RU2831785C2 - Pmel17 antibodies and conjugates based thereon - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed are: antibodies or antigen-binding fragments thereof, which bind to human PMEL17 protein, which contain certain amino acid sequences, method for production and use thereof for treating or preventing cancer in a patient in need thereof, conjugates of an antibody and a drug, which bind to a human PMEL17 protein, containing a specific structure, method for their preparation and use for treating or preventing cancer in a patient in need thereof, pharmaceutical compositions for treating or preventing cancer in a patient in need thereof; method of treating or preventing cancer in a patient in need thereof. Also disclosed are: nucleic acid, which codes an antibody or antigen-binding fragment, a host cell for producing an antibody or an antigen-binding fragment, a diagnostic reagent for diagnosing a disease associated with PMEL17 expression.

EFFECT: invention is used to treat cancer, where cancer expresses PMEL17, cancer contains mutation of GNAQ gene and/or GNA11 gene or cancer expresses PMEL17 and contains mutation of GNAQ gene and/or GNA11 gene.

47 cl, 20 dwg, 10 tbl, 2 ex

Description

List of sequences

[0000] This application contains a sequence listing that was filed electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on December 6, 2019 is named PAT058359-WO-PCT_SL.txt and is 285253 bytes in size.

Field of technology to which the invention relates

[0001] The present invention generally relates to antibodies to PMEL17 or fragments thereof, conjugates thereof, including conjugates thereof with a GNAQ/GNA11 inhibitor, and uses thereof for the treatment or prevention of cancer.

Background of the invention

[0002] PMEL17 (also referred to as gp100 and SILV) is a single-span type I transmembrane protein produced by melanocytes and involved in melanin synthesis. As PMEL17 matures, it is transiently expressed on the cell surface before being targeted to melanosomes, where PMEL17 is broken down into distinct domains that multimerize to form fibrillar sheets. This structure then serves as a scaffold for melanin entrapment. PMEL17 expression in melanosomes is regulated by MITF, a lineage oncogene, and has been found to be upregulated in a variety of primary and metastatic subcutaneous and uveal melanomas. Transient cell surface expression and subsequent internalization of PMEL17 makes it a suitable target for the development of an antibody-drug conjugate (ADC) for the treatment of melanoma.

PMEL17 and Cancer

[0003] As PMEL17 matures, it undergoes extensive processing by proprotein convertases. The protein is cleaved between V467/K468, forming two subdomains, Mα at the N-terminus and Mβ at the C-terminus, presumably supported by a disulfide bridge. Following release from the Golgi, some PMEL17 molecules are transiently expressed on the cell surface. Most PMEL17 is then redirected to melanocytes for further maturation, while some PMEL17 appears to be eliminated. After further enzymatic cleavage, PMEL17 is disassembled into distinct domains that reorganize to form fibrillar sheets in which melanin polymerization occurs (Valencia JC, et al. Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes . J Cell Sci. 2006 Mar 15;119(Pt 6):1080-91; Theos AC, et al. The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res. 2005 Oct;18(5):322-36).

[0004] PMEL17 is a potential therapeutic target for the treatment of melanoma. PMEL17 is a direct transcriptional target of MITF, a melanoma lineage oncogene, as demonstrated by mRNA expression studies (Du J, et al. MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma . Am J Pathol. 2003 Jul;163(1):333-43). PMEL17 expression is restricted to melanocyte lineages, which include skin melanocytes, hair bulb melanocytes, retinal pigment epithelium, ciliated pigmented epithelium, and possibly choroidal melanocytes. PMEL17 is also expressed at high levels in tumors of melanocytic origin such as subcutaneous and uveal melanoma. In contrast, mRNA studies have demonstrated that PMEL17 expression is restricted to other tumor types and normal tissues (Wagner SN, Wagner C, Schultewolter T, Goos M. Analysis of Pmel17/gp100 expression in primary human tissue specimens: implications for melanoma immuno-and gene-therapy . Cancer Immunol Immunother. 1997 Jun;44(4):239-47). In addition, ADC and ImmTAC-based compounds targeting PMEL17 have been previously described to specifically kill melanoma in vivo and in vitro and are currently undergoing clinical trials (Chen Y, et al. The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma. J Biol Chem. 2012 Jul 13;287(29):24082-91. doi:10.1074/jbc.M112.361485. Epub 2012 May 21).

GNAQ/GNA11 and Cancer

[0005] The GNAQ and GNA11 genes encode the alpha subunit of the heterotrimeric G proteins Gq/11, which are nearly ubiquitously expressed and act as binary molecular switches that cycle between active, guanosine triphosphate (GTP)-bound, and inactive, guanosine diphosphate (GDP)-bound states. GTP-bound Gαq and Gα11 activate the β-isoforms of phospholipase C, which initiates a variety of signaling pathways through the generation of the second messengers IP3 and DAG. Termination of signaling is mediated by GTP hydrolysis mediated by the intrinsic GTPase activity of these Gα proteins. Gq and G11 have been shown to be involved in a wide range of physiological functions, including platelet activation, myocardial hypertrophy, and regulation of smooth muscle tone.

[0006] Oncogenic mutations in GNAQ or GNA11 occur in up to 90% of uveal melanoma (UM) cases and ~2-3% of cutaneous melanoma. Approximately 95% of these mutations affect codon 209 (Q209) in the Ras-like domain, resulting in complete or partial loss of GTPase activity and thus blocking GNAQ/11 in its active state. Q209 GNAQ/11 are dominantly acting oncogenes that transform melanocytes by triggering activation of multiple pathways including PKC/MAPK, Rho/Rac, β-catenin, and YAP. Although the PKC/MAPK pathway has been shown to be one of the factors contributing to GNAQ-mediated tumorigenesis, multiple lines of evidence suggest that mutant GNAQ/11 regulates additional pathways that are also likely to play a role in UM tumorigenesis (i.e., YAP, β-catenin). Interestingly, another somatic activating mutation in GNAQ (R183Q) has recently been described as the cause of Sturge-Weber syndrome (SWS), a neurocutaneous disorder characterized by capillary malformation (port-wine stains) as well as vascular malformations of the choroidal and leptomeningeal vessels. Thus, GNAQ and GNA11 represent potential therapeutic targets for the treatment of uveal and cutaneous melanoma.

Antibody-drug conjugates

[0007] Antibody drug conjugates ("ADCs") have found use in local delivery of cytotoxic agents in cancer treatment (see, e.g., Lambert, Curr. Opinion In Pharmacology 5:543-549, 2005). ADCs enable targeted delivery of a drug moiety that can achieve maximum efficacy with minimal toxicity. ADCs comprise an antibody selected for its ability to bind to the cell targeted by the therapeutic intervention, coupled to a drug selected for its cytostatic or cytotoxic activity. Thus, binding of the antibody to the target cell delivers the drug to the site where its therapeutic effect is desired.

[0008] A variety of antibodies have been disclosed for use in ADCs that recognize and selectively bind to target cells, such as cancer cells. Despite extensive work with ADCs, binding of an antibody to a specific target of interest is not sufficient to predict success in ADC applications. Examples of factors that may impact the therapeutic efficacy of an ADC (other than the intrinsic properties of the target) include various aspects that need to be modified by fine-tuning, such as optimal antibody affinity as a balance between target-mediated distribution (TMDD) and efficacy-driving effects, assessment of Fc-mediated functions (antibody-dependent cell-mediated cytotoxicity, ADCC), conjugation mode (site-specific or not), the ratio of drug/payload molecules of such conjugate with each antibody ("DAR" or "drug/antibody ratio"), linker cleavability or stability, ADC stability, and the tendency of the ADC to form aggregates.

[0009] There remains a need for antibodies, attachment methods, and cytotoxic payloads with improved properties for use as effective therapeutic ADC-based compositions and methods related thereto.

Brief description of the present invention

[0010] In one embodiment of the present application, an antibody or antigen-binding fragment thereof that binds PMEL17 comprising

a heavy chain variable region comprising a heavy chain CDR1 (complementarity determining region 1) of SEQ ID NO: 1, 4, 5 or 7, a heavy chain CDR2 (complementarity determining region 2) of SEQ ID NO: 2, 6 or 8 and a heavy chain CDR3 (complementarity determining region 3) of SEQ ID NO: 3 or 9; and a light chain variable region comprising a light chain CDR1 (complementarity determining region 1) of SEQ ID NO: 14, 17 or 20, a light chain CDR2 (complementarity determining region 2) of SEQ ID NO: 15 or 18 and a light chain CDR3 (complementarity determining region 3) of SEQ ID NO: 16 or 19;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:33, 36, 37 or 39, a heavy chain CDR2 of SEQ ID NO:34, 38 or 40; a heavy chain CDR3 of SEQ ID NO:35 or 41; a light chain CDR1 of SEQ ID NO:46, 49 or 52; a light chain CDR2 of SEQ ID NO:47 or 50 and a light chain CDR3 of SEQ ID NO:48 or 51;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:5, 7, 57 or 60, a heavy chain CDR2 of SEQ ID NO:58, 61 or 62; a heavy chain CDR3 of SEQ ID NO:59 or 63; a light chain CDR1 of SEQ ID NO:68, 71 or 74; a light chain CDR2 of SEQ ID NO:69 or 72 and a light chain CDR3 of SEQ ID NO:70 or 73;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:79, 82, 83 or 85, a heavy chain CDR2 of SEQ ID NO:80, 84 or 86; a heavy chain CDR3 of SEQ ID NO:81 or 87; a light chain CDR1 of SEQ ID NO:92, 95 or 98; a light chain CDR2 of SEQ ID NO:93 or 96 and a light chain CDR3 of SEQ ID NO:94 or 97;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:103, 106, 107 or 109, a heavy chain CDR2 of SEQ ID NO:104, 108 or 110; a heavy chain CDR3 of SEQ ID NO:105 or 111; a light chain CDR1 of SEQ ID NO:49, 52 or 116; a light chain CDR2 of SEQ ID NO:47 or 50; and a light chain CDR3 of SEQ ID NO:117 or 118;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:123, 126, 127 or 129, a heavy chain CDR2 of SEQ ID NO:124, 128 or 130; a heavy chain CDR3 of SEQ ID NO:125 or 131; a light chain CDR1 of SEQ ID NO:136, 139 or 142; a light chain CDR2 of SEQ ID NO:137 or 140 and a light chain CDR3 of SEQ ID NO:138 or 141;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:123, 126, 127 or 129, a heavy chain CDR2 of SEQ ID NO:124, 128 or 130; a heavy chain CDR3 of SEQ ID NO:147 or 148; a light chain CDR1 of SEQ ID NO:153, 156 or 158; a light chain CDR2 of SEQ ID NO:50 or 154 and a light chain CDR3 of SEQ ID NO:155 or 157;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:103, 106, 107 or 109, a heavy chain CDR2 of SEQ ID NO:104, 108 or 110; a heavy chain CDR3 of SEQ ID NO:163 or 164; a light chain CDR1 of SEQ ID NO:49, 52 or 116; a light chain CDR2 of SEQ ID NO:47 or 50 and a light chain CDR3 of SEQ ID NO:169 or 170;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:175, 178, 179 or 181, a heavy chain CDR2 of SEQ ID NO:176, 180 or 182; a heavy chain CDR3 of SEQ ID NO:177 or 183; a light chain CDR1 of SEQ ID NO:49, 52 or 116; a light chain CDR2 of SEQ ID NO:47 or 50 and a light chain CDR3 of SEQ ID NO:188 or 189;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, a heavy chain CDR2 of SEQ ID NO: 104, 108 or 110; a heavy chain CDR3 of SEQ ID NO: 194 or 195; a light chain CDR1 of SEQ ID NO: 49, 52 or 116; a light chain CDR2 of SEQ ID NO: 47 or 50; and a light chain CDR3 of SEQ ID NO: 200 or 201;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO:206, 209, 210 or 212, a heavy chain CDR2 of SEQ ID NO:207, 211 or 213; a heavy chain CDR3 of SEQ ID NO:208 or 214; a light chain CDR1 of SEQ ID NO:153, 156 or 158; a light chain CDR2 of SEQ ID NO:50 or 154 and a light chain CDR3 of SEQ ID NO:219 or 220;

a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 206, 209, 210 or 212, a heavy chain CDR2 of SEQ ID NO: 207, 211 or 213; a heavy chain CDR3 of SEQ ID NO: 225 or 226; a light chain CDR1 of SEQ ID NO: 136, 139 or 142; a light chain CDR2 of SEQ ID NO: 137 or 140 and a light chain CDR3 of SEQ ID NO: 231 or 232;

a heavy chain variable region that comprises a heavy chain variable region that comprises HCDR1 of SEQ ID NO: 206, 209, 210 or 212, HCDR2 of SEQ ID NO: 207, 211 or 213 and HCDR3 of SEQ ID NO: 237 or 238; and a light chain variable region that comprises LCDR1 of SEQ ID NO: 243, 245 or 247, LCDR2 of SEQ ID NO: 47 or 50 and LCDR3 of SEQ ID NO: 244 or 246;

a heavy chain variable region that comprises a heavy chain variable region that comprises HCDR1 of SEQ ID NO: 206, 209, 210 or 212, HCDR2 of SEQ ID NO: 207, 211 or 213 and HCDR3 of SEQ ID NO: 252 or 253; and a light chain variable region that comprises LCDR1 of SEQ ID NO: 153, 156 or 158, LCDR2 of SEQ ID NO: 50 or 154 and LCDR3 of SEQ ID NO: 258 or 259;

CDR1 of the heavy chain under SEQ ID NO:1, CDR2 of the heavy chain under SEQ ID NO:2, CDR3 of the heavy chain under SEQ ID NO:3, CDR1 of the light chain under SEQ ID NO:14, CDR2 of the light chain under SEQ ID NO:15 and CDR3 of the light chain under SEQ ID NO:16;

CDR1 of the heavy chain under SEQ ID NO: 4, CDR2 of the heavy chain under SEQ ID NO: 2, CDR3 of the heavy chain under SEQ ID NO: 3, CDR1 of the light chain under SEQ ID NO: 14, CDR2 of the light chain under SEQ ID NO: 15 and CDR3 of the light chain under SEQ ID NO: 16;

CDR1 of the heavy chain under SEQ ID NO:5, CDR2 of the heavy chain under SEQ ID NO:6, CDR3 of the heavy chain under SEQ ID NO:3, CDR1 of the light chain under SEQ ID NO:17, CDR2 of the light chain under SEQ ID NO:18 and CDR3 of the light chain under SEQ ID NO:19;

CDR1 of the heavy chain under SEQ ID NO:7, CDR2 of the heavy chain under SEQ ID NO:8, CDR3 of the heavy chain under SEQ ID NO:9, CDR1 of the light chain under SEQ ID NO:20, CDR2 of the light chain under SEQ ID NO:18 and CDR3 of the light chain under SEQ ID NO:16;

CDR1 of the heavy chain under SEQ ID NO:33, CDR2 of the heavy chain under SEQ ID NO:34, CDR3 of the heavy chain under SEQ ID NO:35, CDR1 of the light chain under SEQ ID NO:46, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:48;

CDR1 of the heavy chain under SEQ ID NO:36, CDR2 of the heavy chain under SEQ ID NO:34, CDR3 of the heavy chain under SEQ ID NO:35, CDR1 of the light chain under SEQ ID NO:46, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:48;

CDR1 of the heavy chain under SEQ ID NO:37, CDR2 of the heavy chain under SEQ ID NO:38, CDR3 of the heavy chain under SEQ ID NO:35, CDR1 of the light chain under SEQ ID NO:49, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:51;

CDR1 of the heavy chain under SEQ ID NO: 39, CDR2 of the heavy chain under SEQ ID NO: 40, CDR3 of the heavy chain under SEQ ID NO: 41, CDR1 of the light chain under SEQ ID NO: 52, CDR2 of the light chain under SEQ ID NO: 50 and CDR3 of the light chain under SEQ ID NO: 48;

CDR1 of the heavy chain under SEQ ID NO:57, CDR2 of the heavy chain under SEQ ID NO:58, CDR3 of the heavy chain under SEQ ID NO:59, CDR1 of the light chain under SEQ ID NO:68, CDR2 of the light chain under SEQ ID NO:69 and CDR3 of the light chain under SEQ ID NO:70;

CDR1 of the heavy chain under SEQ ID NO:60, CDR2 of the heavy chain under SEQ ID NO:58, CDR3 of the heavy chain under SEQ ID NO:59, CDR1 of the light chain under SEQ ID NO:68, CDR2 of the light chain under SEQ ID NO:69 and CDR3 of the light chain under SEQ ID NO:70;

CDR1 of the heavy chain under SEQ ID NO:5, CDR2 of the heavy chain under SEQ ID NO:61, CDR3 of the heavy chain under SEQ ID NO:59, CDR1 of the light chain under SEQ ID NO:71, CDR2 of the light chain under SEQ ID NO:72 and CDR3 of the light chain under SEQ ID NO:73;

CDR1 of the heavy chain under SEQ ID NO:7, CDR2 of the heavy chain under SEQ ID NO:62, CDR3 of the heavy chain under SEQ ID NO:63, CDR1 of the light chain under SEQ ID NO:74, CDR2 of the light chain under SEQ ID NO:72 and CDR3 of the light chain under SEQ ID NO:70;

CDR1 of the heavy chain under SEQ ID NO:79, CDR2 of the heavy chain under SEQ ID NO:80, CDR3 of the heavy chain under SEQ ID NO:81, CDR1 of the light chain under SEQ ID NO:92, CDR2 of the light chain under SEQ ID NO:93 and CDR3 of the light chain under SEQ ID NO:94;

CDR1 of the heavy chain under SEQ ID NO:82, CDR2 of the heavy chain under SEQ ID NO:80, CDR3 of the heavy chain under SEQ ID NO:81, CDR1 of the light chain under SEQ ID NO:92, CDR2 of the light chain under SEQ ID NO:93 and CDR3 of the light chain under SEQ ID NO:94;

CDR1 of the heavy chain under SEQ ID NO:83, CDR2 of the heavy chain under SEQ ID NO:84, CDR3 of the heavy chain under SEQ ID NO:81, CDR1 of the light chain under SEQ ID NO:95, CDR2 of the light chain under SEQ ID NO:96 and CDR3 of the light chain under SEQ ID NO:97;

CDR1 of the heavy chain under SEQ ID NO: 85, CDR2 of the heavy chain under SEQ ID NO: 86, CDR3 of the heavy chain under SEQ ID NO: 87, CDR1 of the light chain under SEQ ID NO: 98, CDR2 of the light chain under SEQ ID NO: 96 and CDR3 of the light chain under SEQ ID NO: 94;

CDR1 of the heavy chain under SEQ ID NO:103, CDR2 of the heavy chain under SEQ ID NO:104, CDR3 of the heavy chain under SEQ ID NO:105, CDR1 of the light chain under SEQ ID NO:116; CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:117;

CDR1 of the heavy chain under SEQ ID NO:106, CDR2 of the heavy chain under SEQ ID NO:104, CDR3 of the heavy chain under SEQ ID NO:105, CDR1 of the light chain under SEQ ID NO:116, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:117;

CDR1 of the heavy chain under SEQ ID NO:107, CDR2 of the heavy chain under SEQ ID NO:108, CDR3 of the heavy chain under SEQ ID NO:105, CDR1 of the light chain under SEQ ID NO:49, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:118;

CDR1 of the heavy chain under SEQ ID NO:109, CDR2 of the heavy chain under SEQ ID NO:110, CDR3 of the heavy chain under SEQ ID NO:111, CDR1 of the light chain under SEQ ID NO:52, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:117;

CDR1 of the heavy chain under SEQ ID NO:123, CDR2 of the heavy chain under SEQ ID NO:124, CDR3 of the heavy chain under SEQ ID NO:125, CDR1 of the light chain under SEQ ID NO:136, CDR2 of the light chain under SEQ ID NO:137 and CDR3 of the light chain under SEQ ID NO:138;

CDR1 of the heavy chain under SEQ ID NO:126, CDR2 of the heavy chain under SEQ ID NO:124, CDR3 of the heavy chain under SEQ ID NO:125, CDR1 of the light chain under SEQ ID NO:136, CDR2 of the light chain under SEQ ID NO:137 and CDR3 of the light chain under SEQ ID NO:138;

CDR1 of the heavy chain under SEQ ID NO:127, CDR2 of the heavy chain under SEQ ID NO:128, CDR3 of the heavy chain under SEQ ID NO:125, CDR1 of the light chain under SEQ ID NO:139, CDR2 of the light chain under SEQ ID NO:140 and CDR3 of the light chain under SEQ ID NO:141;

CDR1 of the heavy chain under SEQ ID NO: 129, CDR2 of the heavy chain under SEQ ID NO: 130, CDR3 of the heavy chain under SEQ ID NO: 131, CDR1 of the light chain under SEQ ID NO: 142, CDR2 of the light chain under SEQ ID NO: 140 and CDR3 of the light chain under SEQ ID NO: 138;

CDR1 of the heavy chain under SEQ ID NO:123, CDR2 of the heavy chain under SEQ ID NO:124, CDR3 of the heavy chain under SEQ ID NO:147, CDR1 of the light chain under SEQ ID NO:153, CDR2 of the light chain under SEQ ID NO:154 and CDR3 of the light chain under SEQ ID NO:155;

CDR1 of the heavy chain under SEQ ID NO:126, CDR2 of the heavy chain under SEQ ID NO:124, CDR3 of the heavy chain under SEQ ID NO:147, CDR1 of the light chain under SEQ ID NO:153, CDR2 of the light chain under SEQ ID NO:154 and CDR3 of the light chain under SEQ ID NO:155;

CDR1 of the heavy chain under SEQ ID NO:127, CDR2 of the heavy chain under SEQ ID NO:128, CDR3 of the heavy chain under SEQ ID NO:147, CDR1 of the light chain under SEQ ID NO:156, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:157;

CDR1 of the heavy chain under SEQ ID NO: 129, CDR2 of the heavy chain under SEQ ID NO: 130, CDR3 of the heavy chain under SEQ ID NO: 148, CDR1 of the light chain under SEQ ID NO: 158, CDR2 of the light chain under SEQ ID NO: 50 and CDR3 of the light chain under SEQ ID NO: 155;

CDR1 of the heavy chain under SEQ ID NO:103, CDR2 of the heavy chain under SEQ ID NO:104, CDR3 of the heavy chain under SEQ ID NO:163, CDR1 of the light chain under SEQ ID NO:116, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:169;

CDR1 of the heavy chain under SEQ ID NO:106, CDR2 of the heavy chain under SEQ ID NO:104, CDR3 of the heavy chain under SEQ ID NO:163, CDR1 of the light chain under SEQ ID NO:116, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:169;

CDR1 of the heavy chain under SEQ ID NO:107, CDR2 of the heavy chain under SEQ ID NO:108, CDR3 of the heavy chain under SEQ ID NO:163, CDR1 of the light chain under SEQ ID NO:49, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:170;

CDR1 of the heavy chain under SEQ ID NO: 109, CDR2 of the heavy chain under SEQ ID NO: 110, CDR3 of the heavy chain under SEQ ID NO: 164, CDR1 of the light chain under SEQ ID NO: 52, CDR2 of the light chain under SEQ ID NO: 50 and CDR3 of the light chain under SEQ ID NO: 169;

CDR1 of the heavy chain under SEQ ID NO:175, CDR2 of the heavy chain under SEQ ID NO:176, CDR3 of the heavy chain under SEQ ID NO:177, CDR1 of the light chain under SEQ ID NO:116, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:188;

CDR1 of the heavy chain under SEQ ID NO:178, CDR2 of the heavy chain under SEQ ID NO:176, CDR3 of the heavy chain under SEQ ID NO:177, CDR1 of the light chain under SEQ ID NO:116, CDR2 of the light chain under SEQ ID NO:47 and CDR3 of the light chain under SEQ ID NO:188;

CDR1 of the heavy chain under SEQ ID NO:179, CDR2 of the heavy chain under SEQ ID NO:180, CDR3 of the heavy chain under SEQ ID NO:177, CDR1 of the light chain under SEQ ID NO:49, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:189;

CDR1 of the heavy chain under SEQ ID NO: 181, CDR2 of the heavy chain under SEQ ID NO: 182, CDR3 of the heavy chain under SEQ ID NO: 183, CDR1 of the light chain under SEQ ID NO: 52, CDR2 of the light chain under SEQ ID NO: 50 and CDR3 of the light chain under SEQ ID NO: 188;

heavy chain CDR1 of SEQ ID NO: 103, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 200;

heavy chain CDR1 of SEQ ID NO: 106, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47 and light chain CDR3 of SEQ ID NO: 200;

heavy chain CDR1 of SEQ ID NO: 107, heavy chain CDR2 of SEQ ID NO: 108, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 49, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 201;

heavy chain CDR1 of SEQ ID NO: 109, heavy chain CDR2 of SEQ ID NO: 110, heavy chain CDR3 of SEQ ID NO: 195, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 200;

CDR1 of the heavy chain under SEQ ID NO:206, CDR2 of the heavy chain under SEQ ID NO:207, CDR3 of the heavy chain under SEQ ID NO:208, CDR1 of the light chain under SEQ ID NO:153, CDR2 of the light chain under SEQ ID NO:154 and CDR3 of the light chain under SEQ ID NO:219;

CDR1 of the heavy chain under SEQ ID NO:209, CDR2 of the heavy chain under SEQ ID NO:207, CDR3 of the heavy chain under SEQ ID NO:208, CDR1 of the light chain under SEQ ID NO:153, CDR2 of the light chain under SEQ ID NO:154 and CDR3 of the light chain under SEQ ID NO:219;

CDR1 of the heavy chain under SEQ ID NO:210, CDR2 of the heavy chain under SEQ ID NO:211, CDR3 of the heavy chain under SEQ ID NO:208, CDR1 of the light chain under SEQ ID NO:156, CDR2 of the light chain under SEQ ID NO:50 and CDR3 of the light chain under SEQ ID NO:220;

CDR1 of the heavy chain under SEQ ID NO: 212, CDR2 of the heavy chain under SEQ ID NO: 213, CDR3 of the heavy chain under SEQ ID NO: 214, CDR1 of the light chain under SEQ ID NO: 158, CDR2 of the light chain under SEQ ID NO: 50 and CDR3 of the light chain under SEQ ID NO: 219;

CDR1 of the heavy chain under SEQ ID NO: 206, CDR2 of the heavy chain under SEQ ID NO: 207, CDR3 of the heavy chain under SEQ ID NO: 225, CDR1 of the light chain under SEQ ID NO: 136, CDR2 of the light chain under SEQ ID NO: 137 and CDR3 of the light chain under SEQ ID NO: 231;

CDR1 of the heavy chain under SEQ ID NO: 209, CDR2 of the heavy chain under SEQ ID NO: 207, CDR3 of the heavy chain under SEQ ID NO: 225, CDR1 of the light chain under SEQ ID NO: 136, CDR2 of the light chain under SEQ ID NO: 137 and CDR3 of the light chain under SEQ ID NO: 231;

heavy chain CDR1 of SEQ ID NO: 210, heavy chain CDR2 of SEQ ID NO: 211, heavy chain CDR3 of SEQ ID NO: 225, light chain CDR1 of SEQ ID NO: 139, light chain CDR2 of SEQ ID NO: 140, and light chain CDR3 of SEQ ID NO: 232;

CDR1 of the heavy chain under SEQ ID NO: 212, CDR2 of the heavy chain under SEQ ID NO: 213, CDR3 of the heavy chain under SEQ ID NO: 226, CDR1 of the light chain under SEQ ID NO: 142; CDR2 of the light chain under SEQ ID NO: 140 and CDR3 of the light chain under SEQ ID NO: 231;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 237, and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 244;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 237, and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 244;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211 and HCDR3 of SEQ ID NO: 237, and a light chain variable region comprising LCDR1 of SEQ ID NO: 245, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 246;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 212, HCDR2 of SEQ ID NO: 213 and HCDR3 of SEQ ID NO: 238, and a light chain variable region comprising LCDR1 of SEQ ID NO: 247, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 244;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 252, and a light chain variable region comprising LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154 and LCDR3 of SEQ ID NO: 258;

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 252, and a light chain variable region comprising LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154 and LCDR3 of SEQ ID NO: 258;

a heavy chain variable region that comprises HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211 and HCDR3 of SEQ ID NO: 252, and a light chain variable region that comprises LCDR1 of SEQ ID NO: 156, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 259; or

a heavy chain variable region comprising HCDR1 of SEQ ID NO: 212, HCDR2 of SEQ ID NO: 213 and HCDR3 of SEQ ID NO: 253, and a light chain variable region comprising LCDR1 of SEQ ID NO: 158, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 258.

[0011] The antibody or antigen-binding fragment thereof that binds PMEL17 of the present application may also comprise:

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:21;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:25;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:29;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:42 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:53;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:64 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:75;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:88 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:99;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:112 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:119;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:132 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:143;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:149 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:159;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:165 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:171;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:184 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:190;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:196 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:202;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:215 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:221;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:227 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:233;

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:239 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:248; or

a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:254 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:260.

[0012] In another embodiment, an antibody or antigen-binding fragment thereof that binds PMEL17 comprises:

a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:23;

a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:27;

a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:31;

a heavy chain comprising the amino acid sequence of SEQ ID NO:44 and a light chain comprising the amino acid sequence of SEQ ID NO:55;

a heavy chain comprising the amino acid sequence of SEQ ID NO:66 and a light chain comprising the amino acid sequence of SEQ ID NO:77;

a heavy chain comprising the amino acid sequence of SEQ ID NO:90 and a light chain comprising the amino acid sequence of SEQ ID NO:101;

a heavy chain comprising the amino acid sequence of SEQ ID NO:114 and a light chain comprising the amino acid sequence of SEQ ID NO:121;

a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:145;

a heavy chain comprising the amino acid sequence of SEQ ID NO:151 and a light chain comprising the amino acid sequence of SEQ ID NO:161;

a heavy chain comprising the amino acid sequence of SEQ ID NO:167 and a light chain comprising the amino acid sequence of SEQ ID NO:173;

a heavy chain comprising the amino acid sequence of SEQ ID NO:186 and a light chain comprising the amino acid sequence of SEQ ID NO:192;

a heavy chain comprising the amino acid sequence of SEQ ID NO:198 and a light chain comprising the amino acid sequence of SEQ ID NO:204;

a heavy chain comprising the amino acid sequence of SEQ ID NO:217 and a light chain comprising the amino acid sequence of SEQ ID NO:223;

a heavy chain comprising the amino acid sequence of SEQ ID NO:229 and a light chain comprising the amino acid sequence of SEQ ID NO:235;

a heavy chain comprising the amino acid sequence of SEQ ID NO:241 and a light chain comprising the amino acid sequence of SEQ ID NO:250; or

a heavy chain comprising the amino acid sequence of SEQ ID NO:256 and a light chain comprising the amino acid sequence of SEQ ID NO:262.

[0013] An antibody or antigen-binding fragment thereof described herein may comprise one or more cysteine substitutions. In one embodiment, the antibody or antigen-binding fragment thereof comprises one or more cysteine substitutions selected from S152C, S375C, or both S152C and S375C, in the heavy chain of the antibody or antigen-binding fragment thereof, wherein the position numbering corresponds to the EU system. An antibody disclosed herein may be a monoclonal antibody.

[0014] In one aspect, the antibody-drug conjugate of the present invention is a conjugate of formula (C):

Ab-(L _A -(D) _n ) _y (C),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

L _A is a linker;

n is 1, 2, 3, or 4 and

y is 1, 2, 3, or 4,

wherein the moiety representing the linker-drug -(L _A -(D) _n ) is covalently attached to the antibody or its antigen-binding fragment.

[0015] In another aspect of the antibody-drug conjugates of formula (C), L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a carbonate group, and a bivalent peptide linker.

[0016] In another aspect, the antibody-drug conjugate of formula (C) is a conjugate of formula (C-1):

(C-1),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates the attachment point to X ₂ , and ** in Y ₁ indicates the attachment point to D;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[0017] The present application also discloses pharmaceutical compositions comprising the antibodies or antigen-binding fragments thereof disclosed herein and a pharmaceutically acceptable carrier. The present application also discloses pharmaceutical compositions comprising the antibody-drug conjugates disclosed herein and a pharmaceutically acceptable carrier.

[0018] The present application also discloses methods of treating or preventing cancer in a patient in need thereof, comprising administering to said patient the antibody-drug conjugates or pharmaceutical compositions disclosed herein, wherein the cancer expresses PMEL17, contains a mutation in the GNAQ or GNA11 gene, or the cancer expresses PMEL17 and contains a mutation in GNAQ, GNA11, or both.

[0019] In some embodiments of the methods of treating or preventing cancer, the antibody-drug conjugate or pharmaceutical composition is administered to the patient in combination with one or more additional therapeutic compounds. In one embodiment, the one or more additional therapeutic compounds are selected from a standard chemotherapeutic agent, an MDM2 inhibitor, an MRC2 inhibitor, a PKC inhibitor, a MAPK inhibitor, a costimulatory molecule, or an immune checkpoint inhibitor. In one embodiment, the costimulatory molecule is selected from an agonist of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, STING, or CD83. In another embodiment, the immune checkpoint inhibitor is selected from an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR beta.

[0020] Also disclosed herein are antibody drug conjugates or pharmaceutical compositions disclosed herein for use as a medicine. In one embodiment, the antibody drug conjugates or pharmaceutical compositions disclosed herein are for use in the treatment or prevention of a PMEL17 expressing cancer or a cancer that contains a GNAQ or GNA11 gene mutation in a patient in need thereof.

[0021] In one embodiment, the present application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions disclosed herein for the treatment or prevention of a PMEL17-expressing cancer in a patient in need thereof.

[0022] In one embodiment, the present application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions disclosed herein for the treatment or prevention of a PMEL17-expressing cancer or a cancer that contains a GNAQ or GNA11 gene mutation in a patient in need thereof. In one embodiment, the present application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions disclosed herein in the manufacture of a medicament.

[0023] In one embodiment, the cancer expresses PMEL17 or contains a mutation in the GNAQ or GNA11 gene. In one embodiment, the cancer is uveal melanoma, subcutaneous melanoma, hepatocellular carcinoma, or a metastatic form of these cancers.

[0024] Also disclosed herein are nucleic acids that encode the antibodies or antigen-binding fragments disclosed herein. In one embodiment, the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 13, 24, 28, 32, 45, 56, 67, 78, 91, 102, 115, 122, 135, 146, 152, 162, 168, 174, 187, 193, 199, 205, 218, 224, 230, 236, 242, 251, 257, or 26. Also disclosed herein are vectors comprising the nucleic acids and host cells comprising the vectors or the nucleic acids. This application also discloses a method for producing the antibodies or antigen-binding fragments disclosed herein, comprising culturing a host cell and recovering the antibody from the cell culture. In one embodiment, the method for recovering the antibody from the cell culture comprises the following steps:

a) removal of cells and filtration of the culture;

b) purification of the culture by affinity chromatography;

c) inactivation of any viruses in the culture by adjusting the pH to 3.4-3.6, then readjusting the pH to 5.8-6.2 and filtering the culture;

d) carrying out purification of the culture by means of cation exchange chromatography and carrying out recovery of the culture on the column;

e) performing anion exchange chromatography on the culture;

f) removal of viruses by nanofiltration;

g) filtering the culture containing the antibody, and

h) obtaining purified antibody.

[0025] The present application also discloses a method for producing a conjugate of an antibody to PMEL17 and a drug, comprising:

(a) preforming a linker-drug moiety of the following formula (B):

R ⁸ -L _B -(D) _n (B),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

R ⁸ is a reactive group;

L _B is a cleavable or non-cleavable linker and

n is 1, 2, 3, or 4;

(b) conjugating said linker-drug moiety to an antibody recovered from a cell culture using the method for producing an antibody or antigen-binding fragment disclosed herein to produce an antibody-drug conjugate; and

(c) performing purification of the antibody-drug conjugate.

[0026] Also disclosed herein is a diagnostic reagent comprising an antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the antibody or antigen-binding fragment thereof is labeled with a radiolabel, a fluorophore, a chromophore, an imaging agent, or a metal ion.

Brief description of graphic materials

[0027] Figs. 1A-1B show illustrative in vitro anti-UM activity data for the GNAQ/11 inhibitors, Compound (A1) and Compound (A2).

[0028] Fig. 2 shows illustrative data on the activity of GNAQ/11 inhibitors, compound (A1) and compound (A2), in inducing apoptosis in uveal melanoma cells.

[0029] Figures 3A-3C show illustrative data on the inhibition of GNAQ/11 by Compound (A1) and Compound (A2). Compound (A1) and Compound (A2) reduced IP1 levels (Figure 3A) and relative proliferation (Figure 3B) in 92.1 cells. Immunoblots of 92.1 cell samples treated with Compound (A1) and Compound (A2) showed a reduction in ERK signaling (Figure 3C).

[0030] Figures 4A-4D show exemplary metabolic stability and PK data for compound (A1). The disappearance of compound (A1) (Figure 4A) as well as the appearance of the ring-opened form of compound (A8) (Figure 4B) were monitored over 24 h. With the exception of rats, the sum of % of compound (A1) remaining and % of compound (A8) formed demonstrated stoichiometry over 24 h (Figure 4C). The PK of compound (A1) following intravenous administration to mice was characterized by very high clearance and moderate to high volume of distribution (Figure 4D).

[0031] Figures 5A-5D show exemplary metabolic stability and PK data for Compound (A1) and Compound (A2). In vitro stability of Compound (A2) was tested in plasma and in the blood of different species (Figure 5A). Compound (A2) showed acceptable chemical stability in three different systems (Figure 5B). PK of Compound (A2) in female balb/c mice showed high clearance and a short half-life (Figure 5C). Compound (A1) and Compound (A2) were stable in buffer at pH 5.6 and in lysosomes for 4 h (Figure 5D).

[0032] Fig. 6A-6B show illustrative data on the in vitro activity of PMEL17-(B1) ADC against uveal melanoma. Data are presented as the mean of 3 independent replicates and relative to PBS-treated cells (control).

[0033] Fig. 7 shows illustrative data on ADC to PMEL17-(B1) inducing apoptosis in uveal melanoma cells. Data are presented as the average of 3 independent replicates.

[0034] Fig. 8A-8B show illustrative in vitro activity data of PMEL17-(B2) ADC and PMEL17 mAb against uveal melanoma. Data are presented as the mean of 3 independent replicates and relative to PBS-treated cells (control).

[0035] Fig. 9 shows exemplary data on GNAQ/11 inhibition by PMEL17-(B1) and PMEL17-(B2) ADCs in uveal melanoma cells. IP1 levels (nM) are presented as the mean of 3 independent replicates.

[0036] Figs. 10A-10D show illustrative data on the binding activity of PMEL17 antibodies to intact platelets and uveal melanoma cells.

[0037] Fig. 11A - 11C show illustrative data on the effect of compound (A1) and ADC to PMEL17-(B1) on human platelet aggregation.

[0038] Figures 12A-12E show illustrative in vivo antitumor activity data for an ADC to PMEL17-(B1). G1-(B1) inhibited tumor growth in a dose-dependent manner (Figure 12A). Values are mean ± SEM; sample size (n=5-12 mice per group). The initial tumor volume at day 0 was approximately 200-250 ^mm3 . No body weight loss was observed for 14 days following treatment (Figure 12B). Values are mean ± SEM; sample size (n=4 mice per group). Treatment with G1-(B1) resulted in inhibition of GNAQ signaling and inhibition of tumor cell proliferation, as evidenced by decreased pERK and Ki67 levels, respectively (Figure 12C). Furthermore, G1-(B1) induced cell apoptosis compared to vehicle-treated and isotype control 3207-(B1) mice, which correlated with the accumulation of G1-(B1) ADC in tumor cells, detectable by IgG staining (Fig. 12C). No changes in MITF and PMEL17 levels were observed following GNAQ inhibition (Fig. 12C). No inhibition of platelet aggregation was observed in G1-(B1)-treated mice over 7 days (Fig. 12D and E).

[0039] Figures 13A-13C show illustrative data on the effects of ADC G1-(B1) in a mouse model of uveal melanoma with liver and lung metastases. Individual images from each mouse are shown at day 45 after i.v. injection of 92.1 cells with luciferase (immediately before treatment initiation) and 12 days post-treatment (Figures 13A and 13B); sample size (n=6 mice per group). The baseline BLI for liver metastases on day 0 was approximately 2.8* ¹⁰⁹ photons/sec/cm2. Lung tumors (bioluminescence signal) are indicated by the black arrow in Figure 13B. The corresponding change in body weight (% from day 15) was assessed 2-3 times per week before and after treatment with 20 mg/kg G1-(B1) (gray circles). Values in Fig. 13C are mean ± SEM; sample size (n=5-6 mice per group). Initial body weight at day 15 was approximately 21 g.

[0040] Figures 14A-14E show exemplary PK data for the ADC G1-(B1). The pharmacokinetic profile (total IgG levels) of G1-(B1) showed a somewhat disproportionate increase in exposure from 7.5 to 30 mg/kg in nude mice (Figure 14A). In tumor-bearing mice, free payload concentrations were measured following administration of either the target-binding G1-(B1) or the isotype control 3207-(B1). A marked (>4-fold) increase in tumor payload delivery of the compound (A1) could be observed with the target-binding ADC (Figure 14B). Conversion of compound (A1) (open circles) to its ring-opened form, compound (A8), (filled circles) upon conjugation with antibody was demonstrated in vivo in mice (Fig. 14C). Exposure patterns in an in vivo efficacy study comparing two different DAR2 formats with the G1-(B1) DAR4 format and the Fc-silenced DAR4 format showed the lowest clearance for the DAR2 (E152C) and Fc-silenced DAR4 ADCs, while the exposure of DAR2 (S375C) declined more rapidly (Fig. 14D). In Fig. 14E shows the concentration of 3207 (isotype control antibody)-(B1) DAR4 (E152C, S375C) and 3207 (isotype control antibody)-(B1) Fc-silenced DAR4 conjugates over time.

[0041] Figs. 15A-15C show illustrative data on the in vitro stability of PMEL17-GNAQ/11i ADC in buffer, mouse, rat, and human plasma and the in vivo stability of PMEL17-GNAQ/11i ADC in mice.

[0042] Figs. 16A-16B show exemplary in vivo efficacy data for G1-E152C-DAR2-(B1), G1-S375C-DAR2-(B1), Fc-silenced G1-(B1) in a uveal melanoma xenograft model. Values are presented as mean ± SEM; sample size (n=5-6 mice per group). Initial tumor volume at day 0 was approximately 300-325 mm ³ .

[0043] Fig. 17A-17B show illustrative data on the in vitro activity of PMEL17-(B1) ADC against uveal melanoma. Data are presented as the average of 3 independent replicates and relative to PBS-treated cells (control).

[0044] Fig. 18 shows illustrative data on the in vivo antitumor activity of an ADC to PMEL17-(B1).

[0045] Figs . 19A-19B show illustrative immunohistochemical data from tumor biopsies from patients with metastatic uveal melanoma.

[0046] Figures 20A-20C show exemplary sensorgram data assessing epitope-specific sorting of antibodies to PMEL. Figure 20A illustrates the steps of binding. Figure 20B shows a sensorgram when the G1 3J LC antibody is immobilized first and 17A9 is allowed to pass. Figure 20C shows a sensorgram when 17A9 is immobilized first and G1 3J LC is allowed to pass. In both cases, binding is observed when the second antibody is allowed to pass, suggesting that G1 3J LC and 17A9 bind to different epitopes of human PMEL.

Detailed description of the invention

Definitions

[0047] Unless otherwise specified, the following terms and phrases used in this document are intended to have the following meanings.

[0048] The term "alkyl" refers to a monovalent saturated hydrocarbon chain containing the stated number of carbon atoms. For example, _C1 - _C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms. An alkyl group may be straight or branched. A typical branched alkyl group contains one, two or three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.

[0049] As used herein, the term "cleavable" refers to a linking group or linker component that connects two moieties by covalent bonds, but is releasable to break the covalent bond between the moieties under physiologically relevant conditions; typically, a cleavable linking group is cleaved in vivo more rapidly in an intracellular environment than when outside the cell, resulting in preferential release of the payload within the target cell. Cleavage may be enzymatic or non-enzymatic, but typically results in release of the payload from the antibody without destruction of the antibody. Upon cleavage, some portion of the linking group or linker component may remain attached to the payload, or release of the payload may occur without any remaining linking group.

[0050] As used herein, the term "non-cleavable" refers to a linker group or component that is substantially resistant to cleavage under physiological conditions, e.g., is at least as stable as the antibody or antigen-binding fragment portion of the conjugate. Such linker groups are sometimes referred to as 'stable', meaning that they are sufficiently resistant to degradation to retain the payload attached to the antibody or antigen-binding fragment until the antibody or antigen-binding fragment itself is at least partially degraded, i.e., degradation of the antibody or antigen-binding fragment precedes cleavage of the linker group in vivo. Upon degradation of the antibody moiety of an ADC with a stable or non-cleavable binding group, part or all of the binding group, such as one or more amino acid groups from the antibody, may remain attached to the payload or drug moiety that is delivered in vivo.

[0051] As used herein, the term "antibody" refers to a polypeptide of the immunoglobulin family that is capable of binding an appropriate antigen in a non-covalent, reversible, and specific manner. For example, a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2, and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), which are interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain the binding domain that interacts with antigen. The constant regions of antibodies can mediate the binding of immunoglobulin to tissues or host factors, which include various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0052] The term "antibody" includes, without limitation, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies (including, for example, anti-Id antibodies to the antibodies of the present invention). The antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (eg, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).

[0053] "Complementarity determining domains" or "complementarity determining regions" ("CDRs") refer interchangeably to the hypervariable regions of the VL and VH. In antibody chains, the CDRs represent the binding site for a target protein and confers specificity for that target protein. There are three CDRs in each human VL or VH (CDR1-3, numbered sequentially from the N-terminus), comprising approximately 15-20% of the variable domains. The CDRs are structurally complementary to the target protein epitope and are thus directly responsible for binding specificity. The remaining portions of the VL or VH, the so-called framework regions, exhibit less amino acid sequence variability (Kuby, Immunology, 4th ed., Chapter 4. W.H. Freeman & Co., New York, 2000).

[0054] The positions of the CDRs and framework regions may be defined using various definitions widely known in the art, such as, definitions according to Kabat, Chotia, the international ImMunoGeneTics (IMGT) database (on the World Wide Web at www.imgt.org/) and AbM (see, for example, Johnsonet al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997)). Definitions of antigen-binding active sites are also described in the following sources: Ruizet al., Nucleic Acids Res., 28:219-221 (2000); and Lefranc, M.P., Nucleic Acids Res., 29:207-209 (2001); MacCallum et al., J. Mol. Biol., 262:732-745 (1996); and Martin et al.,Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989); Martin et al., Methods Enzymol., 203:121-153 (1991) and Rees et al., in Sternberg M.J.E. (ed.), Protein Structure Prediction, Oxford University Press, Oxford, 141-172 (1996).

[0055] Both the light and heavy chains are subdivided into regions of structural and functional homology. The terms "constant" and "variable" are used in a functional sense. In this regard, it should be understood that the variable domains from portions of both the light (VL) and heavy (VH) chains determine antigen recognition and specificity. In contrast, the constant domains of the light chain (CL) and heavy chain (CH1, CH2, or CH3) impart important biological properties such as secretion, placental trafficking, Fc receptor binding, complement binding, etc. The domains of the constant region are conventionally numbered in ascending order as they are distant from the antigen-binding site or amino terminus of the antibody. The N-terminus is the variable region, and the C-terminus is the constant region; The CH3 and CL domains actually contain the carboxy-terminal domains of the heavy and light chains, respectively.

[0056] As used herein, the term "antigen-binding fragment" refers to one or more portions of an antibody that retain the ability to specifically interact (e.g., by binding, steric hindrance, stabilization/destabilization, spatial distribution) to an epitope of an antigen. Examples of binding fragments include, but are not limited to, single-chain Fv (scFv), camelid antibodies, disulfide-linked Fv (sdFv), Fab fragments, F(ab') fragments, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragment, consisting of the VH and CH1 domains; Fv fragment, consisting of the VL and VH domains of one arm of an antibody; dAb fragment (Wardet al., Nature 341:544–546, 1989), which consists of the VH domain; and the isolated complementarity determining region (CDR) or other epitope-binding fragments of the antibody.

[0057] Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods using a synthetic linker, allowing them to be produced as a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (known as a single-chain Fv ("scFv"); see, For example, Birdet al., Science 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883, 1988). It is envisaged that such single chain antibodies are also encompassed by the term "antigen-binding fragment." Such antigen-binding fragments are prepared using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies.

[0058] Antigen-binding fragments can also be included in single-domain antibodies, maxi-antibodies, mini-antibodies, single-domain antibodies, intra-antibodies, diabodies, tri-antibodies, tetra-antibodies, v-NAR and bis-scFv (see, For example, Hollinger and Hudson, Nature Biotechnology 23:1126–1136, 2005). Antigen-binding fragments can be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, which describes monobodies based on the polypeptide fibronectin).

[0059] Antigen-binding fragments can be incorporated into single-chain molecules containing a pair of tandem Fv segments (VH-CH1-VH-CH1) that, together with complementary light chain polypeptides, form a pair of antigen-binding regions (Zapata et al. , Protein Eng. 8:1057-1062, 1995 and U.S. Patent No. 5,641,870).

[0060] As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides comprising antibodies and antigen-binding fragments that are characterized by a substantially identical amino acid sequence or are derived from the same genetic source. The term also encompasses preparations based on antibody molecules of the same molecular composition. A monoclonal antibody composition exhibits a single specificity and binding affinity for a particular epitope.

[0061] As used herein, the term "human antibody" encompasses antibodies having variable regions in which both the framework and CDR regions are derived from human-derived sequences. In addition, if the antibody comprises a constant region, the constant region is also derived from such human sequences, such as, human germline sequences, or mutant variants of human germline sequences, or an antibody containing consensus framework sequences obtained by analysis of human framework sequences, such as described in Knappiket al., J. Mol. Biol. 296:57-86, 2000). Also contemplated are antibodies derived from human sequences wherein one or more CDRs have been mutated during affinity maturation or for purposes of manufacturing/conjugation to a payload. See Kilpatricket al., "Rapid development of affinity matured monoclonal antibodies using RIMMS", Hybridoma. 1997 Aug;16(4):381-9.

[0062] The human antibodies of the present invention may include amino acid residues that are not encoded in human sequences (e.g., mutations introduced by random or site-directed mutagenesisin vitroor due to somatic mutationsin vivo, or a conservative substitution that promotes stability or facilitates fabrication).

[0063] As used herein, the term "recognize" refers to an antibody or antigen-binding fragment thereof that seeks out its epitope and interacts (e.g., bind) to it, regardless of whether the epitope is linear or conformational. The term "epitope" refers to a site on an antigen to which an antibody or antigen-binding fragment of the present invention specifically binds. Epitopes can be formed by either contiguous amino acids or non-contiguous amino acids placed adjacent to each other by tertiary folding of the protein. Epitopes formed from contiguous amino acids are generally retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are generally lost upon treatment with denaturing solvents. An epitope typically comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in a unique spatial conformation. Methods for determining the spatial conformation of epitopes include prior art techniques such as X-ray crystallography and 2-dimensional nuclear magnetic resonance (see, For example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G. E. Morris, Ed. (1996)).

[0064] As used herein, the term "affinity" refers to the strength of interaction between an antibody and an antigen at individual antigenic sites. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen through weak non-covalent forces at many sites; the more interactions, the stronger the affinity.

[0065] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities. However, an isolated antibody that specifically binds to one antigen may have cross-reactivity with other antigens. Moreover, an isolated antibody may be substantially free of other cellular materials and/or chemicals.

[0066] The term "corresponding human germline sequence" refers to a nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that has the highest assessed amino acid sequence identity to a reference variable region amino acid sequence or subsequence, compared to all other known variable region amino acid sequences encoded in human immunoglobulin variable region germline sequences. The corresponding human germline sequence may also refer to a human variable region amino acid sequence or subsequence that has the highest assessed amino acid sequence identity to a reference variable region amino acid sequence or subsequence, compared to all other variable region amino acid sequences evaluated. The corresponding human germline sequence may be framework regions only, complementarity determining regions only, framework and complementarity determining regions, a variable segment (as defined above), or other combinations of sequences or subsequences that comprise a variable region. Sequence identity may be determined using the methods described herein, such as aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art. The corresponding human germline nucleic acid or amino acid sequence may have at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a reference nucleic acid sequence or variable region amino acid sequence. The corresponding human germline sequences can be determined, for example, using the international ImMunoGeneTics (IMGT) database, which is publicly available (on the World Wide Web at www.imgt.org/) and V-base (on the World Wide Web at vbase.mrc-cpe.cam.ac.uk).

[0067] The phrase "specifically binds" or "selectively binds" when used in the context of describing the interaction between an antigen (e.g., protein) and an antibody, antibody fragment, or antibody-derived binding agent, refers to a binding reaction that is determinative for establishing the presence of an antigen in a heterogeneous population of proteins and other biological substances, such as in a biological sample, for example, blood, blood serum, blood plasma, or a tissue sample. Thus, under certain designated immunoassay conditions, antibodies or binding agents having a particular binding specificity bind to a particular antigen at least two times stronger than background levels and do not bind significantly to other antigens present in the sample. In one embodiment, under the designated immunoassay conditions, an antibody or binding agent having a particular binding specificity binds to a particular antigen at least ten (10) times stronger than background levels and does not bind significantly to other antigens present in the sample. Specific binding by an antibody or binding agent under such conditions may require that the antibody or agent be selected for its specificity for a particular protein. If desired or necessary, this selection may be accomplished by rejecting antibodies that cross-react with molecules from another species (e.g., mouse or rat) or other subtypes. Alternatively, in some embodiments, antibodies or antibody fragments that cross-react with certain desired molecules are selected.

[0068] A variety of immunoassay formats can be used to select antibodies that are specifically reactive to a particular protein. For example, ELISA solid-phase immunoassays have traditionally been used to select antibodies that are specifically reactive to a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998), which describes immunoassay formats and conditions that can be used to determine specific immune reactivity). Typically, a specific or selective binding reaction will result in a signal at least twice the background level, and more typically at least 10-100 times the background level.

