ile Ser Thr Ala Tyr Leu65 70 75 80Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Arg His Ser Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120219107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 219Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Val 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105220125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 220Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Thr Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile His Pro Ala Asp Ser Asp Thr Arg Tyr Asn Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125221107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 221Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Val Ser Gln Gly Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105222125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 222Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Ser Asn Tyr 20 25 30Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Asp Asn Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asp Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125223107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 223Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70

75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Ser Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105224124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 224Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Ala Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Thr Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Asn Pro Ser Gln 50 55 60Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu65 70 75 80Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Arg His Gly Arg Gly Tyr Gly Gly Tyr Glu Gly Ala Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120225107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 225Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105226125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 226Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125227107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 227Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105228107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 228Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105229107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 229Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105230107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 230Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105231107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 231Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105232107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 232Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105233107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 233Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105234107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 234Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105235107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 235Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105236107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 236Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105237107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 237Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105238123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 238Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120239107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 239Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105240107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 240Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Gly Ile Ser Asp Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105241107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 241Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105242107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 242Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105243123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 243Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120244107PRTArtificial SequenceDescription of Artificial Sequence

Synthetic polypeptide 244Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Arg Ser Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1052455PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 245Asn Tyr Trp Ile Gly1 524617PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 246Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe Gln1 5 10 15Gly24714PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 247His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile1 5 1024811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 248Arg Ser Ser Gln Gly Ile Arg Ser Asp Leu Gly1 5 102497PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 249Asp Ala Ser Asn Leu Glu Thr1 52509PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 250Gln Gln Ala Asn Gly Phe Pro Leu Thr1 5251123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 251Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Leu 50 55 60Gln Gly Gln Val Thr Ile Ser Val Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Asn Ser Leu Lys Pro Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120252107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 252Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Ser 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10525317PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 253Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Leu Gln1 5 10 15Gly25411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 254Arg Ala Ser Gln Gly Ile Gly Asp Ser Leu Ala1 5 102559PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 255Gln Gln Leu Asn Gly Tyr Pro Ile Thr1 5256107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 256Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10525711PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 257Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly1 5 10258123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 258Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Leu Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12025917PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 259Ile Ile Tyr Pro Gly Asp Ser Leu Thr Arg Tyr Ser Pro Ser Phe Gln1 5 10 15Gly260123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 260Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120261123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 261Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Gly Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120262107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 262Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1052635PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 263Thr Tyr Trp Ile Gly1 526411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 264Arg Ala Ser Gln Gly Val Ile Ser Ala Leu Ala1 5 102657PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 265Asp Ala Ser Ile Leu Glu Ser1 52669PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 266Gln Gln Phe Asn Ser Tyr Pro Leu Thr1 526711PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 267Arg Ala Ser Gln Gly Val Gly Ser Ala Leu Ala1 5 102687PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 268Asp Ala Ser Thr Leu Glu Ser1 5269330PRTHomo sapiens 269Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330270330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 270Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330271330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 271Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330272330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 272Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330273330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 273Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330274330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 274Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330275453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 275Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu225 230 235 240Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450276453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 276Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450277453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 277Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450278453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 278Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450279453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 279Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu225 230 235 240Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450280453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 280Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450281453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 281Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450282453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 282Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450283107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 283Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105284214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 284Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Arg Ser Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys

Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210285214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 285Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 2102865PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 286Thr Ser Trp Ile Gly1 528714PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 287His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile1 5 1028811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 288Arg Ala Ser Gln Gly Ile Gly Ser Ala Leu Ala1 5 1028910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 289Cys Gln Gln Leu Asn Gly Tyr Pro Leu Thr1 5 10290453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 290Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Val Tyr65 70 75 80Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr 100 105 110Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu225 230 235 240Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 450291214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 291Asp Ile Gln Met Thr Gln Thr Thr Ser Ala Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Gly Cys Arg Ala Ser Gln Asp Leu Ser Asn His 20 25 30Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Arg Asn Leu Glu Gln65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 2102925PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 292Ser Tyr Trp Ile Asn1 529317PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 293Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe Lys1 5 10 15Asp29414PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 294Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr1 5 1029511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 295Arg Ala Ser Gln Asp Leu Ser Asn His Leu Tyr1 5 102967PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 296Tyr Thr Ser Arg Leu His Ser1 52979PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 297Gln Gln Gly Tyr Thr Leu Pro Tyr Thr1 5298123PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 298Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Val Tyr65 70 75 80Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr 100 105 110Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120299107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 299Asp Ile Gln Met Thr Gln Thr Thr Ser Ala Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Gly Cys Arg Ala Ser Gln Asp Leu Ser Asn His 20 25 30Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Arg Asn Leu Glu Gln65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 1053005PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 300Glu Tyr Tyr Met Tyr1 530117PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 301Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe Lys1 5 10 15Lys3029PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 302Gly Lys Phe Asn Tyr Arg Phe Ala Tyr1 530316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 303Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Asn1 5 10 153047PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 304Leu Val Ser Lys Leu Glu Ser1 53059PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 305Met Gln Phe Thr His Tyr Pro Tyr Thr1 5306118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 306Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Leu Met 35 40 45Gly Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe 50 55 60Lys Lys Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Lys Phe Asn Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115307112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 307Asp Val Val Met Thr Gln Ser Pro Pro Ser Leu Leu Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Ser Gly Asn Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45Pro Gln Pro Leu Ile Tyr Leu Val Ser Lys Leu Glu Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Gly Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Phe 85 90 95Thr His Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110308118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 308Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Gln Arg Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Glu Tyr 20 25 30Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Leu Val 35 40 45Gly Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe 50 55 60Lys Lys Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Lys Phe Asn Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115309112PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 309Asp Val Val Met Thr Gln Ser Pro Pro Ser Leu Leu Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Ser Gly Asn Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45Pro Gln Pro Leu Ile Tyr Leu Val Ser Lys Leu Glu Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Gly Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Phe 85 90 95Thr His Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110310120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 310Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120311109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 311Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105312351PRTHomo sapiens 312Met Ser Phe Pro Cys Lys Phe Val Ala Ser Phe Leu Leu Ile Phe Asn1 5 10 15Val Ser Ser Lys Gly Ala Val Ser Lys Glu Ile Thr Asn Ala Leu Glu 20 25 30Thr Trp Gly Ala Leu Gly Gln Asp Ile Asn Leu Asp Ile Pro Ser Phe 35 40 45Gln Met Ser Asp Asp Ile Asp Asp Ile Lys Trp Glu Lys Thr Ser Asp 50 55 60Lys Lys Lys Ile Ala Gln Phe Arg Lys Glu Lys Glu Thr Phe Lys Glu65 70 75 80Lys Asp Thr Tyr Lys Leu Phe Lys Asn Gly Thr Leu Lys Ile Lys His 85 90 95Leu Lys Thr Asp Asp Gln Asp Ile Tyr Lys Val Ser Ile Tyr Asp Thr 100 105 110Lys Gly Lys Asn Val Leu Glu Lys Ile Phe Asp Leu Lys Ile Gln Glu 115