[0069] The term "equilibrium dissociation constant (KD [M])" refers to the dissociation rate constant (kd [time-1]) divided by the association rate constant (ka [time-1, M-1]). Equilibrium dissociation constants can be measured using any method known in the art. Typically, the antibodies of the present invention will have an equilibrium dissociation constant of less than about ^10-7 or ^10-8 M, such as less than about ^10-9 M or ^10-10 M, in some embodiments less than about ^10-11 M, ^10-12 M, or ^10-13 M.

[0070] The term "bioavailability" refers to systemic availability (i.e. levels in the blood/plasma) of a given amount of drug administered to a patient. Bioavailability is an absolute term that refers to both the time (rate) it takes for a drug to reach the general circulation from an administered dosage form and the total amount (quantity) of drug in it.

[0071] As used herein, the phrase "consisting essentially of" refers to the genera or species of active pharmaceutical agents included in a method or composition, as well as any excipients that are not active for the intended purpose of the methods or compositions. In some embodiments, the phrase "consisting essentially of" expressly excludes the inclusion of one or more additional active agents other than the antibody drug conjugate of the present invention. In some embodiments, the phrase "consisting essentially of" expressly excludes the inclusion of one or more additional active agents other than the antibody drug conjugate of the present invention and a second agent administered together.

[0072] The term "amino acid" refers to naturally occurring, synthetic, and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids include amino acids encoded in the genetic code as well as those amino acids that have been subsequently modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., have an α-carbon that is bonded to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., to homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogues have modified R-groups (for example, norleucine) or modified peptide backbones, but retain the same basic chemical structure as the naturally occurring amino acid. Amino acid mimetics refer to chemical compounds that have a structure different from the general chemical structure of the amino acid, but which function similarly to the naturally occurring amino acid.

[0073] The term "conservatively modified variant" applies to both amino acid sequences and nucleic acid sequences. When applied to specific nucleic acid sequences, conservatively modified variants refer to those nucleic acids that encode identical or substantially identical amino acid sequences, or, if the nucleic acid does not encode an amino acid sequence, substantially identical sequences. Due to the degeneracy of the genetic code, any given protein is encoded by a large number of functionally identical nucleic acids. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Thus, at each position where the codon specifies alanine, the codon can be changed to any of the corresponding codons described without changing the encoded polypeptide. Such nucleic acid variants are "silent variations," which are one kind of variation with conservative modifications. In this document, each nucleic acid sequence that encodes a polypeptide also describes each possible silent variant of the nucleic acid. One skilled in the art will recognize that each codon in a nucleic acid (except AUG, which is typically the only codon for methionine, and TGG, which is typically the only codon for tryptophan) can be modified to produce a functionally identical molecule. Accordingly, each silent variant of a nucleic acid that encodes a polypeptide is implicitly defined in each described sequence.

[0074] In the case of polypeptide sequences, "conservatively modified variants" encompass individual substitutions, deletions, or additions in a polypeptide sequence that result in the replacement of an amino acid with an amino acid of chemically similar properties. Tables of conservative substitutions providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, the polymorphic variants, interspecies homologs, and alleles of the present invention. The following eight groups contain amino acids that are conservative substitutions for each other: 1) alanine (A), glycine (G); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W); 7) serine (S), threonine (T) and 8) cysteine (C), methionine (M) (see, For example, Creighton, Proteins (1984)). In some embodiments, the term "conservative sequence modifications" is used to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of an antibody comprising the amino acid sequence.

[0075] As used herein, the term "optimized" refers to a nucleotide sequence encoding an amino acid sequence that has been altered to use codons preferred by the producing cell or organism, typically a eukaryotic cell, such as a yeast cell, a Pichia cell, a fungal cell, a Trichoderma cell, a Chinese hamster ovary (CHO) cell, or a human cell. The optimized nucleotide sequence is designed to retain as much or as little of the amino acid sequence originally encoded by the original nucleotide sequence, which is also known as the "parent" sequence.

[0076] The terms "percent identity" or "percent identity" in the context of two or more nucleic acid or polypeptide sequences refer to the degree to which two or more sequences or subsequences are the same. Two sequences are "identical" if they have the same sequence of amino acids or nucleotides over the region being compared. Two sequences are "substantially identical" if the two sequences have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% identity over a specified region or, if not specified, over the entire sequence), when compared and aligned to provide maximum correspondence over a comparison window or a specified region, as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 30 nucleotides (or 10 amino acids) in length, or more preferably over a region that is 100-500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

[0077] In sequence comparison, typically one sequence serves as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, the test and reference sequences are entered into a computer, if necessary, subsequence coordinates are set, and the algorithm's software parameters for analyzing the sequences are set. Default software parameters may be used, or alternative parameters may be set. Based on the software parameters, the sequence comparison algorithm then calculates percent sequence identity values for the test sequences relative to the reference sequence.

[0078] As used herein, a "comparison window" refers to a segment of any number of contiguous positions selected from the group consisting of from 20 to 600, typically from about 50 to about 200, more typically from about 100 to about 150, in which a sequence can be compared to a reference sequence of the same number of contiguous positions after the two sequences have been optimally aligned. Methods for aligning sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be performed, for example, by the Smith-Waterman local homology search algorithm, Adv. Appl. Math. 2:482c (1970), by the Needleman-Wunsch homology region alignment algorithm, J. Mol. Biol. 48:443 (1970), by the Pearson-Lipman similarity search method, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by computer implementations of such algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, For example, Brentet al., Current Protocols in Molecular Biology, 2003).

[0079] Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschulet al.,Nuc. Acids Res. 25:3389-3402, 1977 and Altschul et al., J. Mol. Biol. 215:403–410, 1990, respectively. Software for performing BLAST analyses is available for public use from the National Center for Biotechnology Information. The first step of the algorithm involves identifying high-similarity sequence pairs (HSPs) by identifying short words of length W in the query sequence that either match or satisfy some threshold score T, with a positive value when aligned with a word of the same length in the database sequence. T is known as the neighboring word score (Altschulet al., (above). These initial adjacent word matches act as "seeds" to begin searches designed to find longer HSPs containing them. Word matches are extended in both directions along each sequence for as long as the overall alignment score can be increased. For nucleotide sequences, overall scores are calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatched residues; always <0). For amino acid sequences, a substitution matrix is used to calculate the overall score. Extension of word matches in each direction stops when the overall alignment score decreases by X relative to its maximum achieved value; the overall score approaches zero or below due to the accumulation of one or more negative-scoring residue alignments; or the end of any of the sequences is reached. The BLAST parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as default parameters a wordlength (W) of 11, an expectation (E) of 10, M=5, N= -4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as default parameters a wordlength of 3, an expectation (E) of 10, and the BLOSUM62 substitution matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915), alignments (B) of 50, expectation (E) of 10, M=5, N= -4, and comparison of both strands.

[0080] The BLAST algorithm also performs statistical analysis of the similarity between two sequences (see, For example, Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5787, 1993). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which indicates the probability with which a match between two nucleotide or amino acid sequences occurred by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability when comparing the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0081] The percent identity between two amino acid sequences can also be determined using the algorithm from E. Meyers and W. Miller Comput. Appl. Biosci. 4:11–17, (1988) which has been incorporated into the ALIGN program (version 2.0), using the PAM120 residue substitution weight table, a gap extension penalty of 12, and a gap opening penalty of 4. Additionally, the percent identity between two amino acid sequences can be determined using the Needleman-Wunsch algorithm, J. Mol. Biol. 48:444-453, (1970), which was incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either the BLOSUM62 matrix or the PAM250 matrix, and a gap opening penalty of 16, 14, 12, 10, 8, 6, or 4, and a gap extension penalty of 1, 2, 3, 4, 5, or 6.

[0082] In addition to the percentage of sequence identity mentioned above, another indication that two nucleic acid or polypeptide sequences are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with antibodies induced by the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, if the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules, or their complementary strands, hybridize to each other under stringent conditions, as described below. Another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0083] The term "nucleic acid" is used herein interchangeably with the term "polynucleotide" and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in single- or double-stranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have binding properties similar to a reference nucleic acid, and which are metabolized similarly to reference nucleotides. Examples of such analogs include, but are not limited to, phosphorothioates, phosphoramidates, methylphosphonates, chiral methylphosphonates, 2-O-methylribonucleotides, peptide nucleic acids (PNA).

[0084] Unless otherwise stated, a particular nucleic acid sequence also obviously encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the specifically specified sequence. In particular, as described in detail below, degenerate codon substitutions can be carried out by creating sequences in which the third position in one or more selected (or all) codons is replaced by any of the canonical nucleosides and/or a deoxyinosine residue (Batzeret al., Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., J. Biol. Chem. 260:2605-2608, 1985 and Rossolini et al., Mol. Cell. Probes 8:91-98, 1994).

[0085] In the context of nucleic acids, the term "operably linked" refers to a functional relationship between two or more segments of a polynucleotide (e.g., DNA). Typically, it refers to the functional relationship of a transcriptional regulatory sequence to a transcribed sequence. For example, a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or modulates transcription of the coding sequence in an appropriate host cell or other expression system. Typically, transcriptional regulatory promoter sequences that are operably linked to a transcribed sequence are physically adjacent to the transcribed sequence, i.e., they function in cis. However, some transcriptional regulatory sequences, such as enhancers, do not need to be physically adjacent or in close proximity to the coding sequences whose transcription they enhance.

[0086] The terms "polypeptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to polymers of amino acids in which one or more amino acid residues are an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to polymers of naturally occurring amino acids and a polymer of non-naturally occurring amino acids. Unless otherwise specified, a particular polypeptide sequence also obviously encompasses conservatively modified variants thereof.

[0087] As used herein, the term "antibody drug conjugate" or "immunoconjugate" refers to a linkage of an antibody or antigen-binding fragment thereof to another agent, such as a chemotherapeutic agent, a toxin, an immunotherapeutic agent, an imaging probe, etc. The linkage may be covalent bonds or non-covalent interactions, such as through electrostatic forces. Various linkers known in the art may be used to form an antibody drug conjugate. Additionally, the antibody drug conjugate may be provided in the form of a fusion protein that can be expressed from a polynucleotide encoding the immunoconjugate. As used herein, a "fusion protein" refers to proteins created by linking two or more genes or gene fragments that originally encoded separate proteins (including peptides and polypeptides). Translation of the fusion gene results in a single protein with functional properties derived from each of the original proteins.

[0088] The term "subject" includes humans and non-human animals. Non-human animals include all vertebrates, such as mammals and non-mammals such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles. Except where noted, the terms "patient" or "subject" are used interchangeably in this document.

[0089] As used herein, the term "cytotoxin" or "cytotoxic agent" refers to any agent that is detrimental to the growth and proliferation of cells and that can function to reduce, inhibit, or destroy a cell or malignant tumor.

[0090] As used herein, the term "anti-cancer agent" refers to any agent that can be used to treat or prevent a cell proliferative disorder such as cancer, including, but not limited to, cytotoxic agents, chemotherapeutic agents, radiation therapy and radiation therapy agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0091] As used herein, the term "drug moiety" or "payload" refers to a chemical moiety that is conjugated to an antibody or antigen-binding fragment of the present invention, and may encompass any therapeutic or diagnostic agent, such as an anti-cancer, anti-inflammatory, anti-infective (e.g., antifungal, antibacterial, antiparasitic, antiviral), or anesthetic agent. For example, the drug moiety may be an anti-cancer agent, such as a cytotoxin. In certain embodiments, the drug moiety is a target inhibitor compound. In addition, the payload may be a biophysical detection probe, a fluorophore, a spin label, an infrared detection probe, an affinity detection probe, a chelator, a spectroscopic detection probe, a radioactive probe, a lipid molecule, a polyethylene glycol, a polymer, a spin label, DNA, RNA, a protein, a peptide, a coating, an antibody, an antibody fragment, a nanoparticle, a quantum dot, a liposome, a PLGA particle, a saccharide, or a polysaccharide.

[0092] In some embodiments, the drug moiety or payload is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (a GNAQ/GNA11 inhibitor). In some embodiments, the GNAQ/11 inhibitor is a molecule that inhibits GNAQ/11-mediated IP3 production and/or exhibits a dose-dependent antiproliferative effect in cells dependent on GNAQ/11 signaling (i.e., GNAQ/11 mutant uveal melanoma cells). In some embodiments, the GNAQ/11 inhibitor is a compound that stabilizes GNAQ/11 in the inactive GDP-bound state and prevents the release of GDP, or binds in the active GTP-bound state and prevents GNAQ/11 from interacting with downstream effectors. In some embodiments, the GNAQ/11 inhibitor functions by inhibiting mutant GNAQ and/or GNA11, such as one containing the Q209L/P mutation. Methods for attaching such drug moieties to a linker compatible with a targeting moiety are provided herein, along with methods known in the art. See, for example, Singh et al., (2009) Therapeutic Antibodies: Methods and Protocols, vol. 525, 445-457.

[0093] GNAQ (the alpha subunit of guanine nucleotide-binding protein G(q), also known as CMC1, G-ALPHA-q, GAQ, SWS, and the alpha-q subunit of the G protein) and GNA11 (the alpha-11 subunit of guanine nucleotide-binding protein, also known as FBH, FBH2, FHH2, GNA-11, HHC2, HYPOC2, and the alpha 11 subunit of the G protein) are closely related GTPases that comprise the α-subunits of heterotrimeric G proteins acting downstream of G protein-coupled receptors (GPCRs). The α-subunits act as a switch for activating G proteins by exchanging guanosine diphosphate (GDP) for guanosine triphosphate (GTP), resulting in the activation of individual downstream effectors. Activation is terminated by intrinsic GTPase activity, where GTP is hydrolyzed to GDP (Van Raamsdonk et al., 2010, N Engl J Med.; 363(23):2191-9). Classical activation of the Gq protein cascade occurs through phospholipase C-β (PLC-β), which hydrolyzes the phospholipid phosphatidylinositol 4,5-bisphosphate to release two highly active second messengers: D-myoinositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Following a transient increase in intracellular Ca ^2+, IP3 is rapidly converted to IP2, IP1, and myoinositol. On the other hand, DAG activates protein kinase C (PKC), which leads to a cascade of phosphorylation of RAF, MEK, and ERK, which translocate to the nucleus to regulate cell proliferation and survival (Krantz et al., 2017, Clin Ophthalmol.; 11:279-289).

[0094] The nucleic acid and amino acid sequences of human GNAQ have been published in GenBank under the following accession numbers:

[0095] NP_002063 (SEQ ID NO:268)

1 mtlesimacc lseeakearr indeierqlr rdkrdarrel kllllgtges gkstfikqmr

61 iihgsgysde dkrgftklvy qniftamqam iramdtlkip ykyehnkaha qlvrevdvek

121 vsafenpyvd aikslwndpg iqecydrrre yqlsdstkyy lndldrvadp aylptqqdvl

181 rvrvpttgii eypfdlqsvi frmvdvggqr serrkwihcf envtsimflv alseydqvlv

241 esdnenrmee skalfrtiit ypwfqnssvi lflnkkdlle ekimyshlvd yfpeydgpqr

301 daqaarefil kmfvdlnpds dkiiyshftc atdtenirfv faavkdtilq lnlkeynlv

[0096] NM_002072 (SEQ ID NO:269)

1 agactatccg ctcccaccgc gcccccggcc cacctggtgg ccccggccct ggccgccgcc

61 cccgcggcgg ttcccggagc tcgtcccgga cgcgcgcccg ggcggcgggg gctcggcggc

121 caccgctgcc tcgggggagc gagggcggga gggtgtgtgt gcgcgctgtg agcaggggggt

181 gccggcgggg ctgcagcgga ggcactttgg aagaatgact ctggagtcca tcatggcgtg

241 ctgcctgagc gaggaggcca aggaagcccg gcggatcaac gacgagatcg agcggcagct

301 ccgcagggac aagcgggacg cccgccggga gctcaagctg ctgctgctcg ggacaggaga

361 gagtggcaag agtacgttta tcaagcagat gagaatcatc catgggtcag gatactctga

421 tgaagataaa aggggcttca ccaagctggt gtatcagaac atcttcacgg ccatgcaggc

481 catgatcaga gccatggaca cactcaagat cccatacaag tatgagcaca ataaggctca

541 tgcacaatta gttcgagaag ttgatgtgga gaaggtgtct gcttttgaga atccatatgt

601 agatgcaata aagagtttat ggaatgatcc tggaatccag gaatgctatg atagacgacg

661 agaatatcaa ttatctgact ctaccaaata ctatcttaat gacttggacc gcgtagctga

721 ccctgcctac ctgcctacgc aacaagatgt gcttagagtt cgagtcccca ccacagggat

781 catcgaatac ccctttgact tacaaagtgt cattttcaga atggtcgatg tagggggcca

841 aaggtcagag agaagaaaat ggatacactg ctttgaaaat gtcacctcta tcatgtttct

901 agtagcgctt agtgaatatg atcaagttct cgtggagtca gacaatgaga accgaatgga

961 ggaaagcaag gctctcttta gaacaattat cacatacccc tggttccaga actcctcggt

1021 tattctgttc ttaaacaaga aagatcttct agaggagaaa atcatgtatt cccatctagt

1081 cgactacttc ccagaatatg atggacccca gagagatgcc caggcagccc gagaattcat

1141 tctgaagatg ttcgtggacc tgaacccaga cagtgacaaa attatctact cccacttcac

1201 gtgcgccaca gacaccgaga atatccgctt tgtctttgct gccgtcaagg acaccatcct

1261 ccagttgaac ctgaaggagt acaatctggt ctaattgtgc ctcctagaca cccgccctgc

1321 ccttccctgg tgggctattg aagatacaca agagggactg tatttctgtg gaaaacaatt

1381 tgcataatac taatttattg ccgtcctgga ctctgtgtga gcgtgtccac agagtttgta

1441 gtaaatatta tgattttatt taaactattc agaggaaaaa cagaggatgc tgaagtacag

1501 tcccagcaca tttcctctct atcttttttt taggcaaaac cttgtgactc agtgtatttt

1561 aaattctcag tcatgcactc acaaagataa gacttgtttc tttctgtctc tctctctttt

1621 tcttttctat ggagcaaaac aaagctgatt tccctttttt cttcccccgc taattcatac

1681 ctccctcctg atgtttttcc caggttacaa tggcctttat cctagttcca ttcttggtca

1741 agtttttctc tcaaatgata cagtcaggac acatcgttcg atttaagcca tcatcagctt

1801 aatttaagtt tgtagttttt gctgaaggat tatatgtatt aatacttacg gttttaaatg

1861 tgttgctttg gatacacaca tagtttcttt tttaatagaa tatactgtct tgtctcactt

1921 tggactggga cagtggatgc ccatctaaaa gttaagtgtc atttctttta gatgtttacc

1981 ttcagccata gcttgattgc tcagagaaat atgcagaagg caggatcaaa gacacacagg

2041 agtcctttct tttgaaatgc cacgtgccat tgtctttcct cccttctttg cttctttttc

2101 ttaccctctc tttcaattgc agatgccaaa aaagatgcca acagacacta cattacccta

2161 atggctgcta cccagaacct ttttataggt tgttcttaat ttttttgttg ttgttgttca

2221 agcttttcct ttcttttttt tcttggtgtt tgggccacga ttttaaaatg acttttatta

2281 tgggtatgtg ttgccaaagc tggctttttg tcaaataaaa tgaatacgaa cttaaaaaat

2341 aaaagctggt atcttaaaat gtaagagagt aagactgtga agcctaaaat gactggctga

2401 gaatgaacca gaaatgccat ttgccaaaca gttgtaacta gaaatttgat tctcacggtc

2461 cattcttttc tttgtcctta agatgacatt gttagtgttc acgtcccatg ttcagtgtcc

2521 aaaccggcaa tgtaaaaagt atcctgtgtg gtttaacagg aaatctgttt atgtctcttt

2581 atttgaaacc agttttactc tcagtggttc tttaagttca atgaagtctg caggaacat

2641 tggttggtag tattattccg acacctttaa tttccaaaat ctgaagttcc tgctagttta

2701 ccaccttcat gatcttcttg aactggtaac tgattaggtt gaacttatgg aagatttgtg

2761 gacttaactc aaaagtaacc tctcagtgtt ctatagaaca tgtatttgtg taactgaacc

2821 taccaggaga aatgtttgga attctatatg tgcaattttt caacaaatgc aaaaaaaata

2881 cagcacatgt attgacaagc ttctgtcaag cagcttgagt tgaaatttga tttaagaaaa

2941 taaatcatga ttgttcaaag ctgctgggac gttagaatta ggccatgata ctggtctcat

3001 tttaactaca gtggtatttg gcactagtgt aaacttccat ataaatcact cttttggaac

3061 aacaaagggg gagggagaaa aatcacggcc tgttaaatga gtaccaaagc cgcccaacag

3121 taatgagatg ttctcatcct tgattctccc agcctcaaac aacacagctt actttttttt

3181 tcccttgctc agaaagtacc tgtaatttaa caaacagact gcctgtaggt atagtgcaat

3241 tacaaatgct ctaatcattg tacatacatc tctcttgata ttgcagcatc catactggct

3301 ttgtaatcat taattttttg gcagattgaa tgtgctgtat tgatatgtat ctatgtaatt

3361 gtattgtatg tctatagcta attcacgttt tgaataatgt tattttattt acttttttaa

3421 gagaggagaa tgtaaatttg tcagtttatt tctgactagg gatattttct ttccatttag

3481 aaaagaagaa aaaaaaaaaa ccttactgtc atacagagcg gtactagcgt cgtgctgtat

3541 aaaatcattt gcacattcct gagtagaggt atactgatta taagacccaa aggtaatttc

3601 atagcaaaat acataaaatc agtcggagct tttatacaaa catggaaacc aactttgtag

3661 aacttttgcc atttgatcta ggattggaat atgagctttt atacaattca tattcttatt

3721 tggcaaatgc acagtttagt attacctctc tgatggcctt tactagaaag gcagttttag

3781 aagctattgt gatccactaa ggaaatgttt taacagctag agaccactgc ttgcctgaaa

3841 gggcgttctt aaatttggtg cagcaaaaaa aaaaaaaaaa aaaaaaaaaa ttaaacaaca

3901 acatttgaag gcctacagtg tgtatagaga aaacctcatc acaagatcat aagtgttaca

3961 gttttaggga atcaagatat tctatttaat agagctatag taaatgtagt caattaaacc

4021 tgatctcaaa gcttgaagaa gctgagcaaa acagggaaag attgttatat ttgtctttat

4081 gaaattggga tggaatttgc tatgcagaat tgaggtttgt ggcttcgctg ttcctgtagg

4141 gtgcatgaca agatcccttc tcttgagaaa ggaaaaaatt gatcacccta gcagcagtga

4201 tgcatagaaa cctaatttta gccacaccag tcaatcgaag ctaaaggatt ttcttttttg

4261 tttcttcggg gttttattga aggggctagg ggcgggacgg gattcttttc agttttgtat

4321 aaaaacaaag tttactcatg ctttatatta tattgtgatt gcaagcgtta taagcgtgtg

4381 ccactggcct cctattgttg atgcttaggt aatggaggcc tgtggtgagt tttatggtga

4441 cttgggcatg tcttattcaa aaacaaaaac ataaaacaca gaaacctttc ttcagcatac

4501 caaggcaagc agccatttca tgactcactt aacacattgc agtgtaccag tttacagatg

4561 atttttccct ttttgcgtga catggcagtt ctaaccccca gagaattcct tatttgtaaa

4621 ttggaagttt ctactatgcc ttacagagct taaattcaga agtttgtgcc tcatatctga

4681 aacaaaggga aataacacac ccattcaaaa gtaaataaat ctcctagaag tttttgtttt

4741 taacatttcc atataaagag ctctgttgaa tgtcatgaat agactggaaa aaaaaatttt

4801 aagaacctgc atatgttgtt tactagcaga tgacaactac aaaaggaatc tgaagaacac

4861 gtaaaacttg tatttttttt tttttggtag attaactagc aggcctattt taaaaaggta

4921 attcagctaa agggcaattt acttttttgt acttcagact atcttgattg tcaaagtgta

4981 cgaactgtaa ttttaaaatt tatactgcca catgattgta aattttagtt gtcttaagtt

5041 aggaattggt gaaaagctat ttatgctgga tttggggtcaa aatgacttat ttgcaaaaaa

5101 ataaataatg ggaagaaagg gctgtataat gaaatactgc aagactcaca tattggttgg

5161 aaatttccct caaatcacct accgattacc cttgatttcc ctttgttttc agtttctcaa

5221 aacgaatgaa atgaaatata gcagaatgtt aacccatata aaaataaagt gtacccaaat

5281 attgtaatgt atattgctgc tcttcttcaa attaaataag ggtttaaaac cacttaattg

5341 gtaatcaaca tctcaattga tacaaataag gtgtgcttgg tatacattaa tattttcttc

5401 caaagatata tctttggtta gaaacacaaa aaaataaaac tagtaatatt gtatgttttat

5461 ctatctctac atatttccag catatgtagc gttaatagat ctgtcctggt aactgtgtct

5521 ttgggatttc attttggttc catcaaatta ggaaaagaaa tggcttagtt gtatatgatt

5581 agctagagat ttttggagcc agacacctgc tgtttagtag ataacttagt acagacccta

5641 aacttgtcat ttgtttttct cacagaatag ccatttcctg ctgtcttccc aatgatcact

5701 gccctttcaa taacactctt gcctctagaa tcatatgttc aaagtatgaa tacacaccta

5761 gcacatagta ggtgctcaaa tattaatttc ctccttgcct tccttatcta ccctgtgtcc

5821 tccatttccc cgtatgattc caacccaata tagcaaatga catttacatg ttatgaaaac

5881 atctattggg taaaatcaga tcttggataa agaaattctg acttttatat aagcttttgg

5941 tagacagaaa aaacagaaag gtattcgttg gtagaacatt tttaagttca ggaaagaaag

6001 ctggaataat actacgtaac tttgtccagg ttactttgac tgaaacacgt ttttggtgga

6061 tttcttttcc tcaaagaact ctctaaatgc aactccttgc tggattcctc acccatcatc

6121 ctgttggaaa cccttactag acctatgtat ttagggagtt ttgtcagaaa acatttttaa

6181 cttgcagtat ttaaaagaat atttactgtt cctaaaatgt cattcaaatg catgtactgt

6241 ctattgtttg gggatgggaa ctagttttgc aaaaaacacc taatgttgta taataatgcc

6301 ccaatgatct tgctggttaa aaatacagta tttttggcca taa

[0097] The nucleic acid and amino acid sequence of human GNA11 has been published in GenBank under the following accession numbers:

[0098] NP_002058 (SEQ ID NO:270)

1 mtlesmmacc lsdevkeskr inaiekqlr rdkrdarrel kllllgtges gkstfikqmr

61 iihgagysee dkrgftklvy qniftamqam irametlkil ykyeqnkana llirevdvek

121 vttfehqyvs aiktlwedpg iqecydrrre yqlsdsakyy ltdvdriatl gylptqqdvl

181 rvrvpttgii eypfdlenii frmvdvggqr serrkwihcf envtsimflv alseydqvlv

241 esdnenrmee skalfrtiit ypwfqnssvi lflnkkdlle dkilyshlvd yfpefdgpqr

301 daqaarefil kmfvdlnpds dkiiyshftc atdtenirfv faavkdtilq lnlkeynlv

[0099] NM_002067 (SEQ ID NO:271)

1 aggttgtccg gcgctgtcgc tcggttgcgg cggctgcggt tggcggtggc tgcggcggcg

61 gcgcgggctg agtgcggccg cgcgggagtc cgcggctggc gcggcccgag cggggacccg

121 gcggctcgcc aggcggcggc cgaggcgggg cgggccggcc cggggccgag ggccggtggc

181 cgaggccgga gggccgcggc gggcggcggc cgaggcggct ccggccaggg ccgggccggg

241 ggccgggggg cggcggcggg caggcggccg cgtcggccgg ggccgggacg atgactctgg

301 agtccatgat ggcgtgttgc ctgagcgatg aggtgaagga gtccaagcgg atcaacgccg

361 agatcgagaa gcagctgcgg cgggacaagc gcgacgcccg gcgcgagctc aagctgctgc

421 tgctcggcac gggcgagagc gggaagagca cgttcatcaa gcagatgcgc atcatccacg

481 gcgccggcta ctcggaggag gacaagcgcg gcttcaccaa gctcgtctac cagaacatct

541 tcaccgccat gcaggccatg atccggggcca tggagacgct caagatcctc tacaagtacg

601 agcagaacaa ggccaatgcg ctcctgatcc gggaggtgga cgtggagaag gtgaccacct

661 tcgagcatca gtacgtcagt gccatcaaga ccctgtggga ggacccgggc atccaggaat

721 gctacgaccg caggcgcgag taccagctct ccgactctgc caagtactac ctgaccgacg

781 ttgaccgcat cgccaccttg ggctacctgc cccaccagca ggacgtgctg cgggtccgcg

841 tgcccaccac cggcatcatc gagtaccctt tcgacctgga gaacatcatc ttccggatgg

901 tggatgtggg gggccagcgg tcggagcgga ggaagtggat ccactgcttt gagaacgtga

961 catccatcat gtttctcgtc gccctcagcg aatacgacca agtcctggtg gagtcggaca

1021 acgagaaccg gatggaggag agcaaagccc tgttccggac catcatcacc tacccctggt

1081 tccagaactc ctccgtcatc ctcttcctca acaagaagga cctgctggag gacaagatcc

1141 tgtactcgca cctggtggac tacttccccg agttcgatgg tccccagcgg gacgcccagg

1201 cggcgcggga gttcatcctg aagatgttcg tggacctgaa ccccgacagc gacaagatca

1261 tctactcaca cttcacgtgt gccaccgaca cggagaacat ccgcttcgtg ttcgcggccg

1321 tgaaggacac catcctgcag ctcaacctca aggagtacaa cctggtctga gcgcccaggc

1381 ccaggggagac gggatggaga cacggggcag gaccttcctt ccacggagcc tgcggctgcc

1441 gggcggggtgg cgctgccgag tccgggccgg ggcctctgcc cgcgggagga gatttttttt

1501 tttcatattt ttaacaaatg gtttttattt cacagttatc aggggatgta catctctccc

1561 tccgtacact tcgcgcacct tctcaccttt tgtcaacggc aaaggcagcc tttttctggc

1621 cttgacttat ggctcgcttt tttctaaaaa aaaaaaaaaa agaaagaaag aaaaaaagca

1681 acgaaacata aaacacacaa gcgccccgtg cccccagtga ctctgggcct cacagagccc

1741 ccgccagcca gcatggggcc ccgccctgca gccagtcacg cgcccccaca ccgcagcccc

1801 ccgtggctgt ccttccaacc ccacgtgctt tttctttctc ctgcccgctt cttttcttca

1861 tcacaaaagg cgtggagact cggagacgga cgtttttccc cttttttaag ttattgacgc

1921 ccagcgcgcc tcgcctcttc acccatcaac gctgtgcttt gcccactgga ctcctgaaga

1981 gggggtgggg ggctccctcg gtcgcccacc ctgggaagtg cctaaccttt tattttattt

2041 tatttttttg aggaaaaaga acgcctgact cacaggttga agaaacaccc tgggccctct

2101 ctcatggccg ggttccccgt ccctctgcag aggctgggaa gggtccccgg gctggagcca

2161 cggggggcttc tctgggctgt gcctccgggg ccaacactgg ctgcttgggg ctgcccgggg

2221 actccagagg gctgcacggc caccctgccc tggctagagc gcaccccacc ggagcccacg

2281 tgggctgggc ggctggaggg atggtccccc ggtgacactg ggagaaaggc cacttggatg

2341 ggggcgtttc tgttttgttc cgctttgtga tgtcaccaat ttggaaacag cgaggtggg

2401 tggggacttt tacagaatat tctcaggtgt gtacccgaga ggcagagaga gggacgtggc

2461 cggcagctct gtgcgtggcc ttgtcccaag cacttgcgcc cgcccccgag cgccgccccc

2521 ggggagcggg aagccagcac tcgcactttg gccaggggcg cgtggaaggt ggtggcaggc

2581 accggcctgg gcagcttcca ggcctggctg gccacgacca cggcccgagg gggagcccgc

2641 caggccacgc cgcactgagc cacagccccg ggggccgcct cccggggccc cttgaggcac

2701 tgaggcaccg agactggttc tccccgagag actcggaagg tggggaacga ggggactgtg

2761 tttggggagg tggctttttc gtctgctgtt gactgaacac tacagcgccc tgtggttccg

2821 ggcttcgcac agctgtccca gggatggatc gcctgtgctg ccttcgcccg ccgccacacc

2881 gggaccctgc acggctgctt ctggcctcga cagatgacaa aagaaacagc cccaaaatac

2941 gaccactcca accagcagtt cccgcctgcc tgcccgccac tgtcaggcct gccctggcct

3001 cctcgtccgc agggctgtct gctggcttct gggggcagaa gagcggggag ccccgtggaa

3061 gggtcagggg agaccaggtc agggcagcta catttctggt gatcagcccc atggggagac

3121 ggggctggcg ggataccccc cccccggctt ccccacacca cttctgtctc acccggaagc

3181 gtcctttttt tgtgccaggt gtctacctaa gagggttggt gccagaagcc ccccatggcg

3241 agtgctgggg cccggcggtg ccctggggga gcagatgggg ccacccctgg cagggccgct

3301 acaacctttt ccagcagcgg agccctctgg ggggcctgtg cttgtggcat ctctgagggc

3361 ctagattgca caaggtgacc tggccgtggc ctgagggtgg agtcgcccag cacgcaggcc

3421 ggggcgctgc ggggctaagt attaggcctt cccagggagg gggcgtgcca agcatcccag

3481 agccgggctg ggaccgccaa aacgtcgtgg cctggatcct ctgggtctga gtgcctgatc

3541 ccctgccccc caaaaaagca gaggtaggtg ttgcaggccc agggcagggg tgcctgcccc

3601 aggagagtcc caggcagtgg ttctcgtgcc agtggcaccc aggggcaagg acagccaacc

3661 cccacccttg ccacgtgtgg ggccacgtgg gcatgtgggg tgtgtgtttt taccttggtg

3721 aatctcacct gccaacgatt tctcgtgagt gccgaccacc ttctccgacc atgttacgcc

3781 cgggcggcag cagcccccgg ccactgcaaa cccatgccct gggtcccccg gctcccccag

3841 ggaggcatcc ccgtgccaat gtcccccagt ggtggcagca gatcctgtgg ccggcctggc

3901 ggacgggacc cagtgatact tgtatattac acagtcctga tttcagacaa tttcaacctt

3961 aatctattta aaaaagaata ttctatacaa gctgttttta agccttttac catttgaaat

4021 gcatgtgttg tgcgcgttgg ggatgggagg aggggctgag gagcggctca gtgtcacctc

4081 ccacagccac cggccctgac ccttaatcca gacaccgatg gaagtcgact tttcatatct

4141 ttctcctgaa atgaactctg ttttaaattg gaataaattt tgttcctaaa

[00100] "Tumor" refers to the growth and proliferation of neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues.

[00101] The term "antitumor activity" means a decrease in the rate of proliferation, viability, or metastatic activity of tumor cells. For example, antitumor activity may be demonstrated by a decrease in the rate of abnormal cell growth that occurs during therapy, or by stabilization or reduction in tumor size, or by prolonged survival due to therapy compared to a control without therapy. Such activity may be assessed using established in vitro or in vivo tumor models, including, but not limited to, xenograft models, allogeneic transplant models, MMTV models, and other known models known in the art for testing antitumor activity.

[00102] The term "malignant tumor" refers to a non-cancerous tumor or cancer. As used herein, the term "cancer" encompasses a malignant tumor that is characterized by deregulated or uncontrolled cell growth. Illustrative types of cancer include: carcinomas, sarcomas, leukemias, and lymphomas.

[00103] The term "cancer" includes primary malignant tumors (e.g., tumors whose cells have not migrated to sites in the subject's body other than the site of the original tumor) and secondary malignant tumors (e.g., tumors that develop as a result of metastasis, the migration of tumor cells to secondary sites of localization that are different from the site of localization of the original tumor).

[00104] The term "PMEL17" (also referred to as premelanosomal protein (PMEL), D12S53E, ME20, ME20-M, ME20M, P1, P100, gp100, SI, SIL, and silver locus protein homolog (SILV)) refers to a type I single-span transmembrane protein produced by melanocytes and involved in the synthesis of melanin. The nucleic acid sequence and amino acid sequence of human PMEL17 have been published in GenBank under the following accession numbers: NP_008859, NP_001307050, NP_001307051, NP_001186982, NP_001186983 (amino acid sequences) and NM_006928, NM_001200053, NM_001200054, NM_001320121, NM_001320122 (nucleotide sequences). As used herein, the term "PMEL17" is used to refer collectively to all naturally occurring isoforms of the PMEL17 protein or its variant.

[00105] NP_008859 (SEQ ID NO:272)

1 mdlvlkrcll hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc

61 wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp

121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg

181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk hflrnqpltf

241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty lepgpvtaqv vlqaaiplts

301 cgsspvpgtt dghrptaeap nttagqvptt evvgttpgqa ptaepsgtts vqvpttevis

361 tapvqmptae stgmtpekvp vsevmgttla emstpeatgm tpaevsivvl sgttaaqvtt

421 tewvettare lpipepegpd assimstesi tgslgplldg tatlrlvkrq vpldcvlyry

481 gsfsvtldiv qgiesaeilq avpsgegdaf eltvscqggl pkeacmeiss pgcqppaqrl

541 cqpvlpspac qlvlhqilkg gsgtyclnvs ladtnslavv stqlimpgqe aglgqvpliv

601 gillvlmavv lasliyrrrl mkqdfsvpql phssshwlrl prifcscpig enspllsgqq

661 v

[00106] NP_001307050 (SEQ ID NO:273)

1 mdlvlkrcll hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc

61 wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp

121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg

181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk hflrnqpltf

241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty lepgpvtaqv vlqaaiplts

301 cgsspvpgtt dghrptaeap nttagqvptt evvgttpgqa ptaepsgtts vqvpttevis

361 tapvqmptae staaqvttte wvettarelp ipepegpdas simstesitg slgplldgta

421 tlrlvkrqvp ldcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk

481 eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla dtnslavvst

541 qlimpvpgil ltgqeaglgq vplivgillv lmavvlasli yrrrlmkqdf svpqlphsss

601 hwlrlprifc scpigenspl lsgqqv

[00107] NP_001307051 (SEQ ID NO:274)

1 mdlvlkrcll hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc

61 wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp

121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg

181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk hflrnqpltf

241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty lepgpvtaqv vlqaaiplts

301 cgsspvpgtt dghrptaeap nttagqvptt evvgttpgqa ptaepsgtts vqvpttevis

361 tapvqmptae staaqvttte wvettarelp ipepegpdas simstesitg slgplldgta

421 tlrlvkrqvp ldcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk

481 eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla dtnslavvst

541 qlimpgqeag lgqvplivgi llvlmavvla sliyrrrlmk qdfsvpqlph ssshwlrlpr

601 ifcscpigen spllsgqqv

[00108]NP_001186982 (SEQ ID NO:275)

1 mdlvlkrcll hlavigalla vgatkgsqvw ggqpvypqet ddacifpdgg pcpsgswsqk

61 rsfvyvwktw gqywqvlggp vsglsigtgr amlgthtmev tvyhrrgsrs yvplahsssa

121 ftitdqvpfs vsvsqlrald ggnkhflrnq pltfalqlhd psgylaeadl sytwdfgdss

181 gtlisralvv thtylepgpv taqvvlqaai pltscgsspv pgttdghrpt aeapnttagq

241 vpttevvgtt pgqaptaeps gttsvqvptt evistapvqm ptaestgmtp ekvpvsevmg

301 ttlaemstpe atgmtpaevs ivvlsgttaa qvtttewvet tarelpipep egpdassims

361 tesitgslgp lldgtatlrl vkrqvpldcv lyrygsfsvt ldivqgiesa eilqavpsge

421 gdafeltvsc qgglpkeacm eisspgcqpp aqrlcqpvlp spacqlvlhq ilkggsgtyc

481 lnvsladtns lavvstqlim pgqeaglgqv plivgillvl mavvlasliy rrrlmkqdfs

541 vpqlphsssh wlrlprifcs cpigenspll sgqqv

[00109] NP_001186983 (SEQ ID NO:276)

1 mdlvlkrcll hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc

61 wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp

121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg

181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk hflrnqpltf

241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty lepgpvtaqv vlqaaiplts

301 cgsspvpgtt dghrptaeap nttagqvptt evvgttpgqa ptaepsgtts vqvpttevis

361 tapvqmptae stgmtpekvp vsevmgttla emstpeatgm tpaevsivvl sgttaaqvtt

421 tewvettare lpipepegpd assimstesi tgslgplldg tatlrlvkrq vpldcvlyry

481 gsfsvtldiv qgiesaeilq avpsgegdaf eltvscqggl pkeacmeiss pgcqppaqrl

541 cqpvlpspac qlvlhqilkg gsgtyclnvs ladtnslavv stqlimpvpg illtgqeagl

601 gqvplivgil lvlmavvlas liyrrrlmkq dfsvpqlphs sshwlrlpri fcscpigens

661 pllsgqqv

[00110] NM_006928 (SEQ ID NO:277)

1 cccagcgctc ctccccgcaa atgatcccgc cccaggggcc tatcccagtc cccccagtgc

61 ctttggttgc tggagggaag aacacaatgg atctggtgct aaaaagatgc cttcttcatt

121 tggctgtgat aggtgctttg ctggctgtgg gggctacaaa agtacccaga aaccaggact

181 ggcttggtgt ctcaaggcaa ctcagaacca aagcctggaa caggcagctg tatccagagt

241 ggacagaagc ccagagactt gactgctgga gaggtggtca agtgtccctc aaggtcagta

301 atgatgggcc tacactgatt ggtgcaaatg cctccttctc tattgccttg aacttccctg

361 gaagccaaaa ggtattgcca gatgggcagg ttatctgggt caacaatacc atcatcaatg

421 ggagccaggt gtggggagga cagccagtgt atccccagga aactgacgat gcctgcatct

481 tccctgatgg tggaccttgc ccatctggct cttggtctca gaagagaagc tttgtttatg

541 tctggaagac ctggggccaa tactggcaag ttctaggggg cccagtgtct gggctgagca

601 ttgggacagg cagggcaatg ctgggcacac acaccatgga agtgactgtc taccatcgcc

661 ggggatcccg gagctatgtg cctcttgctc attccagctc agccttcacc attactgacc

721 aggtgccttt ctccgtgagc gtgtcccagt tgcgggcctt ggatggaggg aacaagcact

781 tcctgagaaa tcagcctctg acctttgccc tccagctcca tgaccccagt ggctatctgg

841 ctgaagctga cctctcctac acctgggact ttggagacag tagtggaacc ctgatctctc

901 gggcacttgt ggtcactcat acttacctgg agcctggccc agtcactgcc caggtggtcc

961 tgcaggctgc cattcctctc acctcctgtg gctcctcccc agttccaggc accacagatg

1021 ggcacaggcc aactgcagag gcccctaaca ccacagctgg ccaagtgcct actacagaag

1081 ttgtgggtac tacacctggt caggcgccaa ctgcagagcc ctctggaacc acatctgtgc

1141 aggtgccaac cactgaagtc ataagcactg cacctgtgca gatgccaact gcagagagca

1201 caggtatgac acctgagaag gtgccagttt cagaggtcat gggtaccaca ctggcagaga

1261 tgtcaactcc agaggctaca ggtatgacac ctgcagaggt atcaattgtg gtgctttctg

1321 gaaccacagc tgcacaggta acaactacag agtgggtgga gaccacagct agagagctac

1381 ctatccctga gcctgaaggt ccagatgcca gctcaatcat gtctacggaa agtattacag

1441 gttccctggg ccccctgctg gatggtacag ccaccttaag gctggtgaag agacaagtcc

1501 ccctggattg tgttctgtat cgatatggtt ccttttccgt caccctggac attgtccagg

1561 gtattgaaag tgccgagatc ctgcaggctg tgccgtccgg tgagggggat gcatttgagc

1621 tgactgtgtc ctgccaaggc gggctgccca aggaagcctg catggagatc tcatcgccag

1681 ggtgccagcc ccctgcccag cggctgtgcc agcctgtgct acccagccca gcctgccagc

1741 tggttctgca ccagatactg aagggtggct cggggacata ctgcctcaat gtgtctctgg

1801 ctgataccaa cagcctggca gtggtcagca cccagcttat catgcctggt caagaagcag

1861 gccttggggca ggttccgctg atcgtgggca tcttgctggt gttgatggct gtggtccttg

1921 catctctgat atataggcgc agacttatga agcaagactt ctccgtaccc cagttgccac

1981 atagcagcag tcactggctg cgtctacccc gcatcttctg ctcttgtccc attggtgaga

2041 acagccccct cctcagtggg cagcaggtct gagtactctc atatgatgct gtgattttcc

2101 tggagttgac agaaacacct atatttcccc cagtcttccc tgggagacta ctattaactg

2161 aaataaatac tcagagcctg aaaaaaaaaa aaaaa

[00111] NM_001200053 (SEQ ID NO:278)

1 gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg

61 gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct

121 acaaaaggga gccaggtgtg gggaggacag ccagtgtatc cccaggaaac tgacgatgcc

181 tgcatcttcc ctgatggtgg accttgccca tctggctctt ggtctcagaa gagaagcttt

241 gtttatgtct ggaagacctg gggccaatac tggcaagttc tagggggccc agtgtctggg

301 ctgagcattg ggacaggcag ggcaatgctg ggcacacaca ccatggaagt gactgtctac

361 catcgccggg gatcccggag ctatgtgcct cttgctcatt ccagctcagc cttcaccatt

421 actgaccagg tgcctttctc cgtgagcgtg tcccagttgc gggccttgga tggagggaac

481 aagcacttcc tgagaaatca gcctctgacc tttgccctcc agctccatga ccccagtggc

541 tatctggctg aagctgacct ctcctacacc tgggactttg gagacagtag tggaaccctg

601 atctctcggg cacttgtggt cactcatact tacctggagc ctggcccagt cactgcccag

661 gtggtcctgc aggctgccat tcctctcacc tcctgtggct cctccccagt tccaggcacc

721 acagatgggc acaggccaac tgcagaggcc cctaacacca cagctggcca agtgcctact

781 acagaagttg tgggtactac acctggtcag gcgccaactg cagagccctc tggaaccaca

841 tctgtgcagg tgccaaccac tgaagtcata agcactgcac ctgtgcagat gccaactgca

901 gagagcacag gtatgacacc tgagaaggtg ccagtttcag aggtcatggg taccacactg

961 gcagagatgt caactccaga ggctacaggt atgacacctg cagaggtatc aattgtggtg

1021 ctttctggaa ccacagctgc acaggtaaca actacagagt gggtggagac cacagctaga

1081 gagctaccta tccctgagcc tgaaggtcca gatgccagct caatcatgtc tacggaaagt

1141 attacaggtt ccctgggccc cctgctggat ggtacagcca ccttaaggct ggtgaagaga

1201 caagtccccc tggattgtgt tctgtatcga tatggttcct tttccgtcac cctggacatt

1261 gtccagggta ttgaaagtgc cgagatcctg caggctgtgc cgtccggtga gggggatgca

1321 tttgagctga ctgtgtcctg ccaaggcggg ctgcccaagg aagcctgcat ggagatctca

1381 tcgccagggt gccagccccc tgcccagcgg ctgtgccagc ctgtgctacc cagcccagcc

1441 tgccagctgg ttctgcacca gatactgaag ggtggctcgg ggacatactg cctcaatgtg

1501 tctctggctg ataccaacag cctggcagtg gtcagcaccc agcttatcat gcctggtcaa

1561 gaagcaggcc ttgggcaggt tccgctgatc gtgggcatct tgctggtgtt gatggctgtg

1621 gtccttgcat ctctgatata taggcgcaga cttatgaagc aagacttctc cgtaccccag

1681 ttgccacata gcagcagtca ctggctgcgt ctaccccgca tcttctgctc ttgtcccatt

1741 ggtgagaaca gccccctcct cagtgggcag caggtctgag tactctcata tgatgctgtg

1801 attttcctgg agttgacaga aacacctata tttcccccag tcttccctgg gagactacta

1861 ttaactgaaa taaatactca gagcctgaaa aaaaaaaaaa aa

[00112] NM_001200054 (SEQ ID NO:279)

1 gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg

61 gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct

121 acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc

181 tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt

241 ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc

301 ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc

361 tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc

421 caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg

481 tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta

541 ggggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc

601 atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc

661 agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg

721 gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag

781 ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga

841 gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct

901 ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc

961 tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca

1021 gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca

1081 gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct

1141 gtgcagatgc caactgcaga gagcacaggt atgacacctg agaaggtgcc agtttcagag

1201 gtcatgggta ccacactggc agagatgtca actccagagg ctacaggtat gacacctgca

1261 gaggtatcaa ttgtggtgct ttctggaacc acagctgcac aggtaacaac tacagagtgg

1321 gtggagacca cagctagaga gctacctatc cctgagcctg aaggtccaga tgccagctca

1381 atcatgtcta cggaaagtat tacaggttcc ctgggccccc tgctggatgg tacagccacc

1441 ttaaggctgg tgaagagaca agtccccctg gattgtgttc tgtatcgata tggttccttt

1501 tccgtcaccc tggacattgt ccagggtatt gaaagtgccg agatcctgca ggctgtgccg

1561 tccggtgagg gggatgcatt tgagctgact gtgtcctgcc aaggcgggct gcccaaggaa

1621 gcctgcatgg agatctcatc gccagggtgc cagccccctg cccagcggct gtgccagcct

1681 gtgctaccca gcccagcctg ccagctggtt ctgcaccaga tactgaaggg tggctcgggg

1741 acatactgcc tcaatgtgtc tctggctgat accaacagcc tggcagtggt cagcaccag

1801 cttatcatgc ctgtgcctgg gattcttctc acaggtcaag aagcaggcct tgggcaggtt

1861 ccgctgatcg tgggcatctt gctggtgttg atggctgtgg tccttgcatc tctgatatat

1921 aggcgcagac ttatgaagca agacttctcc gtaccccagt tgccacatag cagcagtcac

1981 tggctgcgtc taccccgcat cttctgctct tgtcccattg gtgagaacag ccccctcctc

2041 agtgggcagc aggtctgagt actctcatat gatgctgtga ttttcctgga gttgacagaa

2101 acacctatat ttcccccagt cttccctggg agactactat taactgaaat aaatactcag

2161 agcctgaaaa aaaaaaaaaa a

[00113] NM_001320121 (SEQ ID NO:280)

1 gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg

61 gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct

121 acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc

181 tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt

241 ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc

301 ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc

361 tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc

421 caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg

481 tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta

541 ggggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc

601 atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc

661 agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg

721 gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag

781 ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga

841 gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct

901 ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc

961 tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca

1021 gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca

1081 gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct

1141 gtgcagatgc caactgcaga gagcacagct gcacaggtaa caactacaga gtgggtggag

1201 accacagcta gagagctacc tatccctgag cctgaaggtc cagatgccag ctcaatcatg

1261 tctacggaaa gtattacagg ttccctgggc cccctgctgg atggtacagc caccttaagg

1321 ctggtgaaga gacaagtccc cctggattgt gttctgtatc gatatggttc ctttttccgtc

1381 accctggaca ttgtccaggg tattgaaagt gccgagatcc tgcaggctgt gccgtccggt

1441 gagggggatg catttgagct gactgtgtcc tgccaaggcg ggctgcccaa ggaagcctgc

1501 atggagatct catcgccagg gtgccagccc cctgcccagc ggctgtgcca gcctgtgcta

1561 cccagcccag cctgccagct ggttctgcac cagatactga agggtggctc ggggacatac

1621 tgcctcaatg tgtctctggc tgataccaac agcctggcag tggtcagcac ccagcttatc

1681 atgcctgtgc ctgggattct tctcacaggt caagaagcag gccttgggca ggttccgctg

1741 atcgtgggca tcttgctggt gttgatggct gtggtccttg catctctgat atataggcgc

1801 agacttatga agcaagactt ctccgtaccc cagttgccac atagcagcag tcactggctg

1861 cgtctacccc gcatcttctg ctcttgtccc attggtgaga acagccccct cctcagtggg

1921 cagcaggtct gagtactctc atatgatgct gtgattttcc tggagttgac agaaacacct

1981 atatttcccc cagtcttccc tgggagacta ctattaactg aaataaatac tcagagcctg

2041 a

[00114] NM_001320122 (SEQ ID NO:281)

1 gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg

61 gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct

121 acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc

181 tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt

241 ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc

301 ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc

361 tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc

421 caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg

481 tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta

541 ggggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc

601 atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc

661 agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg

721 gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag

781 ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga

841 gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct

901 ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc

961 tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca

1021 gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca

1081 gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct

1141 gtgcagatgc caactgcaga gagcacagct gcacaggtaa caactacaga gtgggtggag

1201 accacagcta gagagctacc tatccctgag cctgaaggtc cagatgccag ctcaatcatg

1261 tctacggaaa gtattacagg ttccctgggc cccctgctgg atggtacagc caccttaagg

1321 ctggtgaaga gacaagtccc cctggattgt gttctgtatc gatatggttc ctttttccgtc

1381 accctggaca ttgtccaggg tattgaaagt gccgagatcc tgcaggctgt gccgtccggt

1441 gagggggatg catttgagct gactgtgtcc tgccaaggcg ggctgcccaa ggaagcctgc

1501 atggagatct catcgccagg gtgccagccc cctgcccagc ggctgtgcca gcctgtgcta

1561 cccagcccag cctgccagct ggttctgcac cagatactga agggtggctc ggggacatac

1621 tgcctcaatg tgtctctggc tgataccaac agcctggcag tggtcagcac ccagcttatc

1681 atgcctggtc aagaagcagg ccttggggcag gttccgctga tcgtgggcat cttgctggtg

1741 ttgatggctg tggtccttgc atctctgata tataggcgca gacttatgaa gcaagacttc

1801 tccgtacccc agttgccaca tagcagcagt cactggctgc gtctaccccg catcttctgc

1861 tcttgtccca ttggtgagaa cagccccctc ctcagtgggc agcaggtctg agtactctca

1921 tatgatgctg tgattttcct ggagttgaca gaaacaccta tatttccccc agtcttccct

1981 gggagactac tattaactga aataaatact cagagcctga

[00115] The term "variant" refers to a polypeptide that has a substantially identical amino acid sequence to a reference polypeptide, or is encoded by a substantially identical nucleotide sequence, and may have one or more activities of the reference polypeptide. For example, a variant may have approximately 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity to a reference polypeptide, while retaining one or more activities of the reference polypeptide.

[00116] As used herein, the terms "treat," "treating," or "treating" any disease or disorder, in one embodiment, refer to reducing the severity of the disease or disorder (i.e., slowing or stopping or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treating" refer to alleviating or reducing the severity of at least one physical parameter, including those that may not be perceived by the patient. In another embodiment, "treat," "treating," or "treating" refers to modulating the disease or disorder either physically (e.g., stabilizing an overt symptom) or physiologically (e.g., stabilizing a physical parameter), or both.

[00117] As used herein, the term "prevent," "preventing," or "preventing" any disease or disorder refers to prophylactic treatment of the disease or disorder or slowing the onset or progression of the disease or disorder.

[00118] The term "therapeutically acceptable amount" or "therapeutically effective dose" refers interchangeably to an amount sufficient to produce the desired result (i.e., reducing tumor size, inhibiting tumor growth, preventing metastasis, inhibiting or preventing viral, bacterial, fungal, or parasitic infection). In some embodiments, a therapeutically acceptable amount does not induce or cause unwanted side effects. In some embodiments, a therapeutically acceptable amount induces or causes side effects, but only those that are acceptable in the judgment of health care professionals given the patient's condition. A therapeutically acceptable amount can be determined by initially administering a low dose and then gradually increasing the dose until the desired effect is achieved. A "prophylactically effective dose" and a "therapeutically effective dose" of the molecules of the present invention can prevent the onset of, or, respectively, result in a reduction in the severity of, disease symptoms, including symptoms associated with cancer.

[00119] The term "coadministration" refers to the presence of two active agents in the blood of an individual. The active agents that are coadministered may be delivered simultaneously or sequentially.

[00120] The present invention provides antibodies, antibody fragments (e.g., antigen-binding fragments) and their drug conjugates, i.e. antibody-drug conjugates or ADCs that bind to PMEL17. In particular, the present invention provides antibodies and antibody fragments (e.g., antigen-binding fragments) that bind to PMEL17 and are internalized following such binding. Antibodies and antibody fragments (e.g., The antibody-drug conjugates (i.e., antigen-binding fragments) of the present invention can be used to prepare antibody-drug conjugates. The present invention further provides antibody-drug conjugates that have desirable pharmacokinetic characteristics and other desirable properties, and thus can be used to treat or prevent PMEL17-expressing cancer. The present invention further provides pharmaceutical compositions comprising the antibody-drug conjugates of the present invention; and methods for making and using such pharmaceutical compositions to treat or prevent cancer.

A fragment representing a medicinal product (D)

[00121] In one aspect, the drug moiety (D) of the antibody-drug conjugate of the present invention is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (GNAQ/GNA11 inhibitor).

[00122] In another aspect, the drug moiety (D) of the antibody-drug conjugate of the present invention is a GNAQ inhibitor.

[00123] In another aspect, the drug moiety (D) of the antibody-drug conjugate of the present invention is a GNA11 inhibitor.

[00124] In another aspect, the drug moiety (D) of the antibody-drug conjugate of the present invention is an inhibitor of GNAQ and GNA11 (GNAQ/GNA11 inhibitor).

[00125] In another aspect, the drug moiety of the antibody-drug conjugate of the present invention is a compound having the structure of formula (A):

(A),

where R ₀ is methyl or ethyl, R ₁ is methyl or isopropyl and R ₂ is methyl or ethyl.

[00126] In another aspect, the drug moiety of the antibody-drug conjugate of the present invention is compound (A1) having the following structure:

(A1).

[00127] In another aspect, the drug moiety of the antibody-drug conjugate of the present invention is compound (A2) having the following structure:

(A2).

[00128] In another aspect, the drug moiety of the antibody-drug conjugate of the present invention is compound (A3) having the following structure:

(A3).

Table 1 shows the inhibitory activity of compounds (A1), (A2) and (A3) obtained using the assay described in Example 5.

Table 1

Compound GI ₅₀ (nM)
92.1GNAQ ^Q209L A1 0.467 A2 22.1 A3 9.3

A fragment representing a linker-drug (L _A -(D) _n )

[00129] In a second aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein each of the one or more drug moieties is independently selected from a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (a GNAQ/GNA11 inhibitor).

[00130] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein each of the one or more drug moieties is independently selected from a GNAQ inhibitor.

[00131] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties attached to a linker (L _A ), wherein each of the one or more drug moieties is independently selected from a GNA11 inhibitor.

[00132] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein each of the one or more drug moieties is independently selected from a GNAQ inhibitor and GNA11 (a GNAQ/GNA11 inhibitor).

[00133] In another aspect, a linker-drug moiety ((L _A -(D) _n )) of an antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (a GNAQ/GNA11 inhibitor).

[00134] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor.

[00135] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a cleavable linker and each of the one or more drug moieties is independently selected from a GNA11 inhibitor.

[00136] In another aspect, a linker-drug moiety ((L _A -(D) _n )) of an antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor and GNA11 (a GNAQ/GNA11 inhibitor).

[00137] In another aspect, a linker-drug moiety ((L _A -(D) _n )) of an antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a non-cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (a GNAQ/GNA11 inhibitor).

[00138] In another aspect, a linker-drug moiety ((L _A -(D) _n )) of an antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a non-cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor.

[00139] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a non-cleavable linker and each of the one or more drug moieties is independently selected from a GNA11 inhibitor.

[00140] In another aspect, a linker-drug moiety ((L _A -(D) _n )) of an antibody-drug conjugate of the present invention comprises one or more drug moieties covalently attached to a linker (L _A ), wherein the linker (L _A ) is a non-cleavable linker and each of the one or more drug moieties is independently selected from a GNAQ inhibitor and GNA11 (a GNAQ/GNA11 inhibitor).

[00141] In another aspect, the linker (L _A ) of the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention has the following formula:

Where

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates an attachment point to X ₂ , and ** in Y ₁ indicates another attachment point;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

[00142] In another aspect, the linker-drug moiety ((L _A -(D) _n )) of the antibody-drug conjugate of the present invention has the following formula:

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates the attachment point to X ₂ , and ** in Y ₁ indicates the attachment point to D;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

Linker-drug compounds (L _B -(D) _n )

[00143] In one aspect, the linker drug of the present invention is a compound having the structure of formula (B), or stereoisomers or pharmaceutically acceptable salts thereof:

R ⁸ -L _B -(D) _n (B),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

R ⁸ is a reactive group;

L _B is a cleavable linker or a non-cleavable linker and

n is equal to 1, 2, 3, or 4.

[00144] In one aspect, the linker drug of the present invention has a structure of formula (B) or stereoisomers or pharmaceutically acceptable salts thereof, wherein

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

R ⁸ is a reactive group;

L _B is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a carbonate group, and a bivalent peptide linker, and

n is equal to 1, 2, 3, or 4.

[00145] In one aspect, the linker drug of the present invention is a compound having the structure of formula (B-1), or stereoisomers or pharmaceutically acceptable salts thereof:

(B-1),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

R⁸ is a reactive group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates the attachment point to X ₂ , and ** in Y ₁ indicates the attachment point to D;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

[00146] Certain aspects and examples of linker-drug compounds of the present invention are presented in the following list of additional numbered embodiments. It should be understood that the features recited in each embodiment can be combined with other recited features to produce additional embodiments of the present invention.

[00147] Embodiment 1. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is a GNAQ inhibitor.

[00148] Embodiment 2. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is a GNA11 inhibitor.

[00149] Embodiment 3. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is a GNAQ and GNA11 inhibitor.

[00150] Embodiment 4. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is

,

where R ⁰ is methyl or ethyl, R ¹ is methyl or isopropyl, R ² is methyl or ethyl and *** indicates the point of attachment to L _B or Y ₁ .

[00151] Embodiment 5. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is

,

where *** indicates the point of attachment to L _B or Y ₁ .

[00152] Embodiment 6. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is

,

where *** indicates the point of attachment to L _B or Y ₁ .

[00153] Embodiment 7. A compound of formula (B) or formula (B-1) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein D is

,

where *** indicates the attachment point to L _B or Y ₁ .

[00154] Embodiment 8. A compound of formula (B) or formula (B-1) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof having a structure of formula (B-2) or a pharmaceutically acceptable salt thereof:

(B-2),

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² is methyl or ethyl and

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00155] Embodiment 9. A compound of formula (B), formula (B-1), or formula (B-2), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (B-2a) or a pharmaceutically acceptable salt thereof:

(B-2a),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00156] Embodiment 10. A compound of formula (B), formula (B-1), or formula (B-2), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (B-2b) or a pharmaceutically acceptable salt thereof:

(B-2b),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00157] Embodiment 11. A compound of formula (B), formula (B-1), or formula (B-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (B-2c) or a pharmaceutically acceptable salt thereof:

(B-2c),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00158] Embodiment 12. A compound of formula (B) or formula (B-1) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof having a structure of formula (B-3) or a pharmaceutically acceptable salt thereof:

(B-3),

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² is methyl or ethyl and

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00159] Embodiment 13. A compound of formula (B), formula (B-1), or formula (B-3), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (B-3a) or a pharmaceutically acceptable salt thereof:

(B-3a),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00160] Embodiment 14. A compound of formula (B), formula (B-1), or formula (B-3), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (B-3b) or a pharmaceutically acceptable salt thereof:

(B-3b),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00161] Embodiment 15. A compound of formula (B), formula (B-1), or formula (B-3), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (B-3c) or a pharmaceutically acceptable salt thereof:

(B-3c),

Where

X ₂ , L ₁ , L ₂ and R ⁸ are as defined in the compounds of formula (B-1) above.

[00162] Embodiment 16. A compound of formula (B-2) according to Embodiment 8, formula (B-3) according to Embodiment 12, or a pharmaceutically acceptable salt thereof:

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

X ₂ is a self-cleaving spacer selected from

where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to group or point of attachment to group;

L ₁ is a bivalent peptide linker containing 2-4 amino acid residues;

L ₂ is a linker,

R ⁸ is selected from , -N ₃ , -ONH ₂ , -NR ⁴ C(=O)CH=CH ₂ , SH, -SSR ¹³ , -S(=O) ₂ (CH=CH ₂ ), -NR ⁴ S(=O) ₂ (CH=CH ₂ ), -NR ⁴ C(=O)CH ₂ Br, -NR ⁴ C(=O)CH ₂ I, -NHC(=O)CH ₂ Br, -NHC(=O)CH ₂ I, -C(=O)NHNH ₂ , , -CO ₂ H, -NH ₂ ,

wherein each R ⁴ is independently selected from H and C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl and -OH;

each R ⁶ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl, -NH ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -CN, -NO ₂ and -OH

And

each R ⁷ is independently selected from H, C _1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C _1-4 alkoxy substituted with -C(=O)OH, and C _1-4 alkyl substituted with -C(=O)OH.

[00163] Embodiment 17. The compound of any one of embodiments 1-16, wherein X ₂ is a self-cleaving spacer selected from

where * in X ₂ indicates the attachment point to L ₁ and ** in X ₂ indicates the attachment point to Y ₁ , the attachment point to group or point of attachment to group.

[00164] Embodiment 18. The compound of any one of embodiments 1-17, wherein X ₂ is , where * in X ₂ indicates the attachment point to L ₁ and ** in X ₂ indicates the attachment point to Y ₁ , the attachment point to the group or a point of joining a group .

[00165] Embodiment 19. The compound of any one of embodiments 1-18, wherein L ₁ is a bivalent peptide linker comprising 2-4 amino acid residues.

[00166] Embodiment 20. The compound of any one of embodiments 1-18, wherein L ₁ is a bivalent peptide linker comprising an amino acid residue selected from valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.

[00167] Embodiment 21. The compound of any one of embodiments 1-18, wherein L ₁ is a bivalent peptide linker comprising at least one valine (Val) or citrulline (Cit) residue.

[00168] Embodiment 22. The compound of any one of embodiments 1-18, wherein L ₁ is a bivalent dipeptide linker selected from ValCit, PheLys, ValAla, and ValLys.

[00169] Embodiment 23. The compound of any one of Embodiments 1-18, wherein L ₁ is a bivalent dipeptide linker selected from

where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ .

[00170] Embodiment 24. The compound of any one of embodiments 1-18 wherein L ₁ is ValCit.

[00171] Embodiment 25. The connection according to any one of embodiments 1-18, wherein

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ .

[00172] Embodiment 26. The compound of any one of embodiments 1-25 wherein L ₂ is a linker.

[00173] Embodiment 27. The compound of any one of embodiments 1-25, wherein L ₂ is a linker selected from

-*C(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _n NHC(=O)(CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _m NHC(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m ** -, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -(CH ₂ ) _m -, -*(CH ₂ ) _m NHC(=O)(CH ₂ ) _m **-, -* (CH ₂ ) _m NHC(=O)(CH ₂ ) _m C(=O)NH(CH ₂ ) _m **-, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m NHC(=O)(CH ₂ ) _m **-, -* *((CH ₂ ) _m O) _p CH ₂ ) _m C(=O )NH(CH ₂ ) _m **-, -* (CH ₂ ) _m C(R ₃ ) ₂ **-, and -* (CH ₂ ) _m C(R ₃ ) ₂ SS(CH ₂ ) _m NHC( =O)(CH ₂ ) _m **-, where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ ;

and where

each R ₃ is independently selected from H and C ₁ -C ₆ alkyl;

each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 and

each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[00174] Embodiment 28. The compound of any one of Embodiments 1-25, wherein L ₂ is -*C(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m **- or -*C(=O)(CH ₂ ) _m **-, wherein the * in L ₂ indicates a point of attachment to L ₁ and the ** in L ₂ indicates a point of attachment to R ₈ ,

and where each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[00175] Embodiment 29. The compound of any one of embodiments 1-25, wherein L ₂ is , or , where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ .

[00176] Embodiment 30. The compound of any one of Embodiments 1-29 wherein R ⁸ is , -N ₃ , -ONH ₂ , -NR ⁴ C(=O)CH=CH ₂ , SH, -SSR ¹³ , -S(=O) ₂ (CH=CH ₂ ), -NR ⁴ S(=O) ₂ (CH=CH ₂ ), -NR ⁴ C(=O)CH ₂ Br, -NR ⁴ C(=O)CH ₂ I, -NHC(=O)CH ₂ Br, -NHC(=O)CH ₂ I, -C(=O)NHNH ₂ , , -CO ₂ H, -NH ₂ ,

wherein each R ⁴ is independently selected from H and C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl and -OH;

each R ⁶ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl, -NH ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -CN, -NO ₂ and -OH

And

each R ⁷ is independently selected from H, C _1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C _1-4 alkoxy substituted with -C(=O)OH, and C _1-4 alkyl substituted with -C(=O)OH.

[00177] Embodiment 31. The compound of any one of Embodiments 1-29 wherein R ⁸ is , -ONH ₂ , , or .

[00178] Embodiment 32. The compound of any one of Embodiments 1-29 wherein R ⁸ is .

[00179] Embodiment 33. A compound of formula (B-2) according to Embodiment 8, or a pharmaceutically acceptable salt thereof:

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

X ₂ represents , where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to the group ;

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ ;

L ₂ is or , where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ ,

And

R ⁸ is .

[00180] Embodiment 34. A compound of formula (B-3) according to Embodiment 12, or a pharmaceutically acceptable salt thereof:

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

X ₂ represents , where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to the group ;

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ ;

L ₂ is or , where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ ,

And

R ⁸ is .

[00181] Embodiment 35. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B1).

[00182] Embodiment 36. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B2).

[00183] Embodiment 37. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B3).

[00184] Embodiment 38. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B4).

[00185] Embodiment 39. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B5).

[00186] Embodiment 40. A compound of formula (B), formula (B-1), or formula (B-2), wherein the compound is

(B6).

[00187] Embodiment 41. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B7).

[00188] Embodiment 42. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B8).

[00189] Embodiment 43. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B9).

[00190] Embodiment 44. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B10).

[00191] Embodiment 45. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B11).

[00192] Embodiment 46. A compound of formula (B), formula (B-1), or formula (B-3), wherein the compound is

(B12).

Antibody-drug conjugates

[00193] In one aspect, the antibody-drug conjugate of the present invention is a conjugate of formula (C):

Ab-(L _A -(D) _n ) _y (C),

Where

D is a fragment that represents the drug;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

L _A is a linker;

n is 1, 2, 3, or 4 and

y is 1, 2, 3, or 4,

wherein the linker-drug moiety (L _A -(D) _n ) is covalently attached to the antibody or antigen-binding fragment thereof.

[00194] In one aspect, the antibody-drug conjugate of the present invention has a structure of formula (C), wherein

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a carbonate group, and a bivalent peptide linker;

n is 1, 2, 3 or 4 and

y is 1, 2, 3, or 4,

wherein the linker-drug moiety (L _A -(D) _n ) is covalently attached to the antibody or antigen-binding fragment thereof.

[00195] In one aspect, the antibody-drug conjugate of formula (C) is a conjugate of formula (C-1):

(C-1),

Where

D is a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and GNA11 inhibitor;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates the attachment point to X ₂ , and ** in Y ₁ indicates the attachment point to D;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00196] In the conjugates of formula (C), one or more linker-drug moieties (L _B -(D) _n ) may be covalently attached to an antibody Ab or an antigen-binding fragment thereof, thereby covalently linking one or more drug moieties D to the antibody Ab or an antigen-binding fragment thereof via a linker, L _A . L _A is any chemical moiety that is capable of linking the antibody Ab or an antigen-binding fragment thereof to one or more drug moieties D. Conjugates of formula (C), wherein one or more drug moieties D are covalently linked to the antibody Ab or an antigen-binding fragment thereof, may be formed using a bifunctional or multifunctional linker reagent having one or more reactive functional groups that are the same or different. One of the reactive functional groups of the bifunctional or multifunctional linker reagent is used to react with a group on the antibody Ab or antigen-binding fragment thereof, such as a thiol or amine (e.g., on a cysteine, the N-terminus, or the side chain of an amino acid such as lysine), to form a covalent bond with one end of the linker L _A . Such reactive functional groups of the bifunctional or multifunctional linker reagent include, but are not limited to, maleimide, thiol, and NHS ester. Another reactive functional group or groups of the bifunctional or multifunctional linker reagent are used to covalently attach one or more drug moieties D to the linker L _A .

[00197] In one aspect, L _A is a cleavable linker. In another aspect, L _A is a non-cleavable linker. In some aspects, L _A is an acid-labile linker, a photolabile linker, a peptidase-cleavable linker, an esterase-cleavable linker, a glycosidase-cleavable linker, a phosphodiesterase-cleavable linker, a linker with a reducible disulfide bond, a hydrophilic linker, or a dicarboxylic acid-based linker.

[00198] In one aspect, L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a carbonate group, and a bivalent peptide linker.

[00199] In one aspect, L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a carbonate group, a bivalent peptide linker, and a bivalent linking group.

[00200] In one aspect, L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, and a bivalent peptide linker.

[00201] In one aspect, L _A is a cleavable linker comprising one or more linker components selected from a self-cleavable spacer, a phosphate group, a bivalent peptide linker, and a bivalent linking group.

[00202] In another aspect, the linker (L _A ) has the following formula:

Where

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , , , , , or , where * in Y ₁ indicates an attachment point to X ₂ and ** in Y ₁ indicates another attachment point;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

[00203] In another aspect, the linker (L _A ) has the following formula:

Where

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , or , where * in Y ₁ indicates the point of attachment to X ₂ ;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

[00204] In another aspect, the linker (L _A ) has the following formula:

Where

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

Y ₁ represents , , or , where * in Y ₁ indicates the point of attachment to X ₂ ;

L ₁ is a bivalent peptide linker and

L ₂ is a bond or linker.

[00205] Although in a particular conjugate molecule the drug to antibody ratio has a precise integer value (e.g. the product of n and y in formula (C)), it is recognized that the value will often be an average value when used to describe a sample containing multiple molecules due to some degree of heterogeneity typically associated with the conjugation step. The average loading for a conjugate sample is referred to herein as the drug to antibody ratio or "DAR". In some aspects, the DAR is from about 1 to about 5, but is typically about 1, 2, 3, or 4. In some aspects, at least 50% of the sample by weight is a compound having an average DAR of plus or minus 2, and preferably at least 50% of the sample is a conjugate having an average DAR of plus or minus 1. Other aspects include conjugates in which the DAR is about 2. In some aspects, a DAR of 'about y' means, that the measured DAR value is within 20% of the product of n and y in formula (I). In some respects, a DAR of ‘approximately n’ means that the measured DAR value is within 20% of n in formula (II).

[00206] In one aspect, the average molar ratio of drug to antibody in the conjugates of formula (C) (i.e. the average of the product of n and y, also known as the drug-to-antibody ratio (DAR), is from about 1 to about 10, from about 1 to about 6 (e.g., 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2, 1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4, 4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0), from about 1 to about 5, from about 1.5 to about 4.5, or from about 2 to about 4.

[00207] In one aspect, the conjugate provided herein is characterized by a substantially high degree of purity and has one or more of the following features: (a) greater than about 90% (e.g., greater than or equal to about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%), preferably greater than about 95% of the conjugate species are monomeric, (b) the level of unconjugated linker in the conjugate-based preparation is less than about 10% (e.g., less than or equal to about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0%) (relative to the total amount of linker), (c) less than 10% of the conjugate molecules are cross-linked (e.g., less than or equal to approximately 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0%), (d) the level of free drug (ADP-inducible platelet aggregation inhibitor, eg, a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ inhibitor and a GNA11 inhibitor) in a conjugate-based preparation is less than about 2% (eg, less than or equal to approximately 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0%) (mol/mol relative to the total amount of drug).

[00208] Certain aspects and examples of antibody-drug conjugates of the present invention are presented in the following list of additional numbered embodiments. It should be understood that the features set forth in each embodiment can be combined with other features set forth to produce additional embodiments of the present invention.

[00209] Embodiment 47. A conjugate of formula (C) or formula (C-1), wherein D is a GNAQ inhibitor.

[00210] Embodiment 48. A conjugate of formula (C) or formula (C-1), wherein D is a GNA11 inhibitor.

[00211] Embodiment 49. A conjugate of formula (C) or formula (C-1), wherein D is an inhibitor of GNAQ and GNA11.

[00212] Embodiment 50. A conjugate of formula (C) or formula (C-1), wherein D is

,

where R ⁰ is methyl or ethyl, R ₁ is methyl or isopropyl, R ₂ is methyl or ethyl and *** indicates the point of attachment to L _A or Y ₁ .

[00213] Embodiment 51. A conjugate of formula (C) or formula (C-1), wherein D is

,

where *** indicates the point of attachment to L _A or Y ₁ .

[00214] Embodiment 52. A conjugate of formula (C) or formula (C-1), wherein D is

,

where *** indicates the point of attachment to L _A or Y ₁ .

[00215] Embodiment 53. A conjugate of formula (C) or formula (C-1), wherein D is

,

where *** indicates the point of attachment to L _A or Y ₁ .

[00216] Embodiment 54. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-2):

(C-2),

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00217] Embodiment 55. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-2a):

(C-2a),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00218] Embodiment 56. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-2b):

(C-2b),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00219] Embodiment 57. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-2c):

(C-2c),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00220] Embodiment 58. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-3):

(C-3),

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00221] Embodiment 59. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-3a):

(C-3a),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00222] Embodiment 60. A conjugate of formula (C) or formula (C-1) having the structure of formula (C-3b):

(C-3b),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00223] Embodiment 61. A conjugate of formula (C) or formula (C-1) having a structure of formula (C-3c):

(C-3c),

Where

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₁ is a bivalent linking group;

X ₂ is a self-cleaving spacer;

L ₁ is a bivalent peptide linker;

L ₂ is a bond or linker, and

y is 1, 2, 3, or 4.

[00224] Embodiment 62. A conjugate of formula (C-2) according to embodiment 54 or a conjugate of formula (C-3) according to embodiment 58:

Where

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

X ₂ is a self-cleaving spacer selected from

where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to group or point of attachment to group;

L ₁ is a bivalent peptide linker containing 2-4 amino acid residues;

L ₂ is a linker;

X ₁ is a bivalent linking group selected from

-*NR ⁴ C(=O)CH ₂ **-, -*NHC(=O)CH ₂ **-, -*S(=O) ₂ CH ₂ CH ₂ **-, -* (CH ₂ ) ₂ S(=O) ₂ CH ₂ CH ₂ **-, -*NR ⁴ S(=O) ₂ CH ₂ CH ₂ **-, -*NR ⁴ C(=O)CH ₂ CH ₂ **-, -NH-, -C(=O)-, -*NHC(=O) **-, -*CH ₂ NHCH ₂ CH ₂ **-, -*NHCH ₂ CH ₂ **-, - S-,

**-, where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab;

and where

each R ⁴ is independently selected from H and C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl and -OH;

each R ⁶ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl, -NH ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -CN, -NO ₂ and -OH

And

each R ⁷ is independently selected from H, C _1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C _1-4 alkoxy substituted with -C(=O)OH, and C _1-4 alkyl substituted with -C(=O)OH,

And

y is 1, 2, 3, or 4.

[00225] Embodiment 63. The conjugate of any one of embodiments 54-62, wherein X ₂ is a self-cleaving spacer selected from

where * in X ₂ indicates the attachment point to L ₁ and ** in X ₂ indicates the attachment point to Y ₁ , or the attachment point to the group , or the point of joining a group .

[00226] Embodiment 64. The conjugate of any one of embodiments 54-63, wherein X ₂ is , where * in X ₂ indicates the attachment point to L ₁ and ** in X ₂ indicates the attachment point to Y ₁ , or the attachment point to the group , or the point of joining a group .

[00227] Embodiment 65. The conjugate of any one of embodiments 54-64, wherein L ₁ is a bivalent peptide linker comprising 2-4 amino acid residues.

[00228] Embodiment 66. The conjugate of any one of embodiments 54-65, wherein L ₁ is a bivalent peptide linker comprising an amino acid residue selected from valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.

[00229] Embodiment 67. The conjugate of any one of embodiments 54-64, wherein L ₁ is a bivalent peptide linker comprising at least one valine (Val) or citrulline (Cit) residue.

[00230] Embodiment 68. The conjugate of any one of embodiments 54-64, wherein L ₁ is a bivalent dipeptide linker selected from ValCit, PheLys, ValAla, and ValLys.

[00231] Embodiment 69. The conjugate of any one of embodiments 54-64, wherein L ₁ is a bivalent dipeptide linker selected from

where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ .

[00232] Embodiment 70. The conjugate of any one of embodiments 54-64, wherein L ₁ is ValCit.

[00233] Embodiment 71. The conjugate of any one of embodiments 54-64, wherein

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ .

[00234] Embodiment 72. The conjugate of any one of embodiments 54-71, wherein L ₂ is a linker.

[00235] Embodiment 73. The conjugate of any one of embodiments 54-71, wherein L ₂ is a linker selected from

-*C(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _n NHC(=O)(CH ₂ ) _m **-, -*C(=O)(CH ₂ ) _m NHC(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m ** -, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m **-, -(CH ₂ ) _m -, -*(CH ₂ ) _m NHC(=O)(CH ₂ ) _m **-, -* (CH ₂ ) _m NHC(=O)(CH ₂ ) _m C(=O)NH(CH ₂ ) _m **-, -* ((CH ₂ ) _m O) _p (CH ₂ ) _m NHC(=O)(CH ₂ ) _m **-, -* *((CH ₂ ) _m O) _p CH ₂ ) _m C(=O )NH(CH ₂ ) _m **-, -* (CH ₂ ) _m C(R ₃ ) ₂ **-, and -* (CH ₂ ) _m C(R ₃ ) ₂ SS(CH ₂ ) _m NHC( =O)(CH ₂ ) _m **-, where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to X ₁ ;

and where

each R ₃ is independently selected from H and C ₁ -C ₆ alkyl;

each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 and

each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[00236] Embodiment 74. The conjugate of any one of Embodiments 54-71, wherein L ₂ is -*C(=O)((CH ₂ ) _m O) _p (CH ₂ ) _m **- or -*C(=O)(CH ₂ ) _m **-, wherein the * in L ₂ indicates a point of attachment to L ₁ and the ** in L ₂ indicates a point of attachment to X ₁ ,

and where each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[00237] Embodiment 75. The conjugate of any one of embodiments 54-71, wherein L ₂ is , or , where * in L ₂ indicates the attachment point to L ₁ and ** in L ₂ indicates the attachment point to X ₁ .

[00238] Embodiment 76. The conjugate of any one of embodiments 54-75,

where X ₁ is a bivalent linking group selected from

-*NR ⁴ C(=O)CH ₂ **-, -*NHC(=O)CH ₂ **-, -*S(=O) ₂ CH ₂ CH ₂ **-, -* (CH ₂ ) ₂ S(=O) ₂ CH ₂ CH ₂ **-, -*NR ⁴ S(=O) ₂ CH ₂ CH ₂ **-, -*NR ⁴ C(=O)CH ₂ CH ₂ **-, -NH-, -C(=O)-, -*NHC(=O) **-, -*CH ₂ NHCH ₂ CH ₂ **-, -*NHCH ₂ CH ₂ **-, - S-,

**-, where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab;

and where

each R ⁴ is independently selected from H and C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl and -OH;

each R ⁶ is independently selected from H, C ₁ -C ₆ alkyl, F, Cl, -NH ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -CN, -NO ₂ and -OH

And

each R ⁷ is independently selected from H, C _1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C _1-4 alkoxy substituted with -C(=O)OH, and C _1-4 alkyl substituted with -C(=O)OH.

[00239] Embodiment 77. The conjugate of any one of embodiments 54-75,

where X ₁ is a bivalent linking group selected from

where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab.

[00240] Embodiment 78. The conjugate of any one of embodiments 54-75,

where X ₁ is a bivalent linking group selected from

where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab.

[00241] Embodiment 79. A conjugate of formula (C-2) according to embodiment 54, wherein

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

X ₁ is a bivalent linking group selected from

where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab,

X ₂ represents , where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to the group ;

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ ;

L ₂ is or , where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ ,

And

y is 1, 2, 3, or 4.

[00242] Embodiment 80. The conjugate of formula (C-3) according to embodiment 58, wherein

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein;

R ⁰ represents methyl or ethyl;

R ¹ is methyl or isopropyl;

R ² represents methyl or ethyl;

X ₁ is a bivalent linking group selected from

where * in X ₁ indicates the point of attachment to L ₂ and ** in X ₁ indicates the point of attachment to Ab,

X ₂ represents , where * in X ₂ indicates the point of attachment to L ₁ and ** in X ₂ indicates the point of attachment to the group ;

L ₁ is (ValCit), where * in L ₁ indicates the attachment point to L ₂ and ** in L ₁ indicates the attachment point to X ₂ ;

L ₂ is or , where * in L ₂ indicates the point of attachment to L ₁ and ** in L ₂ indicates the point of attachment to R ₈ ,

And

y is 1, 2, 3, or 4.

[00243] Embodiment 81. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00244] Embodiment 82. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00245] Embodiment 83. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00246] Embodiment 84. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00247] Embodiment 85. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00248] Embodiment 86. A conjugate of formula (C), formula (C-1) or formula (C-2) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00249] Embodiment 87. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00250] Embodiment 88. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00251] Embodiment 89. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00252] Embodiment 90. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00253] Embodiment 91. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00254] Embodiment 92. A conjugate of formula (C), formula (C-1) or formula (C-3) having the structure:

Where

y is 2 or 4 and

Ab is an antibody or its antigen-binding fragment that binds to the human PMEL17 protein.

[00255] In addition, antibodies, antibody fragments (e.g., The antigen-binding fragments) or functional equivalents of the present invention may be conjugated to a drug moiety that modifies a desired biological response. Drug moieties should not be construed as limited to classical chemical therapeutic agents. For example, a drug moiety may be a protein, peptide, or polypeptide having a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, Pseudomonas exotoxin, cholera toxin, or diphtheria toxin; a protein such as tumor necrosis factor, α-interferon, β-interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, a cytokine, an apoptotic agent, an antiangiogenic agent, or a biological response modifier such as, for example, a lymphokine.

[00256] In one embodiment, antibodies, antibody fragments (e.g., antigen-binding fragments) or functional equivalents of the present invention are conjugated to a moiety that is a drug, such as a cytotoxin, a drug (e.g., immunosuppressant) or radiotoxin. Examples of cytotoxins include, but are not limited to, taxanes (see, For example, International (PCT) Patent Applications Nos. WO 01/38318 and PCT/US03/02675), DNA alkylating agents (e.g., CC-1065 analogues), anthracyclines, tubulysin analogues, duocarmycin analogues, auristatin E, auristatin F, maytansinoids and cytotoxic agents containing a reactive polyethyleneglycol moiety (see, For example, Sasseet al., J. Antibiot. (Tokyo), 53, 879-85 (2000), Suzawa et al., Bioorg. Med. Chem., 8, 2175-84 (2000), Ichimura et al., J. Antibiot. (Tokyo), 44, 1045-53 (1991), Francisco et al., Blood (2003) (electronic publication ahead of print publication), U.S. Patent Nos. 5,475,092, 6,340,701, 6,372,738, and 6,436,931, U.S. Patent Application Publication No. 2001/0036923 A1, pending U.S. Patent Application Serial Nos. 10/024,290 and 10/116,053, and International (PCT) Patent Application No. WO 01/49698), taxon, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoside, vincristine, vinblastine, t. colchicine, doxorubicin, daunorubicin, dihydroxyanthracinatedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin, as well as their analogues or homologues. Therapeutic agents also include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, decarbazine), destructive agents (e.g. mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cis-dichlorodiamineplatinum(II) (DDP), cisplatin, anthracyclines (eg, daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg, dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC) and antimitotic agents (eg, vincristine and vinblastine). (See, for example, US20090304721 from Seattle Genetics).

[00257] Other examples of cytotoxins that can be conjugated to the antibodies, antibody fragments (antigen-binding fragments) or functional equivalents of the present invention include duocarmycins, calicheamicins, maytansines and auristatins, and derivatives thereof.

[00258] Various types of cytotoxins, linkers and methods for conjugating therapeutic agents to antibodies are known in the art, see, For example, Saitoet al., (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail et al., (2003) Cancer Immunol. Immunother. 52:328-337; Payne, (2003) Cancer Cell 3:207-212; Allen, (2002) Nat. Rev. Cancer 2:750-763; Pastan and Kreitman, (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter and Springer, (2001) Adv. Drug Deliv. Rev. 53:247-264.

[00259] Antibodies, antibody fragments (e.g., The antigen-binding fragments) or functional equivalents of the present invention can also be conjugated with a radioactive isotope to create cytotoxic radiopharmaceuticals called radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for diagnostic or therapeutic use include, but are not limited to, iodine-131, indium-111, yttrium-90, and lutetium-177. Methods for producing radioimmunoconjugates are defined in the art. Examples of commercially available radioimmunoconjugates include Zevalin™ (DEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similar approaches can be used to produce radioimmunoconjugates using the antibodies of the present invention. In some embodiments, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), which can be attached to the antibody via a linker molecule. Such linker molecules are widely known in the art and are described in Denardoet al., (1998) Clin Cancer Res. 4(10):2483-90; Peterson et al., (1999) Bioconjug. Chem. 10(4):553-7 and Zimmerman et al., (1999) Nucl. Med. Biol. 26(8):943–50, each of which is incorporated by reference in its entirety.

[00260] Antibodies, antibody fragments (e.g., antigen-binding fragments) or functional equivalents of the present invention may also be conjugated to a heterologous protein or polypeptide (or fragment thereof, preferably a polypeptide of at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids) to create fusion proteins. In particular, the present invention provides fusion proteins comprising an antibody fragment (e.g., antigen-binding fragment) described herein (e.g., Fab fragment, Fd fragment, Fv fragment, F(ab)₂-fragment, VH domain, VH CDR, VL domain or VL CDR), and heterologous protein, polypeptide or peptide.

[00261] Additional fusion proteins can be produced by gene shuffling, motif shuffling, exon shuffling, and/or codon shuffling techniques (collectively referred to as "DNA shuffling"). DNA shuffling can be used to alter the activity of the antibodies of the present invention or fragments thereof (e.g., obtaining antibodies or their fragments with higher affinity levels and lower dissociation rates). See in general U.S. Patents 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Pattenet al., (1997) Curr. Opinion Biotechnol. 8:724-33; Harayama, (1998) Trends Biotechnol. 16(2):76-82; Hansson et al., (1999) J. Mol. Biol. 287:265-76 and Lorenzo and Blasco, (1998) Biotechniques 24(2):308-313 (each of which patents and publications is hereby incorporated by reference in its entirety). Antibodies or fragments thereof, or encoded antibodies or fragments thereof, may be altered by subjecting them to random mutagenesis by error-producing PCR, random nucleotide insertion, or other means prior to recombination. A polynucleotide encoding an antibody or fragment thereof that specifically binds an antigen may be recombinant with one or more components, motifs, stretches, portions, domains, fragments, etc., of one or more heterologous molecules.

[00262] Moreover, antibodies, antibody fragments (e.g., antigen-binding fragments) or functional equivalents of the present invention may be conjugated to marker sequences, such as a peptide, to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexahistidine peptide (SEQ ID NO: 267), such as, in particular, the tag provided in the pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA 91311), of which many are commercially available. As described in Gentzet al., (1989) Proc. Natl. Acad. Sci. USA 86:821-824, for example, hexahistidine (SEQ ID NO: 267) allows for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin ("HA") tag, which corresponds to an epitope derived from the hemagglutinin protein of influenza virus (Wilsonet al., (1984) Cell 37:767), and the "FLAG" label (A. Einhaueret al., J. Biochem. Biophys. Methods 49: 455-465, 2001). According to the present invention, in order to increase the effectiveness of antibodies or antigen-binding fragments, they can also be conjugated with tumor-penetrating peptides.

[00263] In other embodiments, antibodies, antibody fragments (e.g., The antigen-binding fragments) or functional equivalents of the present invention are conjugated to a diagnostic or detectable agent. Such immunoconjugates may be useful for monitoring or predicting the occurrence, development, progression and/or severity of a disease or disorder as part of a clinical testing procedure, such as determining the efficacy of a particular therapy. Such diagnostics and detection may be accomplished by linking the antibody to detectable substances, including, but not limited to, various enzymes such as, but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase or acetylcholinesterase; prosthetic groups such as, but not limited to, streptavidin/biotin and avidin/biotin; fluorescent compounds such as, but not limited to, Alexa Fluor 350, Alexa Fluor 405, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 500, Alexa Fluor 514, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 610, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, Alexa Fluor 750, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; luminescent compounds such as, but not limited to, luminol; bioluminescent compounds such as, but not limited to, luciferase, luciferin, and aequorin; radioactive compounds such as, but not limited to, iodine (¹³¹I,¹²⁵I,¹²³I and¹²¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹¹⁵In,¹¹³In,¹¹²In and¹¹¹In), technetium (⁹⁹Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga,⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F),¹⁵³Sm,¹⁷⁷Lu,¹⁵⁹Gd,¹⁴⁹Pm,¹⁴⁰La,¹⁷⁵Yb,¹⁶⁶Ho,⁹⁰Y,⁴⁷Sc,¹⁸⁶Re,¹⁸⁸Re,¹⁴²Pr,¹⁰⁵Rh,⁹⁷Ru,⁶⁸Ge,⁵⁷Co,⁶⁵Zn,⁸⁵Sr,³²P,¹⁵³Gd,¹⁶⁹Yb,⁵¹Cr,⁵⁴Mn,⁷⁵Se,⁶⁴Cu,¹¹³Sn, and¹¹⁷Sn; and positron-active metals using various types of positron emission tomography, and non-radioactive ions of paramagnetic metals.

[00264] Antibodies, antibody fragments (e.g., The antigen-binding fragments) or functional equivalents of the present invention may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

3. Conjugation and production of ADC

Methods for producing conjugates based on an antibody of formula (C), formula (C-1) and formula (C-2)

[00265] The general reaction scheme for the formation of conjugates of formula (C) is shown in Scheme 1 below:

diagram 1,

wherein RG ₁ is a reactive group on the antibody Ab or antigen-binding fragment thereof, by way of example only a thiol, amine or ketone group, which reacts with a compatible reactive group, R ⁸ , attached to the linker-drug compound, thereby providing a covalent linkage of the antibody Ab or antigen-binding fragment thereof to one or more moieties representing the linker-drug. Non-limiting examples of such reactions involving the groups RG ₁ and R ⁸ are a maleimide group (R ⁸ ), which reacts with a thiol group (RG ₁ ) to produce a succinimide ring, or a hydroxylamine group (R ⁸ ), which reacts with a ketone group (RG ₁ ) to produce an oxime.

In one embodiment, D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (GNAQ/GNA11 inhibitor), L _a is a linker further comprising a bivalent linking group formed by reaction of RG ₁ and R ⁸ , n is 1, 2, 3, or 4, and y is 1, 2, 3, or 4.

[00266] The general reaction scheme for the formation of conjugates of formula (C-1) is shown in Scheme 2 below:

scheme 2,

wherein RG ₁ is a reactive group on the antibody Ab or antigen-binding fragment thereof, by way of example only a thiol, amine or ketone group, which reacts with a compatible reactive group R ⁸ attached to a linker-drug moiety, thereby providing a covalent linkage of the antibody Ab or antigen-binding fragment thereof to one or more linker-drug moieties. Non-limiting examples of such reactions involving RG ₁ and R ⁸ groups include a maleimide group (R ⁸ ) which reacts with a thiol group (RG ₁ ) to form a succinimide ring, or a hydroxylamine group (R ⁸ ) which reacts with a ketone group (RG ₁ ) to form an oxime.

In one embodiment, D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (a GNAQ/GNA11 inhibitor), X ₁ is a bivalent linking group formed by the reaction of RG ₁ and R ⁸ (e.g., a succinimide ring or an oxime), Y ₁ is a phosphate group, X ₂ is a self-cleaving spacer, L ₁ is a bivalent peptide linker, L ₂ is a bond or linker, and y is 1, 2, 3, or 4.

[00267] The general reaction scheme for the formation of conjugates of formula (C-2) is shown in Scheme 3 below:

diagram 3,

wherein RG ₁ is a reactive group on the antibody Ab or antigen-binding fragment thereof, by way of example only a thiol, amine, or ketone, that reacts with a compatible reactive group R ⁸ attached to a linker-drug moiety, thereby providing a covalent linkage of the antibody Ab or antigen-binding fragment thereof to one or more linker-drug moieties. Non-limiting examples of such reactions involving RG ₁ and R ⁸ groups include a maleimide group (R ⁸ ) that reacts with a thiol group (RG ₁ ) to form a succinimide ring, or a hydroxylamine group (R ⁸ ) that reacts with a ketone group (RG ₁ ) to form an oxime.

In this case, R ⁰ is methyl or ethyl, R ¹ is methyl or isopropyl, R ² is methyl or ethyl, X ₁ is a bivalent linking group formed by the reaction of RG ₁ and R ⁸ (e.g., a succinimide ring or oxime), X ₂ is a self-cleaving spacer, L ₁ is a bivalent peptide linker, L ₂ is a bond or linker, and y is 1, 2, 3, or 4.

[00268] The general reaction scheme for the formation of conjugates of formula (C-2) is shown in Scheme 4 below:

diagram 4,

wherein RG ₁ is a reactive group on the antibody Ab or antigen-binding fragment thereof, by way of example only a thiol, amine or ketone group, which reacts with a compatible reactive group R ⁸ attached to a linker-drug moiety, thereby providing a covalent linkage of the antibody Ab or antigen-binding fragment thereof to one or more linker-drug moieties. Non-limiting examples of such reactions involving RG ₁ and R ⁸ groups include a maleimide group (R ⁸ ) which reacts with a thiol group (RG ₁ ) to form a succinimide ring, or a hydroxylamine group (R ⁸ ) which reacts with a ketone group (RG ₁ ) to form an oxime.

In this case, R ⁰ is methyl or ethyl, R ¹ is methyl or isopropyl, R ² is methyl or ethyl, X ₁ is a bivalent linking group formed by the reaction of RG ₁ and R ⁸ (e.g., a succinimide ring or oxime), X ₂ is a self-cleaving spacer, L ₁ is a bivalent peptide linker, L ₂ is a bond or linker, and y is 1, 2, 3, or 4.

Method of conjugation with engineered cysteine residues of an antibody

[00269] The conjugates of the present invention can be prepared using cysteine residues engineered into the antibody, such as by site-directed mutagenesis. Such site-specific conjugates are homogeneous and have improved properties (Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS, Lu Y, Meng YG, Ng C, Yang J, Lee CC, Duenas E, Gorrell J, Katta V, Kim A, McDorman K, Flagella K, Venook R, Ross S, Spencer SD, Lee Wong W, Lowman HB, Vandlen R, Sliwkowski MX, Scheller RH, Polakis P, Mallet W. (2008) Nature Biotechnology 26:925-932.)

[00270] Because engineered cysteines in antibodies expressed in mammalian cells are modified by adducts (disulfides) such as glutathione (GSH) and/or cysteine during biosynthesis (Chen et al . 2009), the initially expressed engineered cysteine residues in the product do not react with thiol-reactive reagents such as maleimide or bromo- or iodo-acetamide groups. To enable conjugation of the payload with the engineered cysteine after expression, the glutathione or cysteine adducts must be removed by reduction of these disulfide adducts, which typically also causes reduction of the native disulfides in the expressed protein. Removal of adducts at engineered cysteines can be accomplished by first exposing the antibody to a reducing agent, such as dithiothreitol (DTT), TCEP, or reduced cysteine, followed by a procedure that allows reoxidation of all native disulfide bonds of the antibody to restore and/or stabilize the functional structure of the antibody.

[00271] Several methods can be used to recover and reoxidize antibodies with engineered cysteine residues to produce antibody-drug conjugates. Attempts to follow previously described literature reoxidation protocols using high concentrations of _CuSO4 resulted in protein precipitation (Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS, Lu Y, Meng YG, Ng C, Yang J, Lee CC, Duenas E, Gorrell J, Katta V, Kim A, McDorman K, Flagella K, Venook R, Ross S, Spencer SD, Lee Wong W, Lowman HB, Vandlen R, Sliwkowski MX, Scheller RH, Polakis P, Mallet W. (2008) Nature Biotechnology 26:925). The present inventors have successfully prepared and produced antibody-drug conjugates using several different antibody reduction and reoxidation methods.

[00272] The following is a method for reducing and reoxidizing antibodies with engineered cysteine residues to produce antibody drug conjugates: Freshly prepared DTT is added to purified Cys-mutated antibodies to a final concentration of 10 mM. After incubation with DTT at room temperature for 1 hour, the mixture is dialyzed against PBS at 4°C for three days with daily buffer changes to remove DTT and reoxidize the native disulfide bonds of the antibody. An alternative method is to remove reducing reagents by passing through a desalting column, such as Sephadex G-25, equilibrated with PBS. After the protein is completely reduced, 1 mM oxidized ascorbate (dihydroascorbic acid) is optionally added to the desalted samples and reoxidation incubations are performed for 20-24 hours.

[00273] In another exemplary method, release of engineered Cys residues is accomplished by adding fully reduced cysteine at a concentration of 20 mM to antibodies bound to a protein A sepharose resin. Reduction of the Cys adducts is achieved by incubation for approximately 30-60 minutes at room temperature, then the reducing agent is rapidly removed by washing the resin with 50 bed volumes of PBS. Reoxidation of the reduced antibody is achieved by incubating the washed slurry at room temperature with or without the addition of 50-2000 nM CuCl ₂ as a catalyst. With the exception of the use of copper sulfate in the examples herein, each of the protocols described herein were used to obtain similar results. Reoxidation reduces intrachain disulfides, while dialysis, desalting, or protein A chromatography removes the reducing agent and the cysteines and glutathiones originally attached to the engineered cysteine(s) of the antibody. Reverse-phase HPLC is typically used to monitor the reoxidation process: antibodies are loaded onto a PLRP-S column (4000 Å, 50 mm x 2.1 mm, Agilent) heated to 80°C and eluted with a linear gradient of 30-45% CH3CN in water containing 0.1% TFA at 1.5 mL/min with peak detection at 215, 254, and 280 nm.

[00274] Following reoxidation, the antibody is conjugated to a linker-drug compound, such as compounds of formula (B), formula (B-1), formula (B-2), or formula (B-3) (see Schemes 1-4). As an example, a compound of formula (B), formula (B-1), formula (B-2), or formula (B-3) is added to the reoxidized Cys mutant antibody in an amount of 5-10 molar equivalents relative to the antibody in PBS buffer (pH 7.2). Incubations are carried out for 1-2 hours. The conjugation process is monitored by reverse phase HPLC, which can separate conjugated antibodies from unconjugated antibodies. The reaction mixtures during the conjugation process were analyzed on a PRLP-S column (4000 Å, 50 mm x 2.1 mm, Agilent) heated to 80°C, and the column was eluted using a linear gradient of 30-60% acetonitrile in water containing 0.1% TFA at a flow rate of 1.5 ml/min. Protein elution from the column was monitored at 280 nm, 254 nm, and 215 nm.

[00275] Alternatively, for antibodies coupled to Protein A resin, after reoxidation of the antibody, the resin is washed with 10 column volumes of PBS, and then the resin is resuspended in an equal volume of PBS and an 8-fold excess of the compound of Formula (B), Formula (B-1), Formula (B-2), or Formula (B-3) (in DMSO) is added and incubated at room temperature for 2 hours. The resin is then washed with 50 column volumes of PBS and the resulting antibody drug conjugate is eluted from the Protein A resin, neutralized with 1/10 volume of 1 M Tris, pH 9.0, and buffer exchanged with an appropriate preparative size exclusion chromatography buffer (if necessary).

[00276] Immunoconjugates are also characterized for the average loading of drug moiety to the binding antibody moiety, commonly referred to as the drug-to-antibody ratio (DAR). The DAR value is extrapolated, for example, from LC-MS data for reconstituted and deglycosylated samples. LC/MS provides the ability to quantify the average number of payload molecules (drug moiety) attached to the antibody in an ADC. HPLC separates the antibody into light and heavy chains, and separates the heavy chain (HC) and light chain (LC) according to the number of linker-payload groups per chain. Mass spectral data allow the identification of component species in a mixture, such as LC, LC+1, LC+2, HC, HC+1, HC+2, etc. Based on the average loading of the LC and HC chains, the average DAR can be calculated for the ADC. The DAR for a given immunoconjugate sample is the average number of drug molecules (payload) attached to a tetrameric antibody containing two light chains and two heavy chains.

[00277] Throughout the text of this application, there may be inconsistencies between the description text and the sequence listing, in which case the description text prevails.