120 125Arg Val Ser Lys Pro Lys Ile Ser Trp Thr Cys Ile Asn Thr Thr Leu 130 135 140Thr Cys Glu Val Met Asn Gly Thr Asp Pro Glu Leu Asn Leu Tyr Gln145 150 155 160Asp Gly Lys His Leu Lys Leu Ser Gln Arg Val Ile Thr His Lys Trp 165 170 175Thr Thr Ser Leu Ser Ala Lys Phe Lys Cys Thr Ala Gly Asn Lys Val 180 185 190Ser Lys Glu Ser Ser Val Glu Pro Val Ser Cys Pro Glu Lys Gly Leu 195 200 205Asp Ile Tyr Leu Ile Ile Gly Ile Cys Gly Gly Gly Ser Leu Leu Met 210 215 220Val Phe Val Ala Leu Leu Val Phe Tyr Ile Thr Lys Arg Lys Lys Gln225 230 235 240Arg Ser Arg Arg Asn Asp Glu Glu Leu Glu Thr Arg Ala His Arg Val 245 250 255Ala Thr Glu Glu Arg Gly Arg Lys Pro His Gln Ile Pro Ala Ser Thr 260 265 270Pro Gln Asn Pro Ala Thr Ser Gln His Pro Pro Pro Pro Pro Gly His 275 280 285Arg Ser Gln Ala Pro Ser His Arg Pro Pro Pro Pro Gly His Arg Val 290 295 300Gln His Gln Pro Gln Lys Arg Pro Pro Ala Pro Ser Gly Thr Gln Val305 310 315 320His Gln Gln Lys Gly Pro Pro Leu Pro Arg Pro Arg Val Gln Pro Lys 325 330 335Pro Pro His Gly Ala Ala Glu Asn Ser Leu Ser Pro Ser Ser Asn 340 345 3503137PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 313Gly Phe Thr Phe Ser Ser Tyr1 53145PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 314Ser Gly Gly Gly Phe1 53159PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 315Ser Ser Tyr Gly Glu Ile Met Asp Tyr1 53169PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 316Ser Ser Tyr Gly Glu Leu Met Asp Tyr1 531711PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 317Arg Ala Ser Gln Arg Ile Gly Thr Ser Ile His1 5 103187PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 318Tyr Ala Ser Glu Ser Ile Ser1 531910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 319Gln Gln Ser His Gly Trp Pro Phe Thr Phe1 5 10320117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 320Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Gly Gly Gly Phe Leu Tyr Tyr Leu Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu65 70 75 80His Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Arg Ser Ser Tyr Gly Glu Ile Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110Val Thr Val Ser Ser 115321117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 321Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Gly Gly Gly Phe Leu Tyr Tyr Leu Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu65 70 75 80His Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Arg Ser Ser Tyr Gly Glu Leu Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110Val Thr Val Ser Ser 115322107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 322Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Arg Ile Gly Thr Ser 20 25 30Ile His Trp Tyr Gln Gln Arg Thr Thr Gly Ser Pro Arg Leu Leu Ile 35 40 45Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser65 70 75 80Glu Asp Val Ala Asp Tyr Tyr Cys Gln Gln Ser His Gly Trp Pro Phe 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Glu 100 105323324PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 323Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala1 5 10 15Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu 50 55 60Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val65 70 75 80Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys 85 90 95Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro 100 105 110Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu 115 120 125Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser 130 135 140Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu145 150 155 160Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr 165 170 175Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn 180 185 190Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro 195 200 205Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln 210 215 220Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val225 230 235 240Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val 245 250 255Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln 260 265 270Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn 275 280 285Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val 290 295 300Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His305 310 315 320Ser Pro Gly Lys324107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 324Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu1 5 10 15Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 20 25 30Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 35 40 45Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu65 70 75 80Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 85 90 95Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 100 105325107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 325Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Tyr65 70 75 80Glu Asp Phe Gly Ile Tyr Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105326118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 326Gln Ile Gln Leu Val Gln Ser Gly Pro Gly Leu Lys Lys Pro Gly Gly1 5 10 15Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Arg Trp Met 35 40 45Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 100 105 110Thr Val Thr Val Ser Ser 1153277PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 327Gly Tyr Thr Phe Thr Asn Tyr1 53286PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 328Asn Thr His Thr Gly Glu1 53299PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 329Arg Gly Tyr Asp Trp Tyr Phe Asp Val1 533011PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 330Arg Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser1 5 103317PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 331Arg Ala Asn Arg Leu Val Asp1 53329PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 332Gln Gln Tyr Asp Glu Ser Pro Trp Thr1 5333107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 333Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45Tyr Arg Ala Asn Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Tyr65 70 75 80Glu Asp Phe Gly Ile Tyr Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105334119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 334Glu Ile Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Thr His Tyr Gly Glu Pro Thr Tyr Ala Asp Ser Phe 50 55 60Lys Gly Thr Arg Thr Phe Ser Leu Asp Asp Ser Lys Asn Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Gly 100 105 110Thr Thr Val Thr Val Ser Ser 1153357PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 335Gly Tyr Thr Phe Thr Asn Tyr1 53366PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 336Asn Thr His Tyr Gly Glu1 533710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 337Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val1 5 1033811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 338Arg Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser1 5 103397PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 339Arg Ala Asn Arg Leu Glu Ser1 53409PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 340Gln Gln Tyr Asp Glu Ser Pro Trp Thr1 53419PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 341Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr1 53427PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 342Ile Ser Tyr Ser Gly Phe Thr1 534311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 343Ala Gly Asp Arg Thr Gly Ser Trp Phe Ala Tyr1 5 103446PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 344Gln Asp Ile Ser Asn Tyr1 53453PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 345Ala Thr Ser13469PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 346Leu Gln Tyr Ala Ser Tyr Pro Phe Thr1 53478PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 347Gly Tyr Ile Phe Thr Asn Tyr Gly1 53488PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 348Ile Asn Thr Tyr Asn Gly Glu Pro1 534911PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 349Ala Arg Gly Asp Tyr Tyr Gly Tyr Glu Asp Tyr1 5 103506PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 350Gln Gly Ile Ser Asn Tyr1 53513PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 351Tyr Thr Ser13529PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 352Gln Gln Tyr Ser Lys Leu Pro Trp Thr1 53539PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 353Phe Ser Leu Ser Thr Ser Gly Met Gly1 53545PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 354Trp Trp Asp Asp Asp1 535510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 355Arg Arg Ala Thr Gly Thr Gly Phe Asp Tyr1 5 103566PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 356Gln Asp Val Gly Thr Ala1 53577PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 357Trp Thr Ser Thr Arg His Thr1 53586PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 358Tyr Asn Ser Tyr Asn Thr1 5359120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 359Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Gly Met Gly Val Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45Trp Val Ala His Ile Trp Trp Asp Asp Asp Val Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Ala Ser Lys Asp Gln Val65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Val Arg Arg Arg Ala Thr Gly Thr Gly Phe Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120360106PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 360Asn Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Val Gly Thr Ala 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile 35 40 45Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55

60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys His Gln Tyr Asn Ser Tyr Asn Thr 85 90 95Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105361120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 361Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120362109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 362Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105363438PRTHomo sapiens 363Met Val Cys Ser Gln Ser Trp Gly Arg Ser Ser Lys Gln Trp Glu Asp1 5 10 15Pro Ser Gln Ala Ser Lys Val Cys Gln Arg Leu Asn Cys Gly Val Pro 20 25 30Leu Ser Leu Gly Pro Phe Leu Val Thr Tyr Thr Pro Gln Ser Ser Ile 35 40 45Ile Cys Tyr Gly Gln Leu Gly Ser Phe Ser Asn Cys Ser His Ser Arg 50 55 60Asn Asp Met Cys His Ser Leu Gly Leu Thr Cys Leu Glu Pro Gln Lys65 70 75 80Thr Thr Pro Pro Thr Thr Arg Pro Pro Pro Thr Thr Thr Pro Glu Pro 85 90 95Thr Ala Pro Pro Arg Leu Gln Leu Val Ala Gln Ser Gly Gly Gln His 100 105 110Cys Ala Gly Val Val Glu Phe Tyr Ser Gly Ser Leu Gly Gly Thr Ile 115 120 125Ser Tyr Glu Ala Gln Asp Lys Thr Gln Asp Leu Glu Asn Phe Leu Cys 130 135 140Asn Asn Leu Gln Cys Gly Ser Phe Leu Lys His Leu Pro Glu Thr Glu145 150 155 160Ala Gly Arg Ala Gln Asp Pro Gly Glu Pro Arg Glu His Gln Pro Leu 165 170 175Pro Ile Gln Trp Lys Ile Gln Asn Ser Ser Cys Thr Ser Leu Glu His 180 185 190Cys Phe Arg Lys Ile Lys Pro Gln Lys Ser Gly Arg Val Leu Ala Leu 195 200 205Leu Cys Ser Gly Phe Gln Pro Lys Val Gln Ser Arg Leu Val Gly Gly 210 215 220Ser Ser Ile Cys Glu Gly Thr Val Glu Val Arg Gln Gly Ala Gln Trp225 230 235 240Ala Ala Leu Cys Asp Ser Ser Ser Ala Arg Ser Ser Leu Arg Trp Glu 245 250 255Glu Val Cys Arg Glu Gln Gln Cys Gly Ser Val Asn Ser Tyr Arg Val 260 265 270Leu Asp Ala Gly Asp Pro Thr Ser Arg Gly Leu Phe Cys Pro His Gln 275 280 285Lys Leu Ser Gln Cys His Glu Leu Trp Glu Arg Asn Ser Tyr Cys Lys 290 295 300Lys Val Phe Val Thr Cys Gln Asp Pro Asn Pro Ala Gly Leu Ala Ala305 310 315 320Gly Thr Val Ala Ser Ile Ile Leu Ala Leu Val Leu Leu Val Val Leu 325 330 335Leu Val Val Cys Gly Pro Leu Ala Tyr Lys Lys Leu Val Lys Lys Phe 340 345 350Arg Gln Lys Lys Gln Arg Gln Trp Ile Gly Pro Thr Gly Met Asn Gln 355 360 365Asn Met Ser Phe His Arg Asn His Thr Ala Thr Val Arg Ser His Ala 370 375 380Glu Asn Pro Thr Ala Ser His Val Asp Asn Glu Tyr Ser Gln Pro Pro385 390 395 400Arg Asn Ser His Leu Ser Ala Tyr Pro Ala Leu Glu Gly Ala Leu His 405 410 415Arg Ser Ser Met Gln Pro Asp Asn Ser Ser Asp Ser Asp Tyr Asp Leu 420 425 430His Gly Ala Gln Arg Leu 43536415PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 364Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro1 5 10 153658PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(7)..(7)Asn or Asp 365Ile Trp Gly Ile Gly Cys Xaa Pro1 536610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 366Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met1 5 1036710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 367Ser Gly Tyr Ser Phe Thr Asp Tyr Thr Met1 5 1036810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 368Ser Gly Phe Thr Phe Ser Asn Tyr Ala Met1 5 1036910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 369Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met1 5 1037010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 370Ser Gly Tyr Ser Phe Thr Ala Tyr Asn Ile1 5 1037110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 371Ser Gly Tyr Ser Phe Thr Ala Tyr Ser Met1 5 1037210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 372Ser Gly Tyr Thr Phe Thr Asn Phe Ala Ile1 5 1037310PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 373Ser Gly Phe Asn Ile Lys Asp Thr Tyr Met1 5 