Table 2. Examples of PMEL17 antibodies of the present invention

G1 E152C_S375C_wt LC SEQ ID NO:1 HCDR1 (combined) GGTFSDYAIT SEQ ID NO:2 HCDR2 (combined) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (combined) EGGLLTDISYSRYWFAY SEQ ID NO:4 HCDR1 (Kabat) DYAIT SEQ ID NO:2 HCDR2 (Kabat) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (Kabat) EGGLLTDISYSRYWFAY SEQ ID NO:5 HCDR1 (Chothia) GGTFSDY SEQ ID NO:6 HCDR2 (Chothia) IPIFGT SEQ ID NO:3 HCDR3 (Chothia) EGGLLTDISYSRYWFAY SEQ ID NO:7 HCDR1 (IMGT) GGTFSDYA SEQ ID NO:8 HCDR2 (IMGT) IIPIFGTA SEQ ID NO:9 HCDR3 (IMGT) AREGGLLTDISYSRYWFAY SEQ ID NO: 10 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA encoding VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACTGCGAACTACGCCCAGAAA TTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCTTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO:12 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFA YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:13 DNA encoding the heavy chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACT GCGAACTACGCCCAGAAATTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCT TACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCT CTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAA AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC TACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:14 LCDR1 (combined) SGDALRDKFVY SEQ ID NO:15 LCDR2 (combined) DDNNRPS SEQ ID NO:16 LCDR3 (combined) QSWDHSYSLVV SEQ ID NO:14 LCDR1 (Kabat) SGDALRDKFVY SEQ ID NO:15 LCDR2 (Kabat) DDNNRPS SEQ ID NO:16 LCDR3 (Kabat) QSWDHSYSLVV SEQ ID NO:17 LCDR1 (Chotia) DALRDKF SEQ ID NO:18 LCDR2 (Chotia) DDN SEQ ID NO:19 LCDR3 (Chotia) WDHSYSLV SEQ ID NO:20 LCDR1 (IMGT) ALRDKF SEQ ID NO:18 LCDR2 (IMGT) DDN SEQ ID NO:16 LCDR3 (IMGT) QSWDHSYSLVV SEQ ID NO:21 VL DIELTQPPSVSVSPGQTASITCSGDALRDKFVYWYQQKPGQAPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSWDHSYSLVVFGGGTKLTVL SEQ ID NO:22 DNA encoding VL GATATCGAACTGACCCAGCCGCCGAGCGTGAGCGTGAGCCCGGGCCAGACCGCGAGCATTACCTGTAGCGGCGATGCTCTGCGTGACAAATTCGTTTACTGGTACCAGCAGAAACCGGGCCAGGCGCCGGTGCTGGTGATCTACGACGACAACAACCGTCCG AGCGGCATCCCGGAACGTTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACCCAGGCGGAAGACGAAGCGGAATTATTACTGCCAGTCTTGGGACCATTCTTACTCTCTGGTTGTGTTTGGCGGCGGCACGAAGTTAACTGTCCTG SEQ ID NO:23 Light chain DIELTQPPSVSVSPGQTASITCSGDALRDKFVYWYQQKPGQAPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSWDHSYSLVVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO:24 DNA encoding the light chain GATATCGAACTGACCCAGCCGCCGAGCGTGAGCGTGAGCCCGGGCCAGACCGCGAGCATTACCTGTAGCGGCGATGCTCTGCGTGACAAATTCGTTTACTGGTACCAGCAGAAACCGGGCCAGGCGCCGGTGCTGGTGATCTACGACGACAACAACCGTC CGAGCGGCATCCCGGAACGTTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACCCAGGCGGAAGACGAAGCGGATTATTACTGCCAGTCTTGGGACCATTCTTACTCTCTGGTTGTGTTTGGCGGCGGCACGAAGTTAACTGTC CTGGGACAACCTAAGGCCGCTCCCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCG TGGAGACAACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCACCCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC G1 E152C_S375C_3JLC SEQ ID NO:1 HCDR1 (combined) GGTFSDYAIT SEQ ID NO:2 HCDR2 (combined) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (combined) EGGLLTDISYSRYWFAY SEQ ID NO:4 HCDR1 (Kabat) DYAIT SEQ ID NO:2 HCDR2 (Kabat) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (Kabat) EGGLLTDISYSRYWFAY SEQ ID NO:5 HCDR1 (Chothia) GGTFSDY SEQ ID NO:6 HCDR2 (Chothia) IPIFGT SEQ ID NO:3 HCDR3(Chothia) EGGLLTDISYSRYWFAY SEQ ID NO:7 HCDR1 (IMGT) GGTFSDYA SEQ ID NO:8 HCDR2 (IMGT) IIPIFGTA SEQ ID NO:9 HCDR3 (IMGT) AREGGLLTDISYSRYWFAY SEQ ID NO:10 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA encoding VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACTGCGAACTACGCCCAGAAA TTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCTTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO:12 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFA YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:13 DNA encoding the heavy chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACT GCGAACTACGCCCAGAAATTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCT TACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCT CTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAA AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC TACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:14 LCDR1 (combined) SGDALRDKFVY SEQ ID NO:15 LCDR2 (combined) DDNNRPS SEQ ID NO:16 LCDR3 (combined) QSWDHSYSLVV SEQ ID NO:14 LCDR1 (Kabat) SGDALRDKFVY SEQ ID NO:15 LCDR2 (Kabat) DDNNRPS SEQ ID NO:16 LCDR3 (Kabat) QSWDHSYSLVV SEQ ID NO:17 LCDR1 (Chotia) DALRDKF SEQ ID NO:18 LCDR2 (Chotia) DDN SEQ ID NO:19 LCDR3 (Chotia) WDHSYSLV SEQ ID NO:20 LCDR1 (IMGT) ALRDKF SEQ ID NO:18 LCDR2 (IMGT) DDN SEQ ID NO:16 LCDR3 (IMGT) QSWDHSYSLVV SEQ ID NO:25 VL SYELTQPLSVSVALGQTARITCSGDALRDKFVYWYQQKPGQAPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCQSWDHSYSLVVFGGGTKLTVL SEQ ID NO:26 DNA encoding VL AGCTACGAGCTGACCCAGCCGCTGTCGGTGTCAGTCGCCCTGGGACAAACTGCCAGGATCACTTGTTCCGGGGACGCATTGCGGGACAAGTTCGTGTACTGGTACCAGCAGAAGCCGGGTCAAGCCCCAGTGCTCGTGATCTACGACGACAACAACCGGCCT TCCGGTATCCCCGAACGCTTCTCCGGATCCAATAGCGGAAACACCGCCACCCTGACCATTTCGAGAGCTCAGGCCGGGGATGAAGCGGACTACTACTGCCAGTCATGGGATCACTCGTACTCCCTCGTCGTGTTTGGAGGCGGCACGAAGCTTACTGTGCTG SEQ ID NO:27 Light chain SYELTQPLSVSVALGQTARITCSGDALRDKFVYWYQQKPGQAPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCQSWDHSYSLVVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO:28 DNA encoding the light chain AGCTACGAGCTGACCCAGCCGCTGTCGGTGTCAGTCGCCCTGGGACAAACTGCCAGGATCACTTGTTCCGGGGACGCATTGCGGGACAAGTTCGTGTACTGGTACCAGCAGAAGCCGGGTCAAGCCCCAGTGCTCGTGATCTACGACGACAACAACCGGC CTTCCGGTATCCCCGAACGCTTCTCCGGATCCAATAGCGGAAACACCGCCACCCTGACCATTTCGAGAGCTCAGGCCGGGGATGAAGCGGACTACTACTGCCAGTCATGGGATCACTCGTACTCCCTCGTCGTGTTTGGAGGCGGCACGAAGCTTACTGTG CTGGGCCAGCCTAAGGCCGCTCCCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCG TGGAGACAACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCACCCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC G1 E152C_S375C_3R LC SEQ ID NO:1 HCDR1 (combined) GGTFSDYAIT SEQ ID NO:2 HCDR2 (combined) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (combined) EGGLLTDISYSRYWFAY SEQ ID NO:4 HCDR1 (Kabat) DYAIT SEQ ID NO:2 HCDR2 (Kabat) GIIPIFGTANYAQKFQG SEQ ID NO:3 HCDR3 (Kabat) EGGLLTDISYSRYWFAY SEQ ID NO:5 HCDR1 (Chothia) GGTFSDY SEQ ID NO:6 HCDR2 (Chothia) IPIFGT SEQ ID NO:3 HCDR3(Chothia) EGGLLTDISYSRYWFAY SEQ ID NO:7 HCDR1 (IMGT) GGTFSDYA SEQ ID NO:8 HCDR2 (IMGT) IIPIFGTA SEQ ID NO:9 HCDR3 (IMGT) AREGGLLTDISYSRYWFAY SEQ ID NO:10 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA encoding VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACTGCGAACTACGCCCAGAAA TTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCTTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO:12 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAITWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGGLLLTDISYSRYWFA YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:13 DNA encoding the heavy chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTGACTACGCTATCACTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGGTATCATCCCGATCTTCGGCACT GCGAACTACGCCCAGAAATTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGTGAAGGTGGTCTGCTGACTGACATCTCTTACTCTCGTTACTGGTTCGCT TACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCT CTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAA AAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC TACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:14 LCDR1 (combined) SGDALRDKFVY SEQ ID NO:15 LCDR2 (combined) DDNNRPS SEQ ID NO:16 LCDR3 (combined) QSWDHSYSLVV SEQ ID NO:14 LCDR1 (Kabat) SGDALRDKFVY SEQ ID NO:15 LCDR2 (Kabat) DDNNRPS SEQ ID NO:16 LCDR3 (Kabat) QSWDHSYSLVV SEQ ID NO:17 LCDR1 (Chotia) DALRDKF SEQ ID NO:18 LCDR2 (Chotia) DDN SEQ ID NO:19 LCDR3 (Chotia) WDHSYSLV SEQ ID NO:20 LCDR1 (IMGT) ALRDKF SEQ ID NO:18 LCDR2 (IMGT) DDN SEQ ID NO:16 LCDR3 (IMGT) QSWDHSYSLVV SEQ ID NO:29 VL SYELTQPPSVSVSPGQTASITCSGDALRDKFVYWYQQKPGQSPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQSWDHSYSLVVFGGGTKLTVL SEQ ID NO:30 DNA encoding VL TCGTACGAGCTCACTCAACCGCCTTCTGTGTCCGTGTCACCCGGGCAGACTGCCTCCATTACCTGTTCGGGAGATGCCCTGCGCGACAAGTTTGTGTACTGGTACCAGCAGAAGCCCGGACAGTCGCCAGTGCTCGTCATCTATGACGACAACAACAGACCT TCCGGTATCCCGGAACGGTTCAGCGGAAGCAATTCCGGCAACACCGCTACCCTGACCATTAGCGGCACTCAGGCCATGGACGAAGCGGATTACTACTGCCAATCTGGGACCACTCATACTCCCTTGTGGTGTTCGGTGGCGGAACGAAGCTGACCGTCCTG SEQ ID NO:31 Light chain SYELTQPPSVSVSPGQTASITCSGDALRDKFVYWYQQKPGQSPVLVIYDDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQSWDHSYSLVVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO:32 DNA encoding the light chain TCGTACGAGCTCACTCAACCGCCTTCTGTGTCCGTGTCACCCGGGCAGACTGCCTCCATTACCTGTTCGGGAGATGCCCTGCGCGACAAGTTTGTGTACTGGTACCAGCAGAAGCCCGGACAGTCGCCAGTGCTCGTCATCTATGACGACAACAACAGAC CTTCCGGTATCCCGGAACGGTTCAGCGGAAGCAATTCCGGCAACACCGCTACCCTGACCATTAGCGGCACTCAGGCCATGGACGAAGCGGATTACTACTGCCAATCTGGGACCACTCATACTCCCTTGTGGTGTTCGGTGGCGGAACGAAGCTGACCGTC CTGGGCCAGCCTAAGGCCGCTCCCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCG TGGAGACAACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCACCCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC G4 E152_S375C SEQ ID NO:33 HCDR1 (combined) GGTFSTYAIS SEQ ID NO:34 HCDR2 (combined) RIIPILGIANYAQKFQG SEQ ID NO:35 HCDR3 (combined) EVRMIFDY SEQ ID NO:36 HCDR1 (Kabat) TYAIS SEQ ID NO:34 HCDR2 (Kabat) RIIPILGIANYAQKFQG SEQ ID NO:35 HCDR3 (Kabat) EVRMIFDY SEQ ID NO:37 HCDR1 (Chothia) GGTFST SEQ ID NO:38 HCDR2 (Chothia) IPILGI SEQ ID NO:35 HCDR3(Chothia) EVRMIFDY SEQ ID NO:39 HCDR1 (IMGT) GGTFSTYA SEQ ID NO:40 HCDR2 (IMGT) IIPILGIA SEQ ID NO:41 HCDR3 (IMGT) AREVRMIFDY SEQ ID NO:42 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREVRMIFDYWGQGTLVTVSS SEQ ID NO:43 DNA encoding VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTACTTACGCTATCTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCATCCCGATCCTGGGCATCGCGA ACTACGCCCAGAAATTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGAAGTTCGTATGATCTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO:44 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREVRMIFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:45 DNA encoding the heavy chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTTAGCTGCAAAGCATCCGGAGGGACGTTTTCTACTTACGCTATCTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCATCCCGATCCTGGG CATCGCGAACTACGCCCAGAAATTTCAGGGCCGGGTGACCATTACCGCCGATGAAAGCACCAGCACCGCCTATATGGAACTGAGCAGCCTGCGCAGCGAAGATACGGCCGTGTATTATTGCGCGGTGAAGTTCGTATGATCTTCGATTACTGGGGCCAAGGCACCCT GGTGACTGTTAGCTCAGCCTCTACGAAAGGCCCAAGCGTATTTCCCCTGGCTCCTTCTAGTAAATCAACCTCAGGTGGTACAGCAGCCCTTGGCTGCCTGGTCAAAGACTATTTCCCCTGTCCGGTGACCGTCTCATGGAACTCAGGTGCTTTGACATCTGGTGTGC ATACATTCCCAGCTGTGCTGCAAAGTAGTGGACTGTACAGCCTTTCCAGCGTGGTCACGGTGCCAAGTAGCTCCTTGGGTACTCAGACTTATATCTGCAATGTGAACCACAAGCCCTCTAACACGAAGGTGGACAAGCGCGTGGAGCCCAAATCTTGCGATAAGACGC ATACTTGTCCCCCATGCCCTGCTCCTGAGCTGTTGGGAGGCCCGTCAGTGTTCTTGTTCCCTCCGAAGCCTAAGGACACTTTGATGATAAGTAGGACACCAGAGGTGACTTGCGTGGTGGTTGATGTGTCCCATGAAGATCCCGAGGTCAAATTTAATTGGTACGTA GATGGTGTCGAAGTTCACAATGCTAAGACTAAGCCAAGGGAAGAGCAGTACAACAGTACATATAGGGTAGTCTCCGTGCTGACAGTCCTCCACCAGGACTGGTTGAACGGCAAGGAATACAAATGTAAGGTGTCAAACAAAGCTCTGCCTGCTCCCATTGAGAAAACA ATCTCTAAAGCCAAAGGCCAGCCGAGAGAGCCCCAAGTCTACACTTTGCCCCCGAGCAGGGAGGAAATGACCAAGAATCAGGTGAGTCTGACGTGCCTCGTCAAAGGATTTTATCCATGCGATATTGCAGTTGAATGGGAGAGCAATGGCCAGCCAGAGAACAACTAT AAAACCACACCACCCGTGCTCGACTCTGATGGCAGCTTCTTCCTCTATAGCAAGCTGACAGTCGATAAATCTCGCTGGCAGCAAGGCAATGTGTTCTCCTGCTCCGTCATGCACGAGGCTTTGCATAACCATTATACTCAAAAATCTCTGTCCCTGTCACCTGGTAAA SEQ ID NO:46 LCDR1 (combined) RASQSISSYLA SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO:48 LCDR3 (combined) QQSYDYYT SEQ ID NO:46 LCDR1 (Kabat) RASQSISSYLA SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO:48 LCDR3 (Kabat) QQSYDYYT SEQ ID NO:49 LCDR1 (Chotia) SQSISSY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO:51 LCDR3 (Chotia) SYDYY SEQ ID NO:52 LCDR1 (IMGT) QSISSY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO:48 LCDR3 (IMGT) QQSYDYYT SEQ ID NO:53 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDYYTFGQGTKVEIK SEQ ID NO:54 DNA encoding VL GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGTCTATTTCTTCTTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAACTATTAATCTACGCTGCTTCTTCT CTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAGTCTTACGACTACTACACCTTTGGCCAGGGCACGAAAGTTGAAATTAAA SEQ ID NO:55 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDYYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:56 DNA encoding the light chain GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGTCTATTTCTTCTTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAACTATTAATCTACGCTGCTTCTTCT CTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAGTCTTACGACTACTACACCTTTGGCCAGGGCACGAAAGTTGAAATTAAAC GTACGGTGGCAGCTCCGTCTGTTTTCATCTTTCCACCTAGCGACGAGCAACTCAAAAGTGGTACAGCATCCGTGGTTTGTCTGCTGAACAATTTTTACCCCAGGGAGGCTAAGGTCCAGTGGAAAGTCGATAACGCTCTTCAGTCTGGCAACAGTCAGGA GAGCGTCACAGAGCAGGACTCTAAGGATAGCACTTATAGTCTGTCCTCCACGCTGACACTGTCTAAAGCGGATTATGAGAAGCACAAGGTTTACGCCTGTGAGGTAACGCACCAAGGACTCTCCTCCCAGTTACCAAATCTTTCAACAGAGGAGAATGT MOR024353 E152C_S375C SEQ ID NO:57 HCDR1 (combined) GGTFSDYAIS SEQ ID NO:58 HCDR2 (combined) GIIPIFGDANYAQKFQG SEQ ID NO:59 HCDR3 (combined) EGSSYFYMAY SEQ ID NO:60 HCDR1 (Kabat) DYAIS SEQ ID NO:58 HCDR2 (Kabat) GIIPIFGDANYAQKFQG SEQ ID NO:59 HCDR3 (Kabat) EGSSYFYMAY SEQ ID NO:5 HCDR1 (Chothia) GGTFSDY SEQ ID NO:61 HCDR2 (Chothia) IPIFGD SEQ ID NO:59 HCDR3(Chotia) EGSSYFYMAY SEQ ID NO:7 HCDR1 (IMGT) GGTFSDYA SEQ ID NO:62 HCDR2 (IMGT) IIPIFGDA SEQ ID NO:63 HCDR3 (IMGT) AREGSSYFYMAY SEQ ID NO:64 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAISWVRQAPGQGLEWMGGIIPIFGDANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGSSYFYMAYWGQGTLVTVSS SEQ ID NO:65 DNA encoding VH CAGGTTCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAAGCAAGCGGCGGCACCTTCAGCGATTACGCCATCTCTTGGGTCCGACAGGCCCCTGGACAAGGCTTGGAATGGATGGGCGGCATCATCCCCATCTTCGGCGACGCCAATT ACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGTCTACAAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGAGGGCAGCAGCTACTTCTACATGGCCTATTGGGGCCAGGGCACCCTGGTCACAGTTAGCTCT SEQ ID NO:66 Heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDYAISWVRQAPGQGLEWMGGIIPIFGDANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGSSYFYMAYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:67 DNA encoding the heavy chain CAGGTTCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAAGCAAGCGGCGGCACCTTCAGCGATTACGCCATCTCTTGGGTCCGACAGGCCCCTGGACAAGGCTTGGAATGGATGGGCGGCATCATCCCCATCTTCGGC GACGCCAATTAGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGTCTACAAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGAGGGCAGCAGCTACTTCTACATGGCCTATTGGGGCCAGGGC ACCCTGGTCACAGTTAGCTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGA CCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACG TGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGAC AATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:68 LCDR1 (combined) SGDNIGSKLAS SEQ ID NO:69 LCDR2 (combined) DDSNRPS SEQ ID NO:70 LCDR3 (combined) AATAGDRWAYV SEQ ID NO:68 LCDR1 (Kabat) SGDNIGSKLAS SEQ ID NO:69 LCDR2 (Kabat) DDSNRPS SEQ ID NO:70 LCDR3 (Kabat) AATAGDRWAYV SEQ ID NO:71 LCDR1 (Chotia) DNIGSKL SEQ ID NO:72 LCDR2 (Chotia) DDS SEQ ID NO:73 LCDR3 (Chotia) TAGDRWAY SEQ ID NO:74 LCDR1 (IMGT) NIGSKL SEQ ID NO:72 LCDR2 (IMGT) DDS SEQ ID NO:70 LCDR3 (IMGT) AATAGDRWAYV SEQ ID NO:75 VL SYELTQPLSVSVALGQTARITCSGDNIGSKLASWYQQKPGQAPVLVIYDDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCAATAGDRWAYVFGGGTKLTVL SEQ ID NO:76 DNA encoding VL AGCTATGAGCTGACACAGCCTCTGTCCGTGTCTGTGGCTCTGGGACAGACCGCCAGAATCACCTGTAGCGGCGACAACATCGGCAGCAAGCTGGCCTCTTGGTATCAGCAGAAGCCTGGACAGGCCCCTGTGCTGGTCATCTACGACGACAGCAATAGACCC AGCGGCATCCCCGAGAGATTCAGCGGCAGCAATAGCGGCAATACCGCCACACTGACCATCAGCAGAGCACAGGCTGGCGACGAGGCCGATTACTATTGTGCTGCCACAGCCGGCGACAGATGGGCCTATGTTTTTGGCGGCGGAACAAAGCTGACCGTGCTG SEQ ID NO:77 Light chain SYELTQPLSVSVALGQTARITCSGDNIGSKLASWYQQKPGQAPVLVIYDDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCAATAGDRWAYVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO:78 DNA encoding the light chain AGCTATGAGCTGACACAGCCTCTGTCCGTGTCTGTGGCTCTGGGACAGACCGCCAGAATCACCTGTAGCGGCGACAACATCGGCAGCAAGCTGGCCTCTTGGTATCAGCAGAAGCCTGGACAGGCCCCTGTGCTGGTCATCTACGACGACAGCAATAGAC CCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAATAGCGGCAATACCGCCACACTGACCATCAGCAGAGCACAGGCTGGCGACGAGGCCGATTACTATTGTGCTGCCACAGCCGGCGACAGATGGGCCTATGTTTTTGGCGGCGGAACAAAGCTGACCGTG CTGGGACAGCCTAAGGCCGCTCCCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCG TGGAGACAACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCACCCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC MOR024354 E152C_S375C SEQ ID NO:79 HCDR1 (combined) GFTFSSFGMS SEQ ID NO:80 HCDR2 (combined) AISYSGSDTYYADSVKG SEQ ID NO:81 HCDR3 (combined) DVGVMDY SEQ ID NO:82 HCDR1 (Kabat) SFGMS SEQ ID NO:80 HCDR2 (Kabat) AISYSGSDTYYADSVKG SEQ ID NO:81 HCDR3 (Kabat) DVGVMDY SEQ ID NO:83 HCDR1 (Chothia) GFTFSSF SEQ ID NO:84 HCDR2 (Chothia) SYSGSD SEQ ID NO:81 HCDR3(Chothia) DVGVMDY SEQ ID NO:85 HCDR1 (IMGT) GFTFSSFG SEQ ID NO:86 HCDR2 (IMGT) ISYSGSDT SEQ ID NO:87 HCDR3 (IMGT) ARDVGVMDY SEQ ID NO:88 VH QVQLLESGGGLVQPGGSLRLSCAASGTFSSFGMSWVRQAPGKGLEWVSAISYSGSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDVGVMDYWGQGTLVTVSS SEQ ID NO:89 DNA encoding VH CAGGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTTTGGCATGAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTGTCCGCCATCAGCTACAGCGGCAGCGATACC TACTACGCCGACAGCGTGAAGGGCAGATTCACCATCTCCAGAGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAGATGTGGGCGTGATGGACTATTGGGGCCAGGGCACACTGGTCACCGTTAGCTCT SEQ ID NO:90 Heavy chain QVQLLESGGGLVQPGGSLRLSCAASGTFSSFGMSWVRQAPGKGLEWVSAISYSGSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDVGVMDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:91 DNA encoding the heavy chain CAGGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTTTGGCATGAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTGTCCGCCATCAGCTACAGCGGCAG CGATACCTACTACGCCGACAGCGTGAAGGGCAGATTCACCATCTCCAGAGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAGATGTGGGCGTGATGGACTATTGGGGCCAGGGCACACTGG TCACCGTTAGCTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTGCAC ACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCAC ACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACAA TCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTAC AAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:92 LCDR1 (combined) SGDNLGTYYAH SEQ ID NO:93 LCDR2 (combined) SQSHRPS SEQ ID NO:94 LCDR3 (combined) GAWDAPSPELV SEQ ID NO:92 LCDR1 (Kabat) SGDNLGTYYAH SEQ ID NO:93 LCDR2 (Kabat) SQSHRPS SEQ ID NO:94 LCDR3 (Kabat) GAWDAPSPELV SEQ ID NO:95 LCDR1 (Chotia) DNLGTYY SEQ ID NO:96 LCDR2 (Chotia) SQS SEQ ID NO:97 LCDR3 (Chotia) WDAPSPEL SEQ ID NO:98 LCDR1 (IMGT) NLGTYY SEQ ID NO:96 LCDR2 (IMGT) SQS SEQ ID NO:94 LCDR3 (IMGT) GAWDAPSPELV SEQ ID NO:99 VL SYELTQPLSVSVALGQTARITCSGDNLGTYYAHWYQQKPGQAPVLVIYSQSHRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCGAWDAPSPELVFGGGTKLTVL SEQ ID NO: 100 DNA encoding VL AGCTATGAGCTGACACAGCCTCTGTCCGTGTCTGTGGCTCTGGGACAGACCGCCAGAATCACCTGTAGCGGCGATAACCTGGGCACCTACTACGCCCACTGGTATCAGCAGAAGCCTGGACAGGCTCCCGTGCTGGTCATCTACAGCCAGTCTCACAGACCC AGCGGCATCCCCGAGAGATTCAGCGGCAGCAATAGCGGCAATACCGCCACACTGACCATCAGCAGAGCACAGGCTGGCGACGAGGCCGATTACTATTGTGGCGCTTGGGACGCCCCATCTCCTGAGCTTGTTTTTGGCGGAGGCACCAAGCTGACAGTGCTG SEQ ID NO: 101 Light chain SYELTQPLSVSVALGQTARITCSGDNLGTYYAHWYQQKPGQAPVLVIYSQSHRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCGAWDAPSPELVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 102 DNA encoding the light chain AGCTATGAGCTGACACAGCCTCTGTCCGTGTCTGTGGCTCTGGGACAGACCGCCAGAATCACCTGTAGCGGCGATAACCTGGGCACCTACTACGCCCACTGGTATCAGCAGAAGCCTGGACAGGCTCCCGTGCTGGTCATCTACAGCCAGTCTCACAGAC CCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAATAGCGGCAATACCGCCACACTGACCATCAGCAGAGCACAGGCTGGCGACGAGGCCGATTACTATTGTGGCGCTTGGGACGCCCCATCTCCTGAGCTTGTTTTTGGCGGAGGCACCAAGCTGACAGTG CTGGGACAGCCTAAGGCCGCTCCCTCCGTGACCCTGTTCCCCCCCAGCTCCGAGGAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCTGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCG TGGAGACAACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCCGAGCAGTGGAAGAGCCACAGAAGCTACAGCTGCCAGGTCACCCACGAGGGCAGCACCGTGGAGAAAACCGTGGCCCCCACCGAGTGCAGC Y010341 E152C_S375C SEQ ID NO: 103 HCDR1 (combined) GFTFSSYAMS SEQ ID NO: 104 HCDR2 (combined) AISGSGGSTYYADSVKG SEQ ID NO: 105 HCDR3 (combined) AFRLYWLDV SEQ ID NO: 106 HCDR1 (Kabat) SYAMS SEQ ID NO: 104 HCDR2 (Kabat) AISGSGGSTYYADSVKG SEQ ID NO: 105 HCDR3 (Kabat) AFRLYWLDV SEQ ID NO: 107 HCDR1 (Chothia) GFTFSSY SEQ ID NO: 108 HCDR2 (Chothia) SGSGGS SEQ ID NO: 105 HCDR3(Chothia) AFRLYWLDV SEQ ID NO: 109 HCDR1 (IMGT) GFTFSSYA SEQ ID NO: 110 HCDR2 (IMGT) ISGSGGST SEQ ID NO: 111 HCDR3 (IMGT) ARAFRLYWLDV SEQ ID NO: 112 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAFRLYWLDVWGQGTLVTVSS SEQ ID NO: 113 DNA encoding VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGCAGCACATAT TACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCCAGAGCCTTCCGGCTGTACTGGCTGGATGTTTGGGGACAGGGCACCCTGGTCACAGTGTCATCT SEQ ID NO: 114 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAFRLYWLDVWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 115 DNA encoding the heavy chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGC AGCACATATTACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCCAGAGCCTTCCGGCTGTACTGGCTGGATGTTTGGGGACAGGGCACC CTGGTCACAGTGTCATCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACC CACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTG GACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACA ATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTAC AAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 116 LCDR1 (combined) RASQSISSYLN SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO: 117 LCDR3 (combined) QQVYSAPVT SEQ ID NO: 116 LCDR1 (Kabat) RASQSISSYLN SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO: 117 LCDR3 (Kabat) QQVYSAPVT SEQ ID NO:49 LCDR1 (Chotia) SQSISSY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO: 118 LCDR3 (Chotia) VYSAPV SEQ ID NO:52 LCDR1 (IMGT) QSISSY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO: 117 LCDR3 (IMGT) QQVYSAPVT SEQ ID NO: 119 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSAPVTFGQGTKVEIK SEQ ID NO: 120 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGTCTACAGCGCCCCTGTGACATTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 121 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSAPVTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 122 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGTCTACAGCGCCCCTGTGACATTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010355 E152C_S375C SEQ ID NO: 123 HCDR1 (combined) GFTFSNYWIS SEQ ID NO: 124 HCDR2 (combined) RIKSKTYGGTTDYAEPVKG SEQ ID NO: 125 HCDR3 (combined) TSRRSYAFDY SEQ ID NO: 126 HCDR1 (Kabat) NYWIS SEQ ID NO: 124 HCDR2 (Kabat) RIKSKTYGGTTDYAEPVKG SEQ ID NO: 125 HCDR3 (Kabat) TSRRSYAFDY SEQ ID NO: 127 HCDR1 (Chothia) GFTFSNY SEQ ID NO: 128 HCDR2 (Chothia) KSKTYGGT SEQ ID NO: 125 HCDR3(Chothia) TSRRSYAFDY SEQ ID NO: 129 HCDR1 (IMGT) GFTFSNYW SEQ ID NO: 130 HCDR2 (IMGT) IKSKTYGGTT SEQ ID NO: 131 HCDR3 (IMGT) ARTSRRSYAFDY SEQ ID NO: 132 VH EVQLVESGGGLVKPGGSLRLSCAASGTFFSNYWISWVRQAPGKGLEWVGRIKSKTYGGTTDYAEPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARTSRRSYAFDYWGQGTLVTVSS SEQ ID NO: 133 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAACTACTGGATCAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAGTGGGTCGGACGGATCAAGAGCAAGACCTACGGCGGCACCACCG ATTATGCCGAGCCTGTGAAGGGCAGATTCACCATCAGCCGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAACCAGCAGAAGAAGCTACGCCTTCGACTACTGGGGCCAGGGCACACTGGTTACCGTTAGCTCT SEQ ID NO: 134 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGTFFSNYWISWVRQAPGKGLEWVGRIKSKTYGGTTDYAEPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARTSRRSYAFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 135 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAACTACTGGATCAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAGTGGGTCGGACGGATCAAGAGCAAGACCTACG GCGGCACCACCGATTATGCCGAGCCTGTGAAGGGCAGATTCACCATCAGCCGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAACCAGCAGAAGAAGCTACGCCTTCGACTACTGGGGCCA GGGCACACTGGTTACCGTTAGCTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTA CGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAG ACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 136 LCDR1 (combined) RASQSISSWLA SEQ ID NO: 137 LCDR2 (combined) DASSLES SEQ ID NO: 138 LCDR3 (combined) QQITRYPVT SEQ ID NO: 136 LCDR1 (Kabat) RASQSISSWLA SEQ ID NO: 137 LCDR2 (Kabat) DASSLES SEQ ID NO: 138 LCDR3 (Kabat) QQITRYPVT SEQ ID NO: 139 LCDR1 (Chotia) SQSISSW SEQ ID NO: 140 LCDR2 (Chotia) DAS SEQ ID NO: 141 LCDR3 (Chotia) ITRYPV SEQ ID NO: 142 LCDR1 (IMGT) QSISSW SEQ ID NO: 140 LCDR2 (IMGT) DAS SEQ ID NO: 138 LCDR3 (IMGT) QQITRYPVT SEQ ID NO: 143 VL DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQITRYPVTFGQGTKVEIK SEQ ID NO: 144 DNA encoding VL GACATCCAGATGACACAGAGCCCCAGCACACTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCTCCTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACGATGCCAGCAGCC TGGAAAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGAGTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGATCACAAGATACCCCGTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 145 Light chain DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQITRYPVTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 146 DNA encoding the light chain GACATCCAGATGACACAGAGCCCCAGCACACTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCTCCTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACGATGCCAGCAGCC TGGAAAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGAGTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGATCACAAGATACCCCGTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010356 E152C_S375C SEQ ID NO: 123 HCDR1 (combined) GFTFSNYWIS SEQ ID NO: 124 HCDR2 (combined) RIKSKTYGGTTDYAEPVKG SEQ ID NO: 147 HCDR3 (combined) VSGYYSHSGGFDV SEQ ID NO: 126 HCDR1 (Kabat) NYWIS SEQ ID NO: 124 HCDR2 (Kabat) RIKSKTYGGTTDYAEPVKG SEQ ID NO: 147 HCDR3 (Kabat) VSGYYSHSGGFDV SEQ ID NO: 127 HCDR1 (Chothia) GFTFSNY SEQ ID NO: 128 HCDR2 (Chothia) KSKTYGGT SEQ ID NO: 147 HCDR3(Chothia) VSGYYSHSGGFDV SEQ ID NO: 129 HCDR1 (IMGT) GFTFSNYW SEQ ID NO: 130 HCDR2 (IMGT) IKSKTYGGTT SEQ ID NO: 148 HCDR3 (IMGT) ARVSGYYSHSGGFDV SEQ ID NO: 149 VH EVQLVESGGGLVKPGGSLRLSCAASGTFFSNYWISWVRQAPGKGLEWVGRIKSKTYGGTTDYAEPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARVSGYYSHSGGFDVWGQGTLVTVSS SEQ ID NO: 150 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAACTACTGGATCAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAGTGGGTCGGACGGATCAAGAGCAAGACCTACGGCGGCACCACCGATTAT GCCGAGCCTGTGAAGGGCAGATTCACCATCAGCCGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGTGTCTGGCTACTACTCTCACAGCGGCGGCTTTGATGTGTGGGGCCAGGGAACACTGGTCACCGTTAGTTCT SEQ ID NO: 151 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGTFFSNYWISWVRQAPGKGLEWVGRIKSKTYGGTTDYAEPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARVSGYYSHSGGFDV WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 152 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAACTACTGGATCAGCTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAGTGGGTCGGACGGATCAAGAGCAAGACCTACGG CGGCACCACCGATTATGCCGAGCCTGTGAAGGGCAGATTCACCATCAGCCGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGTGTCTGGCTACTACTCTCACAGCGGCGGCTTTGATGTGT GGGGCCAGGGAACACTGGTCACCGTTAGTTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTG ACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGC GACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTG GTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAA AGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC TACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 153 LCDR1 (combined) RASQGISNYLA SEQ ID NO: 154 LCDR2 (combined) AASTLQS SEQ ID NO: 155 LCDR3 (combined) QKTWRTPGT SEQ ID NO: 153 LCDR1 (Kabat) RASQGISNYLA SEQ ID NO: 154 LCDR2 (Kabat) AASTLQS SEQ ID NO: 155 LCDR3 (Kabat) QKTWRTPGT SEQ ID NO: 156 LCDR1 (Chotia) SQGISNY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO: 157 LCDR3 (Chotia) TWRTPG SEQ ID NO: 158 LCDR1 (IMGT) QGISNY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO: 155 LCDR3 (IMGT) QKTWRTPGT SEQ ID NO: 159 VL DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKTWRTPGTFGQGTKVEIK SEQ ID NO: 160 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTACTGTCAGAAAACCTGGCGGACCCCTGGCACATTTGGCCAGGGAACAAAGGTGGAAATCAAG SEQ ID NO: 161 Light chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKTWRTPGTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 162 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTACTGTCAGAAAACCTGGCGGACCCCTGGCACATTTGGCCAGGGAACAAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010415 E152C_S375C SEQ ID NO: 103 HCDR1 (combined) GFTFSSYAMS SEQ ID NO: 104 HCDR2 (combined) AISGSGGSTYYADSVKG SEQ ID NO: 163 HCDR3 (combined) SRLIAPWLDY SEQ ID NO: 106 HCDR1 (Kabat) SYAMS SEQ ID NO: 104 HCDR2 (Kabat) AISGSGGSTYYADSVKG SEQ ID NO: 163 HCDR3 (Kabat) SRLIAPWLDY SEQ ID NO: 107 HCDR1 (Chothia) GFTFSSY SEQ ID NO: 108 HCDR2 (Chothia) SGSGGS SEQ ID NO: 163 HCDR3(Chothia) SRLIAPWLDY SEQ ID NO: 109 HCDR1 (IMGT) GFTFSSYA SEQ ID NO: 110 HCDR2 (IMGT) ISGSGGST SEQ ID NO: 164 HCDR3 (IMGT) ARSRLIAPWLDY SEQ ID NO: 165 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSRLIAPWLDYWGQGTLVTVSS SEQ ID NO: 166 DNA encoding VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGCAGCACATATT ACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGCAGACTGATCGCCCCTTGGCTGGATTATTGGGGCCAGGGCACACTGGTCACCGTGTCATCT SEQ ID NO: 167 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSRLIAPWLDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 168 DNA encoding the heavy chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGC AGCACATATTACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGCAGACTGATCGCCCCTTGGCTGGATTATTGGGGCCAGGGC ACACTGGTCACCGTGTCATCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGA CCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACG TGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGAC AATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 116 LCDR1 (combined) RASQSISSYLN SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO: 169 LCDR3 (combined) QQVYGSPPT SEQ ID NO: 116 LCDR1 (Kabat) RASQSISSYLN SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO: 169 LCDR3 (Kabat) QQVYGSPPT SEQ ID NO:49 LCDR1 (Chotia) SQSISSY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO: 170 LCDR3 (Chotia) VYGSPP SEQ ID NO:52 LCDR1 (IMGT) QSISSY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO: 169 LCDR3 (IMGT) QQVYGSPPT SEQ ID NO: 171 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYGSPPTFGQGTKVEIK SEQ ID NO: 172 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGTCTACGGCAGCCCTCCTACATTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 173 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYGSPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 174 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGTCTACGGCAGCCCTCCTACATTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010417 E152C_S375C SEQ ID NO: 175 HCDR1 (combined) GYSFTSYWIG SEQ ID NO: 176 HCDR2 (combined) IIYPGDSDTRYSPSFQG SEQ ID NO: 177 HCDR3 (combined) GSSAASGLSGDL SEQ ID NO: 178 HCDR1 (Kabat) SYWIG SEQ ID NO: 176 HCDR2 (Kabat) IIYPGDSDTRYSPSFQG SEQ ID NO: 177 HCDR3 (Kabat) GSSAASGLSGDL SEQ ID NO: 179 HCDR1 (Chothia) GYSFTSY SEQ ID NO: 180 HCDR2 (Chothia) YPGDSD SEQ ID NO: 177 HCDR3(Chothia) GSSAASGLSGDL SEQ ID NO: 181 HCDR1 (IMGT) GYSFTSYW SEQ ID NO: 182 HCDR2 (IMGT) IYPGDSDT SEQ ID NO: 183 HCDR3 (IMGT) ARGSSAASGLSGDL SEQ ID NO: 184 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGSSAASGLSGDLWGQGTLVTVSS SEQ ID NO: 185 DNA encoding VH GAAGTTCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCTCCTGCAAAGGCAGCGGCTACAGCTTCACCAGCTACTGGATCGGCTGGGTCCGACAGATGCCTGGCAAAGGCCTTGAGTGGATGGGCATCATCTACCCCGGCGACAGCGACACCAGATACA GCCCTAGCTTTCAGGGCCAAGTGACCATCAGCGCCGACAAGAGCATCAGCACAGCCTACCTGCAGTGGTCCAGCCTGAAGGCCTCTGACACCGCCATGTACTACTGTGCCAGAGGAAGCTCTGCCGCCTCTGGACTGTCTGGCGATCTTTGGGGACAGGGCACACTGGTCACAGTGTCTAGT SEQ ID NO: 186 Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGSSAASGLSGDLWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 187 DNA encoding the heavy chain GAAGTTCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCTCCTGCAAAGGCAGCGGCTACAGCTTCACCAGCTACTGGATCGGCTGGGTCCGACAGATGCCTGGCAAAGGCCTTGAGTGGATGGGCATCATCTACCCCGGCGACAGCG ACACCAGATACAGCCCTAGCTTTCAGGGCCAAGTGACCATCAGCGCCGACAAGAGCATCAGCACAGCCTACCTGCAGTGGTCCAGCCTGAAGGCCTCTGACACCGCCATGTACTACTGTGCCAGAGGAAGCTCTGCCGCCTCTGGACTGTCTGGCGATCTTTGGGGACA GGGCACACTGGTCACAGTGTCTAGTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTA CGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAG ACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 116 LCDR1 (combined) RASQSISSYLN SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO: 188 LCDR3 (combined) QQDYYSPFT SEQ ID NO: 116 LCDR1 (Kabat) RASQSISSYLN SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO: 188 LCDR3 (Kabat) QQDYYSPFT SEQ ID NO:49 LCDR1 (Chotia) SQSISSY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO: 189 LCDR3 (Chotia) DYYSPF SEQ ID NO:52 LCDR1 (IMGT) QSISSY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO: 188 LCDR3 (IMGT) QQDYYSPFT SEQ ID NO: 190 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYYSPFTFGQGTKVEIK SEQ ID NO: 191 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGACTACTACAGCCCCTCACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 192 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYYSPFTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 193 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGGACTACTACAGCCCCTCACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010429 E152C_S375C SEQ ID NO: 103 HCDR1 (combined) GFTFSSYAMS SEQ ID NO: 104 HCDR2 (combined) AISGSGGSTYYADSVKG SEQ ID NO: 194 HCDR3 (combined) AYKLSWLDL SEQ ID NO: 106 HCDR1 (Kabat) SYAMS SEQ ID NO: 104 HCDR2 (Kabat) AISGSGGSTYYADSVKG SEQ ID NO: 194 HCDR3 (Kabat) AYKLSWLDL SEQ ID NO: 107 HCDR1 (Chothia) GFTFSSY SEQ ID NO: 108 HCDR2 (Chothia) SGSGGS SEQ ID NO: 194 HCDR3 (Chothia) AYKLSWLDL SEQ ID NO: 109 HCDR1 (IMGT) GFTFSSYA SEQ ID NO: 110 HCDR2 (IMGT) ISGSGGST SEQ ID NO: 195 HCDR3 (IMGT) ARAYKLSWLDL SEQ ID NO: 196 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAYKLSWLDLWGQGTLVTVSS SEQ ID NO: 197 DNA encoding VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGCAGCACATAT TACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCCAGAGCCTACAAGCTGAGCTGGCTGGATCTTTGGGGCCAGGGCACACTGGTCACAGTGTCATCT SEQ ID NO: 198 Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAYKLSWLDLWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 199 DNA encoding the heavy chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGACTGGTTCAACCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTACGCCATGAGCTGGGTCCGACAGGCTCCTGGCAAAGGCCTTGAATGGGTGTCCGCCATCTCTGGCTCTGGCGGC AGCACATATTACGCCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCCAGAGCCTACAAGCTGAGCTGGCTGGATCTTTGGGGCCAGGGCACA CTGGTCACAGTGTCATCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACC CACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTG GACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACA ATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTAC AAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 116 LCDR1 (combined) RASQSISSYLN SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO:200 LCDR3 (combined) QQVWYAPVT SEQ ID NO: 116 LCDR1 (Kabat) RASQSISSYLN SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO:200 LCDR3 (Kabat) QQVWYAPVT SEQ ID NO:49 LCDR1 (Chotia) SQSISSY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO:201 LCDR3 (Chotia) VWYAPV SEQ ID NO:52 LCDR1 (IMGT) QSISSY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO:200 LCDR3 (IMGT) QQVWYAPVT SEQ ID NO:202 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVWYAPVTFGQGTKVEIK SEQ ID NO:203 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAAGCAAGTTTGGTACGCCCCTGTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO:204 Light chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVWYAPVTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:205 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCAGCAGCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCTCTC TGCAGTCTGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAAGCAAGTTTGGTACGCCCCTGTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010900 E152C_S375C SEQ ID NO:206 HCDR1 (combined) GFTFSNAWMS SEQ ID NO:207 HCDR2 (combined) RIKSKTDAGTTDYAAPVKG SEQ ID NO:208 HCDR3 (combined) TIYPSAPSSSLDY SEQ ID NO:209 HCDR1 (Kabat) NAWMS SEQ ID NO:207 HCDR2 (Kabat) RIKSKTDAGTTDYAAPVKG SEQ ID NO:208 HCDR3 (Kabat) TIYPSAPSSSLDY SEQ ID NO:210 HCDR1 (Chothia) GFTFSNA SEQ ID NO:211 HCDR2 (Chothia) KSKTDAGT SEQ ID NO:208 HCDR3(Chothia) TIYPSAPSSSLDY SEQ ID NO:212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO:213 HCDR2 (IMGT) IKSKTDATGTT SEQ ID NO:214 HCDR3 (IMGT) ARTIYPSAPSSSLDY SEQ ID NO:215 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARTIYPSAPSSSLDYWGQGTLVTVSS SEQ ID NO:216 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATGCCGGCACCACCGATTAT GCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAACAATCTACCCCAGCGCTCCTAGCAGCAGCCTGGATTATTGGGGCCAGGGCACACTGGTCACCGTGTCATCT SEQ ID NO:217 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARTIYPSAPSSSLDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:218 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATGC CGGCACCACCGATTATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAACAATCTACCCCAGCGCTCCTAGCAGCAGCCTGGATTATT GGGGCCAGGGCACACTGGTCACCGTGTCATCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTG ACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGC GACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTG GTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAA AGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC TACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 153 LCDR1 (combined) RASQGISNYLA SEQ ID NO: 154 LCDR2 (combined) AASTLQS SEQ ID NO:219 LCDR3 (combined) QQLIFFPLT SEQ ID NO: 153 LCDR1 (Kabat) RASQGISNYLA SEQ ID NO: 154 LCDR2 (Kabat) AASTLQS SEQ ID NO:219 LCDR3 (Kabat) QQLIFFPLT SEQ ID NO: 156 LCDR1 (Chotia) SQGISNY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO:220 LCDR3 (Chotia) LIFFPL SEQ ID NO: 158 LCDR1 (IMGT) QGISNY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO:219 LCDR3 (IMGT) QQLIFFPLT SEQ ID NO:221 VL DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQLIFFPLTFGQGTKVEIK SEQ ID NO:222 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTATTGCCAGCAGCTGATCTTCTTCCCTCTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO:223 Light chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQLIFFPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:224 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTATTGCCAGCAGCTGATCTTCTTCCCTCTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010903 E152C_S375C SEQ ID NO:206 HCDR1 (combined) GFTFSNAWMS SEQ ID NO:207 HCDR2 (combined) RIKSKTDAGTTDYAAPVKG SEQ ID NO:225 HCDR3 (combined) ASHRLHSLFDV SEQ ID NO:209 HCDR1 (Kabat) NAWMS SEQ ID NO:207 HCDR2 (Kabat) RIKSKTDAGTTDYAAPVKG SEQ ID NO:225 HCDR3 (Kabat) ASHRLHSLFDV SEQ ID NO:210 HCDR1 (Chothia) GFTFSNA SEQ ID NO:211 HCDR2 (Chothia) KSKTDAGT SEQ ID NO:225 HCDR3(Chothia) ASHRLHSLFDV SEQ ID NO:212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO:213 HCDR2 (IMGT) IKSKTDATGTT SEQ ID NO:226 HCDR3 (IMGT) ARASHRLHSLFDV SEQ ID NO:227 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARASHRLHSLFDVWGQGTLVTVSS SEQ ID NO:228 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAACCGATGCCGGCACCACCGAT TATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGTGCCAGAGCCTCTCACAGACTGCACAGCCTGTTTGACGTGTGGGGCCAGGGAACACTGGTCACCGTTAGTTCT SEQ ID NO:229 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARASHRLHSLFDVWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:230 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATG CCGGCACCACCGATTATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGTGCCAGAGCCTCTCACAGACTGCACAGCCTGTTTGACGTGTGGGGC CAGGGAACACTGGTCACCGTTAGTTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTT CCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGAC AAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGT ACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAG ACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 136 LCDR1 (combined) RASQSISSWLA SEQ ID NO: 137 LCDR2 (combined) DASSLES SEQ ID NO:231 LCDR3 (combined) QQGLFYPHT SEQ ID NO: 136 LCDR1 (Kabat) RASQSISSWLA SEQ ID NO: 137 LCDR2 (Kabat) DASSLES SEQ ID NO:231 LCDR3 (Kabat) QQGLFYPHT SEQ ID NO: 139 LCDR1 (Chotia) SQSISSW SEQ ID NO: 140 LCDR2 (Chotia) DAS SEQ ID NO:232 LCDR3 (Chotia) GLFYPH SEQ ID NO: 142 LCDR1 (IMGT) QSISSW SEQ ID NO: 140 LCDR2 (IMGT) DAS SEQ ID NO:231 LCDR3 (IMGT) QQGLFYPHT SEQ ID NO:233 VL DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGLFYPHTFGQGTKVEIK SEQ ID NO:234 DNA encoding VL GACATCCAGATGACACAGAGCCCCAGCACACTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCTCCTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACGATGCCAGCAGCC TGGAAAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGAGTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTATTGTCAGCAGGGCCTGTTCTACCCTCACACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO:235 Light chain DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGLFYPHTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:236 DNA encoding the light chain GACATCCAGATGACACAGAGCCCCAGCACACTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGAGCATCTCCTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACGATGCCAGCAGCC TGGAAAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGAGTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTATTGTCAGCAGGGCCTGTTCTACCCTCACACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010906 E152C_S375C SEQ ID NO:206 HCDR1 (combined) GFTFSNAWMS SEQ ID NO:207 HCDR2 (combined) RIKSKTDAGTTDYAAPVKG SEQ ID NO:237 HCDR3 (combined) DEYPWGWFDV SEQ ID NO:209 HCDR1 (Kabat) NAWMS SEQ ID NO:207 HCDR2 (Kabat) RIKSKTDAGTTDYAAPVKG SEQ ID NO:237 HCDR3 (Kabat) DEYPWGWFDV SEQ ID NO:210 HCDR1 (Chothia) GFTFSNA SEQ ID NO:211 HCDR2 (Chothia) KSKTDAGT SEQ ID NO:237 HCDR3(Chothia) DEYPWGWFDV SEQ ID NO:212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO:213 HCDR2 (IMGT) IKSKTDATGTT SEQ ID NO:238 HCDR3 (IMGT) ARDEYPWGWFDV SEQ ID NO:239 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDEYPWGWFDVWGQGTLVTVSS SEQ ID NO:240 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAACCGATGCCGGCACCACCG ATTATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGATGAGTACCCCTGGGGATGGTTCGATGTGTGGGGACAGGGAACCCTGGTCACCGTTAGTTCT SEQ ID NO:241 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDEYPWGWFDVWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:242 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATG CCGGCACCACCGATTATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGATGAGTACCCCTGGGGATGGTTCGATGTGTGGGGACA GGGAACCCTGGTCACCGTTAGTTCTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTA CGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAG ACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO:243 LCDR1 (combined) RASQGISSWLA SEQ ID NO:47 LCDR2 (combined) AASSLQS SEQ ID NO:244 LCDR3 (combined) QQYIFYPLT SEQ ID NO:243 LCDR1 (Kabat) RASQGISSWLA SEQ ID NO:47 LCDR2 (Kabat) AASSLQS SEQ ID NO:244 LCDR3 (Kabat) QQYIFYPLT SEQ ID NO:245 LCDR1 (Chotia) SQGISSW SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO:246 LCDR3 (Chotia) YIFYPL SEQ ID NO:247 LCDR1 (IMGT) QGISSW SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO:244 LCDR3 (IMGT) QQYIFYPLT SEQ ID NO:248 VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYIFYPLTFGQGTKVEIK SEQ ID NO:249 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCTCCGTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCTCTTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTATGCCGCTTCCAGTC TGCAGAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGTACATCTTCTACCCTCTGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 250 Light chain DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYIFYPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:251 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCTCCGTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCTCTTCTTGGCTGGCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTATGCCGCTTCCAGTC TGCAGAGCGGCGTGCCAAGCAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACTTCGCCACCTACTACTGCCAGCAGTACATCTTCTACCCTCTGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Y010910 E152C_S375C SEQ ID NO:206 HCDR1 (combined) GFTFSNAWMS SEQ ID NO:207 HCDR2 (combined) RIKSKTDAGTTDYAAPVKG SEQ ID NO:252 HCDR3 (combined) VASPSAPGGFDY SEQ ID NO:209 HCDR1 (Kabat) NAWMS SEQ ID NO:207 HCDR2 (Kabat) RIKSKTDAGTTDYAAPVKG SEQ ID NO:252 HCDR3 (Kabat) VASPSAPGGFDY SEQ ID NO:210 HCDR1 (Chothia) GFTFSNA SEQ ID NO:211 HCDR2 (Chothia) KSKTDAGT SEQ ID NO:252 HCDR3(Chothia) VASPSAPGGFDY SEQ ID NO:212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO:213 HCDR2 (IMGT) IKSKTDATGTT SEQ ID NO:253 HCDR3 (IMGT) ARVASPSAPGGFDY SEQ ID NO:254 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARVASPSAPGGFDYWGQGTLVTVSS SEQ ID NO:255 DNA encoding VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATGCCGGCACCACCGATT ATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGTGGCTTCTCCTTCTGCTCCCGGCGGATTCGATTATTGGGGCCAGGGAACACTGGTCACCGTGTCTAGT SEQ ID NO:256 Heavy chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARVASPSAPGGFDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPCPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:257 DNA encoding the heavy chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTTGTGAAACCTGGCGGCTCTCTGAGACTGAGCTGTGCCGCTTCCGGCTTCACCTTCAGCAATGCCTGGATGAGCTGGGTCCGACAGGCCCCTGGAAAAGGCCTTGAGTGGGTCGGACGGATCAAGAGCAAGACCGATG CCGGCACCACCGATTATGCTGCCCCTGTGAAGGGCAGATTCACCATCAGCAGGGACGACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGTGGCTTCTCCTTCTGCTCCCGGCGGATTCGATTATTGG GGCCAGGGAACACTGGTCACCGTGTCTAGTGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCTGTCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGAC TTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCG ACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAA GACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCTGTGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 153 LCDR1 (combined) RASQGISNYLA SEQ ID NO: 154 LCDR2 (combined) AASTLQS SEQ ID NO:258 LCDR3 (combined) QQSLFAPFT SEQ ID NO: 153 LCDR1 (Kabat) RASQGISNYLA SEQ ID NO: 154 LCDR2 (Kabat) AASTLQS SEQ ID NO:258 LCDR3 (Kabat) QQSLFAPFT SEQ ID NO: 156 LCDR1 (Chotia) SQGISNY SEQ ID NO:50 LCDR2 (Chotia) AAS SEQ ID NO:259 LCDR3 (Chotia) SLFAPF SEQ ID NO: 158 LCDR1 (IMGT) QGISNY SEQ ID NO:50 LCDR2 (IMGT) AAS SEQ ID NO:258 LCDR3 (IMGT) QQSLFAPFT SEQ ID NO:260 VL DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQSLFAPFTFGQGTKVEIK SEQ ID NO:261 DNA encoding VL GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTACTGTCAGCAGAGCCTGTTCGCCCCTTTCACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO:262 Light chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQSLFAPFTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:263 DNA encoding the light chain GACATCCAGATGACACAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGAGACAGAGTGACCATCACCTGTAGAGCCAGCCAGGGCATCAGCAACTACCTGGCCTGGTATCAGCAGAAACCCGGCAAGGTGCCCAAGCTGCTGATCTACGCTGCCAGCACAC TGCAGAGCGGAGTGCCTAGCAGATTTTCTGGCAGCGGCTCCGGCACCGATTTCACCCTGACCATATCTAGCCTGCAGCCAGAGGACGTGGCCACCTACTACTGTCAGCAGAGCCTGTTCGCCCCTTTCACCTTTGGCCAGGGCACCAAGGTGGAAATCAAG CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC

[00278] Other antibodies of the present invention include antibodies in which amino acids or nucleic acids encoding amino acids have been mutated, but are characterized by at least 60, 70, 80, 90, or 95 percent identity to the sequences described in Table 2. In some embodiments, 1, 2, 3, 4, or 5 amino acids have been mutated in the variable regions compared to the variable regions shown in the sequence described in Table 2, while retaining substantially the same therapeutic activity as the antibodies listed in Table 2.

[00279] Since each of these antibodies can bind PMEL17, the sequences (amino acid sequences and nucleotide sequences encoding the amino acid sequences) of the VH, VL, full-length light chain, and full-length heavy chain can be "mixed and matched" to create other PMEL17-binding antibodies of the present invention. Such "mixed and matched" PMEL17-binding antibodies can be tested using binding assays known in the art (e.g., (varieties of ELISA and other assays described in the Examples section). When such chains are mixed and matched, the VH sequence of a particular VH/VL pair should be replaced with a structurally similar VH sequence. Likewise, the full-length heavy chain sequence of a particular full-length heavy chain/full-length light chain pair should be replaced with a structurally similar full-length heavy chain sequence. Likewise, the VL sequence of a particular VH/VL pair should be replaced with a structurally similar VL sequence. Likewise, the full-length light chain sequence of a particular full-length heavy chain/full-length light chain pair should be replaced with a structurally similar full-length light chain sequence. Accordingly, in one aspect, the present invention provides an isolated monoclonal antibody or antigen binding region thereof, having a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 42, 64, 88, 112, 132, 149, 165, 184, 196, 215, 227, 239 or 254; and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 25, 29, 53, 75, 99, 119, 143, 159, 171, 190, 202, 221, 233, 248 or 260; wherein the antibody specifically binds to PMEL17.

[00280] In another aspect, the present invention provides (i) an isolated monoclonal antibody having a full-length heavy chain comprising an amino acid sequence optimized for expression in a cell of a mammalian expression system selected from the group consisting of SEQ ID NOs: 12, 44, 66, 90, 114, 134, 151, 167, 186, 198, 217, 229, 241, or 256; and a full-length light chain comprising an amino acid sequence optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NOs: 23, 27, 31, 55, 77, 101, 121, 145, 161, 173, 192, 204, 223, 235, 250 or 262; or (ii) a functional protein comprising an antigen-binding portion thereof.

[00281] In another aspect, the present invention provides PMEL17-binding antibodies that comprise the heavy chain and light chain CDR1, CDR2, and CDR3 described in Table 2, or combinations thereof. The amino acid sequences of the VH CDR1 antibodies are shown, for example, under SEQ ID NOs: 1, 4, 5, 7, 33, 36, 37, 39, 57, 60, 79, 82, 83, 85, 103, 106, 107, 109, 123, 126, 127, 129, 175, 178, 179, 181, 206, 209, 210, and 212. The amino acid sequences of the VH CDR2 antibodies are shown, for example, under SEQ ID NOs: 2, 6, 8, 34, 38, 40, 58, 61, 62, 80, 84, 86, 104, 108, 110, 124, 128, 130, 176, 180, 182, 207, 211, and 213. The amino acid sequences of the VH CDR3 antibodies are shown, for example, under SEQ ID NOs: 3, 9, 35, 41, 59, 63, 81, 87, 105, 111, 125, 131, 147, 148, 163, 164, 177, 183, 194, 195, 208, 214, 225, 226, 237, 238, 252, and 253. The amino acid sequences of the VL CDR1 antibodies are shown, for example, under SEQ ID NOs: 14, 17, 20, 46, 49, 52, 68, 71, 74, 92, 95, 98, 116, 136, 139, 142, 153, 156, 158, 243, 245, and 247. The amino acid sequences of the CDR2 of the VL antibodies are shown, for example, under SEQ ID Nos: 15, 18, 47, 50, 69, 72, 93, 96, 137, 140, and 154. The amino acid sequences of the CDR3 of the VL antibodies are shown, for example, under SEQ ID NOs: 16, 19, 48, 51, 70, 73, 94, 97, 117, 118, 138, 141, 155, 157, 169, 170188, 189, 200, 201, 219, 220, 231, 232, 244, 246, 258, and 259.

[00282] Given that each of these antibodies can bind PMEL17 and that antigen binding specificity is primarily mediated by the CDR1, 2 and 3 regions, the VH CDR1, CDR2 and CDR3 sequences and the VL CDR1, CDR2 and CDR3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies may be mixed and matched. Such "mixed and matched" PMEL17-binding antibodies may be tested using binding assays known in the art and described in the Examples section (e.g., variants of ELISA). When VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence should be replaced with structurally similar CDR sequence(s). Likewise, when VL CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VL sequence should be replaced with structurally similar CDR sequence(s). It will be readily apparent to one of ordinary skill in the art that novel VH and VL sequences can be created by replacing one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences shown herein for the monoclonal antibodies of the present invention.

[00283] Accordingly, in some embodiments, the present invention provides an isolated monoclonal antibody or antigen binding region thereof comprising a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 4, 5, 7, 33, 36, 37, 39, 57, 60, 79, 82, 83, 85, 103, 106, 107, 109, 123, 126, 127, 129, 175, 178, 179, 181, 206, 209, 210, and 212; A heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 8, 34, 38, 40, 58, 61, 62, 80, 84, 86, 104, 108, 110, 124, 128, 130, 176, 180, 182, 207, 211, and 213; A heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 35, 41, 59, 63, 81, 87, 105, 111, 125, 131, 147, 148, 163, 164, 177, 183, 194, 195, 208, 214, 225, 226, 237, 238, 252, and 253; A light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 17, 20, 46, 49, 52, 68, 71, 74, 92, 95, 98, 116, 136, 139, 142, 153, 156, 158, 243, 245, and 247; A light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 18, 47, 50, 69, 72, 93, 96, 137, 140, and 154; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 19, 48, 51, 70, 73, 94, 97, 117, 118, 138, 141, 155, 157, 169, 170, 188, 189, 200, 201, 219, 220, 231, 232, 244, 246, 258, and 259; wherein the antibody specifically binds PMEL17.

[00284] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 1, 4, 5, or 7, a heavy chain CDR2 of SEQ ID NO: 2, 6, or 8; a heavy chain CDR3 of SEQ ID NO: 3 or 9; a light chain CDR1 of SEQ ID NO: 14, 17, or 20; a light chain CDR2 of SEQ ID NO: 15 or 18; and a light chain CDR3 of SEQ ID NO: 16 or 19.

[00285] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 33, 36, 37, or 39, a heavy chain CDR2 of SEQ ID NO: 34, 38, or 40; a heavy chain CDR3 of SEQ ID NO: 35 or 41; a light chain CDR1 of SEQ ID NO: 46, 49, or 52; a light chain CDR2 of SEQ ID NO: 47 or 50, and a light chain CDR3 of SEQ ID NO: 48 or 51.

[00286] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 5, 7, 57, or 60, a heavy chain CDR2 of SEQ ID NO: 58, 61, or 62; a heavy chain CDR3 of SEQ ID NO: 59 or 63; a light chain CDR1 of SEQ ID NO: 68, 71, or 74; a light chain CDR2 of SEQ ID NO: 69 or 72; and a light chain CDR3 of SEQ ID NO: 70 or 73.

[00287] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 79, 82, 83, or 85, a heavy chain CDR2 of SEQ ID NO: 80, 84, or 86; a heavy chain CDR3 of SEQ ID NO: 81 or 87; a light chain CDR1 of SEQ ID NO: 92, 95, or 98; a light chain CDR2 of SEQ ID NO: 93 or 96; and a light chain CDR3 of SEQ ID NO: 94 or 97.

[00288] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 103, 106, 107, or 109, a heavy chain CDR2 of SEQ ID NO: 104, 108, or 110; a heavy chain CDR3 of SEQ ID NO: 105 or 111; a light chain CDR1 of SEQ ID NO: 49, 52, or 116; a light chain CDR2 of SEQ ID NO: 47 or 50; and a light chain CDR3 of SEQ ID NO: 117 or 118.

[00289] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 123, 126, 127, or 129, a heavy chain CDR2 of SEQ ID NO: 124, 128, or 130; a heavy chain CDR3 of SEQ ID NO: 125 or 131; a light chain CDR1 of SEQ ID NO: 136, 139, or 142; a light chain CDR2 of SEQ ID NO: 137 or 140; and a light chain CDR3 of SEQ ID NO: 138 or 141.

[00290] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments (i.e., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 123, 126, 127, or 129, a heavy chain CDR2 of SEQ ID NO: 124, 128, or 130; a heavy chain CDR3 of SEQ ID NO: 147 or 148; a light chain CDR1 of SEQ ID NO: 153, 156, or 158; a light chain CDR2 of SEQ ID NO: 50 or 154; and a light chain CDR3 of SEQ ID NO: 155 or 157.

[00291] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 103, 106, 107, or 109, a heavy chain CDR2 of SEQ ID NO: 104, 108, or 110; a heavy chain CDR3 of SEQ ID NO: 163 or 164; a light chain CDR1 of SEQ ID NO: 49, 52, or 116; a light chain CDR2 of SEQ ID NO: 47 or 50; and a light chain CDR3 of SEQ ID NO: 169 or 170.

[00292] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 175, 178, 179, or 181, a heavy chain CDR2 of SEQ ID NO: 176, 180, or 182; a heavy chain CDR3 of SEQ ID NO: 177 or 183; a light chain CDR1 of SEQ ID NO: 49, 52, or 116; a light chain CDR2 of SEQ ID NO: 47 or 50; and a light chain CDR3 of SEQ ID NO: 188 or 189.

[00293] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 103, 106, 107, or 109, a heavy chain CDR2 of SEQ ID NO: 104, 108, or 110; a heavy chain CDR3 of SEQ ID NO: 194 or 195; a light chain CDR1 of SEQ ID NO: 49, 52, or 116; a light chain CDR2 of SEQ ID NO: 47 or 50; and a light chain CDR3 of SEQ ID NO: 200 or 201.

[00294] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 206, 209, 210, or 212, a heavy chain CDR2 of SEQ ID NO: 207, 211, or 213; a heavy chain CDR3 of SEQ ID NO: 208 or 214; a light chain CDR1 of SEQ ID NO: 153, 156, or 158; a light chain CDR2 of SEQ ID NO: 50 or 154; and a light chain CDR3 of SEQ ID NO: 219 or 220.

[00295] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments (i.e., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain CDR1 of SEQ ID NO: 206, 209, 210, or 212, a heavy chain CDR2 of SEQ ID NO: 207, 211, or 213; a heavy chain CDR3 of SEQ ID NO: 225 or 226; a light chain CDR1 of SEQ ID NO: 136, 139, or 142; a light chain CDR2 of SEQ ID NO: 137 or 140; and a light chain CDR3 of SEQ ID NO: 231 or 232.

[00296] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region that comprises HCDR1 under SEQ ID NO: 206, 209, 210 or 212, HCDR2 under SEQ ID NO: 207, 211 or 213 and HCDR3 under SEQ ID NO: 237 or 238; and a light chain variable region that comprises LCDR1 under SEQ ID NO: 243, 245 or 247, LCDR2 under SEQ ID NO: 47 or 50 and LCDR3 under SEQ ID NO: 244 or 246.

[00297] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region that comprises HCDR1 under SEQ ID NO: 206, 209, 210 or 212, HCDR2 under SEQ ID NO: 207, 211 or 213 and HCDR3 under SEQ ID NO: 252 or 253; and a light chain variable region that comprises LCDR1 under SEQ ID NO: 153, 156 or 158, LCDR2 under SEQ ID NO: 50 or 154 and LCDR3 under SEQ ID NO: 258 or 259.

[00298] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:1, heavy chain CDR2 of SEQ ID NO:2, heavy chain CDR3 of SEQ ID NO:3, light chain CDR1 of SEQ ID NO:14, light chain CDR2 of SEQ ID NO:15 and light chain CDR3 of SEQ ID NO:16;

b) heavy chain CDR1 of SEQ ID NO: 4, heavy chain CDR2 of SEQ ID NO: 2, heavy chain CDR3 of SEQ ID NO: 3, light chain CDR1 of SEQ ID NO: 14, light chain CDR2 of SEQ ID NO: 15 and light chain CDR3 of SEQ ID NO: 16;

c) heavy chain CDR1 of SEQ ID NO:5, heavy chain CDR2 of SEQ ID NO:6, heavy chain CDR3 of SEQ ID NO:3, light chain CDR1 of SEQ ID NO:17, light chain CDR2 of SEQ ID NO:18 and light chain CDR3 of SEQ ID NO:19 or

d) heavy chain CDR1 of SEQ ID NO:7, heavy chain CDR2 of SEQ ID NO:8, heavy chain CDR3 of SEQ ID NO:9, light chain CDR1 of SEQ ID NO:20, light chain CDR2 of SEQ ID NO:18 and light chain CDR3 of SEQ ID NO:16.

[00299] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:33, heavy chain CDR2 of SEQ ID NO:34, heavy chain CDR3 of SEQ ID NO:35, light chain CDR1 of SEQ ID NO:46, light chain CDR2 of SEQ ID NO:47 and light chain CDR3 of SEQ ID NO:48;

b) heavy chain CDR1 of SEQ ID NO:36, heavy chain CDR2 of SEQ ID NO:34, heavy chain CDR3 of SEQ ID NO:35, light chain CDR1 of SEQ ID NO:46, light chain CDR2 of SEQ ID NO:47 and light chain CDR3 of SEQ ID NO:48;

c) heavy chain CDR1 of SEQ ID NO:37, heavy chain CDR2 of SEQ ID NO:38, heavy chain CDR3 of SEQ ID NO:35, light chain CDR1 of SEQ ID NO:49, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:51 or

d) heavy chain CDR1 of SEQ ID NO: 39, heavy chain CDR2 of SEQ ID NO: 40, heavy chain CDR3 of SEQ ID NO: 41, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 48.

[00300] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise CDR sequences selected from a) the heavy chain CDR1 of SEQ ID NO:57, the heavy chain CDR2 of SEQ ID NO:58, the heavy chain CDR3 of SEQ ID NO:59, the light chain CDR1 of SEQ ID NO:68, the light chain CDR2 of SEQ ID NO:69, and the light chain CDR3 of SEQ ID NO:70; b) the heavy chain CDR1 of SEQ ID NO:60, the heavy chain CDR2 of SEQ ID NO:58, the heavy chain CDR3 of SEQ ID NO:59, the light chain CDR1 of SEQ ID NO:68, the light chain CDR2 of SEQ ID NO:69, and the light chain CDR3 of SEQ ID NO:70;

c) heavy chain CDR1 of SEQ ID NO:5, heavy chain CDR2 of SEQ ID NO:61, heavy chain CDR3 of SEQ ID NO:59, light chain CDR1 of SEQ ID NO:71, light chain CDR2 of SEQ ID NO:72 and light chain CDR3 of SEQ ID NO:73 or d) heavy chain CDR1 of SEQ ID NO:7, heavy chain CDR2 of SEQ ID NO:62, heavy chain CDR3 of SEQ ID NO:63, light chain CDR1 of SEQ ID NO:74, light chain CDR2 of SEQ ID NO:72 and light chain CDR3 of SEQ ID NO:70.

[00301] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:79, heavy chain CDR2 of SEQ ID NO:80, heavy chain CDR3 of SEQ ID NO:81, light chain CDR1 of SEQ ID NO:92, light chain CDR2 of SEQ ID NO:93, and light chain CDR3 of SEQ ID NO:94;

b) heavy chain CDR1 of SEQ ID NO:82, heavy chain CDR2 of SEQ ID NO:80, heavy chain CDR3 of SEQ ID NO:81, light chain CDR1 of SEQ ID NO:92, light chain CDR2 of SEQ ID NO:93, and light chain CDR3 of SEQ ID NO:94;

c) heavy chain CDR1 of SEQ ID NO:83, heavy chain CDR2 of SEQ ID NO:84, heavy chain CDR3 of SEQ ID NO:81, light chain CDR1 of SEQ ID NO:95, light chain CDR2 of SEQ ID NO:96 and light chain CDR3 of SEQ ID NO:97 or

d) heavy chain CDR1 of SEQ ID NO: 85, heavy chain CDR2 of SEQ ID NO: 86, heavy chain CDR3 of SEQ ID NO: 87, light chain CDR1 of SEQ ID NO: 98, light chain CDR2 of SEQ ID NO: 96 and light chain CDR3 of SEQ ID NO: 94.

[00302] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:103, heavy chain CDR2 of SEQ ID NO:104, heavy chain CDR3 of SEQ ID NO:105, light chain CDR1 of SEQ ID NO:116; light chain CDR2 of SEQ ID NO:47 and light chain CDR3 of SEQ ID NO:117;

b) heavy chain CDR1 of SEQ ID NO:106, heavy chain CDR2 of SEQ ID NO:104, heavy chain CDR3 of SEQ ID NO:105, light chain CDR1 of SEQ ID NO:116, light chain CDR2 of SEQ ID NO:47 and light chain CDR3 of SEQ ID NO:117;

c) heavy chain CDR1 of SEQ ID NO:107, heavy chain CDR2 of SEQ ID NO:108, heavy chain CDR3 of SEQ ID NO:105, light chain CDR1 of SEQ ID NO:49, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:118 or

d) heavy chain CDR1 of SEQ ID NO:109, heavy chain CDR2 of SEQ ID NO:110, heavy chain CDR3 of SEQ ID NO:111, light chain CDR1 of SEQ ID NO:52, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:117.

[00303] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:123, heavy chain CDR2 of SEQ ID NO:124, heavy chain CDR3 of SEQ ID NO:125, light chain CDR1 of SEQ ID NO:136, light chain CDR2 of SEQ ID NO:137 and light chain CDR3 of SEQ ID NO:138;

b) heavy chain CDR1 of SEQ ID NO:126, heavy chain CDR2 of SEQ ID NO:124, heavy chain CDR3 of SEQ ID NO:125, light chain CDR1 of SEQ ID NO:136, light chain CDR2 of SEQ ID NO:137, and light chain CDR3 of SEQ ID NO:138;

c) heavy chain CDR1 of SEQ ID NO:127, heavy chain CDR2 of SEQ ID NO:128, heavy chain CDR3 of SEQ ID NO:125, light chain CDR1 of SEQ ID NO:139, light chain CDR2 of SEQ ID NO:140 and light chain CDR3 of SEQ ID NO:141 or

d) heavy chain CDR1 of SEQ ID NO: 129, heavy chain CDR2 of SEQ ID NO: 130, heavy chain CDR3 of SEQ ID NO: 131, light chain CDR1 of SEQ ID NO: 142, light chain CDR2 of SEQ ID NO: 140 and light chain CDR3 of SEQ ID NO: 138.

[00304] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:123, heavy chain CDR2 of SEQ ID NO:124, heavy chain CDR3 of SEQ ID NO:147, light chain CDR1 of SEQ ID NO:153, light chain CDR2 of SEQ ID NO:154 and light chain CDR3 of SEQ ID NO:155;

b) heavy chain CDR1 of SEQ ID NO:126, heavy chain CDR2 of SEQ ID NO:124, heavy chain CDR3 of SEQ ID NO:147, light chain CDR1 of SEQ ID NO:153, light chain CDR2 of SEQ ID NO:154 and light chain CDR3 of SEQ ID NO:155;

c) heavy chain CDR1 of SEQ ID NO:127, heavy chain CDR2 of SEQ ID NO:128, heavy chain CDR3 of SEQ ID NO:147, light chain CDR1 of SEQ ID NO:156, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:157 or

d) heavy chain CDR1 of SEQ ID NO: 129, heavy chain CDR2 of SEQ ID NO: 130, heavy chain CDR3 of SEQ ID NO: 148, light chain CDR1 of SEQ ID NO: 158, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 155.

[00305] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:103, heavy chain CDR2 of SEQ ID NO:104, heavy chain CDR3 of SEQ ID NO:163, light chain CDR1 of SEQ ID NO:116, light chain CDR2 of SEQ ID NO:47 and light chain CDR3 of SEQ ID NO:169;

b) heavy chain CDR1 of SEQ ID NO:106, heavy chain CDR2 of SEQ ID NO:104, heavy chain CDR3 of SEQ ID NO:163, light chain CDR1 of SEQ ID NO:116, light chain CDR2 of SEQ ID NO:47, and light chain CDR3 of SEQ ID NO:169;

c) heavy chain CDR1 of SEQ ID NO:107, heavy chain CDR2 of SEQ ID NO:108, heavy chain CDR3 of SEQ ID NO:163, light chain CDR1 of SEQ ID NO:49, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:170 or

d) heavy chain CDR1 of SEQ ID NO: 109, heavy chain CDR2 of SEQ ID NO: 110, heavy chain CDR3 of SEQ ID NO: 164, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 169.

[00306] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:175, heavy chain CDR2 of SEQ ID NO:176, heavy chain CDR3 of SEQ ID NO:177, light chain CDR1 of SEQ ID NO:116, light chain CDR2 of SEQ ID NO:47, and light chain CDR3 of SEQ ID NO:188;

b) heavy chain CDR1 of SEQ ID NO:178, heavy chain CDR2 of SEQ ID NO:176, heavy chain CDR3 of SEQ ID NO:177, light chain CDR1 of SEQ ID NO:116, light chain CDR2 of SEQ ID NO:47, and light chain CDR3 of SEQ ID NO:188;

c) heavy chain CDR1 of SEQ ID NO:179, heavy chain CDR2 of SEQ ID NO:180, heavy chain CDR3 of SEQ ID NO:177, light chain CDR1 of SEQ ID NO:49, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:189 or

d) heavy chain CDR1 under SEQ ID NO: 181, heavy chain CDR2 under SEQ ID NO: 182, heavy chain CDR3 under SEQ ID NO: 183, light chain CDR1 under SEQ ID NO: 52, light chain CDR2 under SEQ ID NO: 50 and light chain CDR3 under SEQ ID NO: 188.

[00307] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO: 103, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47 and light chain CDR3 of SEQ ID NO: 200;

b) heavy chain CDR1 of SEQ ID NO: 106, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47 and light chain CDR3 of SEQ ID NO: 200;

c) heavy chain CDR1 of SEQ ID NO: 107, heavy chain CDR2 of SEQ ID NO: 108, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 49, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 201 or

d) heavy chain CDR1 of SEQ ID NO: 109, heavy chain CDR2 of SEQ ID NO: 110, heavy chain CDR3 of SEQ ID NO: 195, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 200.

[00308] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO:206, heavy chain CDR2 of SEQ ID NO:207, heavy chain CDR3 of SEQ ID NO:208, light chain CDR1 of SEQ ID NO:153, light chain CDR2 of SEQ ID NO:154, and light chain CDR3 of SEQ ID NO:219;

b) heavy chain CDR1 of SEQ ID NO:209, heavy chain CDR2 of SEQ ID NO:207, heavy chain CDR3 of SEQ ID NO:208, light chain CDR1 of SEQ ID NO:153, light chain CDR2 of SEQ ID NO:154 and light chain CDR3 of SEQ ID NO:219;

c) heavy chain CDR1 of SEQ ID NO:210, heavy chain CDR2 of SEQ ID NO:211, heavy chain CDR3 of SEQ ID NO:208, light chain CDR1 of SEQ ID NO:156, light chain CDR2 of SEQ ID NO:50 and light chain CDR3 of SEQ ID NO:220 or

d) heavy chain CDR1 of SEQ ID NO: 212, heavy chain CDR2 of SEQ ID NO: 213, heavy chain CDR3 of SEQ ID NO: 214, light chain CDR1 of SEQ ID NO: 158, light chain CDR2 of SEQ ID NO: 50 and light chain CDR3 of SEQ ID NO: 219.

[00309] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) heavy chain CDR1 of SEQ ID NO: 206, heavy chain CDR2 of SEQ ID NO: 207, heavy chain CDR3 of SEQ ID NO: 225, light chain CDR1 of SEQ ID NO: 136, light chain CDR2 of SEQ ID NO: 137 and light chain CDR3 of SEQ ID NO: 231;

b) heavy chain CDR1 of SEQ ID NO: 209, heavy chain CDR2 of SEQ ID NO: 207, heavy chain CDR3 of SEQ ID NO: 225, light chain CDR1 of SEQ ID NO: 136, light chain CDR2 of SEQ ID NO: 137, and light chain CDR3 of SEQ ID NO: 231;

c) heavy chain CDR1 of SEQ ID NO: 210, heavy chain CDR2 of SEQ ID NO: 211, heavy chain CDR3 of SEQ ID NO: 225, light chain CDR1 of SEQ ID NO: 139, light chain CDR2 of SEQ ID NO: 140 and light chain CDR3 of SEQ ID NO: 232 or

d) heavy chain CDR1 of SEQ ID NO: 212, heavy chain CDR2 of SEQ ID NO: 213, heavy chain CDR3 of SEQ ID NO: 226, light chain CDR1 of SEQ ID NO: 142; light chain CDR2 of SEQ ID NO: 140 and light chain CDR3 of SEQ ID NO: 231.

[00310] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) a heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 237, and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 244;

b) a heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 237, and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 244;

c) a heavy chain variable region that comprises HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211 and HCDR3 of SEQ ID NO: 237, and a light chain variable region that comprises LCDR1 of SEQ ID NO: 245, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 246; or

d) a heavy chain variable region that comprises HCDR1 under SEQ ID NO: 212, HCDR2 under SEQ ID NO: 213 and HCDR3 under SEQ ID NO: 238, and a light chain variable region that comprises LCDR1 under SEQ ID NO: 247, LCDR2 under SEQ ID NO: 50 and LCDR3 under SEQ ID NO: 244.

[00311] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 contain CDR sequences selected from

a) a heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 252, and a light chain variable region comprising LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154 and LCDR3 of SEQ ID NO: 258;

b) a heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207 and HCDR3 of SEQ ID NO: 252, and a light chain variable region comprising LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154 and LCDR3 of SEQ ID NO: 258;

c) a heavy chain variable region that comprises HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211 and HCDR3 of SEQ ID NO: 252, and a light chain variable region that comprises LCDR1 of SEQ ID NO: 156, LCDR2 of SEQ ID NO: 50 and LCDR3 of SEQ ID NO: 259; or

d) a heavy chain variable region that comprises HCDR1 under SEQ ID NO: 212, HCDR2 under SEQ ID NO: 213 and HCDR3 under SEQ ID NO: 253, and a light chain variable region that comprises LCDR1 under SEQ ID NO: 158, LCDR2 under SEQ ID NO: 50 and LCDR3 under SEQ ID NO: 258.

[00312] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:21.

[00313] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:25.

[00314] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:29.

[00315] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:42 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:53.

[00316] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:64 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:75.

[00317] In a particular embodiment, the antibody or antibody fragment (e.g., Antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:88 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:99.

[00318] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:112 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:119.

[00319] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 132 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143.

[00320] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:149 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:159.

[00321] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:165 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:171.

[00322] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:184 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:190.

[00323] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:196 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:202.

[00324] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:215 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:221.

[00325] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:227 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:233.

[00326] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:239 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:248.

[00327] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:254 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:260.

[00328] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:23.

[00329] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:27.

[00330] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:12 and a light chain comprising the amino acid sequence of SEQ ID NO:31.

[00331] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:44 and a light chain comprising the amino acid sequence of SEQ ID NO:55.

[00332] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:66 and a light chain comprising the amino acid sequence of SEQ ID NO:77.

[00333] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:90 and a light chain comprising the amino acid sequence of SEQ ID NO:101.

[00334] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:114 and a light chain comprising the amino acid sequence of SEQ ID NO:121.

[00335] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:145.

[00336] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:151 and a light chain comprising the amino acid sequence of SEQ ID NO:161.

[00337] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:167 and a light chain comprising the amino acid sequence of SEQ ID NO:173.

[00338] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:186 and a light chain comprising the amino acid sequence of SEQ ID NO:192.

[00339] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:198 and a light chain comprising the amino acid sequence of SEQ ID NO:204.

[00340] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:217 and a light chain comprising the amino acid sequence of SEQ ID NO:223.

[00341] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:229 and a light chain comprising the amino acid sequence of SEQ ID NO:235.

[00342] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:241 and a light chain comprising the amino acid sequence of SEQ ID NO:250.

[00343] In a particular embodiment, the antibody or antibody fragment (e.g., antigen-binding fragments) that specifically bind to PMEL17 comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:256 and a light chain comprising the amino acid sequence of SEQ ID NO:262.

[00344] In certain embodiments, an antibody that specifically binds to PMEL17 is an antibody or antibody fragment (e.g., antigen-binding fragment), which are described in Table 2.

1. Identification of epitopes and antibodies that bind to the same epitope

[00345] The present invention also provides antibodies and antibody fragments (e.g., antigen-binding fragments) that specifically bind to the same epitope as the PMEL17 antibodies described in Table 2 or cross-compete with the antibodies described in Table 2. Therefore, additional antibodies and antibody fragments (e.g., antigen-binding fragments) can be identified based on their ability to cross-compete (e.g., to competitively inhibit binding in a statistically significant manner) with other antibodies of the present invention in PMEL17 binding assays, such as BIACORE, or assays known to those skilled in the art for measuring binding. The ability of a test antibody to inhibit binding of antibodies and antibody fragments (e.g., antigen-binding fragments) of the present invention with PMEL17 (e.g., human PMEL17) demonstrates that the antibody being tested can compete with such an antibody or antibody fragment (e.g., antigen-binding fragments) for binding to PMEL17; however, according to a non-limiting theory, such an antibody may bind to the same or a related (e.g., (structurally similar or spatially close or overlapping) to an epitope on the PMEL17 protein as the antibody or antibody fragment (e.g., antigen-binding fragments) with which it competes. In certain embodiments, antibodies that bind to the same epitope on PMEL17 as antibodies or antibody fragments (e.g., The antigen-binding fragments) described in Table 2 are human or humanized monoclonal antibodies. Such human or humanized monoclonal antibodies can be produced and isolated as described herein.

2. Additional modification of the framework region in the Fc region

[00346] The immunoconjugates of the present invention may comprise modified antibodies or antigen-binding fragments thereof that further comprise modifications of framework residues within the VH and/or VL, such as, to improve the properties of the antibody. In some embodiments, framework modifications are made to reduce the immunogenicity of the antibody. For example, one approach is to "down-mutate" one or more framework residues toward the corresponding germline sequence. More specifically, an antibody that has undergone a somatic mutation may comprise framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the framework sequences of the antibody with the germline sequences from which the antibody is derived. To return the framework sequences to their germline configuration, somatic mutations can be introduced to "down-mutate" the germline sequence, such as by site-directed mutagenesis. Such "down-mutated" antibodies are also intended to be encompassed by the present invention.

[00347] Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T-cell epitopes, thereby reducing the potential immunogenicity of the antibody. This approach is also referred to as "deimmunization" and is described in more detail in U.S. Patent Application Publication No. 20030153043 to Carr et al.

[00348] In addition to or as an alternative to modifications made within the framework or CDR regions, the antibodies of the present invention can be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity (ADCC). In addition, an antibody of the present invention can be chemically modified (e.g., The antibody may be modified to alter its glycosylation pattern, again to alter one or more functional properties of the antibody. Each of these embodiments is described in more detail below.

[00349] In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, such as, increases or decreases. This approach is further described in U.S. Patent No. 5,677,425 to Bodmeret al.The number of cysteine residues in the CH1 hinge region is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.

[00350] In some embodiments, the antibody or antibody fragment disclosed herein comprises modified or engineered amino acid residues, such as one or more cysteine residues as sites for conjugation to the drug moiety (Junutula JR,et al., Nat Biotechnol 2008, 26:925-932). In one embodiment, the present invention provides a modified antibody or antibody fragment comprising a substitution of one or more amino acids with cysteine at the positions described herein. The sites for cysteine substitution are located in the constant regions of the antibody or antibody fragment and are thus applicable to a variety of antibodies or antibody fragments, with the sites being selected to provide stable and uniform conjugates. The modified antibody or fragment may have one, two or more cysteine substitutions, and such substitutions may be used in combination with the other modification and conjugation methods described herein. Methods for inserting cysteine at specific locations in an antibody are known in the art, see, for example, Lyonset al, (1990) Protein Eng., 3:703-708, WO 2011/005481, WO2014/124316, WO 2015/138615. In certain embodiments, the modified antibody comprises a substitution of one or more amino acids to cysteine in its constant region at a position selected from positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 191, 195, 197, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, 390, 392, 398, 400 and 422 of the heavy chain of the antibody, and wherein the numbering of the positions corresponds to the EU system. In some embodiments, the modified antibody or antibody fragment comprises a substitution of one or more amino acids to cysteine in its constant region at a position selected from positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of the light chain of an antibody or antibody fragment, wherein the numbering of the positions corresponds to the system EU and where the light chain is the human kappa light chain. In some embodiments, the modified antibody or antibody fragment comprises a combination of two or more amino acid substitutions to cysteine in its constant regions, where the combinations include substitutions at positions 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, or position 107 light chain of the antibody, wherein the numbering of the positions corresponds to the EU system. In some embodiments, the modified antibody or fragment of such an antibody comprises a single amino acid substitution to cysteine in its constant regions, wherein the substitution is at position 375 of the heavy chain of the antibody, position 152 of the heavy chain of the antibody, position 360 of the heavy chain of the antibody, position 107 of the light chain of the antibody, position 165 of the light chain of the antibody or position 159 of the light chain of the antibody, wherein the numbering of the positions corresponds to the EU system, and wherein the light chain is a kappa chain. In specific embodiments, the modified antibody or antibody fragment comprises a combination of two amino acid substitutions to cysteine in its constant regions, where the combinations comprise substitutions at positions 375 of the antibody heavy chain and position 152 of the antibody heavy chain, where the numbering of the positions follows the EU system. In specific embodiments embodiments, the modified antibody or fragment of such an antibody comprises a substitution of one amino acid for cysteine at position 360 of the heavy chain of the antibody, where the numbering of the positions corresponds to the EU system. In other specific embodiments, the modified antibody or fragment of such an antibody comprises a substitution of one amino acid for cysteine at position 107 of the light chain of the antibody , and where the numbering of the provisions corresponds to the EU system, and where the light chain is a kappa chain.

[00351] In additional embodiments, antibodies or antibody fragments (e.g., antigen-binding fragment) useful in the immunoconjugates of the present invention include modified or engineered antibodies, such as an antibody modified to incorporate one or more other reactive amino acids (other than cysteine), including Pcl, pyrrolysine, peptide tags (such as the S6, A1, and ybbR tags), and unnatural amino acids, in place of at least one amino acid from the native sequence, thereby providing a reactive site on the antibody or antigen-binding fragment for conjugation to a drug moiety or a linker-drug moiety with a complementary reactive group. For example, antibodies or antibody fragments can be modified to incorporate Pcl or pyrrolysine (W. Ou,et al., (2011) PNAS 108(26), 10437-10442; WO2014124258) or unnatural amino acids (J.Y. Axup, et al., Proc Natl Acad Sci U S A, 109 (2012), pp. 16101-16106; for a review see C.C. Liu and P.G. Schultz (2010) Annu Rev Biochem 79, 413-444; C.H. Kim, et al., (2013) Curr Opin Chem Biol. 17, 412-419) as drug conjugation sites. Similarly, peptide tags can be introduced into the antibody for enzymatic conjugation methods (Strop P.,et al., Chem Biol. 2013, 20(2):161-7; Rabuka D., Curr Opin Chem Biol. 2010 Dec;14(6):790-6; Rabuka D, et al., Nat Protoc. 2012, 7(6):1052-67). Another example is the use of 4'-phosphopantetheinyl transferases (PPTases) for conjugation of coenzyme A analogues (WO2013184514) and (Grünewaldet al., (2015)Bioconjugate Chem. 26 (12), 2554-62). Methods for conjugating such modified or engineered antibodies to payloads or linker-payload combinations are known in the art.

[00352] In another embodiment, the Fc hinge region of the antibody is mutated to reduce the biological half-life of the antibody. More specifically, one or more amino acid mutations are introduced into the border region between the CH2-CH3 domains of the Fc hinge region, such that the antibody exhibits impaired binding to staphylococcal protein A (SpA) compared to the binding of the native Fc hinge domain to SpA. This approach is described in more detail in U.S. Patent No. 6,165,745 to Ward et al.

[00353] In other embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the ability to bind the antigen of the original antibody. The effector ligand for which the affinity is altered can be, for example, an Fc receptor or complement component C1. This approach is described, for example, in in U.S. Patent Nos. 5,624,821 and 5,648,260, both by Winteret al.

[00354] In another embodiment, one or more amino acids selected from the amino acid residues can be replaced with a different amino acid residue, resulting in an antibody characterized by altered C1q binding and/or reduced or abolished complement-dependent cytotoxicity (CDC). This approach is described, for example, in US Patent No. 6,194,551 by Idusogieet al.

[00355] In another embodiment, one or more amino acid residues are altered so as to thereby alter the ability of the antibody to fix complement. This approach is described, for example, in PCT publication WO 94/29351 by Bodmeret al.Allotypic amino acid residues include, but are not limited to, the heavy chain constant region of the IgG1, IgG2, and IgG3 subclasses and the light chain constant region of the kappa chain isotypes, as described in Jefferiset al., MAbs. 1:332–338 (2009).

[00356] Fusion protein complexes with an antibody comprising such mutations mediate reduced or absent antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, amino acid residues L234 and L235 in the constant region of IgG1 are replaced with A234 and A235. In some embodiments, amino acid residue N267 in the constant region of IgG1 is replaced with A267. In some embodiments, amino acid residues D265 and P329 in the constant region of IgG1 are replaced with A265 and A329. Other mutations that suppress the Fc of antibodies can also be used.

[00357] In another embodiment, one or more amino acid residues are altered so as to thereby alter the ability of the antibody to fix complement. This approach is described, for example, in in PCT publication WO 94/29351 by Bodmeret al.In a specific embodiment, one or more amino acids of an antibody or antigen-binding fragment thereof of the present invention are replaced with one or more allotypic amino acid residues. Allotypic amino acid residues also include, but are not limited to, the constant region of the heavy chain of the IgG1, IgG2, and IgG3 subclasses, as well as the constant region of the light chain of the kappa isotype, as described in Jefferiset al., MAbs. 1:332–338 (2009).

[00358] In another embodiment, the glycosylation pattern of the antibody is modified. For example, an aglycosylated antibody can be produced (i.e., (i.e., an antibody that lacks glycosylation). The glycosylation pattern may be altered, for example, to increase the affinity of the antibody for an "antigen." Such carbohydrate modifications may be accomplished, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one may make one or more amino acid substitutions that result in the elimination of one or more glycosylation sites within the framework region of the variable region, thereby eliminating glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for the antigen. Such an approach is described, for example, US Patents Nos. 5,714,350 and 6,350,861 to Coet al.

[00359] In another embodiment, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Patent No. 6,277,375 to Ward. Alternatively, to increase the biological half-life, the antibody can be altered within the CH1 or CL region such that it contains a salvage receptor binding epitope taken from two loops of the CH2 domain of the Fc region of IgG, as described in U.S. Patent Nos. 5,869,046 and 6,121,022 to Presta et al.

3. Obtaining antibodies to PMEL17

[00360] Antibodies to PMEL17 and fragments of such antibodies (e.g., Antigen-binding fragments) can be produced by any means known in the art, including but not limited to recombinant expression, chemical synthesis, and enzymatic cleavage of antibody tetramers, while full-length monoclonal antibodies can be produced, for example, using hybridomas or by recombinant production. Recombinant expression can be carried out in any suitable host cells known in the art, such as mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.

[00361] The present invention further provides polynucleotides encoding the antibodies described herein, such as, polynucleotides encoding variable regions or segments of heavy or light chains containing complementarity determining regions as described herein. In some embodiments, the polynucleotide encoding the heavy chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to a polynucleotide selected from the group consisting of SEQ ID NOs: 11, 43, 65, 89, 113, 133, 150, 166, 185, 197, 216, 228, 240, and 255. In some embodiments, the polynucleotide encoding the light chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to a polynucleotide selected from the group consisting of SEQ ID NOs: 22, 26, 30, 54, 76, 100, 120, 144, 160, 172, 191, 203, 222, 234, 249, and 261.

[00362] In some embodiments, the polynucleotide encoding the heavy chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID NOs: 13, 45, 67, 91, 115, 135, 152, 168, 187, 199, 218, 230, 242, and 257. In some embodiments, the polynucleotide encoding the light chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID NO: 24, 28, 32, 56, 78, 102, 122, 146, 162, 174, 193, 205, 224, 236, 251, and 263.

[00363] The polynucleotides of the present invention may encode only the variable region sequence of an antibody to PMEL17. They may also encode both the variable region and the constant region of the antibody. Some of the polynucleotide sequences encode a polypeptide that comprises the variable regions of both the heavy chain and the light chain of one of the exemplary murine antibodies to PMEL17. Some other polynucleotides encode two polypeptide segments that are substantially identical to the variable regions of the heavy chain and light chain, respectively, of one of the murine antibodies.

[00364] Polynucleotide sequences can be obtained by solid-phase DNA synthesisde novoor by PCR mutagenesis of an existing sequence (e.g. sequences, which are described in the Examples section below), encoding an antibody to PMEL17 or a binding fragment thereof. Direct chemical synthesis of nucleic acids can be carried out using methods known in the art, such as the phosphotriester method from Naranget al., Meth. Enzymol. 68:90, 1979; phosphodiester method from Brownet al., Meth. Enzymol. 68:109, 1979; diethylphosphoramidite method from Beaucageet al., Tetra Lett., 22:1859, 1981 and the solid support method of U.S. Patent No. 4,458,066. The introduction of mutations into a polynucleotide sequence by PCR can be carried out as described, for example, in PCR Technology: Principles and Applications for DNA Amplification, H.A. Erlich (Ed.), Freeman Press, NY, NY, 1992; PCR Protocols: A Guide to Methods and Applications, Innis et al. (Ed.), Academic Press, San Diego, CA, 1990; Mattila et al., Nucleic Acids Res. 19:967, 1991 and Eckert et al., PCR Methods and Applications 1:17, 1991.

[00365] Also provided herein are expression vectors and host cells for producing the above-described anti-PMEL17 antibodies. Various expression vectors can be used to express polynucleotides encoding chains or binding fragments of an anti-PMEL17 antibody. Both viral and non-viral expression vectors can be used to produce antibodies in a mammalian host cell. Non-viral vectors and systems include plasmids, episomal vectors, typically with an expression cassette for protein or RNA expression, and human artificial chromosomes (see, For example, Harringtonet al., Nat Genet. 15:345, 1997). For example, non-viral vectors useful for the expression of PMEL17-binding polynucleotides and polypeptides in mammalian cells (e.g., human) include pThioHis A, B, and C, pcDNA™ 3.1/His, pEBVHis A, B, and C (Invitrogen, San Diego, CA), MPSV vectors, and a variety of other vectors known in the art for expressing other proteins. Useful viral vectors include retrovirus, adenovirus, adeno-associated virus, herpes virus, SV40, papillomavirus, Epstein-Barr virus HBP, vaccinia virus, and Semliki Forest virus (SFV) vectors. See higher Brentet al.; Smith, Annu. Rev. Microbiol. 49:807, 1995 and Rosenfeld et al., Cell 68:143, 1992.

[00366] The choice of expression vector depends on the intended host cells in which the vector is to be expressed. Expression vectors typically contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to polynucleotides encoding a chain or fragment of an antibody to PMEL17. In some embodiments, an inducible promoter is used to prevent expression of the inserted sequences under conditions other than the inducing conditions. Inducible promoters include, for example, arabinose, lacZ, metallothionein, or heat shock protein promoters. Cultures of transformed organisms can be propagated under non-inducing conditions without population bias toward coding sequences whose expression products are better tolerated by the host cells. In addition to promoters, other regulatory elements may be necessary or required for efficient expression of the PMEL17 antibody chain or fragment. Such elements typically include an ATG translation initiation codon and an adjacent ribosome binding site or other sequences. In addition, expression efficiency can be increased by incorporating enhancers appropriate to the cell system used (see, For example, Scharfet al.,Results Probl. Cell Differ. 20:125, 1994 and Bittner et al., Meth. Enzymol., 153:516, 1987). For example, the SV40 enhancer or the CMV enhancer can be used to increase expression in mammalian host cells.

[00367] Expression vectors may also provide for the position of a secretion signal sequence to form a fusion protein with the polypeptides encoded by the inserted anti-PMEL17 antibody sequences. More commonly, the inserted anti-PMEL17 antibody sequences are linked to the signal sequences prior to incorporation into the vector. Vectors to be used to produce the sequences encoding the variable domains of the light and heavy chains of the anti-PMEL17 antibody sometimes also encode constant regions or portions thereof. Such vectors allow the expression of the variable regions as fusion proteins with the constant regions, resulting in intact antibodies or fragments thereof. Typically, such constant regions are human.

[00368] Host cells harboring and expressing PMEL17 antibody chains may be either prokaryotic or eukaryotic.E. coliis one prokaryotic host useful for cloning and expressing the polynucleotides of the present invention. Other suitable microbial hosts include bacilli such as Bacillus subtilis and other enterobacteria such as Salmonella, Serratia, and various Pseudomonas species. Expression vectors can also be created for these prokaryotic hosts, which typically contain expression control sequences compatible with the host cell (e.g., origin of replication). In addition, any number of a variety of well-known promoters will be present, such as, for example, the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or the promoter system from lambda phage. Typically, promoters control expression, optionally via an operator sequence, and have ribosome binding site sequences, etc., for initiation and termination of transcription and translation. Other microorganisms, such as yeast, can also be used to express the PMEL17 binding polypeptides of the present invention. Insect cells in combination with baculovirus vectors can also be used.

[00369] In some preferred embodiments, mammalian host cells are used to express and produce the PMEL17 binding polypeptides of the present invention. For example, they can be either a hybridoma cell line expressing endogenous immunoglobulin genes (e.g., hybridoma clones from myeloma cells as described in the Examples section), or a mammalian cell line carrying an exogenous expression vector (e.g., myeloma cells (eg, SP2/0 myeloma cells, given below). They encompass any normal mortal or normal or abnormal immortal animal or human cells. For example, a number of suitable host cell lines capable of secreting intact immunoglobulins have been developed, including CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, transformed B cells, and hybridomas. The use of mammalian tissue culture for expression of polypeptides is discussed in general terms, e.g. in Winnacker, From Genes to Clones, VCH Publishers, N.Y., N.Y., 1987. Expression vectors for mammalian host cells may include expression control sequences such as an origin of replication, a promoter, and an enhancer (see, For example, Queenet al., Immunol. Rev. 89:49-68, 1986), and necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcription terminator sequences. Such expression vectors typically contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type specific, developmental stage specific, and/or modulated or regulated. Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus large late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human CMV immediate-early promoter), the constitutive CMV promoter, and promoter-enhancer combinations known in the art.

[00370] Methods for introducing expression vectors containing polynucleotide sequences of interest vary depending on the type of host cell. For example, calcium chloride transfection is commonly used for prokaryotic cells, while calcium phosphate treatment or electroporation can be used for other host cells (see above in general Sambrooket al.). A Laboratory Manual, 4^thed.). Other methods include, for example, electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic methods, virosomes, immunoliposomes, polycation:nucleic acid conjugates, naked DNA, artificial virions, fusion with the structural protein VP22 of the herpes virus (Elliot and O'Hare, Cell 88:223, 1997), agent-enhanced DNA uptake and transductionex vivo. In order to ensure long-term production of recombinant proteins in high yield, stable expression will often be required. For example, cell lines that stably express chains or binding fragments of the PMEL17 antibody can be produced using expression vectors of the present invention that contain viral origins of replication or endogenous expression elements and a selectable marker gene. Following introduction of the vector, the cells can be allowed to grow for 1-2 days in enriched medium before being transferred to selective media. The purpose of the selectable marker is to confer resistance to selection factors, and its presence allows cells that successfully express the introduced sequences to grow in selective media. Proliferation of stable, stably transfected cells can be achieved using tissue culture techniques appropriate to the cell type.

Applications in therapy

[00371] Antibodies, antibody fragments (e.g., antigen-binding fragments) and antibody-drug conjugates of the present invention are useful in a variety of applications, including, but not limited to, treating or preventing cancer, such as solid cancers or hematological malignancies. In some embodiments, antibodies, antibody fragments (e.g., antigen-binding fragments) and antibody-drug conjugates of the present invention are useful for inhibiting tumor growth, inducing differentiation, reducing tumor volume, and/or reducing tumorigenicity of a tumor. The methods of use may bein vitro,ex vivo or in vivomethods.

[00372] In one aspect, antibodies, antibody fragments (e.g., The antibody-drug conjugates (antigen-binding fragments) and antibody-drug conjugates of the present invention are useful for detecting the presence of PMEL17 in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. In some embodiments, the biological sample comprises a cell or tissue. In certain embodiments, such tissues include normal and/or cancerous tissues that express PMEL17 at higher levels than other tissues.

[00373] In one aspect of the present invention, a method for detecting the presence of PMEL17 in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an antibody to PMEL17 under conditions that allow the antibody to bind to the antigen and detecting whether a complex is formed between the antibody and the antigen.

[00374] In one aspect, the present invention provides a method for diagnosing a disorder associated with increased expression of PMEL17. In certain embodiments, the method comprises contacting a test cell with an anti-PMEL17 antibody; determining the expression level (either quantitatively or qualitatively) of PMEL17 on the test cell by detecting binding of the anti-PMEL17 antibody to a PMEL17 antigen; and comparing the expression level of PMEL17 in the test cell to the expression level of PMEL17 on a control cell (e.g., A method comprising: using a test cell that expresses PMEL17 at levels comparable to a normal cell (a normal cell derived from the same tissue as the test cell or a cell that expresses PMEL17 at levels comparable to those of a normal cell), wherein a higher level of PMEL17 expression on the test cell compared to a control cell indicates the presence of a disorder associated with increased PMEL17 expression. In certain embodiments, the test cell is obtained from an individual suspected of having a disorder associated with increased PMEL17 expression. In some embodiments, the disorder is a cell proliferative disorder, such as a cancer or a tumor. In certain embodiments, the method comprises measuring the copy number of the PMEL17 gene in the test cell.

[00375] In certain embodiments, a diagnostic or detection method such as those described above comprises detecting binding of an anti-PMEL17 antibody to PMEL17 expressed on the surface of a cell or in a membrane preparation obtained from a cell expressing PMEL17 on its surface. An exemplary assay for detecting binding of an anti-PMEL17 antibody to PMEL17 expressed on the surface of a cell is a "FACS assay."

[00376] Certain other methods may be used to detect binding of an anti-PMEL17 antibody to PMEL17. Such methods include, but are not limited to, antigen binding assays that are well known in the art, such as Western blotting, radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), sandwich assays, immunoprecipitation assays, fluorescent immunoassays, protein A immunoassays, and immunohistochemistry (IHC).

[00377] In certain embodiments, the PMEL17 antibodies are labeled. Labels include, but are not limited to, labels or moieties that are detected directly (such as fluorescent, chromophore, electron-dense, chemiluminescent, and radioactive labels), as well as moieties, such as enzymes or ligands, that are detected indirectly, such as, due to an enzymatic reaction or molecular interaction.

[00378] In certain embodiments, the anti-PMEL17 antibodies are immobilized on an insoluble matrix. Immobilization results in separation of the anti-PMEL17 antibody from any PMEL17 protein that remains free in solution. This is traditionally accomplished by either insolubilizing the anti-PMEL17 antibody prior to the assay procedure by adsorption to a water-insoluble matrix or surface (Bennich et al, U.S. Patent No. 3,720,760), or by covalent attachment (e.g., using glutaraldehyde crosslinking), or by insolubilizing the anti-PMEL17 antibody after formation of a complex between the anti-PMEL17 antibody and the PMEL17 protein, e.g., by immune precipitation.

[00379] Any of the above diagnostic or detection embodiments may be carried out using an immunoconjugate of the present invention instead of or in addition to an antibody to PMEL17.

[00380] In one embodiment of the present invention, a method of treating or preventing a disease is provided comprising administering antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention. The present invention also provides the use of antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention for treating or preventing a disease in a patient. In some embodiments, the present invention provides antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention for use in the treatment or prevention of a disease in a patient. In further embodiments, the present invention provides the use of antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention in the manufacture of a medicament intended for the treatment or prevention of a disease in a patient.

[00381] In some embodiments, the disease being treated using antibodies, antibody fragments (e.g., antigen-binding fragments) and antibody-drug conjugates of the present invention is a cancer. In certain embodiments, the cancer is characterized by the presence of cells expressing PMEL17 to which the antibodies, antibody fragments (e.g., antigen-binding fragments) and antibody drug conjugates of the present invention. In certain embodiments, the cancer is characterized by an increase in PMEL17 expression compared to the expression level in a healthy patient. In some embodiments, PMEL17 expression can be measured by an increase in PMEL17 RNA. In other embodiments, the cancer is characterized by an increase in PMEL17 DNA copy number. Other methods for measuring or determining PMEL17 expression levels are known to those skilled in the art. In certain embodiments, the cancer is characterized by a mutation, such as an activating mutation affecting Q209 or R183, in the GNAQ and/or GNA11 gene. Examples of diseases that can be treated and/or prevented include, but are not limited to, melanoma, uveal melanoma, hepatocellular carcinoma, and the metastatic form of these cancers.

[00382] The present invention provides methods for treating or preventing cancer comprising administering a therapeutically effective amount of antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention. In some embodiments, the cancer is a solid cancer, such as melanoma, uveal melanoma, hepatocellular carcinoma, or a metastatic form of these cancers. In some embodiments, the subject is a human. In some embodiments, the cancer is a resistant cancer and/or a recurrent cancer.

[00383] In some embodiments, the present invention provides methods for inhibiting tumor growth comprising administering to a subject a therapeutically effective amount of antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention. In some embodiments, the tumor is a solid cancer, such as melanoma, uveal melanoma, hepatocellular carcinoma, or a metastatic form of these cancers. In some embodiments, the subject is a human. In some embodiments, the subject has a tumor or has had a tumor removed.

[00384] In some embodiments, the tumor expresses PMEL17 to which PMEL17 antibodies bind. In some embodiments, the tumor overexpresses human PMEL17. In some embodiments, the tumor has an increased copy number of the PMEL17 gene. In some embodiments, the tumor has a mutation, such as an activating mutation involving Q209 or R183, in the GNAQ and/or GNA11 gene.

[00385] The present invention also provides methods for selecting patients for treatment with antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention, comprising administering a therapeutically effective amount of said antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates. In certain aspects of the present invention, the methods comprise selecting a patient by measuring the expression of PMEL17. In certain aspects of the present invention, the methods comprise selecting a patient by identifying a mutation, such as an activating mutation involving Q209 or R183, in the GNAQ or GNA11 gene. In some embodiments, the methods comprise measuring the expression level of PMEL17 in the patient, and determining the GNAQ and/or GNA11 gene.