1037410PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 374Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Met1 5 1037510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 375Ser Gly Phe Ser Leu Thr Asn Tyr Asp Val1 5 1037610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 376Ser Gly Phe Thr Phe Ser Asn Tyr Gly Met1 5 1037710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 377Ser Gly Tyr Ile Phe Ala Asn Tyr Gly Met1 5 1037810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 378Ser Gly Tyr Asn Phe Thr Asn Tyr Gly Met1 5 1037910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 379Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met1 5 1038010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 380Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Ile1 5 1038110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 381Ser Gly Asn Thr Phe Thr Asn Phe Tyr Leu1 5 1038210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 382Ser Glu Phe Thr Phe Ser Asn Tyr Ala Met1 5 1038310PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 383Ser Gly Tyr Thr Phe Thr Ser Tyr Arg Met1 5 1038410PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 384Ser Gly Tyr Met Phe Thr Asn His Gly Met1 5 1038510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 385Ser Gly Tyr Met Phe Thr Asn Tyr Gly Met1 5 1038610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 386Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met1 5 1038710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 387Ser Gly Phe Asn Ile Lys Asp Tyr Tyr Ile1 5 1038810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 388Ser Gly Tyr Thr Phe Ile Asn Tyr Gly Met1 5 1038910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 389Ser Gly Tyr Thr Phe Thr Asp Tyr Phe Ile1 5 1039010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 390Ser Gly Tyr Ile Phe Thr Gly Tyr Asn Ile1 5 1039110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 391Leu Ile Asn Pro Tyr Asn Gly Gly Thr Thr1 5 1039210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 392Leu Ile Asn Pro Tyr Asn Gly Gly Thr Met1 5 103939PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 393Ser Ile Ser Ser Gly Gly Asn Thr Phe1 53949PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 394Ser Ile Ser Ser Gly Gly Ser Thr Tyr1 539510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 395Ser Ile Asp Pro Tyr Tyr Gly Asp Thr Lys1 5 1039610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 396Leu Ile Ser Ser Asn Ser Gly Asp Val Ser1 5 1039710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 397Leu Ile Ser Thr Ser Ser Gly Asp Val Ser1 5 1039810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 398Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys1 5 1039910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 399Met Ile His Pro Ser Asp Ser Glu Thr Arg1 5 104009PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 400Val Ile Trp Ser Gly Gly Asn Thr Asp1 540110PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 401Ala Ile Asn Ser Asn Gly Asp Ile Thr Tyr1 5 1040210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 402Leu Ile Asn Pro Tyr Asn Gly Gly Thr Arg1 5 1040310PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 403Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr1 5 1040410PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 404Trp Ile Tyr Pro Gly Gly Gly Asn Thr Arg1 5 1040510PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 405Cys Ile Tyr Pro Gly Asn Val Lys Thr Lys1 5 1040610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 406Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr1 