[00386] In the case of treatment or prevention of diseases, a suitable dose of antibodies, antibody fragments (e.g., antigen-binding fragments) or antibody-drug conjugates of the present invention depends on various factors such as the type of disease to be treated, the severity and course of the disease, the response of the disease, previous therapy, the clinical history of the patient, etc. The antibody or agent may be administered once or over a course of treatment lasting from several days to several months, or until a cure is achieved, or until an alleviation of the disease state is achieved (e.g., tumor size reduction). Optimal dosing regimens can be calculated based on measurements of drug accumulation in the patient's body and will vary depending on the relative potency of the individual antibodies, antibody fragments (e.g., antigen-binding fragment) or antibody-drug conjugates. The treating physician can estimate the frequency of repeat dosing based on measured residence times and drug concentrations in body fluids or tissues.

Combination therapy

[00387] In certain cases, an antibody, antibody fragment (e.g., The antigen-binding fragment) or antibody-drug conjugate of the present invention is combined with other therapies such as surgery and radiation therapy, therapeutic agents such as other anti-cancer agents, anti-allergy agents, anti-nausea agents (or anti-emetics), analgesics, cytoprotective agents, and combinations thereof.

[00388] In one embodiment, the antibody, antibody fragment (e.g., antigen-binding fragment) or antibody-drug conjugate of the present invention is combined in a pharmaceutical combination formulation with a second compound having anticancer properties, or a dosage regimen provides for combination therapy with it. The second compound of the pharmaceutical combination formulation or dosage regimen may have activities that are complementary to the antibody or immunoconjugate of the combination, so that they do not adversely affect each other. For example, an antibody, antibody fragment (e.g., The antibody-drug conjugate (antigen-binding fragment) of the present invention may be administered in combination with, but is not limited to, a chemotherapeutic agent, immunomodulatory agents, a tyrosine kinase inhibitor, a GNAQ/GNA11 downstream signaling pathway inhibitor, IAP inhibitors, Bcl2 inhibitors, Mcl1 inhibitors, and other GNAQ/GNA11 inhibitors.

[00389] As used herein, the term "pharmaceutical combination" refers to either a fixed combination in unit dosage form or a non-fixed combination or kit of parts for combined administration, wherein two or more therapeutic agents can be administered independently at the same time or separately within time intervals, particularly where such time intervals allow for the demonstration of cooperative, e.g. synergistic effect of combination partners.

[00390] The term "combination therapy" refers to the administration of two or more therapeutic agents for the treatment or prevention of a therapeutic condition or disorder described herein. Such administration encompasses co-administration of the therapeutic agents substantially simultaneously, such as in a single capsule having a fixed ratio of the active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., capsules, powders and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the required dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In any event, the treatment regimen will provide the beneficial effects of the combination of medicinal products in the treatment or prevention of the conditions or disorders described herein.

[00391] Combination therapy may provide "synergy" and be "synergistic," i.e. the effect achieved when the active ingredients are administered together exceeds the sum of the effects that result from administration of the compounds separately. A synergistic effect may be achieved when the active ingredients are: (1) formulated together and administered or delivered simultaneously as a single dose combination formulation; (2) delivered sequentially or in parallel as separate formulations; or (3) by some other schedule. When delivered as alternation therapy, a synergistic effect may be achieved when the compounds are administered or delivered one after the other, e.g. by means of different injections in separate syringes. In general, during alternation therapy, the effective dose of each active ingredient is administered one after the other, i.e. series, while in combination therapy, an effective dose of two or more active ingredients is administered together.

[00392] Standard chemotherapeutic agents considered for use in combination therapy options include anastrozole (Arimidex ^® ), bicalutamide (Casodex ^® ), bleomycin sulfate (Blenoxane ^® ), busulfan (Myleran ^® ), injectable busulfan (Busulfex ^® ), capecitabine (Xeloda ^® ), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin ^® ), carmustine (BiCNU ^® ), chlorambucil (Leukeran ^® ), cisplatin (Platinol ^® ), cladribine (Leustatin ^® ), cyclophosphamide (Cytoxan ^® or Neosar ^® ), cytarabine, cytosine arabinoside (Cytosar-U ^® ), cytarabine liposomal injection (DepoCyt ^® ), dacarbazine (DTIC-Dome ^® ), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine ^® ), daunorubicin citrate liposomal injection (DaunoXome ^® ), dexamethasone, docetaxel (Taxotere ^® ), doxorubicin hydrochloride (Adriamycin ^® , Rubex ^® ), etoposide (Vepesid ^® ), fludarabine phosphate (Fludara ^® ), 5-fluorouracil (Adrucil ^® , Efudex ^® ), flutamide (Eulexin ^® ), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea ^® ), idarubicin (Idamycin ^® ), ifosfamide (IFEX ^® ), irinotecan (Camptosar ^® ), L-asparaginase (ELSPAR ^® ), leucovorin calcium, melphalan (Alkeran ^® ), 6-mercaptopurine (Purinethol ^® ), methotrexate (Folex ^® ), mitoxantrone (Novantrone ^® ), mylotarg, paclitaxel (Taxol ^® ), phoenix (yttrium 90/MX-DTPA), pentostatin, polyferospan 20 with carmustine implant (Gliadel ^® ), tamoxifen citrate (Nolvadex ^® ), teniposide (Vumon ^® ), 6-thioguanine, thiotepa, tirapazamine (Tirazone ^® ), topotecan hydrochloride injection (Hycamptin ^® ), vinblastine (Velban ^® ), vincristine (Oncovin ^® ) and vinorelbine (Navelbine ^® ), and pemetrexed.

[00393] In one aspect, the present invention provides a method of treating or preventing cancer by administering to a subject in need thereof an antibody-drug conjugate of the present invention in combination with one or more MDM2 inhibitors, PKC inhibitors, PRC2 inhibitors, MAPK inhibitors, GPCR inhibitors, tyrosine kinase inhibitors, including but not limited to BTK inhibitors, EGFR inhibitors, Her2 inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors.

[00394] For example, MDM2 inhibitors include, but are not limited to, RG7112 (RO5045337); RG7388 (RO5503781, idazanutlin); MI-77301 (SAR405838); MK-8242 (SCH-900242); AMG232; CGM097; DS3032b; HDM201, and ALRN-6924.

[00395] For example, PKC inhibitors include, but are not limited to, balanol; riluzole; staurosporine; enzastaurin; δV1-1 (KAI-9803 or delcasertib); εV1-2 (KAI-1678); aprinocarsen; midostaurin (PKC412); UCN-01 (7-hydroxy-staurosporine); rottlerin (5,7-dihydroxy-2,2-dimethyl-6-(2,4,6-trihydroxy-3-methyl-5-acetylbenzyl)-8-cinnamoyl-1,2-chromene), and bryostatin 1.

[00396] For example, PRC2 inhibitors include, but are not limited to, EI1; EPZ011989; EPZ005687; tetramethylpiperidinylbenzamides; UNC1999, and GSK126.

[00397] For example, MAPK inhibitors include, but are not limited to, vemurafenib (Zelboraf); dabrafenib (Tafinlar); encorafenib (Braftovi); trametinib (Mekinist); cobimetinib (Cotellic); binimetinib (Mektovi), and ulixertinib.

[00398] For example, tyrosine kinase inhibitors include, but are not limited to, ibrutinib (PCI-32765); erlotinib hydrochloride (Tarceva ^® ); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent ^® ); bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Patent No. 6,780,996); dasatinib (Sprycel ^® ); pazopanib (Votrient ^® ); sorafenib (Nexavar ^® ); Zaktima (ZD6474) and imatinib or imatinib mesylate (Gilvec ^® and Gleevec ^® ).

[00399] Epidermal growth factor receptor (EGFR) inhibitors include, but are not limited to, erlotinib hydrochloride (Tarceva ^® ), gefitinib (Iressa ^® ); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovok ^® ); vandetanib (Caprelsa ^® ); lapatinib (Tykerb ^® ); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); canertinib dihydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); mubritinib (TAK165); pelitinib (EKB569); afatinib (BIBW2992); neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8) and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI166, CAS 187724-61-4).

[00400] Antibodies that bind EGFR include, but are not limited to, cetuximab (Erbitux ^® ); panitumumab (Vectibix ^® ); matuzumab (EMD-72000); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1), and ch806 (mAb-806, CAS 946414-09-1).

[00401] Inhibitors of the human epidermal growth factor receptor 2 (Her2 receptor) (also known as Neu, ErbB-2, CD340, or p185) include, but are not limited to, trastuzumab (Herceptin ^® ); pertuzumab (Omnitarg ^® ); trastuzumab emtansine (Kadcyla ^® ); neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide and described in PCT Publication No. WO 05/028443); lapatinib or lapatinib ditosylate (Tykerb ^® ); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS 599626, CAS 714971-09-2); canertinib dihydrochloride (PD183805 or CI-1033) and N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8).

[00402] Her3 inhibitors include, but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.

[00403] Met inhibitors include, but are not limited to, cabozatinib (XL184, CAS 849217-68-1); foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); crizotinib (Xalkori ^® , PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindolin-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (MK2461, CAS 917879-39-1); 6-[[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]thio]quinoline (SGX523, CAS 1022150-57-7) and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7).

[00404] IGF1R inhibitors include, but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. For a review, see, e.g., in Yee, JNCI, 104; 975 (2012).

[00405] In another aspect, the present invention provides a method of treating or preventing cancer by administering to a subject in need thereof an antibody-drug conjugate of the present invention in combination with one or more inhibitors of the GNAQ/GNA11 downstream signaling pathway, including but not limited to β-arrestin inhibitors, GRK inhibitors, MAPK inhibitors, PI3K inhibitors, JAK inhibitors, etc.

[00406] For example, phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, idelalisib (Zydelig, GS-1101, Cal-101), 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT Publication No. WO 06/122806); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (also known as BKM120 or NVP-BKM120 and described in PCT Publication No. WO2007/084786); tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5-(acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-cyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8) and 8-phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6).

[00407] In another aspect, the present invention provides a method of treating or preventing cancer by administering to a subject in need thereof an antibody-drug conjugate of the present invention in combination with one or more pro-apoptotic agents, including but not limited to IAP inhibitors, Bcl2 inhibitors, MCl1 inhibitors, Trail agents, Chk inhibitors.

[00408] For example, IAP inhibitors include, but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include, but are not limited to, those disclosed in WO04/005284, WO 04/007529, WO05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US2006/0014700, US2006/0025347, WO 06/069063, WO 06/010118, WO 06/017295, and WO08/134679, all of which are incorporated herein by reference.

[00409] BCL-2 inhibitors include, but are not limited to, venetoclax (also known as GDC-0199, ABT-199, RG7601); 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); tetrocarcin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromone-3-carboxylate (HA14-1); oblimersen (G3139, Genasense ^® ); Bak BH3 peptide; (-)-gossypol acetic acid (AT-101); 4-[4-[(4'-chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl] -N -[[4-[[(1 R )-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9) and navitoclax (ABT-263, CAS 923564-51-6).

[00410] Pro-apoptotic receptor (PARA) agonists, including DR4 (TRAILR1) and DR5 (TRAILR2), include, but are not limited to dulanermin (AMG-951, RhApo2L/TRAIL); mapatumumab (HRS-ETR1, CAS 658052-09-6); lexatumumab (HGS-ETR2, CAS 845816-02-6); apomab (Apomab ^® ); conatumumab (AMG655, CAS 896731-82-1) and tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).

[00411] Checkpoint kinase (CHK) inhibitors include, but are not limited to, 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl- 1H -pyrazol-4-yl)-5-( 3R )-3-piperidinyl-pyrazolo[1,5- a ]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isogranulathimide, debromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1 H -diindolo[1,2,3- fg :3',2',1'- kl ]pyrrolo[3,4- i ][1,6]benzodiazocin-1,3(2 H )-dione (SB-218078, CAS 135897-06-2) and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO: 282)) and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr).

[00412] In a further embodiment of the present invention, there is provided a method of treating or preventing cancer by administering to a subject in need thereof an antibody-drug conjugate of the present invention in combination with one or more immunomodulators (e.g., one or more of a costimulatory molecule activator or an immune checkpoint molecule inhibitor).

[00413] In some embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is selected from an agonist (e.g., agonist antibody or antigen-binding fragment thereof, or soluble fusion protein) OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, STING or CD83 ligand.

[00414] In some embodiments, the immunomodulator is an immune checkpoint molecule inhibitor. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR-beta. In one embodiment, the immune checkpoint molecule inhibitor inhibits PD-1, PD-L1, LAG-3, TIM-3, or CTLA4, or any combination thereof. The term "inhibiting" or "inhibiting" refers to a decrease in a certain parameter, such as activity of a given molecule, for example, immune checkpoint inhibitor. For example, this term refers to inhibition of the activity of, for example, PD-1 or PD-L1 activity by at least 5%, 10%, 20%, 30%, 40%, 50% or more. Thus, inhibition does not necessarily have to be 100%.

[00415] Inhibition of an inhibitory molecule may occur at the DNA, RNA, or protein level. In some embodiments, an inhibitory nucleic acid (e.g., dsRNA, siRNA or shRNA). In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as soluble ligand (eg, Ig binding PD-1 or Ig binding CTLA-4) or an antibody or antigen-binding fragment thereof that binds to an inhibitory molecule; for example, an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR-beta, or a combination thereof.

[00416] In one embodiment, the antibody molecule is a whole antibody or a fragment thereof (e.g., Fab, F(ab')₂, Fv or a single-chain Fv fragment (scFv)). In other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected from, for example, from the constant regions of the heavy chain of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4, more particularly the heavy chain constant region of IgG1 or IgG4 (e.g., IgG1 or IgG4). In one embodiment, the heavy chain constant region is derived from human IgG1 or human IgG4. In one embodiment, the constant region is altered, for example, mutated to modify the properties of the antibody molecule (e.g. (increasing or decreasing one or more of Fc receptor binding, antibody glycosylation, cysteine residue count, effector cell function, or complement function).

[00417] In some embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for PD-1 or PD-L1 and a second binding specificity, such as a second binding specificity for TIM-3, LAG-3 or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. Any combination of the above molecules can be formulated into a multispecific antibody molecule, such as, a trispecific antibody that has a first binding specificity for PD-1 or PD-1 and a second and third binding specificity for two or more of TIM-3, LAG-3, or PD-L2.

[00418] In some embodiments, the immunomodulator is an inhibitor of PD-1, for example human PD-1. In another embodiment, the immunomodulator is a PD-L1 inhibitor, such as PD-L1 of a human. In one embodiment, the PD-1 or PD-L1 inhibitor is an antibody molecule to PD-1 or PD-L1. The PD-1 or PD-L1 inhibitor may be administered alone or in combination with other immunomodulators, such as in combination with a LAG-3, TIM-3 or CTLA4 inhibitor. In an exemplary embodiment, a PD-1 or PD-L1 inhibitor, such as an antibody molecule to PD-1 or PD-L1, administered in combination with a LAG-3 inhibitor, such as an anti-LAG-3 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, such as an antibody molecule to PD-1 or PD-L1, administered in combination with a TIM-3 inhibitor, such as an anti-TIM-3 antibody molecule. In other embodiments, a PD-1 or PD-L1 inhibitor, such as an anti-PD-1 antibody molecule, administered in combination with a LAG-3 inhibitor, such as an antibody molecule to LAG-3, and a TIM-3 inhibitor, for example, an anti-TIM-3 antibody molecule. Other combinations of immunomodulators with a PD-1 inhibitor (e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR) are also contemplated within the present invention. Any of the antibody molecules known in the art or disclosed herein can be used in the above combination of immune checkpoint molecule inhibitors.

[00419] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pidilizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. Patent No. 8,008,449 and PCT Publication No. WO2006/121168.

[00420] In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name KEYTRUDA, formerly lambrolizumab, also known as Merck 3745, MK-3475, or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab is disclosed, for example, in Hamid, O.et al. (2013)New England Journal of Medicine 369 (2): 134-44, PCT Publication No. WO2009/114335 and US Patent No. 8354509.

[00421] In some embodiments, the anti-PD-1 antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in PCT Publication No. WO2009/101611. Other anti-PD1 antibodies are disclosed in U.S. Patent No. 8,609,089, U.S. Patent Application Publication No. 2010028330, and/or U.S. Patent Application Publication No. 20120114649. Other anti-PD1 antibodies include AMP 514 (Amplimmune).

[00422] In some embodiments, the PD-1 inhibitor is PDR001, also known as spartalizumab, or any other PD-1 antibody disclosed in WO2015/112900.

[00423] In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g. an immunoadhesin comprising the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224.

[00424] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as A09-246-2), disclosed, for example, WO 2013/0179174, and has the sequence disclosed therein (or a sequence substantially identical or similar thereto, e.g., a sequence that is characterized by at least 85%, 90%, 95% or higher identity with the specified sequence).

[00425] In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in PCT Publication No. WO2007/005874.

[00426] In one embodiment, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is the PD-L1 antibody described in PCT Publication No. WO 2010/077634 (heavy and light chain variable region sequences are shown as SEQ ID Nos: 20 and 21, respectively).

[00427] In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech/Roche). MDPL3280A is an Fc-optimized human IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human anti-PD-L1 monoclonal antibodies are disclosed in U.S. Patent No. 7,943,743 and U.S. Patent Application Publication No. 20120039906.

[00428] In other embodiments, the PD-L2 inhibitor is AMP-224. AMP-224 is a soluble PD-L2-Fc fusion protein receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Amplimmune; e.g., disclosed in PCT Publication Nos. WO2010/027827 and WO2011/066342).

[00429] In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016. In one embodiment, the LAG-3 inhibitor is LAG525 or any other anti-LAG3 antibody disclosed in WO2015/138920.

[00430] In one embodiment, the TIM-3 inhibitor is an anti-TIM3 antibody molecule. In one embodiment, the TIM-3 inhibitor is MBG453 or any other anti-TIM3 antibody disclosed in WO2015/117002.

Pharmaceutical compositions

[00431] To prepare pharmaceutical or sterile compositions containing immunoconjugates, the immunoconjugates of the present invention are mixed with a pharmaceutically acceptable carrier or excipient. The compositions may further comprise one or more other therapeutic agents that are suitable for the treatment or prevention of cancer expressing PMEL17 (including, but not limited to, subcutaneous melanoma, uveal melanoma, hepatocellular carcinoma, and the metastatic form of these cancers).

[00432] Therapeutic and diagnostic compositions can be obtained by mixing with physiologically acceptable carriers, excipients or stabilizers in the form of, for example, lyophilized powders, suspensions, aqueous solutions, lotions or suspensions (see, For example, Hardmanet al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y., 2001; Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y., 2000; Avis, et al. (eds.), Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY, 1993; Lieberman, et al. (eds.), Pharmaceutical Dosage Forms: tablets, Marcel Dekker, NY, 1990; Lieberman, et al. (eds.) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY, 1990; Weiner and Kotkoskie, Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y., 2000).

[00433] The choice of administration regimen for a therapeutic agent depends on several factors, including the rate of serum or tissue metabolism of the subject, the level of symptoms, the immunogenicity of the subject, and the availability of target cells in the biological matrix. In some embodiments, the administration regimen maximizes the amount of therapeutic agent delivered to the patient consistent with an acceptable level of side effects. Accordingly, the amount of biological agent delivered depends in part on the particular subject and the severity of the condition being treated. Guidelines for selecting appropriate doses of antibodies, cytokines, and small molecules are available (see, For example, Wawrzynczak, Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK, 1996; Kresina (ed.), Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, N.Y., 1991; Bach (ed.), Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, N.Y., 1993; Baert et al., New Engl. J. Med. 348:601-608, 2003; Milgrom et al., New Engl. J. Med. 341:1966-1973, 1999; Slamon et al., New Engl. J. Med. 344:783-792, 2001; Beniaminovitz et al., New Engl. J. Med. 342:613-619, 2000; Ghosh et al., New Engl. J. Med. 348:24-32, 2003; Lipsky et al., New Engl. J. Med. 343:1594-1602, 2000).

[00434] The determination of the appropriate dose is performed by the attending physician, for example, using parameters or factors that are known or expected from the state of the art to affect the treatment or prevention or are predicted to affect the treatment or prevention. Typically, dosing is started at a level slightly below the optimal dose and then increased in small steps until the desired or optimal effect is achieved, compared with any negative side effects. Important diagnostic indicators include, for example, indicators that are symptoms of inflammation, or the level of inflammatory cytokines produced.

[00435] The actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may vary in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response in a particular patient, effective with respect to the composition and route of administration, and not toxic to the patient. The dosage level selected will depend on a number of pharmacokinetic factors, including the activity of the particular compositions of the present invention or ester, salt, or amide thereof used, the route of administration, the time of administration, the rate of elimination of the particular compound used, the duration of treatment, other drugs, compounds, and/or materials used in combination with the particular compositions used, the age, sex, body weight, condition, general health, and medical history of the patient being treated, and similar factors known in the medical art.

[00436] Compositions containing antibodies or fragments thereof of the present invention can be administered by continuous infusion or by doses at intervals of, for example, one day, one week, or administered 1-7 times per week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. Doses may be administered intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, or by inhalation. A specific dosing protocol is one that provides the maximum dose or frequency of dosing that will avoid significant unwanted side effects.

[00437] For the immunoconjugates of the present invention, the dose administered to a patient can be from 0.0001 mg/kg to 100 mg/kg of the patient's body weight. The dose may be from 0.0001 mg/kg to 30 mg/kg, from 0.0001 mg/kg to 20 mg/kg, from 0.0001 mg/kg and 10 mg/kg, from 0.0001 mg/kg to 5 mg/kg, from 0.0001 to 2 mg/kg, from 0.0001 to 1 mg/kg, from 0.0001 mg/kg to 0.75 mg/kg, from 0.0001 mg/kg to 0.5 mg/kg, from 0.0001 mg/kg to 0.25 mg/kg, from 0.0001 to 0.15 mg/kg, from 0.0001 to 0.10 mg/kg, from 0.001 to 0.5 mg/kg, from 0.01 to 0.25 mg/kg or from 0.01 to 0.10 mg/kg of the patient's body weight. The dose of antibodies or fragments thereof according to the present invention can be calculated using the patient's weight in kilograms (kg) multiplied by the dose to be administered in mg/kg.

[00438] Doses of the immunoconjugates of the present invention may be repeated, and the administrations may be separated by less than 1 day, at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, 4 months, 5 months, or at least 6 months. In some embodiments, the immunoconjugates of the present invention may be given twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, or less frequently. In a particular embodiment, doses of the immunoconjugates of the present invention are repeated every 2 weeks.

[00439] The effective amount for a particular patient may vary depending on such factors as the condition being treated, the general health of the patient, the route, route and dose of administration, and the severity of adverse effects (see, For example, Maynardet al., A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla., 1996; Dent, Good Laboratory and Good Clinical Practice, Urch Publ., London, UK, 2001).

[00440] The introduction route may be, for example, topical or cutaneous application, injection or infusion by subcutaneous, intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intraspinal, intralesional route, or by a sustained-release system or implant (see, For example, Sidmanet al., Biopolymers 22:547-556, 1983; Langer et al., J. Biomed. Mater. Res. 15:167-277, 1981; Langer, Chem. Tech. 12:98-105, 1982; Epstein et al.,Proc. Natl. Acad. Sci. USA 82:3688-3692, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030-4034, 1980; U.S. Patent Nos. 6,350,466 and 6,316,024). If desired, the composition may also contain a solubilizing agent and a local anesthetic such as lidocaine to relieve pain at the injection site, or both. In addition, inhalation administration may also be used, such as by using an inhaler or nebulizer and a composition with the agent in the form of an aerosol. See, For example, U.S. Patent Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos. WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated herein by reference in its entirety.

[00441] The composition of the present invention is also administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by one skilled in the art, the route and/or mode of administration will vary depending on the desired results. Selected routes of administration of the immunoconjugates of the present invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intraspinal, or other parenteral routes of administration, such as by injection or infusion. Parenteral administration may represent routes of administration other than enteral and local administration typically accomplished by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. Alternatively, the composition of the present invention may be administered via a route other than parenteral, such as a topical, epidermal, or mucosal route, such as intranasally, orally, vaginally, rectally, sublingually, or topically. In one embodiment, the immunoconjugates of the present invention are administered by infusion. In another embodiment, the immunoconjugates of the present invention are administered subcutaneously.

[00442] If the immunoconjugates of the present invention are administered in a controlled release or sustained release system, a pump may be used to effect the controlled or sustained release (see Langer, above; Sefton, C.R.C. Crit. Ref Biomed. Eng. 14:20, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med. 321:574, 1989). Polymeric materials can be used to effect controlled or sustained release of the therapies of the present invention (see, For example, Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla., 1974; Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York, 1984; Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61, 1983; see also Levy et al., Science 228:190, 1985; During et al., Ann. Neurol. 25:351, 1989; Howard et al., J. Neurosurg. 7 1:105, 1989; U.S. Patent No. 5,679,377; U.S. Patent No. 5,916,597; U.S. Patent No. 5,912,015; U.S. Patent No. 5,989,463; U.S. Patent No. 5,128,326; PCT Publication No. WO 99/15154; and PCT Publication No. WO 99/20253. Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene vinyl acetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), copolymers(lactide and glycolide) (PLGA), and polyorthoesters. In one embodiment, the polymer used in the sustained release formulation is inert, free of leachable impurities, shelf stable, sterile, and biodegradable. The controlled or sustained release system can be placed near the prophylactic or therapeutic target, requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984).

[00443] Controlled release systems are reviewed by Langer, Science 249:1527-1533, 1990). Any technique known to one skilled in the art can be used to prepare sustained release formulations containing one or more immunoconjugates of the present invention. See, For example, US Patent No. 4,526,938, PCT Publication WO 91/05548, PCT Publication WO 96/20698, Ninget al., Radiotherapy & Oncology 39:179-189, 1996; Song et al., PDA Journal of Pharmaceutical Science & Technology 50:372-397, 1995; Cleek et al.,Pro. Int'l. Symp. Control. Rel. Bioact. Mater. 24:853-854, 1997; and Lam et al., Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760, 1997, each of which is incorporated herein by reference in its entirety.

[00444] When the immunoconjugates of the present invention are administered topically, they may be formulated in the form of an ointment, cream, transdermal patch, lotion, gel, spray, aerosol, solution, emulsion, or other form widely known to one of skill in the art. See, For example, Remington's Pharmaceutical Sciences and Introduction to Pharmaceutical Dosage Forms, 19th ed., Mack Pub. Co., Easton, Pa. (1995). In the case of non-sprayable topical dosage forms, viscous-semi-solid or solid forms are generally used, containing a carrier or one or more excipients compatible with topical application and, in some cases, having a dynamic viscosity greater than that of water. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are sterilized if necessary or mixed with excipients (e.g., preservatives, stabilizers, wetting agents, buffers or salts) to influence various properties such as, for example, osmotic pressure. Other suitable topical dosage forms include spray aerosol preparations where the active ingredient, sometimes in combination with a solid or liquid inert carrier, is packaged in a mixture with a volatile substance under pressure (e.g. propellant gas such as freon) or in a spray bottle. If necessary, humectants or wetting agents can also be added to the pharmaceutical compositions and dosage forms. Examples of such additional ingredients are widely known in the art.

[00445] When the compositions containing the immunoconjugates are administered intranasally, they may be formulated in the form of an aerosol, spray, mist, or in the form of drops. In particular, for convenience, the prophylactic or therapeutic agents for use according to the present invention may be delivered in the form of a spray aerosol from pressurized bags or by nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g. consisting of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[00446] Methods of co-administration or treatment using a second therapeutic agent, such as cytokine, steroid, chemotherapeutic agent, antibiotic, or radiation are known in the art (see, For example, Hardmanet al., (eds.) (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10^thed., McGraw-Hill, New York, N.Y.; Poole and Peterson (eds.) (2001) Pharmacotherapeutics for Advanced Practice: A Practical Approach, Lippincott, Williams & Wilkins, Phila., Pa.; Chabner and Longo (eds.) (2001) Cancer Chemotherapy and Biotherapy, Lippincott, Williams & Wilkins, Phila., Pa.). An effective amount of a therapeutic agent can reduce symptoms by at least 10%; at least 20%; at least about 30%; at least 40%; or at least 50%.

[00447] Complementary therapies (eg, prophylactic or therapeutic agents) that can be used in combination with the immunoconjugates of the present invention can be administered at intervals of less than 5 minutes, at intervals of less than 30 minutes, at intervals of 1 hour, at intervals of about 1 hour, at intervals of about 1 to about 2 hours, at intervals of about 2 hours to about 3 hours, at intervals of about 3 hours to about 4 hours, at intervals of about 4 hours to about 5 hours, at intervals of about 5 hours to about 6 hours, at intervals of about 6 hours to about 7 hours, at intervals of about 7 hours to about 8 hours, at intervals of about 8 hours to about 9 hours, at intervals of about 9 hours to about 10 hours, at intervals of about 10 hours to about 11 hours, at intervals of about 11 hours to about 12 hours, at intervals of about 12 hours to 18 hours, at intervals of 18 hours to 24 hours, at an interval of 24 hours to 36 hours, at an interval of 36 hours to 48 hours, at an interval of 48 hours to 52 hours, at an interval of 52 hours to 60 hours, at an interval of 60 hours to 72 hours, at an interval of 72 hours to 84 hours, at an interval of 84 hours to 96 hours, or at an interval of 96 hours to 120 hours from the administration of the immunoconjugates of the present invention. Two or more therapies may be administered during the same patient visit.

[00448] In some embodiments, the immunoconjugates of the present invention may be formulated to ensure precise distributionin vivo. For example, the blood-brain barrier (BBB) does not allow many highly hydrophilic compounds to pass through. To ensure that the therapeutic compounds of the present invention cross the BBB (if necessary), they can be formulated, for example, in liposomes. For methods of making liposomes, see, For example, in U.S. Patents Nos. 4,522,811; 5,374,548 and 5,399,331. Liposomes may contain one or more moieties that are selectively transported to specific cells or organs, thereby improving targeted drug delivery (see, For example, Ranade, (1989) J. Clin. Pharmacol. 29:685). Illustrative targeting moieties include folate or biotin (see, For example, US Patent No. 5,416,016 by Lowet al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (Bloemanet al., (1995) FEBS Lett. 357:140; Owais et al., (1995) Antimicrob. Agents Chemother. 39:180); surface-active protein receptor A (Briscoeet al., (1995) Am. J. Physiol. 1233:134); p 120 (Schreier et al., (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; IJ Fidler (1994) Immunomethods 4:273.

[00449] The present invention provides protocols for administering to a subject in need thereof a pharmaceutical composition comprising the immunoconjugates of the present invention, alone or in combination with other therapies. Therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the present invention may be administered to a subject simultaneously or sequentially. The therapy (e.g., prophylactic or therapeutic agents) of the combination therapies of the present invention may also be administered cyclically. Cyclic therapy involves the administration of a first agent of therapy (e.g., the first prophylactic or therapeutic agent) for a period of time, followed by the introduction of a second therapeutic agent (e.g. a second prophylactic or therapeutic agent) over a period of time and repeating such sequential administration, i.e. cycle, in order to reduce the development of resistance to one of the types of therapy (for example, means), to prevent or reduce the side effects of one of the types of therapy (for example, funds) and/or to improve the effectiveness of types of therapy.

[00450] Types of therapy (eg, prophylactic or therapeutic agents) from the types of combination therapy of the present invention can be applied to a subject simultaneously.

[00451] The term "concurrently" is not limited to the use of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather means that a pharmaceutical composition comprising the antibodies or fragments thereof of the present invention are administered to a subject sequentially and within a time interval such that the antibody-drug conjugates of the present invention can act in concert with the other therapy(s) to provide a greater benefit than if they were administered in a different manner. For example, each therapy can be administered to a subject at the same time or sequentially in any order at different times; however, if they are not administered at the same time, they should be administered close enough in time to provide the desired therapeutic or prophylactic effect. Each therapy can be administered to a subject separately, in any suitable form and by any suitable route. In various embodiments, the therapies (e.g., prophylactic or therapeutic agents) are administered to a subject at intervals of less than 5 minutes, at intervals of less than 15 minutes, at intervals of less than 30 minutes, at intervals of less than 1 hour, at intervals of about 1 hour, at intervals of about 1 hour, at intervals of about 1 hour to about 2 hours, at intervals of about 2 hours to about 3 hours, at intervals of about 3 hours to about 4 hours, at intervals of about 4 hours to about 5 hours, at intervals of about 5 hours to about 6 hours, at intervals of about 6 hours to about 7 hours, at intervals of about 7 hours to about 8 hours, at intervals of about 8 hours to about 9 hours, at intervals of about 9 hours to about 10 hours, at intervals of about 10 hours to about 11 hours, at intervals of about 11 hours to about 12 hours, at intervals of 24 hours, at intervals of 48 hours, at intervals of 72 hours, or at intervals of 1 week. In other embodiments, two or more therapies (e.g., prophylactic or therapeutic agents) are administered during the same patient visit.

[00452] The prophylactic or therapeutic agents of the combination therapy may be administered to the subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapy may be administered to the subject simultaneously in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to the subject via the same or different routes of administration. The prophylactic or therapeutic agents of the combination therapy may be administered to the subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapy may be administered to the subject simultaneously in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to the subject via the same or different routes of administration.

Examples

Example 1: Synthesis of Illustrative Linker-Drug Compounds

Example 1-1: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl (2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B1)

Step 1: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl-(2S,3R)-3-((hydroxyhydrophosphoryl)oxy)-4-methyl-2-propionamidopentanoate (1-1):

[00453] Imidazole (102 mg, 1.49 mmol, 15 equiv) was dissolved in acetonitrile (ACN) (1.4 mL) and cooled in an ice bath (disintegration of ImH was observed and the mixture was lifted out of the ice bath to dissolve ImH) while it remained cold. Phosphorus trichloride (1.0 M in ACN) (499 μL, 0.499 mmol, 5 equiv) was then added dropwise (resulting in a white suspension) and the mixture was stirred for 10 min. Triethylamine (250 μL, 1.796 mmol, 18 equiv) was then added and the mixture was stirred for 40 min to give (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl (2S,3R)-3-hydroxy-4-methyl-2-propionamidopentanoate (A1) (100 mg, 0.100 mmol, 1.0 equiv, compound (A1) by the method described in example 3-1) with the addition of ACN (1.7 mL). The yellowish-orange heterogeneous mixture was warmed to room temperature and stirred for a total of 60 minutes. The mixture was treated with water (0.2 mL) and the material was purified by reverse phase flash chromatography (0-100% ACN/water, 40 gram C18 column, neutral mobile phase), the product fractions were collected and lyophilized to give the H-phosphonate (1-1) as a yellowish-white amorphous powder. LCMS: MH+ = 1066.3, 0.78 min (Acquity UPLC BEH C18 1.7 µm column, 2-98%, 2 min, run with water/MeCN +0.1% NH ₄ OH, basic method).

Step 2: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl (2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B1):

[00454] (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl-(2S,3R)-3-((hydroxyhydrophosphoryl)oxy)-4-methyl-2-propionamidopentanoate(1-1) (100 mg, 0.094 mmol, 1.0 eq.) And (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (108 mg, 0.188 mmol, 2.0 equiv, CAS# 2055041-37-5) (both lyophilized powders) were transferred to a 10 mL vial and dissolved in pyridine (4 mL). Pivaloyl chloride (0.058 mL, 0.469 mmol, 5 equiv) was then added dropwise to give a pale yellow solution. The mixture was stirred at room temperature for 10 min, and then an additional 1.0 equiv of pivaloyl chloride was added. A freshly prepared solution of iodine (47.6 mg, 0.188 mmol, 2.0 equiv.) in pyridine-water (14:1, 750 µL) was added to give a dark brown clear solution. The mixture was stirred for 25 min and directly purified by reverse phase flash chromatography (40 g C-18 column, 0% Ac/MeCN for 3 min, then 0-60% ACN/water for 15 min, neutral mode) to give (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B-1). HRMS; MH+ = 1638.7700, 2.84 min.

Example 1-2: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylp ropyl (2S,3R)-2-acetamido-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methylpentanoate (B2)

Step 1: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl (2S,3R)-2-acetamido-3-((hydroxyhydrophosphoryl)oxy)-4-methylpentanoate (1-2):

[00455] Imidazole (85 mg, 1.25 mmol, 15 equiv) was dissolved in acetonitrile (ACN) (2.5 mL) and cooled in an ice bath (disintegration of ImH was observed and the mixture was lifted out of the ice bath to dissolve ImH) while it remained cold. Phosphorus trichloride (36.4 μL dissolved in 0.5 mL MeCN, 0.417 mmol, 5 equiv) was then added dropwise (resulting in a white suspension) and the mixture was stirred for 10 min. Triethylamine (174 µl, 1.25 mmol, 15 equiv) was then added and the mixture was stirred for 40 min to give (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl (2S,3R)-2-acetamido-3-hydroxy-4-methylpentanoate (A2) (80 mg, 0.084 mmol, 1.0 equiv of compound (A2) by the method described in Example 3-2 with the addition of ACN (1.7 mL). The yellowish-orange heterogeneous mixture was warmed to room temperature and stirred for a total of 30 min. The mixture was treated with water (1 mL) and the material was purified by reverse phase flash chromatography (0-100% ACN/water, 40 gram C18 column, neutral mobile phase), the product fractions were collected and lyophilized to give the H-phosphonate (1-2) as a yellowish-white amorphous powder. LCMS: MH+ = 1024.3, 0.78 min (Acquity UPLC BEH C18 1.7 μm column, 2-98%, 2 min, run with water/MeCN +0.1% NH ₄ OH, basic method).

Stage 2: synthesis (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12 ,16,22-hexameth yl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpr opil-(2S,3R)-2-acetamido-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5 -dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methylpentanoate:

[00456] (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl-(2S,3R)-2-acetamido-3-((hydroxyhydrophosphoryl)oxy)-4-methylpentanoate(1-2) (50 mg, 0.049 mmol, 1.0 eq.) And (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5) (33.7 mg, 0.059 mmol, 1.2 equiv) (both lyophilized powders) were transferred to a 10 mL vial and dissolved in pyridine (1 mL). Then, pivaloyl chloride (0.042 mL, 0.342 mmol, 7 equiv) was added dropwise to give a pale yellow solution. The mixture was stirred at room temperature for 30 min. A freshly prepared solution of iodine (49.6 mg, 0.195 mmol, 4 equiv.) in pyridine-water (20:1, 500 µL) was added to give a dark brown clear solution. The mixture was stirred for 30 min and directly purified by reverse phase flash chromatography (40 g C-18 column, 0% Ac/MeCN for 3 min, then 0-70% ACN/water for 15 min, neutral mode) to give (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B2). HRMS; MH+ = 1595.7200, 2.25 min.

Example 1-3: synthesis (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12 ,16,22-hexameth yl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpro pil-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H -pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B3)

(B3)

[00457] Compound (B3) can be prepared using procedures similar to the methods described in Example 1-1, except for step 1, where compound (A3) (from Example 3-3) is used instead of compound (A1).

Example 1-4: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)- 2-methylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-me tilbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B4)

(B4)

[00458] Compound (B4) was prepared using procedures similar to those described in Example 1-1, except for step 2, where (S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 1949793-46-7) was used instead of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5). HRMS; MH+ = 1594.5400, 2.88 min.

Example 1-5: synthesis (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12 ,16,22-hexa methyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-m ethylpropyl-(2S,3R)-2-acetamido-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methylpentanoate (B5)

(B5)

[00459] Compound (B5) can be prepared using procedures similar to the methods described in Example 1-1, except for Step 1, where Compound (A2) (from Example 3-2) was used instead of Compound (A1), and Step 2, where (S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 1949793-46-7) was used instead of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5).

Example 1-6: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methyl butanamido)-5-ureidopentanamido)benzyl)oxy)(hydroxy)phosphoryl)oxy)-4-methyl-2-propionamidopentanoate (B6)

(B6)

[00460] Compound (B6) can be prepared using procedures similar to the methods described in Example 1-1, except for Step 1, where Compound (A3) (from Example 3-3) was used instead of Compound (A1), and Step 2, where (S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 1949793-46-7) was used instead of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5).

Example 1-7: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)- 2-methylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propane mido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methyl-2-propionamidopentanoate (B7)

[00461] Compound (B7) can be obtained by reacting chloroformate (1-3) with (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5). Chloroformate (1-3) can be obtained by reacting compound (A1) with phosgene.

Example 1-8: synthesis (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12 ,16,22-hexa methyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-m ethylpropyl-(2S,3R)-2-acetamido-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5 -dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methylpentanoate (B8)

(B8)

[00462] Compound (B8) can be obtained using the method described in Example 1-7, except that compound (A2) is used instead of compound (A1).

Example 1-9: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-meth ylpropyl (2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methyl-2-propionamidopentanoate ( B9)

(B9)

[00463] Compound (B9) can be obtained using the method described in Example 1-7, except that compound (A3) is used instead of compound (A1).

Example 1-10: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6 -yl)-2-methylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methyl-2-propionamidopentanoate ( B10)

(B10)

[00464] Compound (B10) can be prepared using the method described in Example 1-7 except that (S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 1949793-46-7) is used instead of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CAS No. 2055041-37-5).

Example 1-11: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl )-2-methylpropyl-(2S,3R)-2-acetamido-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-i l)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methylpentanoate ( B11)

(B11)

[00465] Compound (B11) can be produced using the method described in Example 1-10, except that compound (A2) is used instead of compound (A1).

Example 1-12: Synthesis of (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)- 2-methylpropyl-(2S,3R)-3-((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)oxy)-4-methyl-2-propionamidopentanoate ( B12)

(B12)

[00466] Compound (B12) can be obtained using the method described in Example 1-10, except that compound (A3) is used instead of compound (A1).

Example 2: Obtaining antibodies to PMEL17

Example 2-1: Generation of PMEL17-expressing cell lines

[00467] Full-length human, cynomolgus macaque, and rat PMEL17 genes were synthesized based on amino acid sequences from the GenBank or Uniprot databases. All synthesized DNA fragments were cloned into appropriate expression vectors.

[00468] Engineered cell lines stably expressing PMEL17 were obtained and cultured under selection conditions suitable for obtaining cell lines stably expressing PMEL17.

Example 2-2: Whole-cell panning against PMEL17

[00469] Phagemid libraries are based on the HuCAL PLATINUM ^® (Knappik et al., 2000) and Ylanthia (Tiller et al., 2013) concepts and use CysDisplayTM technology to express Fabs on the phage surface (Lohning, 2001).

[00470] For each panning, approximately 4× ¹⁰¹³ HuCAL ^PLATINUM® phage antibodies or approximately 1× ^{1014 Ylanthia®} phage antibodies were blocked in PBS/5% FCS. In parallel, 0.5-1.0× ¹⁰⁷ target cells expressing PMEL17 antigen and 0.5-1.0× ¹⁰⁷ adsorbent cells without PMEL17 antigen expression per phage pool were resuspended in 1 ml PBS/5% FCS for blocking on ice. Blocked target cells were centrifuged, resuspended in pre-blocked phage particles, and incubated for 2 h at 4°C on a shaker. Phage-cell complexes were washed three times in PBS/5% FCS. Specifically bound phage were eluted from target cells by a 10 min acid elution with 0.1 M glycine-HCl/0.5 M NaCl, pH 2.2. After centrifugation, the supernatant (eluate) was neutralized by adding 2 M unbuffered Tris. To remove phage binding to cell surface molecules other than the target antigen, post-adsorption was performed three times with 0.5-1.0× ¹⁰⁷ adsorption cells each. The final supernatant was used to infect 14 ml of E. coli TG1 culture grown to an OD600 of 0.6-0.8. The culture was incubated for 45 min in a water bath at 37°C for phage infection. The bacterial pellet was resuspended in 2x YT medium, plated on LB/Cam agar plates and incubated overnight at 30°C. Colonies were scraped from the plates and used for phage release and phage amplification. The amplified phage was used for the next round of panning. The second and third rounds of whole-cell panning were performed according to the protocol for the first round.

Example 2-3: Subcloning, expression and screening of Fab fragments

[00471] To ensure rapid expression of soluble Fab, Fab-encoding inserts of the selected HuCAL PLATINUM® phage were subcloned from the ^pMORPH® 30 display vector into the ^pMORPH® x11_FH expression vector. Subcloning was accomplished by triple digestion with EcoRI, XbaI, and BmtI. Following transformation into E. coli TG1-F, expression of individual clones and preparation of periplasmic extracts containing HuCAL® Fab fragments were performed as previously described (Rauchenberger et al., 2003).

[00472] Fab-encoding inserts of the selected Ylanthia® phage were subcloned from the pYPdis10 display vector into the pYBex10_Fab_FH expression vector. Subcloning was accomplished by triple digestion with XbaI, EcoRI-HF, and PstI-HF. Following transformation into E. coli TG1-F, expression of individual clones and preparation of periplasmic extracts containing Ylanthia® Fab fragments were performed as previously described (Rauchenberger et al., 2003).

[00473] Expression of Fab fragments encoded by pMORPH ^® x11_Fab_FH and pYBex10_Fab_FH in E. coli TG1 ^F- cells was performed in shake flask cultures using 500 ml 2x YT medium supplemented with 0.1% glucose and 34 μg/ml chloramphenicol. Cultures were shaken at 30°C until an OD ₆₀₀ value of 0.5 was reached. Fab expression was induced by adding IPTG (isopropyl-β-D-thiogalactopyranoside) at a final concentration of 0.75 mM and further culturing for 20 h at 30°C. Cells were harvested and disrupted using lysozyme. His ₆ -tagged (SEQ ID NO: 267) Fab fragments were isolated using IMAC (Bio-Rad, Germany) and eluted using imidazole. Buffer exchange to 1x Dulbecco's PBS (pH 7.2) was performed using PD10 columns (GE Healthcare, Germany). Samples were sterilized-filtered (0.2 μm). Protein concentrations were determined by UV spectrophotometry. Sample purity was analyzed on a 15% SDS-PAGE gel under denaturing reducing conditions. Homogeneity of Fab preparations was determined in the native state by size exclusion chromatography (HP-SEC) with calibration standards.

[00474] For FACS screening, purified Fabs were titrated on various PMEL17 expressing and PMEL17 non-expressing (control) cell lines. Cells were harvested using Accutase, adjusted to ~4× ¹⁰⁶ cells/mL in FACS buffer (PBS, 3% FCS, and 0.02% sodium azide), and stored on ice to avoid internalization. 15 µL of the cell suspension per well were transferred to 384-well V-bottom plates (Greiner, cat.# 781280) and incubated with 15 µL of Fabs at various concentrations (generally from 200 to 3.5× ^10-3 nM) for 1 h at 4°C with gentle shaking. After incubation, cells were washed three times with FACS buffer. After each wash step, cells were centrifuged (250 xg, 4 min, 4°C) and carefully resuspended. 15 μl of PE-conjugated (PE-conjugated goat anti-human IgG antibody specific for F(ab`)2 fragment, 1:150 in FACS buffer; Jackson Immuno Research, cat. #109-116-097) or Alexa Fluor-conjugated (Alexa Fluor-conjugated goat anti-human IgG antibody specific for F(ab`)2 fragment, 1:150 in FACS buffer; Jackson Immuno Research, cat. #109-606-097) detection antibody were added and samples were incubated for 45 min to 1 h on ice in the dark with gentle shaking. After 3 washing steps, cells were resuspended in 30 µl FACS buffer and samples were measured using the IntelliCyt HTFC instrument.

[00475] To further verify the specificity of the identified antibodies, the antigen was immunologically immobilized from the cell lysate and used as a coating material for ELISA-based screening. Cells expressing PMEL17 and not expressing PMEL17 (used as a negative control) were centrifuged (250 g, 5 min) and resuspended in lysis buffer (MSD Tris Lysis Buffer, Meso Scale Discovery, R60TX-2) containing protease inhibitors (EDTA-free complete protease inhibitor cocktail, Roche, 11 873 580 001) at 1 x 10 ⁷ to 1 x 10 ⁸ cells/mL and incubated for 30 min at 4°C. The lysate was centrifuged at 13,000 rpm for 5 min to remove cell debris and the supernatant was aliquoted and stored at -80°C. Preliminary testing showed that the lysate could be frozen and thawed 3 times without significant loss of signal in the ELISA.

[00476] For ELISA-based screening, IgG to His was immobilized overnight in a 384-well maxisorb plate (R&D systems, MAB050) at 10 μg/ml, 20 μl per well. The plates were blocked with 3% BSA and 20 μl of purified Fab were transferred at different concentrations (mainly from 400 to 0.2 nM) to each well for 1 h. The plate was washed 3 times and 20 μl of cell lysate containing PMEL17 was added at a concentration of 2 x 10 ⁵ lysed cells/well for 1 h. After 3 additional washes, the presence of PMEL17 was detected using a biotinylated PMEL17 antibody (5 μg/ml, 20 μl/well) and streptavidin-ECL (Dianova, 13MSA37, 1:1500, 20 μl/well). 20 μl/well of 1X MSD Reading Buffer (Meso Scale Discovery, R92TC-2) was added to the plate and signals were detected using an MSD Sector Imager 6000.

Example 2-4: Conversion to IgG

[00477] Conversion of selected Fabs to IgG was accomplished using a PCR-based method in a 96-well format. The bacterial Fab expression vectors pMORPH ^® x11_FH and pYBex10_Fab_FH were converted to mammalian IgG expression vectors, pMORPH ^® 4 and pYMex10 (for the HuCAL and Ylanthia clones, respectively).

[00478] Plasmid pMORPHx11_FH DNA was first amplified by PCR using a biotinylated primer specific for the phoA leader region and a non-biotinylated primer specific for the bacterial CL domain. The amplified product was captured on streptavidin beads, digested with BsiWI or HpaI (for clones VLkappa or VLlambda, respectively), washed, and then digested again with MfeI. This procedure resulted in the release of purified vector backbone into the supernatant, which no longer contained the bacterial light chain constant region (CL) and the phoA heavy chain leader sequence. The mammalian kappa or lambda-specific pIN expression cassette was then cloned into a vector backbone carrying the mammalian CL, polyA site, CMV promoter, and mammalian heavy chain leader sequence. In a second PCR step, the newly generated Fab insert was again amplified using a biotinylated primer specific for the CH1 region and a non-biotinylated primer binding within the bacterial ompA leader sequence. The PCR product was captured on streptavidin beads, digested with EcoRV, washed, and digested with BlpI, releasing the purified insert into the supernatant. Finally, the inserts were cloned into the Fab_Cys acceptor vector for expression in mammalian cells.

[00479] The pYBex10_Fab_FH plasmid DNA was first amplified by PCR using a biotinylated primer specific for the phoA leader region and a non-biotinylated primer specific for the bacterial CL domain. The amplified product was captured on streptavidin beads, digested with NheI, washed, and then digested again with KpnI. This procedure resulted in the release into the supernatant of a purified vector backbone that no longer contained the bacterial light chain constant region (CL) and the phoA heavy chain leader sequence. The mammalian kappa or lambda-specific pIN expression cassette was then cloned into the vector backbone carrying the mammalian CL, polyA site, CMV promoter, and mammalian heavy chain leader sequence. In a second PCR step, the newly generated Fab insert was amplified again using a biotinylated primer specific for the CH1 region and a non-biotinylated primer binding within the bacterial ompA leader sequence. The PCR product was captured on streptavidin beads, digested with XhoI, washed and digested with NdeI, releasing the purified insert into the supernatant. Finally, the inserts were cloned into the Fab_Cys acceptor vector for expression in mammalian cells.

[00480] Following transformation of E. coli XL-1 blue cells, individual clones were monitored by colony selection PCR and sequencing of the entire insert region.

Example 2-5: Human IgG confirmatory screening

[00481] Single colony DNA preparations were prepared using the appropriate DNA preparation kit in combination with the ^BioRobot® 8000 instrument. Individual DNA concentrations were determined by UV spectrophotometry. Eukaryotic HEK293 c18 cells (ATCC# CRL-10852) were used in a 96-well expression system to generate conditioned cell culture supernatants containing full-length IgG. Eukaryotic HEK293 c18 cells were seeded in a 96-well flat-bottom plate at a density of ~4× ¹⁰⁴ cells/50 µl/well the day before and transfected with equal amounts of Ig expression vector DNA. After incubation for 40-50 h at 37°C and 6% CO2, the culture supernatants were transferred to a 96-well U-bottom plate and cleared by centrifugation. The resulting Ig supernatants were tested by anti-Fd capture ELISA to calculate the Ig concentration according to known standards and stored at -20°C for subsequent use in specificity and/or functional screening assays.

[00482] DNA of the clones of interest was sequenced with primer CMV_HC_for (CTC TAG CGC CAC CAT GAA ACA (SEQ ID NO: 264)) for the VH domain and IgG_const_for (AGC CCA GCA ACA CCA AGG (SEQ ID NO: 265)) for the Fc domain, followed by sequencing of the light chain with the T7 promoter primer (TAA TAC GAC TCA CTA TAG GG (SEQ ID NO: 266)) to obtain complete IgG sequence information.

[00483] FACS screening was performed in a 384-well plate format using the IntelliCyt HTFC screening platform. Cells were harvested using Accutase, adjusted to ~4 x 10 ⁶ cells/mL in FACS buffer (PBS, 3% FCS, and 0.02% sodium azide), and stored on ice to avoid internalization. 15 µL of cell suspension per well was transferred to 384-well V-bottom plates (Greiner, cat. # 781280) and incubated with 15 µL of supernatant containing IgG (or diluted purified control antibodies) for 1 hour at 4°C with gentle shaking. After incubation, cells were washed three times with FACS buffer. After each wash step, cells were centrifuged (250 x g, 4 min, 4°C) and gently resuspended. 15 μl of PE-conjugated detection antibody (PE-conjugated goat anti-human IgG, specific for F(ab`)2 fragment, 1:150 in FACS buffer; Jackson Immuno Research, cat. #109-116-097) were added and samples were incubated for 45 min to 1 h on ice in the dark with gentle shaking. After 3 wash steps, cells were resuspended in 30 μl of FACS buffer and samples were measured using the IntelliCyt HTFC instrument.

Example 2-6: Production of human IgG and human Fab_Cys

[00484] Eukaryotic HKB11 cells were transfected with the ^pMORPH® 4 or pYMex10 DNA expression vector encoding both IgG heavy and light chains. Cell culture supernatant was harvested at day 3 or 7 post-transfection. Cell culture supernatant was subjected to standard Protein A affinity chromatography (MabSelect SURE, GE Healthcare) and Capture Select IgG-CH1 (BAC) for human IgG and human Fab_Cys, respectively. Unless otherwise stated, buffer exchange was performed with 1x Dulbecco's PBS (pH 7.2, Invitrogen) and samples were sterile filtered (0.2 μm pore size). IgG purity was analyzed under denaturing, reducing, and non-reducing conditions using the Labchip System (GXII, Perkin Elmer, USA) or by SDS-PAGE. Protein concentrations were determined by UV spectrophotometry and HP-SEC was performed to analyze native IgG preparations.

Example 2-7: Production of G1 and G4 antibodies to PMEL17

[00485] For the first round of panning, approximately 4×10 ¹³ HuCAL PLATINUM ^® phage were blocked using PBS/5% FBS. In parallel, 1.0×10 ⁷ target cells expressing PMEL17 antigen and 1.5-3.0×10 ⁷ adsorbent cells without PMEL17 antigen expression per phage pool were resuspended in 1 ml PBS/5% FCS for blocking on ice. To preclear non-specific binding, phage were incubated with 0.5×10 ⁷ adsorbent cells without PMEL17 antigen expression per phage pool for 30 min on ice. After incubation, the cells were pelleted by centrifugation and the supernatant was added to a fresh sample of 0.5 x ¹⁰⁷ adsorption cells without PMEL17 antigen expression. The same incubation conditions were used and the preabsorption was again performed against a fresh sample of 0.5 x ¹⁰⁷ adsorption cells without PMEL17 antigen expression for a total of three preabsorption cycles. After the final preabsorption, the supernatant was added to 1.0 x ¹⁰⁷ target cells expressing PMEL17 antigen and incubated on ice for 2 h with occasional mixing. Phage-cell complexes were washed three times in PBS/5% FCS. Elution of specifically bound phage from target cells was performed by a 10-min acid elution with 0.1 M glycine-HCl/0.5 M NaCl, pH 2.5. After centrifugation, the supernatant (eluate) was neutralized by adding 2 M unbuffered Tris and this eluate was used to infect 14 ml of E. coli TG1 F' culture grown to an _OD600 of 0.6-0.8. The culture was incubated for 20 min at 37°C and then for another 25 min at 37°C with shaking at 200 rpm for phage infection. The bacterial pellets were resuspended in 2x YT medium, plated on LB/chloramphenicol agar plates and incubated overnight at 30°C. Colonies were scraped from the plates and used for phage release and phage amplification. The amplified phage was used for another round of panning. The second and third rounds of panning were performed similarly except that only approximately 1 x 10 ¹² HuCAL phage were used to reduce background and improve preclearance efficiency. After the final round of panning, plasmid DNA was prepared from each phage yield and the Fab-containing inserts were cloned into a bacterial expression vector. Following ligation and transformation, individual colonies were picked by plating in 2XT/chloramphenicol and cultured. Fab expression was induced by adding 0.25 mM IPTG in overnight cultures in 96-well microtiter plates at 25°C. Cell pellets were lysed with 0.1% lysozyme in PBS and then blocked with BSA to a final concentration of 1%. FACS staining was performed on PMEL17 expressing and control cells.

Example 2-8: Apparent affinities of antibodies to PMEL17

[00486] Purified IgGs were titrated on various PMEL17 expressing and non-PMEL17 expressing (control) cell lines to determine EC50 values. Cells were harvested using Accutase, adjusted to ~4× ¹⁰⁶ cells/mL in FACS buffer (PBS, 3% FCS and 0.02% sodium azide) and stored on ice to avoid internalization. 15 µL of cell suspension per well were transferred to 384-well V-bottom plates (Greiner, cat.# 781280) and incubated with 15 µL of IgG at various concentrations (generally from 200 to 3.5× ^10-3 nM) for 1 hour at 4°C with gentle shaking. After incubation, cells were washed three times with FACS buffer. After each washing step, cells were centrifuged (250 x g, 5 min, 4°C) and carefully resuspended. 15 μl of detection antibody conjugated with PE (PE-conjugated goat anti-human IgG specific for F(ab`)2 fragment, 1:150 in FACS buffer; Jackson Immuno Research, cat. #109-116-097) or Alexa Fluor (Alexa Fluor-conjugated goat anti-human IgG specific for F(ab`)2 fragment, 1:150 in FACS buffer; Jackson Immuno Research, cat. #109-606-097) were added and samples were incubated for 45 min to 1 h on ice in the dark with gentle shaking. After 3 washing steps, cells were resuspended in 30 µl FACS buffer and samples were measured using the IntelliCyt HTFC instrument. EC50 values were calculated using Graphpad Prism software. The melanoma cell line G-361 expresses human PMEL17 at a lower level compared to the human PMEL17-overexpressing HKB11 cell line and therefore allows for a more accurate ranking of clones based on their apparent affinity for the cells. Table 3 shows that various EC50 values were achieved, ranging from ~200 pM to ~70 nM.

Table 3. Apparent affinities (FACS, EC50 (nM)) and cross-reactivity of antibodies to PMEL17.

G-361 (PE) G-361 (Alexa Fluor) HKB11-macaque
(Alexa Fluor) HKB11-rat
(Alexa Fluor) B16-F10
(mouse)
(Alexa Fluor) UACC-62 (PE) Cross-specificity profile (based on C14 antibody detection) Y101341 0.4 2.6 1.8 1,2 Negative human/macaque/rat/mouse Y010906 - 2.0 2.0 21.7 139.8 Negative human/macaque/rat/mouse Y010900 - 1.3 1,2 9.3 >100 Negative human/macaque/rat/mouse Y010355 0.5 3.9 0.8 0.8 Negative human/macaque/rat/mouse Y010356 1.6 4.5 1.4 1.4 Negative human/macaque/rat/mouse Y010429 2.5 10.7 1.5 60.2 Negative human/macaque/rat MOR024354 - 1.7 2.1 2.4 >100 Negative human/macaque/rat Y010415 0.3 5.4 0.4 >100 Negative human/macaque/rat Y010903 - 3.2 2.0 5.6 927.5 Negative human/macaque/(mouse) Y010910 - 10.0 3.5 13.7 41.1 Negative human/macaque/(mouse) MOR024353 - 62.8 1.6 7.5 >100 Negative human/macaque Y010417 2.8 6.3 >100 >100 Negative human/macaque

Example 2-9: Cross-reactivity of antibodies to PMEL17

[00487] IgG cross-specificity was assessed in dose-dependent FACS of G-361 (human melanoma), cynomolgus monkey HKB11-PMEL17, rat HKB11-PMEL17, and B16-F10 (mouse PMEL17-expressing melanoma) (Table 3). Testing for G-361 was performed using a PE-labeled detection antibody. In contrast, it was necessary to use an Alexa-Fluor-labeled detection antibody to test candidates on other cell lines in order to achieve detectable signals.

[00488] IgGs have been classified into several epitope groups according to their cross-specificity profiles. However, the different cross-reactivity profiles of IgGs suggest that they target at least 4 epitopes (human/macaque/rat/mouse, human/macaque/rat, human/macaque/mouse, and human/macaque).

Example 2-10: ADC Analysis

[00489] IgGs were tested dose-dependently for their ability to internalize and induce death of various PMEL17-expressing cells, both in the payload ADC assay and after direct conjugation.

[00490] For the ADC payload assay, Fab-ZAP (goat anti-human mAb coupled to saporin; ATS Biotechnology, Cat. #IT-51), which specifically binds to human Fc and is coupled to the cytotoxic element saporin, was used. Cells were harvested using Accutase and adjusted to 5 x 10 ⁴ cells/mL. 50 μL of the cell suspension was transferred per well to a 96-well white flat-bottomed plate (Corning, 3610) and incubated overnight at 37°C, 5% CO2. The following day, candidate antibodies were incubated at various concentrations (most commonly 44 to 7 x 10 ^-3 nM) with Fab-ZAP at 8 nM for 30 min at 37°C. Then 50 μl/well of IgG-Fab-ZAP complexes were added to the target cells. Wells with cells only, cells incubated with IgG candidates only (= 100% viability control) and cells incubated with Fab-ZAP only (to check for non-specific killing by the secondary reagent) were prepared as controls. The final concentrations of IgG ranged from 22 to 3.5 x 10 ^-3 nM and 4 nM Fab-ZAP. The plates were incubated for 72 h at 37 °C and 5% CO2. The number of viable cells was estimated using a CellTiter-Glo (Promega, #G7571) and luminescence was detected with a Tecan Infinite 500. Viability was then normalized to the cells + IgG only control.

[00491] Almost all IgGs could effectively kill G-361 melanoma cells (maximum killing >80%) and showed limited killing of 293T cells not expressing PMEL17 (maximum killing <30%). G-361 killing was also achieved in the EC50 range, which may be related to affinity or epitope. Cross-specificity could also be confirmed for most IgGs reactive with human/macaque/rat/mouse, human/macaque/rat and human/macaque/mouse, i.e., IgGs specific for mouse PMEL17 can also kill B16-F10 (mouse melanoma).

Example 2-11: Construction of antibodies to PMEL17

[00492] In general, all construction processes were performed using PCR-based strategies. The construction processes included the following aspects: germline engineering of antibodies, removal of PTM sites, pI engineering, and codon optimization. Following synthesis and assembly by PCR with overlapping primers, the re-engineered VH and VL fragments were subcloned into the appropriate vector backbones for subsequent IgG expression.

Example 3: Synthesis of compounds A1-A3

Example 3-1: A method for isolating (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-22-isopropyl-3-((R)-1-methoxyethyl)-4,9,10,12,16-pentamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl-(2S,3R)-3-hydroxy-4-methyl-2-propionamidopentanoate (A1) from dried leaves of Ardisia crenata

(A1)

[00493] Compound A1 was isolated by the methods described in Japanese Patent Publication No. JP62283999. Step 1: Extraction: 25 kg of dried Ardisia crenata leaves were ground to a fine powder and extracted with 500 L of methanol. After filtration, the extract was evaporated to dryness. The residue was dissolved in 100 L of ethyl acetate and extracted five times with 100 L of deionized water (sodium chloride was added to improve phase separation). The organic layer was evaporated to dryness. The residue was dissolved in 50 L of acetonitrile/water (9/1) and extracted with 50 L of heptane. The acetonitrile/water layer was evaporated until only water remained. It was then extracted with 50 L of ethyl acetate. The ethyl acetate layer was evaporated to dryness to yield 109 g of crude extract.

[00494] Step 2: Defatting: The crude extract was dissolved in 25 L of acetonitrile/water (9/1) and extracted three times with 25 L of heptane. The acetonitrile/water layer was evaporated until only water remained. It was then extracted with 25 L of ethyl acetate. The ethyl acetate layer was evaporated to dryness to obtain 40 g of crude extract.

[00495] Step 3: Flash chromatography: The crude extract was dissolved in acetone/methanol (1/1), adsorbed onto 100 g Isolute (diatomaceous earth) and evaporated to dryness. Flash chromatography was performed on silica gel with a ternary solvent system with cyclohexane (eluent A), ethyl acetate (eluent B) and methanol (eluent C) (experimental details: column: RediSep Rf 120 g; flow rate: 85 ml/min; gradient: 0 min: 75% A, 25% B, 0% C; 3 min: 75% A, 25% B, 0% C; 10 min: 0% A, 100% B, 0% C; 17.5 min: 0% A, 90% B 10% C; 25 min: 0% A, 50% B, 50% C; 30 min: 0% A, 50% B, 50% C; different segments of the gradient are linearly related in time). Four cycles were performed with 10 g of extract in each. Time fractionation was used and the collected fractions were analyzed using UPLC-UV-MS for the presence of compound (A1). Fractions containing compound (A1) were pooled and evaporated to dryness to yield a fraction of 25 g.

[00496] Step 4: Size exclusion chromatography (SEC): A 25 g fraction was dissolved in 400 ml of methanol and further fractionated by SEC on a column (length 25 cm, diameter 12.5 cm) packed with Sephadex LH20 and methanol as eluent. Fractions of 200 ml each were collected and the collected fractions were analyzed by UPLC-UV-MS for the presence of compound (A1). Fractions containing compound (A1) were pooled and evaporated to dryness to obtain an enriched fraction of 6.2 g.

[00497] Step 5: 1st preparative HPLC: The enriched fraction of 6.2 g was dissolved in 12 mL of methanol/dimethyl sulfoxide (1/1) and further fractionated by preparative HPLC (experimental details: column: Sunfire C18, 30×150 mm, particle size 5 μm; eluent A: deionized water with 0.1% formic acid, eluent B: methanol with 0.1% formic acid; flow rate 60 mL/min; gradient: 0 min: 35% A, 65% B; 0.5 min: 35% A, 65% B; 17 min: 15% A, 85% B; 15.0 min: 0% A, 100% B; 19 min: 0% A, 100% B; 19.1 min: 35% A, 65% B; 20 min: 35% A, 65% B; different segments of the gradient are linearly related in time). Fractionation was initiated by mass spectrometry. Fifteen cycles were carried out with the enriched fraction weighing 410 mg each. Fractions containing compound (A1) were pooled and evaporated to dryness to give a semi-purified fraction weighing 488 mg with a calculated content of compound (A1) of 70%.

[00498] Step 6: ^2nd Preparative HPLC: The semi-purified fraction of 488 mg was dissolved in 4 mL of methanol and further fractionated by preparative HPLC (experimental details: column: X-Select PFP, 19×250 mm, particle size 5 μm; eluent A: deionized water with 0.1% formic acid, eluent B: acetonitrile with 0.1% formic acid; flow rate 30 mL/min; gradient: 0 min: 45% A, 55% B; 0.5 min: 45% A, 55% B; 24 min: 25% A, 75% B; 24.0 min: 0% A, 100% B; 27.5 min: 0% A, 100% B; 27.6 min: 45% A, 55% B; 30.5 min: 45% A, 55% B; different segments of the gradient are linearly related in time). Fractionation was initiated by mass spectrometry. Five cycles were performed with the semi-purified fraction weighing 98 mg each. Fractions containing compound (A1) were pooled and evaporated to dryness to yield 287 mg of compound (A1) with a purity of > 95%.

[00499] Compound (A1): retention time: 4.73 min, molecular formula [M+H]+: C49H76N7O15+, calculated monoisotopic mass [M+H]+: 1002.5394 Da, actual mass: 1002.5391 Da. Experimental details: Column: ACQUITY UPLC BEH C18, 2.1×100 mm, particle size 1.7 μm; eluent A: deionized water with 0.1% formic acid, eluent B: acetonitrile with 0.1% formic acid; flow rate 0.9 mL/min; Linear gradient: 0 min: 95% A, 5% B to 6.4 min: 0% A, 100% B. ¹ H NMR (600 MHz, Acetonitrile- d ₃ ) δ 8.36 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 10.0 Hz, 1H), 7.38-7.22 (m, 6H), 6.94 (d, J = 4.4 Hz, 1H), 6.77 (d, J = 9.9 Hz, 1H), 5.39 (d, J = 9.8 Hz, 1H), 5.34 (dd, J = 8.8, 3.8 Hz, 1H), 5.31-5.25 (m, 2H), 5.21-5.15 (m, 2H), 5.11 (dd, J =9.9, 1.9 Hz, 1H), 4.90-4.84 (m, 1H), 4.70 (q, J =6.9 Hz, 1H), 4.39 (dd, J =7.7, 2.1 Hz, 1H), 4.10 (d, J =9.8 Hz, 1H), 3.82-3.74 (m, 1H), 3.60 (ddd, J =9.8, 4.4, 2.0 Hz, 1H), 3.38 (s, 3H), 3.23 (s, 3H), 3.16-3.11 (m, 1H), 2.94-2.85 (m, 1H), 2.84 (s, 3H), 2.66 (s, 3H), 2.55-2.43 (m, 2H), 2.16 (s, 3H), 1.96-1.90 (m, 1H), 1.89-1.74 (m, 2H), 1.37 (d, J =7.0 Hz, 3H), 1.32 (d, J =6.6 Hz, 3H), 1.19 (d, J =6.5 Hz, 3H), 1.17 (d, J =6.0 Hz, 3H), 1.12 (d, J =7.7 Hz, 3H), 1.06 (d, J =6.8 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.88 (d, J =6.6 Hz, 3H), 0.85 (d, J =7.0 Hz, 3H), 0.77 (d, J =6.5 Hz, 3H).

Example 3-2: Method for preparing (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl (2S,3R)-2-acetamido-3-hydroxy-4-methylpentanoate (A2)

(A2)

Compound (A2) was prepared by the methods described in [M. Taniguchi et al., Tetrahedron 59 (2003) 4533-4538]. Isolation was performed by the methods described for compound (A1) in Example 3-1. The material was then characterized by UPLC-UV-HRMS, 1D-NMR and 2D-NMR experiments. Compound (A2): retention time: 4.20 min, molecular formula [M+H]+: C46H70N7O15+, calculated monoisotopic mass [M+H]+: 960.4924 Da, actual mass: 960.4914 Da. ^1H NMR (600 MHz, _{1,4 -} dioxane _-d8 ) δ 8.36 (d, J =9.2 Hz, 1H), 7.37 (d, J =10.0 Hz, 1H), 7.31-7.21 (m, 4H), 7.21-7.16 (m, 2H), 6.79-6.72 (m, 2H), 5.40-5.37 (m, 1H), 5.36-5.33 (m, 1H), 5.30-5.28 (m, 2H), 5.20 (dd, J =9.0, 3.7 Hz, 1H), 5.13 (d, J =1.9 Hz, 1H), 5.04 (dd, J =9.9, 1.4 Hz, 1H), 4.89-4.82 (m, 1H), 4.73 (q, J =6.9 Hz, 1H), 4.39 (dd, J =8.0, 2.0 Hz, 1H), 4.04 (d, J =9.9 Hz, 1H), 3.80-3.73 (m, 1H), 3.65 (ddd, J =9.8, 4.3, 1.9 Hz, 1H), 3.37 (s, 3H), 3.21 (s, 3H), 3.11 (dd, J =14.7, 3.7 Hz, 1H), 2.89 (dd, J =14.7, 8.9 Hz, 1H), 2.84 (s, 3H), 2.62 (s, 3H), 2.14(s, 3H), 2.12(s, 3H), 1.99-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.35 (d, J =6.8 Hz, 3H), 1.30 (d, J =6.5 Hz, 3H), 1.18-1.14 (m, 6H), 1.11 (d, J =6.5 Hz, 3H), 1.04 (d, J =6.7 Hz, 3H), 0.86 (d, J =6.8 Hz, 3H), 0.78 (d, J =6.6 Hz, 4H).

Example 3-3: Method for preparing (R)-1-((3S,6S,9S,12S,18R,21S,22R)-21-acetamido-18-benzyl-3-((R)-1-methoxyethyl)-4,9,10,12,16,22-hexamethyl-15-methylene-2,5,8,11,14,17,20-heptaoxo-1,19-dioxa-4,7,10,13,16-pentaazacyclodocosan-6-yl)-2-methylpropyl (2S,3R)-3-hydroxy-4-methyl-2-propionamidopentanoate (A3)

(A3)

Compound (A3) was prepared by the methods described in [M. Taniguchi et al. Tetrahedron 59 (2003) 4533-4538]. Isolation was performed by the methods described for compound (A1) in Example 3-1. The material was then characterized by UPLC-UV-HRMS, 1D-NMR and 2D-NMR experiments. Compound (A3): retention time: 4.42 min, molecular formula [M+H]+: C47H72N7O15+, calculated monoisotopic mass [M+H]+: 974.5081 Da, actual mass: 974.5098 Da. ^1H NMR (600 MHz, _{1,4 -} dioxane -d8 ) δ 8.37 (d, J =9.1 Hz, 1H), 7.38 (d, J =9.9 Hz, 1H), 7.31-7.23 (m, 4H), 7.22-7.16 (m, _1H ), 7.12 (d, J =7.7 Hz, 1H), 6.78-6.72 (m, 2H), 5.41-5.33 (m, 2H), 5.32-5.26 (m, 2H), 5.20 (dd, J =8.8, 3.7 Hz, 1H), 5.12 (d, J =2.2 Hz, 1H), 5.04 (dd, J =9.9, 1.7 Hz, 1H), 4.89-4.81 (m, 1H), 4.72 (q, J =7.0 Hz, 1H), 4.40 (dd, J =7.8, 2.1 Hz, 1H), 4.04 (d, J =9.8 Hz, 1H), 3.81-3.73 (m, 1H), 3.68-3.64 (m, 1H), 3.38 (s, 3H), 3.21 (s, 3H), 3.11 (dd, J =14.6, 3.7 Hz, 1H), 2.89 (dd, J =14.7, 8.9 Hz, 1H), 2.83 (s, 3H), 2.62 (s, 3H), 2.51-2.41 (m, 2H), 2.14 (s, 3H), 1.99-1.89 (m, 1H), 1.78-1.68 (m, 1H), 1.34 (d, J =6.9 Hz, 3H), 1.30 (d, J =6.5 Hz, 3H), 1.18-1.14 (m, 6H), 1.13-1.08 (m, 6H), 1.04 (d, J =6.7 Hz, 3H), 0.86 (d, J =6.8 Hz, 3H), 0.78 (d, J =6.6 Hz, 3H).

Example 4: Method for producing anti-PMEL17 antibody-drug conjugates

[00500] The antibody was incubated with RMP protein A resin (GE) at a ratio of 10 mg Ab to 1 ml resin in PBS for 15 min with mixing in a disposable column of appropriate size. Cysteine-HCl was added to a final concentration of 20 mM and incubated with mixing for 30 min at room temperature to allow reactive cysteines to deblock. The resin was quickly washed with 50 column volumes of PBS on a vacuum manifold. The resin was then resuspended in an equal volume of PBS containing 250 nM CuCl ₂ . Conversion of antibody interchain disulfides was monitored at time points. At each time point, 25 μl of the resin suspension were removed, 1 μl of 20 mM compound (B1) or compound (B2) was added and the tube was gently tapped several times. The resin was centrifuged, the supernatant was removed and then eluted using 50 μl of antibody elution buffer (Thermo). The resin was pelleted and the supernatant was analyzed by reverse phase chromatography using an Agilent PLRP-S 4000A, 5 μm, 4.6 x 50 mm column (buffer A is water, 0.1% TFA, buffer B is acetonitrile, 0.1% TFA, the column is maintained at 80°C, flow rate is 1.5 ml/min).

[00501] Once the interchain disulfide bonds of the antibody were determined to be reformed, the resin was washed with 10 column volumes of PBS, resuspended in an equal volume of PBS, and 8 equivalents of the payload with linker (20 mM) in DMSO were added, followed by incubation at room temperature for 2 hours. The resin was then washed with 50 column volumes of PBS. The ADC was eluted from the protein A resin with antibody elution buffer and neutralized with 1/10 volume of 1 M Tris, pH 9.0. The ADC was then buffer exchanged with PBS or another suitable buffer, and preparative size exclusion chromatography was performed if necessary to remove aggregates (S200 Increase; GE). The following analyses were performed: analytical SEC to determine the percentage of monomer, mass spectroscopy to determine DAR, LAL assay to determine endotoxin loading, and protein concentration was determined using the extinction coefficient at A280 and the molecular weight of the antibody.

Example 5: In vitro activity of GNAQ/11 inhibitors, compound (A1) and compound (A2), against uveal melanoma

[00502] Uveal melanoma 92.1 and pancreatic ductal adenocarcinoma MIAPACA cells were seeded at low cell density in 96-well plates and treated with increasing concentrations of compound (A1) or compound (A2) as indicated. After drug treatment for 96 or 120 hours, cell viability and proliferation were determined using a resazurin-based viability assay. Briefly, cells were incubated with a resazurin-based solution and color change was detected by optical density using a spectrophotometer and used to record cell viability. Data are presented as the mean of 3 independent replicates and relative to PBS-treated cells (control). Table 4 shows the 50% growth inhibitory concentration (GI ₅₀ ) for compound (A2) and compound (A1). Compound (A2) and compound (A1) exhibited strong target-dependent activity against UM (Fig. 1).

Table 4. Growth inhibitory activity of compound (A1) and compound (A2) in UM cells

Cell line Mutation Connection (A1)
GI ₅₀ , nM Connection (A2)
GI ₅₀ , nM 92.1 GNAQ ^Q209L 0.18 7.7 MIAPACA WT > 10 µM > 10 µM

Example 6: Compound (A1) and compound (A2) induce apoptosis in uveal melanoma cells

[00503] 92.1 and MIAPACA cells were seeded in 96-well plates (5000 cells/well) and treated with increasing concentrations of compound (A1), compound (A2), and a fixed dose of staurosporine (100 nM, positive control) as indicated. After treatment with the drugs for 96 h, cells were analyzed by fluorescence-activated flow cytometry using an anti-annexin V antibody conjugated to a fluorescent dye. Data are shown as the mean of 3 independent replicates. Compound (A2) and compound (A1) induced apoptosis in UM cells in a GNAQ/11-dependent manner (Figure 2).

Example 7: GNAQ/11 inhibition assay by compound (A1) and compound (A2) in uveal melanoma cells

[00504] 92.1 uveal melanoma cells were treated with increasing concentrations of compound (A1) or compound (A2) as indicated. Following overnight drug treatment, cells were processed to determine IP1 levels using TR-FRET (time-resolved fluorescence resonance energy transfer) or protein levels by Western blotting. Figure 3A shows IP1 levels (nM) in 92.1 cells treated with DMSO (control), compound (A2), or compound (A1). Figure 3B shows the correlation between IP1 levels and relative proliferation in compound (A1)-treated 92.1 cells. Figure 3C shows immunoblots of 92.1 cell samples treated with compound (A1) and compound (A2) to determine the effect on ERK signaling.

Example 8: Metabolic stability and PK parameters of compound (A1)

[00505] The stability of compound (A1) in blood plasma was studied in mouse, rat, monkey and human plasma and compared to buffer. Both the disappearance of compound (A1) (Fig. 4A) and the appearance of a ring-opened form of compound (A1) having the structure of compound (A4) , connections (A6) or connections (A8) (Fig. 4B) were monitored for 24 h. It is evident that the transformation in human plasma occurs somewhat faster than in other species. With the exception of rats, the sum of % of compound remaining (A1) and % of compound formed (A8) is stoichiometry within 24 h, indicating that no other transformations appear to play a significant role (Fig. 4C).

[00506] The PK of compound (A1) following intravenous administration to mice was characterized by very high clearance and moderate to large volume of distribution. There was a somewhat disproportionate increase in exposure over the dose range of 0.2-0.8 mg/kg (Figure 4D). Table 5 below summarizes all PK parameters.

Table 5. PK values of compound (A1)

Dose (mg/kg) 0.2 0.4 0.8 Cmax (nM) 31 83 240 Cmax/D (nM/(mg/kg)) 156 208 300 AUCinf (nM*h) 16 47 137 AUCinf/D (nM*h/(mg/kg)) 82 118 171 C0 (nM) 43 108 380 C0/D (nM/(mg/kg)) 217 270 475 CL [ml/min/kg] 204 141 97 Vss [l/kg] 8.6 4.9 4.6

Example 9: Metabolic stability and PK parameters of compound (A2)

[00507] The in vitro stability of Compound (A2) was tested in plasma and in the blood of different species (Figure 5A). Compound (A2) showed acceptable chemical stability in three different systems (Figure 5B). The PK of Compound (A2) in female balb/c mice showed high clearance and a short half-life (Figure 5C). Table 6 summarizes some of the PK values. Compound (A2) showed high intrinsic clearance in mouse, rat, and human liver microsomes, but low clearance in hepatocytes, likely due to limited membrane permeability (Table 7). Incubation of Compound (A2) with liver S9 fraction and with plasma showed similar half-lives. Compound (A2) and Compound (A1) were stable in buffer at pH 5.6 and in lysosomes for 4 h (Figure 5D).

Table 6. PK parameters of compound (A2) in female balb/c mice (1 mg/kg i.v.)

CL (ml⋅min ^-1 ⋅kg ^-1 ) 175 ± 29 t _1/2 (h) 0.4 ± 0.01 AUC i.v. d.n. (nM⋅h) 101 ± 16

Table 7. Connection stability (A2)

Mouse Rat Human Liver microsomes (µl/min/kg) 107 33 44 Hepatocytes (µl/min/10 ⁶ cells) - 8 <4 t1/2 (h) in liver S9 (+/- NADPH) 1.9 / >2 >2 / >2 1.9 / >2 t1/2 (h) in blood plasma 2.1 4.1 2.0

Example 10: In vitro activity of PMEL17-(B1) ADC against uveal melanoma

[00508] Parental and untreated control (NT) or PMEL17-shRNA-transduced 92.1 cells were seeded at low cell density in 96-well plates and treated with increasing concentrations of 3207-(B1) (isotype control), G4-(B1), and G1-(B1) in the presence or absence of doxycycline as indicated. Following drug treatment for 96 or 120 hours, cell viability and proliferation were determined using a resazurin-based viability assay. Briefly, cells were incubated with a resazurin-based solution and color change was detected by optical density using a spectrophotometer and used to record cell viability. Data are presented as the mean of 3 independent replicates and relative to PBS-treated cells (control) (Figure 6). ADCs to PMEL17-(B1) inhibit uveal melanoma cell proliferation in a PMEL17- and dose-dependent manner.

Example 11: ADC to PMEL17-(B1) induces apoptosis in uveal melanoma cells

[00509] 92.1 cells were seeded in 96-well plates (5000 cells per well) and treated with increasing concentrations of compound (A1), 3207-(B1) (isotype control), G4-(B1), and G1-(B1) as indicated. After treatment with drugs for 96 h, cells were analyzed by fluorescence-activated flow cytometry using an anti-annexin V antibody conjugated to a fluorescent dye. Data are presented as the mean of 3 independent replicates. Both G4-(B1) and G1-(B1) induced apoptosis in 92.1 cells in a dose-dependent manner (Fig. 7).

Example 12: In vitro activity of PMEL17-(B2) ADC and PMEL17 mAb against uveal melanoma

[00510] Uveal melanoma 92.1 cells were seeded at low cell density in 96-well plates and treated with increasing concentrations of 3207-(B2) (isotype control), G4-(B2), and G1-(B2), and anti-PMEL17-G1 and -G4 mAbs as indicated. Following drug treatment for 96 or 120 hours, cell viability and proliferation were determined using a resazurin-based viability assay. Data are presented as the mean of 3 independent replicates and relative to PBS-treated cells (control) (Figure 8). Anti-PMEL17-(B2) ADC and anti-PMEL17 mAb exhibited minimal antiproliferative effects in uveal melanoma cells.

Example 13: GNAQ/11 inhibition assay using anti-PMEL17-(B1) and anti-PMEL17-(B2) ADCs in uveal melanoma cells

[00511] 92.1 uveal melanoma cells were treated with DMSO, compound (A1) (8 nM), and increasing concentrations of isotype-(B1), anti-PMEL17-(B1), and anti-PMEL17-(B2) ADCs as indicated. Following 2 days of drug treatment, cells were processed for IP1 levels using TR-FRET (time-resolved fluorescence resonance energy transfer). IP1 levels (nM) are the average of 3 independent replicates. Both G1-(B1) and G1-(B2) inhibited mutant GNAQ and GNA11 in a dose-dependent manner, as evidenced by decreased IP1 levels (Figure 9).

Example 14: Binding assay of PMEL17 antibodies to intact platelets and uveal melanoma cells

[00512] Uveal melanoma cell line 92.1 and platelets isolated from human platelet-rich plasma (PRP from 3 human donors) were analyzed by fluorescence-activated flow cytometry using PMEL17 antibodies G1 (black line) and G4 (gray line) and a fluorescent dye-conjugated anti-human IgG secondary antibody or the conjugated secondary antibody alone (light gray line) (Fig. 10). Unlike uveal melanoma 92.1 cells, human platelets do not exhibit cell surface expression of PMEL17.

Example 15: Effect of Compound (A1) and ADC to PMEL17-(B1) on Human Platelet Aggregation

[00513] Human platelet-rich plasma (PRP) was incubated with ADC 17A9-(B1), B1-conjugated anti-PMEL Ab, or compound (A1) (0.1, 1, and 150 nM) for 4, 16, or 24 h. Platelet aggregation was then measured following treatment with thrombin receptor activating peptide 6 (TRAP6) at a concentration of 32 μM. While compound (A1) induced platelet aggregation, anti-PMEL17-(B1) antibody did not induce platelet aggregation over 24 h (Fig. 11).

Example 16: ADC to PMEL17-(B1) Inhibits Tumor Growth in a Mouse Model

[00514] Female nude mice bearing subcutaneous 92.1 luciferase xenografts were treated with a single i.v. injection of 3207-(B1), G1-(B1), or vehicle at the indicated doses. Treatment (single i.v. injection) was performed 17 days after tumor inoculation. Values are mean ± SEM; sample size (n=5-12 mice per group). Initial tumor volume at day 0 was approximately 200-250 mm ³ . G1-(B1) inhibited tumor growth in a dose-dependent manner (Fig. 12A).

[00515] Changes in body weight of female naive nude mice following G1-(B1) treatment were monitored at the indicated doses. Treatment (single i.v. injection) was performed on day 0. Values are mean ± SEM; sample size (n=4 mice per group). Initial body weight on day 0 was approximately 24 g. Body weight was measured daily for 14 days following drug treatment. No loss of body weight was observed for 14 days following treatment (Figure 12B).

[00516] Immunohistochemistry was performed on tumor tissue from subcutaneous 92.1 luciferase xenografts treated with vehicle, 3207-(B1) (7.5 mg/kg body weight), or G1-(B1) (7.5 mg/kg body weight). Tumors were fixed in 10% (v/v) neutral-buffered formalin for 24 h at room temperature, then washed with PBS, processed for dehydration, cleared, and embedded in paraffin. 3-μm-thick sections were prepared and processed for hematoxylin and eosin (H&E) staining and immunohistochemistry. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue sections using the Bond-RX (Leica), a fully automated staining system for anti-hIgG (ThermoFischer) and anti-gp100 (PMEL17) (clone EP4863; Abcam) and the Discovery XT (Ventana Medical System), a fully automated staining system for anti-Ki67 (clone Sp6; NeoMarkers), anti-pERK1/2 (clone D13.14.4E; Cell Signaling), anti-MITF (Sigma), and anti-cleaved caspase-3 (Cell Signaling). Briefly, G1-(B1) treatment resulted in inhibition of GNAQ signaling and inhibition of tumor cell proliferation, as evidenced by decreased pERK and Ki67 levels, respectively (Fig. 12C). Furthermore, G1-(B1) induced cell apoptosis compared to vehicle and 3207-(B1)-treated mice, which correlated with the accumulation of G1-(B1) ADC in tumor cells, detected by IgG staining (Fig. 12C). No changes in MITF and PMEL17 levels were observed after G1-(A1) treatment (Fig. 12C).

[00517] Whole blood platelet aggregation was tested in naive mice treated with vehicle, G1-(B1) (20 mg/kg body weight), or compound (A1) (0.01, 0.03, 0.1, and 0.3 mg/kg body weight). Animals were sacrificed 5 min after a single i.v. administration and blood was collected via the vena cava. Whole blood aggregation was measured 1 h later after platelet activation with 6.5 μM ADP (Fig. 12D). Unlike compound (A1), G1-(B1) did not have any significant effect on ADP-induced platelet aggregation in vivo.

[00518] Whole blood platelet aggregation was measured in naive mice treated with vehicle and G1-(B1) (7.5 and 30 mg/kg body weight) at 24 hours or 7 days post-dose. Mice were sacrificed at 24 hours or 7 days after a single i.v. injection and blood was collected via the vena cava. Whole blood aggregation was measured 1 hour later following platelet activation with 6.5 μM ADP. Mice treated with G1-(B1) showed no inhibition of platelet aggregation over 7 days (Fig. 12E).

Example 17: Effect of G1-(B1) on a mouse model of uveal melanoma with liver and lung metastases

[00519] Female NOD-Scid mice were injected intravenously with 92.1 luciferase-laced cells (approximately 2 million cells per animal) and bioluminescence was measured twice weekly to assess tumor formation. After 45 days, all injected mice had developed liver and lung metastases as detected by bioluminescence signal (BLI) (Figs. 13A and 13B). Tumor-bearing mice were treated with a single intravenous injection of G1-(B1) (20 mg/kg body weight) and bioluminescence was monitored over time as an indicator of tumor progression. Individual images from each mouse are shown at day 45 post-injection of 92.1 luciferase-laced cells (immediately prior to treatment initiation) and 12 days post-treatment (Figs. 13A and 13B); sample size (n=6 mice per group). The baseline BLI for liver metastases at day 0 was approximately 2.8*10 ⁹ photons/sec/cm ² . Lung tumors (bioluminescence signal) are indicated by the black arrow in Fig. 13B. The reduction in bioluminescence in vivo and ex vivo indicates that G1-(B1) induced regression of liver and lung metastases after a single 20 mg/kg i.v. dose.

[00520] The corresponding change in body weight (% from day 15) was assessed 2-3 times per week before and after treatment with 20 mg/kg G1-(B1) (gray circles). Values are mean ± SEM; sample size (n=5-6 mice per group). The initial body weight at day 15 was approximately 21 g. Treatment with G1-(B1) resulted in restoration of body weight in the uveal melanoma model with liver and lung metastases.

Example 18: PK indicators ADC G1-(B1).

[00521] The pharmacokinetic profile of G1-(B1) showed a somewhat disproportionate increase in exposure from 7.5 to 30 mg/kg in nude mice (Fig. 14A). Clearance, volume of distribution, and half-life were within the typical range for an ADC. Table 8 summarizes some PK parameters.

[00522] Free payload concentrations were measured in tumor-bearing mice following administration of either the target-binding G1-(B1) or the isotype control 3207-(B1). A marked (>4-fold) increase in tumor payload delivery of compound (A1) could be observed with the targeting ADC (Figure 14B). Conversion of compound (A1) (open circles) to its ring-opened form of compound (A1) having the structure of compound (A4) , connections (A6) or connections (A8) (filled circles), when conjugated to antibody, was shown in vivo in mice (Fig. 14C). Exposure modes in an in vivo efficacy study comparing two different DAR2 formats with the DAR4 format for G1-(B1) and the Fc-silenced DAR4 format showed the lowest clearance for the DAR2(E152C) ADC and the Fc-silenced DAR4, while the exposure of DAR2(S375C) decreased faster (Fig. 14D). From the comparison of the PK of untargeted 3207-ADC (Fig. 14E), it can be concluded that Fc silencing has a significant impact on reducing the clearance of the DAR4 format.

Table 8. PK-indicators of ADC G1-(B1)

"Nude" mice - dose (mg/kg) 7.5 30 AUC _last (mcg/ml*h) 6`779 ± 1`061 45`346 ± 3`785 AUC _last (mcg/ml*h) with normalized dose 904 1`511 AUC <sub>inf</sub> (mcg/ml*h) 9`211 ± 2`337 73`680 ± 9`867 AUC extrap. (%) 25 ± 9 38 ± 3 CL (ml/h/kg) 0.9 ± 0.3 0.4 ± 0.05 Vz (l/kg) 0.21 ± 0.01 0.15 ± 0.01 approx. t _elim. (h) 176 ± 37 259 ± 25

Example 19: In vitro stability of ADC to PMEL17-GNAQ/11i in buffer, mouse, rat and human plasma and in vivo stability of ADC to PMEL17-GNAQ/11i in mice

[00523] Anti-PMEL17G1_E152C_S375C_(B2) (G1-(B2)) antibody was added at a concentration of 100 μg/mL to the appropriate matrix and incubated at 37ºC. Samples were collected at 0, 1, 2, and 4 hours and snap frozen at -70ºC. Aliquots of each sample were immunoprecipitated using Capture Select FcXL beads and incubated with papain-containing buffer to release the payload from the ADC captured on the beads. The released payload was then analyzed by HPLC MS to determine the relative levels of (A2)-PO ₄ (i.e., from , see example 1.2) and the ring-opened compound (A2)-PO ₄ having the structure of the compound (A5)-PO ₄ (i.e. the compound (A5)-PO ₄ from ), compounds (A7)-PO ₄ or compounds (A9)-PO ₄ (where the ring-opened (A2)-PO ₄ compound is the inactive payload). The graph shows the percentage of released payload that was present as the (A2)-PO ₄ compound throughout the experiment (Fig. 15A).

[00524] Anti-PMEL17G1_E152C_S375C_(B1) antibody (G1-(B1)), anti-PMEL17G1_E152C_(B1) antibody (G1-E152C-DAR2-(B1)), anti-PMEL17G1_S375C_(B1) antibody (G1-S375C-DAR2-(B1)) and Fc-silenced anti-PMEL17G1_E152C_S375C_(B1) antibody (Fc-silenced G1-(B1)) were added at a concentration of 100 μg/mL to the appropriate matrix and incubated at 37ºC. Samples were collected at 0, 2, 4 and 6 hours and snap frozen at -70ºC. Aliquots of each sample were immunoprecipitated using Capture Select FcXL beads and incubated with papain-containing buffer to release the payload from the ADC captured on the beads. The released payload was then analyzed by HPLC MS to determine the relative levels of (A1)-PO ₄ and the ring-opened compound (A1)-PO ₄ having the structure of the compound (A4)-PO ₄ , compounds (A6)-PO ₄ , or compounds (A8)-PO ₄ (where the compounds (A1)-PO ₄ with an open ring (represent the inactive payload). The graph shows the percentage of released payload that was present as the (A1)-PO ₄ compound throughout the experiment for each of the different ADC designs (Fig. 15B).

[00525] Each anti-PMEL17G1_E152C_S375C_(B1) antibody (G1-(B1)), anti-PMEL17G1_E152C_(B1) antibody (G1-E152C-DAR2-(B1)), anti-PMEL17G1_S375C_(B1) antibody (G1-S375C-DAR2-(B1)) and Fc-silenced anti-PMEL17G1_E152C_S375C_(B1) antibody (Fc-silenced G1-(B1)) were administered intravenously to nude mice at a dose of 20 mg/kg (body weight). Nine mice were dosed with each of the ADC constructs described above. Three animals per group (ADC-based construct) were bled after sacrifice to collect serum samples for analysis at 24 h, 7, and 14 days post-dose. Aliquots of each sample were immunoprecipitated using Capture Select FcXL beads and incubated with papain-containing buffer to release the payload from the ADC captured on the beads. The released payload was then analyzed by HPLC MS to determine the relative levels of (A1)-PO ₄ and the ring-opened compound (A1)-PO ₄ having the structure of the compound (A4)-PO ₄ , compounds (A6)-PO ₄ or compounds (A8)-PO ₄ (where the ring-opened (A1)-PO ₄ compounds represent the inactive payload). The graph shows the percentage of payload present on the ADC in the active form of (A1)-PO ₄ (assuming (A1)-PO ₄ + (A8)-PO ₄ = 100%) (Fig. 15C). The baseline values were estimated from the in vitro experiments.

Example 20: In vivo efficacy of G1-E152C-DAR2-(B1), G1-S375C-DAR2-(B1), Fc-silenced G1-(B1) in a uveal melanoma xenograft model

[00526] Female nude mice bearing subcutaneous 92.1 luciferase xenografts were treated with 3207-E152C_S375C-DAR4-(B1), G1-E152C_S375C-DAR4-(B1), G1-E152C-DAR2-(B1), G1-S375C-DAR2-(B1), Fc-silenced 3207-(B1), and Fc-silenced G1-DAR4 at 7.5 mg/kg. Treatments (single i.v. injection) were given 17 days after tumor inoculation. Values are presented as mean ± SEM; sample size (n=5-6 mice per group). The initial tumor volume at day 0 was approximately 300-325 ^mm3 (Fig. 16). G1-E152C-DAR2-(B1), Fc-silenced G1-DAR4, and G1-E152C_S375C-DAR4-(B1) exhibited comparable antitumor activity in the 92.1 uveal melanoma xenograft model, whereas G1-S375C-DAR2-(B1) and non-targeted 3207-ADC had no effect on tumor growth.

Example 21: In vitro activity of G1-3J-DAR4-(B1), G1-3R-DAR4-(B1), G1-DAR4-(B1), G1-3J-DAR2(E152C)-(B1), Fc-silenced G1-3J-DAR2(E152C)-(B1), 3207-DAR2(E152C)-(B1) and G1-DAR2(E152C)-(B1)

[00527] In Fig. 17A, 92.1 (left panel) and MP41 (right panel) cells were seeded at low cell density in 96-well plates and treated with increasing concentrations of G1-3J-DAR4-(B1), G1-3R-DAR4-(B1), G1-DAR4-(B1) as indicated. Following drug treatment for 96 or 120 hours, cell viability and proliferation were determined using a resazurin-based viability assay. Briefly, cells were incubated with a resazurin-based solution and color change was detected by optical density using a spectrophotometer and used to record cell viability. Data are presented as the average of 3 independent replicates and relative to PBS-treated cells (control). The GI50 value (concentration for 50% maximal inhibition of cell proliferation) for each ADC and cell line is shown in Table 9. ADCs to PMEL17-(B1) inhibited uveal melanoma cell proliferation in a PMEL17- and dose-dependent manner.

Table 9. Growth inhibitory activity of G1-3J-DAR4-(B1), G1-3R-DAR4-(B1), G1-DAR4-(B1) in UM cells

Cell line G1-3J-DAR4-(B1)
GI ₅₀ , nM G1-3R-DAR4-(B1)
GI ₅₀ , nM G1-DAR4-(B1)
GI ₅₀ , nM 92.1 0,850 0.811 0.722 MP41 0.582 0.654 0.563

[00528] Figure 17B shows the results of a cell proliferation assay in cell line 92.1 using G1-3J-DAR2(E152C)-(B1), Fc-silenced G1-3J-DAR2(E152C)-(B1), 3207-DAR2(E152C)-(B1), and G1-DAR2(E152C)-(B1) described in Figure 17A. The GI50 is shown in Table 10.

Table 10. Growth inhibitory activity of G1-3J-DAR2(E152C)-(B1), Fc-silenced G1-3J-DAR2(E152C)-(B1), 3207-DAR2(E152C)-(B1), and G1-DAR2(E152C)-(B1) in UM cells

Cell line G1-3J-DAR2 (E152C)-(B1)
GI ₅₀ , nM Fc-silent G1-3J -DAR2 (E152C)-(B1)
GI ₅₀ , nM 3207-DAR2 (E152C)-(B1)
GI ₅₀ , nM G1-DAR2 (E152C)-(B1)
GI ₅₀ , nM 92.1 0.309 0.278 >150 0.365

Example 22: ADC to PMEL17-(B1) Inhibits Tumor Growth in a Mouse Model

[00529] Female nude mice bearing subcutaneous 92.1 luciferase xenografts were treated with a single intravenous injection of 3207-(B1), G1-3J(E152C), G1-3J-DAR2(E152C)-(B1), Fc-silenced G1-3J-DAR2(E152C)-(B1), G1-DAR2(E152C)-(B1), or vehicle at the indicated doses. Treatment (single intravenous injection) was performed 14-17 days after tumor inoculation. Values are mean ± SEM; sample size (n=5-12 mice per group). Initial tumor volume at day 0 was approximately 200-250 mm3. G1-3J-DAR2(E152C)-(B1) and Fc-silenced G1-3J-DAR2(E152C)-(B1) inhibited tumor growth in a dose-dependent manner (Fig. 18).

Example 23: Immunohistochemical analysis of tumor biopsies from patients with metastatic uveal melanoma

[00530] Tumors were fixed in 10% (v/v) neutral buffered formalin for 24 h at room temperature, then washed with PBS, processed for dehydration, cleared, and embedded in paraffin. 3 μm thick sections were prepared and processed for immunohistochemistry. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue sections using a fully automated Bond-RX system (Leica) to stain with anti-gp100 (PMEL17) antibodies (mouse monoclonal HMB45). Metastatic uveal melanoma samples exhibited high and relatively uniform expression of PMEL17 (Fig. 19A). Quantification of PMEL17 expression levels and the proportion of PMEL17-positive cells in metastatic uveal melanoma patient samples (Fig. 19B, Fig. 19C).

Example 24: Competitive Binding Analysis

[00531] SPR was used for epitope-specific sorting of PMEL antibodies on a T200 Biacore instrument (Cat. #28975001, GE Healthcare Life Sciences).

[00532] Surface plasmon resonance (SPR) is a method for measuring bimolecular interactions in real time in a label-free environment. Molecules are immobilized on a sensor surface over which a sample solution is passed. The interaction between the immobilized molecule and the passed sample causes a change in the refractive index. The change in the refractive index is a change in the angle with which low-intensity polarized light is reflected from a glass plane, which is a substrate. This change in angle is caused by the binding or dissociation of molecules from the sensor surface, proportional to the mass of the bound material, and is recorded by the device on a sensogram. The sensogram shows an increasing response as the molecules interact, the response remains constant if the interaction reaches equilibrium, and the response decreases when the sample is replaced with a buffer and the interaction partners dissociate. From the responses of association and dissociation events, the association rate (ka), the dissociation rate (kd), and the total affinity (KD) are determined. For epitope-specific sorting, KDs have not been determined.

[00533] In the first step, the G1 LC 3J and 17A9 antibodies were directly immobilized on the surface of the CM5 chip via amino group immobilization to achieve approximately 2000 RU on flow cell 2 and flow cell 3, respectively. Flow cell 1 had no antibody immobilized on it and served as the reference Fc. The immobilized antibodies on Fc2 and Fc3 are the main antibodies in this experiment.

[00534] Following immobilization, human PMEL was passed in a second step at 20 nM through all flow cells for 60 seconds at 30 µL/min.

[00535] In the third and final step, either the G1 LC 3J antibody alone, or the G1 LC 3J antibody with the 17A9 antibody, or the 17A9 antibody alone, or the 17A9 antibody with the G1 LC 3J antibody, was passed through Fc2 (Fig. 20A). The antibodies were passed at a total concentration of 500 nM through both flow cells for 120 seconds at 30 μl/min for association, followed by a dissociation phase of 120 seconds at 30 μl/min with running buffer.

[00536] As expected, when G1 LC 3J was the primary antibody, no binding signal was observed when G13J was passed. Binding of 100 RU was observed when 17A9 was passed, suggesting that it binds to a different epitope than G1 LC 3J (Figure 20B). Similar trends were observed when 17A9 was the primary antibody. In step 3, no binding to itself was observed, but binding was observed when G1 LC 3J was passed (Figure 20C). This indicates that G1 LC 3J and 17A9 bind to different epitopes.

[00537] Regeneration was performed at the end of each cycle on all flow cells. The regeneration buffer was Glycine 2.0, which was passed at 30 μl/min for 30 seconds.

[00538] Data were analyzed using Biacore T200 Evaluation software version 3.0.

[00539] It should be understood that the examples and embodiments described herein are intended for illustrative purposes only and that various modifications or changes in context thereof will occur to those skilled in the art and are intended to be included within the spirit and scope of the present application and the scope of the appended claims.