5 1040710PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 407Arg Ile Asp Pro Tyr Asp Ser Gly Thr His1 5 1040810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 408Trp Ile Asp Pro Glu Asn Gly Arg Thr Glu1 5 1040910PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 409Glu Ile Tyr Pro Gly Ser Ser Asn Thr Tyr1 5 1041010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 410Ala Val Tyr Pro Gly Asn Gly Asp Thr Ser1 5 1041115PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 411Cys Ala Arg Asp Tyr Tyr Gly Ser Ser Pro Asp Phe Asp Tyr Trp1 5 10 1541215PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 412Cys Ala Arg Asp Asn Tyr Gly Ser Ser Pro Asp Phe Asp Tyr Trp1 5 10 1541315PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 413Cys Ala Arg Asp Asn Tyr Gly Ser Ser Pro Tyr Phe Asp Tyr Trp1 5 10 1541416PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 414Cys Val Arg Tyr Tyr Tyr Gly Val Thr Tyr Trp Tyr Phe Asp Val Trp1 5 10 1541516PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 415Cys Val Arg Tyr Tyr Tyr Gly Ile Arg Tyr Trp Tyr Phe Asp Val Trp1 5 10 1541616PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 416Cys Ala Arg Arg Met Ile Thr Met Gly Asp Trp Tyr Phe Asp Val Trp1 5 10 1541716PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 417Cys Ala Arg Arg Met Ile Thr Thr Gly Asp Trp Tyr Phe Asp Val Trp1 5 10 1541814PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 418Cys Ala Arg His Tyr Gly Ala His Asn Tyr Phe Asp Tyr Trp1 5 1041914PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 419Cys Ala Arg His Tyr Gly Ala Asn Asn Tyr Phe Asp Tyr Trp1 5 1042016PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 420Cys Ala Arg Glu Glu Asn Tyr Tyr Gly Thr Tyr Tyr Phe Asp Tyr Trp1 5 10 1542114PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 421Cys Ala Arg Trp Gly Asp His Asp Asp Ala Met Asp Phe Trp1 5 1042217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 422Cys Ala Arg Asn His Gly Asp Gly Tyr Phe Asn Trp Tyr Phe Asp Val1 5 10 15Trp42317PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 423Cys Ala Arg Asn His Gly Asp Gly Tyr Tyr Asn Trp Tyr Phe Asp Val1 5 10 15Trp42411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 424Cys Ala Arg Gly Thr Ala Trp Phe Thr Tyr Trp1 5 1042514PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 425Cys Ala Arg Asp Gly Asp Asp Gly Trp Asp Ile Asp Val Trp1 5 1042613PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 426Cys Ala Arg Arg Gly Thr Tyr Trp His Phe Asp Val Trp1 5 1042713PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 427Cys Ala Arg Arg Gly Ser Tyr Trp His Phe Asp Val Trp1 5 1042812PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 428Cys Ala Arg Arg Ser Thr Leu Val Phe Asp Tyr Trp1 5 1042912PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 429Cys Ala Arg Asn Gly Tyr Trp Tyr Phe Asp Val Trp1 5 1043016PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 430Cys Ala Lys Glu Gly Asp Tyr Asp Gly Thr Ala Tyr Phe Asp Tyr Trp1 5 10 1543112PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 431Cys Ala Arg Arg Arg Asp Gly Asn Phe Asp Tyr Trp1 5 1043210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 432Cys Val Arg His Gly Tyr Phe Asp Val Trp1 5 104339PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 433Cys Ala Phe Tyr Asp Gly Ala Tyr Trp1 54349PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 434Cys Ala Ser Tyr Asp Pro Asp Tyr Trp1 543514PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 435Cys Ala Arg Asp Thr Thr Ala Thr Tyr Tyr Phe Asp Tyr Trp1 5 1043612PRTArtificial SequenceDescription of Artificial

Sequence Synthetic peptide 436Cys Ala Arg Arg Val Ala Thr Tyr Phe Asp Val Trp1 5 1043712PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 437Cys Thr Arg Arg Ser His Ile Thr Leu Asp Tyr Trp1 5 1043812PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 438Cys Ala Arg Arg Arg Thr Thr Ala Phe Asp Tyr Trp1 5 1043915PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 439Cys Asn Asn Gly Asn Tyr Val Arg His Tyr Tyr Phe Asp Tyr Trp1 5 10 1544012PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 440Cys Thr Arg Arg Arg Glu Ile Thr Phe Asp Tyr Trp1 5 1044112PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 441Cys Ala Arg Ser Gly Ile Ser Pro Phe Thr Tyr Trp1 5 1044211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 442Cys Ala Lys Tyr Asp Arg Phe Phe Ala Ser Trp1 5 10

Claims

1. An anti-CD1117 antibody-drug conjugate (ADC) comprising an antibody, or an antigen-binding fragment thereof, conjugated to an amatoxin via a linker, wherein the ADC has the structure of formula (I): ##STR00082## or a stereoisomer thereof; wherein: Q is S; L is a non-cleavable linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody, or antigen-binding fragment thereof; and Ab is the antibody, or the antigen binding fragment thereof, wherein the antibody, or the antigen binding fragment thereof, is selected from the group consisting of a) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; and a light chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the light chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; b) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO: 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243; and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO: 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244; c) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID No: 11, 12, and 13, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 14, 15, and 16, respectively; d) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 245, 246, and 247, respectively, and a light chain comprising alight chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 248, 249, and 250, respectively; e) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10; and f) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 243, and alight chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 244.

2. The ADC of claim 1, having the structure of formula (Ia): ##STR00083##

3. The ADC of claim 1, having the structure of formula (Ib): ##STR00084##

4. The ADC of claim 1 wherein L comprises one or more of a bond, --(C.dbd.O)--, a --C(O)NH-- group, an --OC(O)NH-- group, C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group; wherein each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro; or each C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 heteroalkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 heteroalkenylene, C.sub.2-C.sub.6 alkynylene, C.sub.2-C.sub.6 heteroalkynylene, C.sub.3-C.sub.6 cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

5. The ADC of claim 4, wherein the solubility enhancing group has the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein: a is 0 or 1; and R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

6. The ADC of claim 1, wherein L comprises a --(CH.sub.2).sub.n-- unit, where n is an integer from 2-6.

7. The ADC of claim 6, wherein L is --(CH.sub.2).sub.n--, where n is 6.

8. The ADC of claim 7, wherein Ab, Z, and L, taken together as Ab-Z-L, is represented by the formula: ##STR00085## wherein S is the sulfur atom of a cysteine residue present in the antibody, or the antigen-binding fragment thereof.

9. An antibody-drug conjugate (ADC) comprising an antibody, or an antigen-binding fragment thereof, conjugated to an amatoxin via a linker, the ADC having the structure of formula (I): ##STR00086## or a stereoisomer thereof; wherein: Q is S; L is a cleavable linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody, or antigen-binding fragment thereof; and Ab is the antibody, or the antigen binding fragment thereof, wherein the antibody, or the antigen binding fragment thereof, is selected from the group consisting of a) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; and a light chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the light chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; b) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO: 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243; and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO: 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244; c) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID No: 11, 12, and 13, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 14, 15, and 16, respectively; d) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 245, 246, and 247, respectively, and a light chain comprising alight chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 248, 249, and 250, respectively; e) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10; and f) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 243, and alight chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 244.

10. The ADC of claim 9, having the structure of formula (Ia): ##STR00087##

11. The ADC of claim 9, having the structure of formula (Ib): ##STR00088##

12. The ADC of claim 9, wherein L comprises one or more of a hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-immolative group, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a --(C.dbd.O)-- group, a --C(O)NH-- group, an --OC(O)NH-- group, a --(CH.sub.2CH.sub.2O).sub.p-- group where p is an integer from 1-6, or a solubility enhancing group; wherein each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro; or each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 heteroalkynyl, C.sub.3-C.sub.6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

13. The ADC of claim 12, wherein the solubility enhancing group has the formula --O.sub.a--C(O)NH--SO.sub.2--NR.sup.1--, wherein: a is 0 or 1; and R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.24 alkyl groups, C.sub.3-C.sub.24 cycloalkyl groups, C.sub.2-C.sub.24 (hetero)aryl groups, C.sub.3-C.sub.24 alkyl(hetero)aryl groups and C.sub.3-C.sub.24 (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR.sup.3, wherein R.sup.3 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

14. The ADC of claim 9, wherein L comprises a peptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg.

15. The ADC of claim 14, further comprising a PAB group.

16. The ADC of claim 15, wherein L is represented by the formula: ##STR00089##

17. An ADC comprising an antibody conjugated to an amatoxin, the ADC having a structure according to formula (II): ##STR00090## or a stereoisomer thereof, wherein Ab is an antibody, or an antigen binding fragment thereof, selected from the group consisting of a) an anti-CD117 antibody, or an antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; and a light chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the light chain variable region amino acid sequence of Ab55, Ab54, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, Ab69, Ab85, Ab86, Ab87, Ab88, Ab89, Ab77, Ab79, Ab81, Ab85, or Ab249; b) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO: 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243; and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO: 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244; c) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID No: 11, 12, and 13, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 14, 15, and 16, respectively; d) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 245, 246, and 247, respectively, and a light chain comprising alight chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos: 248, 249, and 250, respectively; e) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10; and f) an anti-CD117 antibody, or antigen binding fragment thereof, comprising a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 243, and alight chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 244.

18. The ADC of claim 17, having the structure of formula (IIa): ##STR00091##

19. The ADC of claim 17, having the structure of formula (IIb): ##STR00092##

20. The ADC of any one of claims 1, 9, or 17, wherein the antibody, or the antigen binding fragment thereof, comprises either an Fc region comprising at least one mutation selected from the group consisting of D265C, H435A, L234A, or L235A (according to EU index); or an Fc region comprising D265C, H435A, L234A, or L235A (according to EU index) mutations.

21. A method of depleting a population of cells in a human subject, said method comprising administering the ADC of any one of claims 1, 9, or 17, to the subject, wherein the ADC comprises an antibody, or an antigen-binding fragment thereof, that specifically binds to an extracellular antigen expressed by cells in the population of cells.

22. A method of conditioning a human subject for cell transplantation, said method comprising administering the ADC of any one of claims 1, 9, or 17, to the human subject such that the endogenous stem or endogenous immune cells in the human subject are depleted, wherein the ADC specifically binds to an extracellular antigen expressed by the endogenous stem or endogenous immune cells.

23. The method of claim 21, further comprising administering to the human subject allogenic stem cells or allogeneic immune cells.

24. A pharmaceutical composition comprising the ADC of any one of claims 1, 9, or 17, and a pharmaceutically acceptable carrier.