--->

SEQUENCE LIST

<110> NOVARTIS AG

<120> ANTIBODIES TO PMEL17 AND CONJUGATES BASED ON THEM

<130> PAT058359-WO-PCT

<140>

<141>

<150> 62/803,110

<151> 2019-02-08

<150> 62/783,565

<151> 2018-12-21

<160> 282

<170> PatentIn version 3.5

<210> 1

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 1

Gly Gly Thr Phe Ser Asp Tyr Ala Ile Thr

1 5 10

<210> 2

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 2

Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 3

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 3

Glu Gly Gly Leu Leu Thr Asp Ile Ser Tyr Ser Arg Tyr Trp Phe Ala

1 5 10 15

Tyr

<210> 4

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 4

Asp Tyr Ala Ile Thr

1 5

<210> 5

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 5

Gly Gly Thr Phe Ser Asp Tyr

1 5

<210> 6

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 6

Ile Pro Ile Phe Gly Thr

1 5

<210> 7

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 7

Gly Gly Thr Phe Ser Asp Tyr Ala

1 5

<210> 8

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 8

Ile Ile Pro Ile Phe Gly Thr Ala

1 5

<210> 9

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 9

Ala Arg Glu Gly Gly Leu Leu Thr Asp Ile Ser Tyr Ser Arg Tyr Trp

1 5 10 15

Phe Ala Tyr

<210> 10

<211> 126

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 10

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr

20 25 30

Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Leu Leu Thr Asp Ile Ser Tyr Ser Arg Tyr Trp

100 105 110

Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 11

<211> 378

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 11

caggtgcaat tggtgcagag cggtgccgaa gtgaaaaaac cgggcagcag cgtgaaagtt 60

agctgcaaag catccggagg gacgttttct gactacgcta tcacttgggt gcgccaggcc 120

ccgggccagg gcctcgagtg gatgggcggt atcatcccga tcttcggcac tgcgaactac 180

gcccagaaat ttcagggccg ggtgaccatt accgccgatg aaagcaccag caccgcctat 240

atggaactga gcagcctgcg cagcgaagat acggccgtgt attattgcgc gcgtgaaggt 300

ggtctgctga ctgacatctc ttactctcgt tactggttcg cttactgggg ccaaggcacc 360

ctggtgactg ttagctca 378

<210> 12

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 12

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr

20 25 30

Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Leu Leu Thr Asp Ile Ser Tyr Ser Arg Tyr Trp

100 105 110

Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr

130 135 140

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

145 150 155 160

Cys Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

165 170 175

His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

180 185 190

Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile

195 200 205

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val

210 215 220

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

225 230 235 240

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr

355 360 365

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro Gly Lys

450 455

<210> 13

<211> 1368

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 13

caggtgcaat tggtgcagag cggtgccgaa gtgaaaaaac cgggcagcag cgtgaaagtt 60

agctgcaaag catccggagg gacgttttct gactacgcta tcacttgggt gcgccaggcc 120

ccgggccagg gcctcgagtg gatgggcggt atcatcccga tcttcggcac tgcgaactac 180

gcccagaaat ttcagggccg ggtgaccatt accgccgatg aaagcaccag caccgcctat 240

atggaactga gcagcctgcg cagcgaagat acggccgtgt attattgcgc gcgtgaaggt 300

ggtctgctga ctgacatctc ttactctcgt tactggttcg cttactgggg ccaaggcacc 360

ctggtgactg ttagctcagc tagcaccaag ggcccaagtg tgtttcccct ggcccccagc 420

agcaagtcta cttccggcgg aactgctgcc ctgggttgcc tggtgaagga ctacttcccc 480

tgtcccgtga cagtgtcctg gaactctggg gctctgactt ccggcgtgca caccttcccc 540

gccgtgctgc agagcagcgg cctgtacagc ctgagcagcg tggtgacagt gccctccagc 600

tctctgggaa cccagaccta tatctgcaac gtgaaccaca agcccagcaa caccaaggtg 660

gacaagagag tggagcccaa gagctgcgac aagacccaca cctgcccccc ctgcccagct 720

ccagaactgc tgggaggggcc ttccgtgttc ctgttccccc ccaagcccaa ggacaccctg 780

atgatcagca ggacccccga ggtgacctgc gtggtggtgg acgtgtccca cgaggaccca 840

gaggtgaagt tcaactggta cgtggacggc gtggaggtgc acaacgccaa gaccaagccc 900

agagaggagc agtacaacag cacctacagg gtggtgtccg tgctgaccgt gctgcaccag 960

gactggctga acggcaaaga atacaagtgc aaagtctcca acaaggccct gccagcccca 1020

atcgaaaaga caatcagcaa ggccaagggc cagccacggg agccccaggt gtacaccctg 1080

ccccccagcc gggaggagat gaccaagaac caggtgtccc tgacctgtct ggtgaagggc 1140

ttctacccct gtgatatcgc cgtggagtgg gagagcaacg gccagcccga gaacaactac 1200

aagaccaccc ccccagtgct ggacagcgac ggcagcttct tcctgtacag caagctgacc 1260

gtggacaagt ccaggtggca gcagggcaac gtgttcagct gcagcgtgat gcacgaggcc 1320

ctgcacaacc actacaccca gaagtccctg agcctgagcc ccggcaag 1368

<210> 14

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 14

Ser Gly Asp Ala Leu Arg Asp Lys Phe Val Tyr

1 5 10

<210> 15

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 15

Asp Asp Asn Asn Arg Pro Ser

1 5

<210> 16

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 16

Gln Ser Trp Asp His Ser Tyr Ser Leu Val Val

1 5 10

<210> 17

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 17

Asp Ala Leu Arg Asp Lys Phe

1 5

<210> 18

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 18

Asp Asp Asn

1

<210> 19

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 19

Trp Asp His Ser Tyr Ser Leu Val

1 5

<210> 20

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 20

Ala Leu Arg Asp Lys Phe

1 5

<210> 21

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 21

Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 22

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 22

gatatcgaac tgacccagcc gccgagcgtg agcgtgagcc cgggccagac cgcgagcatt 60

acctgtagcg gcgatgctct gcgtgacaaa ttcgtttact ggtaccagca gaaaccgggc 120

caggcgccgg tgctggtgat ctacgacgac aacaaccgtc cgagcggcat cccggaacgt 180

tttagcggat ccaacagcgg caacaccgcg accctgacca ttagcggcac ccaggcggaa 240

gacgaagcgg attattactg ccagtcttgg gaccattctt actctctggt tgtgtttggc 300

ggcggcacga agttaactgt cctg 324

<210> 23

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 23

Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys

100 105 110

Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln

115 120 125

Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly

130 135 140

Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly

145 150 155 160

Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala

165 170 175

Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser

180 185 190

Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val

195 200 205

Ala Pro Thr Glu Cys Ser

210

<210> 24

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 24

gatatcgaac tgacccagcc gccgagcgtg agcgtgagcc cgggccagac cgcgagcatt 60

acctgtagcg gcgatgctct gcgtgacaaa ttcgtttact ggtaccagca gaaaccgggc 120

caggcgccgg tgctggtgat ctacgacgac aacaaccgtc cgagcggcat cccggaacgt 180

tttagcggat ccaacagcgg caacaccgcg accctgacca ttagcggcac ccaggcggaa 240

gacgaagcgg attattactg ccagtcttgg gaccattctt actctctggt tgtgtttggc 300

ggcggcacga agttaactgt cctgggacaa cctaaggccg ctccctccgt gaccctgttc 360

ccccccagct ccgaggaact gcaggccaac aaggccaccc tggtgtgcct gatcagcgac 420

ttctaccctg gcgccgtgac cgtggcctgg aaggccgaca gcagccccgt gaaggccggc 480

gtggagacaa ccacccccag caagcagagc aacaacaagt acgccgccag cagctacctg 540

agcctgaccc ccgagcagtg gaagagccac agaagctaca gctgccaggt cacccacgag 600

ggcagcaccg tggagaaaac cgtggccccc accgagtgca gc 642

<210> 25

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 25

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 26

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 26

agctacgagc tgacccagcc gctgtcggtg tcagtcgccc tgggacaaac tgccaggatc 60

acttgttccg gggacgcatt gcgggacaag ttcgtgtact ggtaccagca gaagccgggt 120

caagccccag tgctcgtgat ctacgacgac aacaaccggc cttccggtat ccccgaacgc 180

ttctccggat ccaatagcgg aaacaccgcc accctgacca tttcgagagc tcaggccggg 240

gatgaagcgg actactactg ccagtcatgg gatcactcgt actccctcgt cgtgtttgga 300

ggcggcacga agcttactgt gctg 324

<210> 27

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 27

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys

100 105 110

Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln

115 120 125

Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly

130 135 140

Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly

145 150 155 160

Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala

165 170 175

Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser

180 185 190

Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val

195 200 205

Ala Pro Thr Glu Cys Ser

210

<210> 28

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 28

agctacgagc tgacccagcc gctgtcggtg tcagtcgccc tgggacaaac tgccaggatc 60

acttgttccg gggacgcatt gcgggacaag ttcgtgtact ggtaccagca gaagccgggt 120

caagccccag tgctcgtgat ctacgacgac aacaaccggc cttccggtat ccccgaacgc 180

ttctccggat ccaatagcgg aaacaccgcc accctgacca tttcgagagc tcaggccggg 240

gatgaagcgg actactactg ccagtcatgg gatcactcgt actccctcgt cgtgtttgga 300

ggcggcacga agcttactgt gctgggccag cctaaggccg ctccctccgt gaccctgttc 360

ccccccagct ccgaggaact gcaggccaac aaggccaccc tggtgtgcct gatcagcgac 420

ttctaccctg gcgccgtgac cgtggcctgg aaggccgaca gcagccccgt gaaggccggc 480

gtggagacaa ccacccccag caagcagagc aacaacaagt acgccgccag cagctacctg 540

agcctgaccc ccgagcagtg gaagagccac agaagctaca gctgccaggt cacccacgag 600

ggcagcaccg tggagaaaac cgtggccccc accgagtgca gc 642

<210> 29

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 29

Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 30

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 30

tcgtacgagc tcactcaacc gccttctgtg tccgtgtcac ccgggcagac tgcctccatt 60

acctgttcgg gagatgccct gcgcgacaag tttgtgtact ggtaccagca gaagcccgga 120

cagtcgccag tgctcgtcat ctatgacgac aacaacagac cttccggtat cccggaacgg 180

ttcagcggaa gcaattccgg caacaccgct accctgacca ttagcggcac tcaggccatg 240

gacgaagcgg attactactg ccaatcctgg gaccactcat actcccttgt ggtgttcggt 300

ggcggaacga agctgaccgt cctg 324

<210> 31

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 31

Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly Asp Ala Leu Arg Asp Lys Phe Val

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp His Ser Tyr Ser Leu

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys

100 105 110

Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln

115 120 125

Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly

130 135 140

Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly

145 150 155 160

Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala

165 170 175

Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser

180 185 190

Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val

195 200 205

Ala Pro Thr Glu Cys Ser

210

<210> 32

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 32

tcgtacgagc tcactcaacc gccttctgtg tccgtgtcac ccgggcagac tgcctccatt 60

acctgttcgg gagatgccct gcgcgacaag tttgtgtact ggtaccagca gaagcccgga 120

cagtcgccag tgctcgtcat ctatgacgac aacaacagac cttccggtat cccggaacgg 180

ttcagcggaa gcaattccgg caacaccgct accctgacca ttagcggcac tcaggccatg 240

gacgaagcgg attactactg ccaatcctgg gaccactcat actcccttgt ggtgttcggt 300

ggcggaacga agctgaccgt cctgggccag cctaaggccg ctccctccgt gaccctgttc 360

ccccccagct ccgaggaact gcaggccaac aaggccaccc tggtgtgcct gatcagcgac 420

ttctaccctg gcgccgtgac cgtggcctgg aaggccgaca gcagccccgt gaaggccggc 480

gtggagacaa ccacccccag caagcagagc aacaacaagt acgccgccag cagctacctg 540

agcctgaccc ccgagcagtg gaagagccac agaagctaca gctgccaggt cacccacgag 600

ggcagcaccg tggagaaaac cgtggccccc accgagtgca gc 642

<210> 33

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 33

Gly Gly Thr Phe Ser Thr Tyr Ala Ile Ser

1 5 10

<210> 34

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 34

Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 35

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 35

Glu Val Arg Met Ile Phe Asp Tyr

1 5

<210> 36

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 36

Thr Tyr Ala Ile Ser

1 5

<210> 37

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 37

Gly Gly Thr Phe Ser Thr Tyr

1 5

<210> 38

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 38

Ile Pro Ile Leu Gly Ile

1 5

<210> 39

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 39

Gly Gly Thr Phe Ser Thr Tyr Ala

1 5

<210> 40

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 40

Ile Ile Pro Ile Leu Gly Ile Ala

1 5

<210> 41

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 41

Ala Arg Glu Val Arg Met Ile Phe Asp Tyr

1 5 10

<210> 42

<211> 117

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 42

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Val Arg Met Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 43

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 43

caggtgcaat tggtgcagag cggtgccgaa gtgaaaaaac cgggcagcag cgtgaaagtt 60

agctgcaaag catccggagg gacgttttct acttacgcta tctcttgggt gcgccaggcc 120

ccgggccagg gcctcgagtg gatgggccgt atcatcccga tcctgggcat cgcgaactac 180

gcccagaaat ttcagggccg ggtgaccatt accgccgatg aaagcaccag caccgcctat 240

atggaactga gcagcctgcg cagcgaagat acggccgtgt attattgcgc gcgtgaagtt 300

cgtatgatct tcgattactg gggccaaggc accctggtga ctgttagctc a 351

<210> 44

<211> 447

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 44

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Val Arg Met Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 45

<211> 1341

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 45

caggtgcaat tggtgcagag cggtgccgaa gtgaaaaaac cgggcagcag cgtgaaagtt 60

agctgcaaag catccggagg gacgttttct acttacgcta tctcttgggt gcgccaggcc 120

ccgggccagg gcctcgagtg gatgggccgt atcatcccga tcctgggcat cgcgaactac 180

gcccagaaat ttcagggccg ggtgaccatt accgccgatg aaagcaccag caccgcctat 240

atggaactga gcagcctgcg cagcgaagat acggccgtgt attattgcgc gcgtgaagtt 300

cgtatgatct tcgattactg gggccaaggc accctggtga ctgttagctc agcctctacg 360

aaaggcccaa gcgtatttcc cctggctcct tctagtaaat caacctcagg tggtacagca 420

gcccttggct gcctggtcaa agactatttc ccctgtccgg tgaccgtctc atggaactca 480

ggtgctttga catctggtgt gcatacattc ccagctgtgc tgcaaagtag tggactgtac 540

agcctttcca gcgtggtcac ggtgccaagt agctccttgg gtactcagac ttatatctgc 600

aatgtgaacc acaagccctc taacacgaag gtggacaagc gcgtggagcc caaatcttgc 660

gataagacgc atacttgtcc cccatgccct gctcctgagc tgttgggagg cccgtcagtg 720

ttcttgttcc ctccgaagcc taaggacact ttgatgataa gtaggacacc agaggtgact 780

tgcgtggtgg ttgatgtgtc ccatgaagat cccgaggtca aatttaattg gtacgtagat 840

ggtgtcgaag ttcacaatgc taagactaag ccaagggaag agcagtacaa cagtacatat 900

agggtagtct ccgtgctgac agtcctccac caggactggt tgaacggcaa ggaatacaaa 960

tgtaaggtgt caaacaaagc tctgcctgct cccattgaga aaacaatctc taaagccaaa 1020

ggccagccga gagagcccca agtctacact ttgcccccga gcagggagga aatgaccaag 1080

aatcaggtga gtctgacgtg cctcgtcaaa ggattttatc catgcgatat tgcagttgaa 1140

tggggagagca atggccagcc agagaacaac tataaaacca caccacccgt gctcgactct 1200

gatggcagct tcttcctcta tagcaagctg acagtcgata aatctcgctg gcagcaaggc 1260

aatgtgttct cctgctccgt catgcacgag gctttgcata accattatac tcaaaaatct 1320

ctgtccctgt cacctggtaa a 1341

<210> 46

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 46

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala

1 5 10

<210> 47

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 47

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 48

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 48

Gln Gln Ser Tyr Asp Tyr Tyr Thr

1 5

<210> 49

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 49

Ser Gln Ser Ile Ser Ser Tyr

1 5

<210> 50

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 50

Ala Ala Ser

1

<210> 51

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 51

Ser Tyr Asp Tyr Tyr

1 5

<210> 52

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 52

Gln Ser Ile Ser Ser Tyr

1 5

<210> 53

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 53

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Tyr Tyr Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 54

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 54

gatatccaga tgacccagag cccgagcagc ctgagcgcca gcgtgggcga tcgcgtgacc 60

attacctgca gagccagcca gtctatttct tcttacctgg cttggtacca gcagaaaccg 120

ggcaaagcgc cgaaactatt aatctacgct gcttcttctc tgcaaagcgg cgtgccgagc 180

cgctttagcg gcagcggatc cggcaccgat ttcaccctga ccattagctc tctgcaaccg 240

gaagactttg cgacctatta ttgccagcag tcttacgact actacacctt tggccagggc 300

acgaaagttg aaattaaa 318

<210> 55

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 55

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Tyr Tyr Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

AsnArgGlyGluCys

210

<210> 56

<211> 639

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 56

gatatccaga tgacccagag cccgagcagc ctgagcgcca gcgtgggcga tcgcgtgacc 60

attacctgca gagccagcca gtctatttct tcttacctgg cttggtacca gcagaaaccg 120

ggcaaagcgc cgaaactatt aatctacgct gcttcttctc tgcaaagcgg cgtgccgagc 180

cgctttagcg gcagcggatc cggcaccgat ttcaccctga ccattagctc tctgcaaccg 240

gaagactttg cgacctatta ttgccagcag tcttacgact actacacctt tggccagggc 300

acgaaagttg aaattaaacg tacggtggca gctccgtctg ttttcatctt tccacctagc 360

gacgagcaac tcaaaagtgg tacagcatcc gtggtttgtc tgctgaacaa tttttacccc 420

agggaggcta aggtccagtg gaaagtcgat aacgctcttc agtctggcaa cagtcaggag 480

agcgtcacag agcaggactc taaggatagc acttatagtc tgtcctccac gctgacactg 540

tctaaagcgg attatgagaa gcacaaggtt tacgcctgtg aggtaacgca ccaaggactc 600

tcctccccag ttaccaaatc tttcaacaga ggagaatgt 639

<210> 57

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 57

Gly Gly Thr Phe Ser Asp Tyr Ala Ile Ser

1 5 10

<210> 58

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 58

Gly Ile Ile Pro Ile Phe Gly Asp Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 59

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 59

Glu Gly Ser Ser Tyr Phe Tyr Met Ala Tyr

1 5 10

<210> 60

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 60

Asp Tyr Ala Ile Ser

1 5

<210> 61

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 61

Ile Pro Ile Phe Gly Asp

1 5

<210> 62

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 62

Ile Ile Pro Ile Phe Gly Asp Ala

1 5

<210> 63

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 63

Ala Arg Glu Gly Ser Ser Tyr Phe Tyr Met Ala Tyr

1 5 10

<210> 64

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 64

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Asp Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Ser Ser Tyr Phe Tyr Met Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 65

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 65

caggttcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60

tcctgcaaag caagcggcgg caccttcagc gattacgcca tctcttgggt ccgacaggcc 120

cctggacaag gcttggaatg gatgggcggc atcatcccca tcttcggcga cgccaattac 180

gcccagaaat tccagggcag agtgaccatc accgccgacg agtctacaag caccgcctac 240

atggaactga gcagcctgag aagcgaggac accgccgtgt actactgtgc cagagaggc 300

agcagctact tctacatggc ctattggggc cagggcaccc tggtcacagt tagctct 357

<210> 66

<211> 449

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 66

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Asp Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Ser Ser Tyr Phe Tyr Met Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 67

<211> 1347

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 67

caggttcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60

tcctgcaaag caagcggcgg caccttcagc gattacgcca tctcttgggt ccgacaggcc 120

cctggacaag gcttggaatg gatgggcggc atcatcccca tcttcggcga cgccaattac 180

gcccagaaat tccagggcag agtgaccatc accgccgacg agtctacaag caccgcctac 240

atggaactga gcagcctgag aagcgaggac accgccgtgt actactgtgc cagagaggc 300

agcagctact tctacatggc ctattggggc cagggcaccc tggtcacagt tagctctgct 360

agcaccaagg gcccaagtgt gtttcccctg gcccccagca gcaagtctac ttccggcgga 420

actgctgccc tgggttgcct ggtgaaggac tacttcccct gtcccgtgac agtgtcctgg 480

aactctgggg ctctgacttc cggcgtgcac accttccccg ccgtgctgca gagcagcggc 540

ctgtacagcc tgagcagcgt ggtgacagtg ccctccagct ctctgggaac ccagacctat 600

atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagagagt ggagcccaag 660

agctgcgaca agacccacac ctgccccccc tgcccagctc cagaactgct gggagggcct 720

tccgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagcag gacccccgag 780

gtgacctgcg tggtggtgga cgtgtcccac gaggacccag aggtgaagtt caactggtac 840

gtggacggcg tggaggtgca caacgccaag accaagccca gagaggagca gtacaacagc 900

acctacaggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagaa 960

tacaagtgca aagtctccaa caaggccctg ccagccccaa tcgaaaagac aatcagcaag 1020

gccaagggcc agccacggga gccccaggtg tacaccctgc cccccagccg ggagaggagatg 1080

accaagaacc aggtgtccct gacctgtctg gtgaagggct tctacccctg tgatatcgcc 1140

gtggagtggg agagcaacgg ccagcccgag aacaactaca agaccacccc cccagtgctg 1200

gacagcgacg gcagcttctt cctgtacagc aagctgaccg tggacaagtc caggtggcag 1260

cagggcaacg tgttcagctg cagcgtgatg cacgaggccc tgcacaacca ctacacccag 1320

aagtccctga gcctgagccc cggcaag 1347

<210> 68

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 68

Ser Gly Asp Asn Ile Gly Ser Lys Leu Ala Ser

1 5 10

<210> 69

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 69

Asp Asp Ser Asn Arg Pro Ser

1 5

<210> 70

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 70

Ala Ala Thr Ala Gly Asp Arg Trp Ala Tyr Val

1 5 10

<210> 71

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 71

Asp Asn Ile Gly Ser Lys Leu

1 5

<210> 72

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 72

Asp Asp Ser

1

<210> 73

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 73

Thr Ala Gly Asp Arg Trp Ala Tyr

1 5

<210> 74

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 74

Asn Ile Gly Ser Lys Leu

1 5

<210> 75

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 75

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Ile Gly Ser Lys Leu Ala

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Thr Ala Gly Asp Arg Trp Ala

85 90 95

Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 76

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 76

agctatgagc tgacacagcc tctgtccgtg tctgtggctc tgggacagac cgccagaatc 60

acctgtagcg gcgacaacat cggcagcaag ctggcctctt ggtatcagca gaagcctgga 120

caggcccctg tgctggtcat ctacgacgac agcaatagac ccagcggcat ccccgagaga 180

ttcagcggca gcaatagcgg caataccgcc acactgacca tcagcagagc acaggctggc 240

gacgaggccg attactattg tgctgccaca gccggcgaca gatgggccta tgtttttggc 300

ggcggaacaa agctgaccgt gctg 324

<210> 77

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 77

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Ile Gly Ser Lys Leu Ala

20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Thr Ala Gly Asp Arg Trp Ala

85 90 95

Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys

100 105 110

Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln

115 120 125

Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly

130 135 140

Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly

145 150 155 160

Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala

165 170 175

Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser

180 185 190

Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val

195 200 205

Ala Pro Thr Glu Cys Ser

210

<210> 78

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 78

agctatgagc tgacacagcc tctgtccgtg tctgtggctc tgggacagac cgccagaatc 60

acctgtagcg gcgacaacat cggcagcaag ctggcctctt ggtatcagca gaagcctgga 120

caggcccctg tgctggtcat ctacgacgac agcaatagac ccagcggcat ccccgagaga 180

ttcagcggca gcaatagcgg caataccgcc acactgacca tcagcagagc acaggctggc 240

gacgaggccg attactattg tgctgccaca gccggcgaca gatgggccta tgtttttggc 300

ggcggaacaa agctgaccgt gctgggacag cctaaggccg ctccctccgt gaccctgttc 360

ccccccagct ccgaggaact gcaggccaac aaggccaccc tggtgtgcct gatcagcgac 420

ttctaccctg gcgccgtgac cgtggcctgg aaggccgaca gcagccccgt gaaggccggc 480

gtggagacaa ccacccccag caagcagagc aacaacaagt acgccgccag cagctacctg 540

agcctgaccc ccgagcagtg gaagagccac agaagctaca gctgccaggt cacccacgag 600

ggcagcaccg tggagaaaac cgtggccccc accgagtgca gc 642

<210> 79

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 79

Gly Phe Thr Phe Ser Ser Phe Gly Met Ser

1 5 10

<210> 80

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 80

Ala Ile Ser Tyr Ser Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 81

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 81

Asp Val Gly Val Met Asp Tyr

1 5

<210> 82

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 82

Ser Phe Gly Met Ser

1 5

<210> 83

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 83

Gly Phe Thr Phe Ser Ser Phe

1 5

<210> 84

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 84

Ser Tyr Ser Gly Ser Asp

1 5

<210> 85

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 85

Gly Phe Thr Phe Ser Ser Phe Gly

1 5

<210> 86

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 86

Ile Ser Tyr Ser Gly Ser Asp Thr

1 5

<210> 87

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 87

Ala Arg Asp Val Gly Val Met Asp Tyr

1 5

<210> 88

<211> 116

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 88

Gln Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Ser Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Val Gly Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 89

<211> 348

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 89

caggttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt caccttcagc agctttggca tgagctgggt ccgacaggcc 120

cctggcaaag gacttgaatg ggtgtccgcc atcagctaca gcggcagcga tacctactac 180

gccgacagcg tgaagggcag attcaccatc tccagagaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagagatgtg 300

ggcgtgatgg actattgggg cccaggcaca ctggtcaccg ttagctct 348

<210> 90

<211> 446

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 90

Gln Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Ser Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Val Gly Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 91

<211> 1338

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 91

caggttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt caccttcagc agctttggca tgagctgggt ccgacaggcc 120

cctggcaaag gacttgaatg ggtgtccgcc atcagctaca gcggcagcga tacctactac 180

gccgacagcg tgaagggcag attcaccatc tccagagaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagagatgtg 300

ggcgtgatgg actattgggg cccaggcaca ctggtcaccg ttagctctgc tagcaccaag 360

ggcccaagtg tgtttcccct ggcccccagc agcaagtcta cttccggcgg aactgctgcc 420

ctgggttgcc tggtgaagga ctacttcccc tgtcccgtga cagtgtcctg gaactctggg 480

gctctgactt ccggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc 540

ctgagcagcg tggtgacagt gccctccagc tctctgggaa cccagaccta tatctgcaac 600

gtgaaccaca agcccagcaa caccaaggtg gacaagagag tggagcccaa gagctgcgac 660

aagacccaca cctgcccccc ctgcccagct ccagaactgc tgggaggggcc ttccgtgttc 720

ctgttccccc ccaagcccaa ggacaccctg atgatcagca ggacccccga ggtgacctgc 780

gtggtggtgg acgtgtccca cgaggaccca gaggtgaagt tcaactggta cgtggacggc 840

gtggaggtgc acaacgccaa gaccaagccc agagaggagc agtacaacag cacctacagg 900

gtggtgtccg tgctgaccgt gctgcaccag gactggctga acggcaaaga atacaagtgc 960

aaagtctcca acaaggccct gccagcccca atcgaaaaga caatcagcaa ggccaagggc 1020

cagccacggg agccccaggt gtacaccctg ccccccagcc gggaggagat gaccaagaac 1080

caggtgtccc tgacctgtct ggtgaagggc ttctacccct gtgatatcgc cgtggagtgg 1140

gagagcaacg gccagcccga gaacaactac aagaccaccc ccccagtgct ggacagcgac 1200

ggcagcttct tcctgtacag caagctgacc gtggacaagt ccaggtggca gcagggcaac 1260

gtgttcagct gcagcgtgat gcacgaggcc ctgcacaacc actacaccca gaagtccctg 1320

agcctgagcc ccggcaag 1338

<210> 92

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 92

Ser Gly Asp Asn Leu Gly Thr Tyr Tyr Ala His

1 5 10

<210> 93

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 93

Ser Gln Ser His Arg Pro Ser

1 5

<210> 94

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 94

Gly Ala Trp Asp Ala Pro Ser Pro Glu Leu Val

1 5 10

<210> 95

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 95

Asp Asn Leu Gly Thr Tyr Tyr

1 5

<210> 96

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 96

Ser Gln Ser

1

<210> 97

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 97

Trp Asp Ala Pro Ser Pro Glu Leu

1 5

<210> 98

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 98

Asn Leu Gly Thr Tyr Tyr

1 5

<210> 99

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 99

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Leu Gly Thr Tyr Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Ser Gln Ser His Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ala Pro Ser Pro Glu

85 90 95

Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 100

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 100

agctatgagc tgacacagcc tctgtccgtg tctgtggctc tgggacagac cgccagaatc 60

acctgtagcg gcgataacct gggcacctac tacgcccact ggtatcagca gaagcctgga 120

caggctcccg tgctggtcat ctacagccag tctcacagac ccagcggcat ccccgagaga 180

ttcagcggca gcaatagcgg caataccgcc acactgacca tcagcagagc acaggctggc 240

gacgaggccg attactattg tggcgcttgg gacgccccat ctcctgagct tgtttttggc 300

ggaggcacca agctgacagt gctg 324

<210> 101

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 101

Ser Tyr Glu Leu Thr Gln Pro Leu Ser Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Asn Leu Gly Thr Tyr Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Ser Gln Ser His Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ala Pro Ser Pro Glu

85 90 95

Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys

100 105 110

Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln

115 120 125

Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly

130 135 140

Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly

145 150 155 160

Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala

165 170 175

Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser

180 185 190

Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val

195 200 205

Ala Pro Thr Glu Cys Ser

210

<210> 102

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 102

agctatgagc tgacacagcc tctgtccgtg tctgtggctc tgggacagac cgccagaatc 60

acctgtagcg gcgataacct gggcacctac tacgcccact ggtatcagca gaagcctgga 120

caggctcccg tgctggtcat ctacagccag tctcacagac ccagcggcat ccccgagaga 180

ttcagcggca gcaatagcgg caataccgcc acactgacca tcagcagagc acaggctggc 240

gacgaggccg attactattg tggcgcttgg gacgccccat ctcctgagct tgtttttggc 300

ggaggcacca agctgacagt gctgggacag cctaaggccg ctccctccgt gaccctgttc 360

ccccccagct ccgaggaact gcaggccaac aaggccaccc tggtgtgcct gatcagcgac 420

ttctaccctg gcgccgtgac cgtggcctgg aaggccgaca gcagccccgt gaaggccggc 480

gtggagacaa ccacccccag caagcagagc aacaacaagt acgccgccag cagctacctg 540

agcctgaccc ccgagcagtg gaagagccac agaagctaca gctgccaggt cacccacgag 600

ggcagcaccg tggagaaaac cgtggccccc accgagtgca gc 642

<210> 103

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 103

Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser

1 5 10

<210> 104

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 104

Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 105

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 105

Ala Phe Arg Leu Tyr Trp Leu Asp Val

1 5

<210> 106

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 106

Ser Tyr Ala Met Ser

1 5

<210> 107

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 107

Gly Phe Thr Phe Ser Ser Tyr

1 5

<210> 108

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 108

Ser Gly Ser Gly Gly Ser

1 5

<210> 109

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 109

Gly Phe Thr Phe Ser Ser Tyr Ala

1 5

<210> 110

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 110

Ile Ser Gly Ser Gly Gly Ser Thr

1 5

<210> 111

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 111

Ala Arg Ala Phe Arg Leu Tyr Trp Leu Asp Val

1 5 10

<210> 112

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 112

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Phe Arg Leu Tyr Trp Leu Asp Val Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 113

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 113

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtgc cagagccttc 300

cggctgtact ggctggatgt ttggggacag ggcaccctgg tcacagtgtc atct 354

<210> 114

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 114

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Phe Arg Leu Tyr Trp Leu Asp Val Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 115

<211> 1344

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 115

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtgc cagagccttc 300

cggctgtact ggctggatgt ttggggacag ggcaccctgg tcacagtgtc atctgctagc 360

accaagggcc caagtgtgtt tcccctggcc cccagcagca agtctacttc cggcggaact 420

gctgccctgg gttgcctggt gaaggactac ttcccctgtc ccgtgacagt gtcctggaac 480

tctggggctc tgacttccgg cgtgcacacc ttccccgccg tgctgcagag cagcggcctg 540

tacagcctga gcagcgtggt gacagtgccc tccagctctc tgggaaccca gacctatatc 600

tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagagtgga gcccaagagc 660

tgcgacaaga cccacacctg ccccccctgc ccagctccag aactgctggg agggccttcc 720

gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 780

acctgcgtgg tggtggacgt gtcccacgag gacccagagg tgaagttcaa ctggtacgtg 840

gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggagcagta caacagcacc 900

tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagaatac 960

aagtgcaaag tctccaacaa ggccctgcca gccccaatcg aaaagacaat cagcaaggcc 1020

aagggccagc cacgggagcc ccaggtgtac accctgcccc ccagccggga ggagatgacc 1080

aagaaccagg tgtccctgac ctgtctggtg aagggcttct acccctgtga tatcgccgtg 1140

gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc agtgctggac 1200

agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1260

ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag 1320

tccctgagcc tgagccccgg caag 1344

<210> 116

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 116

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 117

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 117

Gln Gln Val Tyr Ser Ala Pro Val Thr

1 5

<210> 118

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 118

Val Tyr Ser Ala Pro Val

1 5

<210> 119

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 119

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ala Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 120

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 120

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gtctacagcg cccctgtgac atttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 121

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 121

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ala Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 122

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 122

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gtctacagcg cccctgtgac atttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 123

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 123

Gly Phe Thr Phe Ser Asn Tyr Trp Ile Ser

1 5 10

<210> 124

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 124

Arg Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr Asp Tyr Ala Glu Pro

1 5 10 15

Val Lys Gly

<210> 125

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 125

Thr Ser Arg Arg Ser Tyr Ala Phe Asp Tyr

1 5 10

<210> 126

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 126

Asn Tyr Trp Ile Ser

1 5

<210> 127

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 127

Gly Phe Thr Phe Ser Asn Tyr

1 5

<210> 128

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 128

Lys Ser Lys Thr Tyr Gly Gly Thr

1 5

<210> 129

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 129

Gly Phe Thr Phe Ser Asn Tyr Trp

1 5

<210> 130

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 130

Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr

1 5 10

<210> 131

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 131

Ala Arg Thr Ser Arg Arg Ser Tyr Ala Phe Asp Tyr

1 5 10

<210> 132

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 132

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr Asp Tyr Ala Glu

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Thr Ser Arg Arg Ser Tyr Ala Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 133

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 133

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aactactgga tcagctgggt ccgacaggcc 120

cctggcaaag gacttgagtg ggtcggacgg atcaagagca agacctacgg cggcaccacc 180

gattatgccg agcctgtgaa gggcagattc accatcagcc gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

accagcagaa gaagctacgc cttcgactac tggggccagg gcacactggt taccgttagc 360

tct 363

<210> 134

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 134

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr Asp Tyr Ala Glu

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Thr Ser Arg Arg Ser Tyr Ala Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 135

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 135

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aactactgga tcagctgggt ccgacaggcc 120

cctggcaaag gacttgagtg ggtcggacgg atcaagagca agacctacgg cggcaccacc 180

gattatgccg agcctgtgaa gggcagattc accatcagcc gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

accagcagaa gaagctacgc cttcgactac tggggccagg gcacactggt taccgttagc 360

tctgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc 420

ggcggaactg ctgccctggg ttgcctggtg aaggactact tcccctgtcc cgtgacagtg 480

tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600

acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720

gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780

cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900

aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960

aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc 1020

agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta cccctgtgat 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaagt ccctgagcct gagccccggc aag 1353

<210> 136

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 136

Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala

1 5 10

<210> 137

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 137

Asp Ala Ser Ser Leu Glu Ser

1 5

<210> 138

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 138

Gln Gln Ile Thr Arg Tyr Pro Val Thr

1 5

<210> 139

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 139

Ser Gln Ser Ile Ser Ser Trp

1 5

<210> 140

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 140

Asp Ala Ser

1

<210> 141

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 141

Ile Thr Arg Tyr Pro Val

1 5

<210> 142

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 142

Gln Ser Ile Ser Ser Trp

1 5

<210> 143

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 143

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Thr Arg Tyr Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 144

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 144

gacatccaga tgacacagag ccccagcaca ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatctcc tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctacgat gccagcagcc tggaaagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgag ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag atcacaagat accccgtgac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 145

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 145

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Thr Arg Tyr Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 146

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 146

gacatccaga tgacacagag ccccagcaca ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatctcc tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctacgat gccagcagcc tggaaagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgag ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag atcacaagat accccgtgac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 147

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 147

Val Ser Gly Tyr Tyr Ser His Ser Gly Gly Phe Asp Val

1 5 10

<210> 148

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 148

Ala Arg Val Ser Gly Tyr Tyr Ser His Ser Gly Gly Phe Asp Val

1 5 10 15

<210> 149

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 149

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr Asp Tyr Ala Glu

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Val Ser Gly Tyr Tyr Ser His Ser Gly Gly Phe Asp

100 105 110

Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 150

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 150

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aactactgga tcagctgggt ccgacaggcc 120

cctggcaaag gacttgagtg ggtcggacgg atcaagagca agacctacgg cggcaccacc 180

gattatgccg agcctgtgaa gggcagattc accatcagcc gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gtgtctggct actactctca cagcggcggc tttgatgtgt ggggccaggg aacactggtc 360

accgttagtt ct 372

<210> 151

<211> 454

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 151

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Tyr Gly Gly Thr Thr Asp Tyr Ala Glu

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Val Ser Gly Tyr Tyr Ser His Ser Gly Gly Phe Asp

100 105 110

Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly

130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro

145 150 155 160

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

165 170 175

Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

180 185 190

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

210 215 220

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

225 230 235 240

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

435 440 445

Ser Leu Ser Pro Gly Lys

450

<210> 152

<211> 1362

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 152

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aactactgga tcagctgggt ccgacaggcc 120

cctggcaaag gacttgagtg ggtcggacgg atcaagagca agacctacgg cggcaccacc 180

gattatgccg agcctgtgaa gggcagattc accatcagcc gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gtgtctggct actactctca cagcggcggc tttgatgtgt ggggccaggg aacactggtc 360

accgttagtt ctgctagcac caagggccca agtgtgtttc ccctggcccc cagcagcaag 420

tctacttccg gcggaactgc tgccctgggt tgcctggtga aggactactt cccctgtccc 480

gtgacagtgt cctggaactc tggggctctg acttccggcg tgcacacctt ccccgccgtg 540

ctgcagagca gcggcctgta cagcctgagc agcgtggtga cagtgccctc cagctctctg 600

ggaacccaga cctatatctg caacgtgaac cacaagccca gcaacaccaa ggtggacaag 660

agagtggagc ccaagagctg cgacaagacc cacacctgcc ccccctgccc agctccagaa 720

ctgctgggag ggccttccgt gttcctgttc ccccccaagc ccaaggacac cctgatgatc 780

agcaggaccc ccgaggtgac ctgcgtggtg gtggacgtgt cccacgagga cccagaggtg 840

aagttcaact ggtacgtgga cggcgtggag gtgcacaacg ccaagaccaa gcccagagag 900

gagcagtaca acagcaccta cagggtggtg tccgtgctga ccgtgctgca ccaggactgg 960

ctgaacggca aagaatacaa gtgcaaagtc tccaacaagg ccctgccagc cccaatcgaa 1020

aagacaatca gcaaggccaa gggccagcca cgggagcccc aggtgtacac cctgcccccc 1080

agccgggagg agatgaccaa gaaccaggtg tccctgacct gtctggtgaa gggcttctac 1140

ccctgtgata tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ctacaagacc 1200

acccccccag tgctggacag cgacggcagc ttcttcctgt acagcaagct gaccgtggac 1260

aagtccaggt ggcagcaggg caacgtgttc agctgcagcg tgatgcacga ggccctgcac 1320

aaccactaca cccagaagtc cctgagcctg agccccggca ag 1362

<210> 153

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 153

Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala

1 5 10

<210> 154

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 154

Ala Ala Ser Thr Leu Gln Ser

1 5

<210> 155

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 155

Gln Lys Thr Trp Arg Thr Pro Gly Thr

1 5

<210> 156

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 156

Ser Gln Gly Ile Ser Asn Tyr

1 5

<210> 157

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 157

Thr Trp Arg Thr Pro Gly

1 5

<210> 158

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 158

Gln Gly Ile Ser Asn Tyr

1 5

<210> 159

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 159

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Thr Trp Arg Thr Pro Gly

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 160

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 160

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ctgtcagaaa acctggcgga cccctggcac atttggccag 300

ggaacaaagg tggaaatcaa g 321

<210> 161

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 161

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Thr Trp Arg Thr Pro Gly

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 162

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 162

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ctgtcagaaa acctggcgga cccctggcac atttggccag 300

ggaacaaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 163

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 163

Ser Arg Leu Ile Ala Pro Trp Leu Asp Tyr

1 5 10

<210> 164

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 164

Ala Arg Ser Arg Leu Ile Ala Pro Trp Leu Asp Tyr

1 5 10

<210> 165

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 165

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Leu Ile Ala Pro Trp Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 166

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 166

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaagcaga 300

ctgatcgccc cttggctgga ttattggggc cagggcacac tggtcaccgt gtcatct 357

<210> 167

<211> 449

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 167

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Leu Ile Ala Pro Trp Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 168

<211> 1347

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 168

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaagcaga 300

ctgatcgccc cttggctgga ttattggggc cagggcacac tggtcaccgt gtcatctgct 360

agcaccaagg gcccaagtgt gtttcccctg gcccccagca gcaagtctac ttccggcgga 420

actgctgccc tgggttgcct ggtgaaggac tacttcccct gtcccgtgac agtgtcctgg 480

aactctgggg ctctgacttc cggcgtgcac accttccccg ccgtgctgca gagcagcggc 540

ctgtacagcc tgagcagcgt ggtgacagtg ccctccagct ctctgggaac ccagacctat 600

atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagagagt ggagcccaag 660

agctgcgaca agacccacac ctgccccccc tgcccagctc cagaactgct gggagggcct 720

tccgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagcag gacccccgag 780

gtgacctgcg tggtggtgga cgtgtcccac gaggacccag aggtgaagtt caactggtac 840

gtggacggcg tggaggtgca caacgccaag accaagccca gagaggagca gtacaacagc 900

acctacaggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagaa 960

tacaagtgca aagtctccaa caaggccctg ccagccccaa tcgaaaagac aatcagcaag 1020

gccaagggcc agccacggga gccccaggtg tacaccctgc cccccagccg ggagaggagatg 1080

accaagaacc aggtgtccct gacctgtctg gtgaagggct tctacccctg tgatatcgcc 1140

gtggagtggg agagcaacgg ccagcccgag aacaactaca agaccacccc cccagtgctg 1200

gacagcgacg gcagcttctt cctgtacagc aagctgaccg tggacaagtc caggtggcag 1260

cagggcaacg tgttcagctg cagcgtgatg cacgaggccc tgcacaacca ctacacccag 1320

aagtccctga gcctgagccc cggcaag 1347

<210> 169

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 169

Gln Gln Val Tyr Gly Ser Pro Pro Thr

1 5

<210> 170

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 170

Val Tyr Gly Ser Pro Pro

1 5

<210> 171

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 171

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Gly Ser Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 172

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 172

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gtctacggca gccctcctac atttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 173

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 173

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Gly Ser Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 174

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 174

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gtctacggca gccctcctac atttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 175

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 175

Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly

1 5 10

<210> 176

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 176

Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1 5 10 15

Gly

<210> 177

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 177

Gly Ser Ser Ala Ala Ser Gly Leu Ser Gly Asp Leu

1 5 10

<210> 178

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 178

Ser Tyr Trp Ile Gly

1 5

<210> 179

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 179

Gly Tyr Ser Phe Thr Ser Tyr

1 5

<210> 180

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 180

Tyr Pro Gly Asp Ser Asp

1 5

<210> 181

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 181

Gly Tyr Ser Phe Thr Ser Tyr Trp

1 5

<210> 182

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 182

Ile Tyr Pro Gly Asp Ser Asp Thr

1 5

<210> 183

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 183

Ala Arg Gly Ser Ser Ala Ala Ser Gly Leu Ser Gly Asp Leu

1 5 10

<210> 184

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 184

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Ser Ala Ala Ser Gly Leu Ser Gly Asp Leu Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 185

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 185

gaagttcagc tggtgcagtc tggcgccgaa gtgaagaagc ctggcgagag cctgaagatc 60

tcctgcaaag gcagcggcta cagcttcacc agctactgga tcggctgggt ccgacagatg 120

cctggcaaag gccttgagtg gatgggcatc atctaccccg gcgacagcga caccagatac 180

agccctagct ttcagggcca agtgaccatc agcgccgaca agagcatcag cacagcctac 240

ctgcagtggt ccagcctgaa ggcctctgac accgccatgt actactgtgc cagaggaagc 300

tctgccgcct ctggactgtc tggcgatctt tggggacagg gcacactggt cacagtgtct 360

agt 363

<210> 186

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 186

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Ser Ala Ala Ser Gly Leu Ser Gly Asp Leu Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 187

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 187

gaagttcagc tggtgcagtc tggcgccgaa gtgaagaagc ctggcgagag cctgaagatc 60

tcctgcaaag gcagcggcta cagcttcacc agctactgga tcggctgggt ccgacagatg 120

cctggcaaag gccttgagtg gatgggcatc atctaccccg gcgacagcga caccagatac 180

agccctagct ttcagggcca agtgaccatc agcgccgaca agagcatcag cacagcctac 240

ctgcagtggt ccagcctgaa ggcctctgac accgccatgt actactgtgc cagaggaagc 300

tctgccgcct ctggactgtc tggcgatctt tggggacagg gcacactggt cacagtgtct 360

agtgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc 420

ggcggaactg ctgccctggg ttgcctggtg aaggactact tcccctgtcc cgtgacagtg 480

tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600

acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720

gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780

cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900

aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960

aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc 1020

agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta cccctgtgat 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaagt ccctgagcct gagccccggc aag 1353

<210> 188

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 188

Gln Gln Asp Tyr Tyr Ser Pro Phe Thr

1 5

<210> 189

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 189

Asp Tyr Tyr Ser Pro Phe

1 5

<210> 190

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Tyr Ser Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 191

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 191

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gactactaca gccccttcac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 192

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 192

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Tyr Ser Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 193

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 193

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag gactactaca gccccttcac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 194

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 194

Ala Tyr Lys Leu Ser Trp Leu Asp Leu

1 5

<210> 195

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 195

Ala Arg Ala Tyr Lys Leu Ser Trp Leu Asp Leu

1 5 10

<210> 196

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 196

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Tyr Lys Leu Ser Trp Leu Asp Leu Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 197

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 197

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtgc cagagcctac 300

aagctgagct ggctggatct ttggggccag ggcacactgg tcacagtgtc atct 354

<210> 198

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 198

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Tyr Lys Leu Ser Trp Leu Asp Leu Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 199

<211> 1344

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 199

gaagttcagc tgctggaatc tggcggagga ctggttcaac ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt cacctttagc agctacgcca tgagctgggt ccgacaggct 120

cctggcaaag gccttgaatg ggtgtccgcc atctctggct ctggcggcag cacatattac 180

gccgactctg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtgc cagagcctac 300

aagctgagct ggctggatct ttggggccag ggcacactgg tcacagtgtc atctgctagc 360

accaagggcc caagtgtgtt tcccctggcc cccagcagca agtctacttc cggcggaact 420

gctgccctgg gttgcctggt gaaggactac ttcccctgtc ccgtgacagt gtcctggaac 480

tctggggctc tgacttccgg cgtgcacacc ttccccgccg tgctgcagag cagcggcctg 540

tacagcctga gcagcgtggt gacagtgccc tccagctctc tgggaaccca gacctatatc 600

tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagagtgga gcccaagagc 660

tgcgacaaga cccacacctg ccccccctgc ccagctccag aactgctggg agggccttcc 720

gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 780

acctgcgtgg tggtggacgt gtcccacgag gacccagagg tgaagttcaa ctggtacgtg 840

gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggagcagta caacagcacc 900

tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagaatac 960

aagtgcaaag tctccaacaa ggccctgcca gccccaatcg aaaagacaat cagcaaggcc 1020

aagggccagc cacgggagcc ccaggtgtac accctgcccc ccagccggga ggagatgacc 1080

aagaaccagg tgtccctgac ctgtctggtg aagggcttct acccctgtga tatcgccgtg 1140

gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc agtgctggac 1200

agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1260

ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag 1320

tccctgagcc tgagccccgg caag 1344

<210> 200

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 200

Gln Gln Val Trp Tyr Ala Pro Val Thr

1 5

<210> 201

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 201

Val Trp Tyr Ala Pro Val

1 5

<210> 202

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 202

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Trp Tyr Ala Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 203

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 203

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcaa gtttggtacg cccctgtgac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 204

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 204

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Trp Tyr Ala Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 205

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 205

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatcagc agctacctga actggtatca gcagaagccc 120

ggcaaggccc ctaaactgct gatctatgcc gccagctctc tgcagtctgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcaa gtttggtacg cccctgtgac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 206

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 206

Gly Phe Thr Phe Ser Asn Ala Trp Met Ser

1 5 10

<210> 207

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 207

Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala Pro

1 5 10 15

Val Lys Gly

<210> 208

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 208

Thr Ile Tyr Pro Ser Ala Pro Ser Ser Ser Leu Asp Tyr

1 5 10

<210> 209

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 209

Asn Ala Trp Met Ser

1 5

<210> 210

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 210

Gly Phe Thr Phe Ser Asn Ala

1 5

<210> 211

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 211

Lys Ser Lys Thr Asp Ala Gly Thr

1 5

<210> 212

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 212

Gly Phe Thr Phe Ser Asn Ala Trp

1 5

<210> 213

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 213

Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr

1 5 10

<210> 214

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 214

Ala Arg Thr Ile Tyr Pro Ser Ala Pro Ser Ser Ser Leu Asp Tyr

1 5 10 15

<210> 215

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 215

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Thr Ile Tyr Pro Ser Ala Pro Ser Ser Ser Leu Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 216

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 216

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

acaatctacc ccagcgctcc tagcagcagc ctggattatt ggggccagg cacactggtc 360

accgtgtcat ct 372

<210> 217

<211> 454

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 217

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Thr Ile Tyr Pro Ser Ala Pro Ser Ser Ser Leu Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly

130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro

145 150 155 160

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

165 170 175

Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

180 185 190

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

210 215 220

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

225 230 235 240

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

435 440 445

Ser Leu Ser Pro Gly Lys

450

<210> 218

<211> 1362

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 218

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

acaatctacc ccagcgctcc tagcagcagc ctggattatt ggggccagg cacactggtc 360

accgtgtcat ctgctagcac caagggccca agtgtgtttc ccctggcccc cagcagcaag 420

tctacttccg gcggaactgc tgccctgggt tgcctggtga aggactactt cccctgtccc 480

gtgacagtgt cctggaactc tggggctctg acttccggcg tgcacacctt ccccgccgtg 540

ctgcagagca gcggcctgta cagcctgagc agcgtggtga cagtgccctc cagctctctg 600

ggaacccaga cctatatctg caacgtgaac cacaagccca gcaacaccaa ggtggacaag 660

agagtggagc ccaagagctg cgacaagacc cacacctgcc ccccctgccc agctccagaa 720

ctgctgggag ggccttccgt gttcctgttc ccccccaagc ccaaggacac cctgatgatc 780

agcaggaccc ccgaggtgac ctgcgtggtg gtggacgtgt cccacgagga cccagaggtg 840

aagttcaact ggtacgtgga cggcgtggag gtgcacaacg ccaagaccaa gcccagagag 900

gagcagtaca acagcaccta cagggtggtg tccgtgctga ccgtgctgca ccaggactgg 960

ctgaacggca aagaatacaa gtgcaaagtc tccaacaagg ccctgccagc cccaatcgaa 1020

aagacaatca gcaaggccaa gggccagcca cgggagcccc aggtgtacac cctgcccccc 1080

agccgggagg agatgaccaa gaaccaggtg tccctgacct gtctggtgaa gggcttctac 1140

ccctgtgata tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ctacaagacc 1200

acccccccag tgctggacag cgacggcagc ttcttcctgt acagcaagct gaccgtggac 1260

aagtccaggt ggcagcaggg caacgtgttc agctgcagcg tgatgcacga ggccctgcac 1320

aaccactaca cccagaagtc cctgagcctg agccccggca ag 1362

<210> 219

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 219

Gln Gln Leu Ile Phe Phe Pro Leu Thr

1 5

<210> 220

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 220

Leu Ile Phe Phe Pro Leu

1 5

<210> 221

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 221

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Leu Ile Phe Phe Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 222

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 222

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ttgccagcag ctgatcttct tccctctgac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 223

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 223

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Leu Ile Phe Phe Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 224

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 224

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ttgccagcag ctgatcttct tccctctgac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 225

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 225

Ala Ser His Arg Leu His Ser Leu Phe Asp Val

1 5 10

<210> 226

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 226

Ala Arg Ala Ser His Arg Leu His Ser Leu Phe Asp Val

1 5 10

<210> 227

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 227

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Ala Ser His Arg Leu His Ser Leu Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 228

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 228

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgtgccaga 300

gcctctcaca gactgcacag cctgtttgac gtgtggggcc agggaacact ggtcaccgtt 360

agttct 366

<210> 229

<211> 452

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 229

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Ala Ser His Arg Leu His Ser Leu Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Pro Gly Lys

450

<210> 230

<211> 1356

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 230

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgtgccaga 300

gcctctcaca gactgcacag cctgtttgac gtgtggggcc agggaacact ggtcaccgtt 360

agttctgcta gcaccaaggg cccaagtgtg tttcccctgg cccccagcag caagtctact 420

tccggcggaa ctgctgccct gggttgcctg gtgaaggact acttcccctg tcccgtgaca 480

gtgtcctgga actctggggc tctgacttcc ggcgtgcaca ccttccccgc cgtgctgcag 540

agcagcggcc tgtacagcct gagcagcgtg gtgacagtgc cctccagctc tctgggaacc 600

cagacctata tctgcaacgt gaaccacaag cccagcaaca ccaaggtgga caagagagtg 660

gagcccaaga gctgcgacaa gacccacacc tgccccccct gcccagctcc agaactgctg 720

ggagggcctt ccgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcagg 780

acccccgagg tgacctgcgt ggtggtggac gtgtcccacg aggacccaga ggtgaagttc 840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900

tacaacagca cctacaggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960

ggcaaagaat acaagtgcaa agtctccaac aaggccctgc cagccccaat cgaaaagaca 1020

atcagcaagg ccaagggcca gccacgggag ccccaggtgt acaccctgcc ccccagccgg 1080

gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccctgt 1140

gatatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1200

ccagtgctgg acagcgacgg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc 1260

aggtggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 1320

tacacccaga agtccctgag cctgagcccc ggcaag 1356

<210> 231

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 231

Gln Gln Gly Leu Phe Tyr Pro His Thr

1 5

<210> 232

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 232

Gly Leu Phe Tyr Pro His

1 5

<210> 233

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 233

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Leu Phe Tyr Pro His

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 234

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 234

gacatccaga tgacacagag ccccagcaca ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatctcc tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctacgat gccagcagcc tggaaagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgag ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ttgtcagcag ggcctgttct accctcacac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 235

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 235

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Leu Phe Tyr Pro His

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 236

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 236

gacatccaga tgacacagag ccccagcaca ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gagcatctcc tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctacgat gccagcagcc tggaaagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgag ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ttgtcagcag ggcctgttct accctcacac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 237

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 237

Asp Glu Tyr Pro Trp Gly Trp Phe Asp Val

1 5 10

<210> 238

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 238

Ala Arg Asp Glu Tyr Pro Trp Gly Trp Phe Asp Val

1 5 10

<210> 239

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 239

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Glu Tyr Pro Trp Gly Trp Phe Asp Val Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 240

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 240

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gatgagtacc cctggggatg gttcgatgtg tggggacagg gaaccctggt caccgttagt 360

tct 363

<210> 241

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 241

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Glu Tyr Pro Trp Gly Trp Phe Asp Val Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 242

<211> 1353

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 242

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gatgagtacc cctggggatg gttcgatgtg tggggacagg gaaccctggt caccgttagt 360

tctgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc 420

ggcggaactg ctgccctggg ttgcctggtg aaggactact tcccctgtcc cgtgacagtg 480

tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600

acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720

gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780

cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900

aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960

aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc 1020

agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccgggag 1080

gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta cccctgtgat 1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca 1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320

acccagaagt ccctgagcct gagccccggc aag 1353

<210> 243

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 243

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

1 5 10

<210> 244

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 244

Gln Gln Tyr Ile Phe Tyr Pro Leu Thr

1 5

<210> 245

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 245

Ser Gln Gly Ile Ser Ser Trp

1 5

<210> 246

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 246

Tyr Ile Phe Tyr Pro Leu

1 5

<210> 247

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 247

Gln Gly Ile Ser Ser Trp

1 5

<210> 248

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 248

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ile Phe Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 249

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 249

gacatccaga tgacacagag ccctagctcc gtgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatctct tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctatgcc gcttccagtc tgcagagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag tacatcttct accctctgac cttcggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 250

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 250

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ile Phe Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 251

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 251

gacatccaga tgacacagag ccctagctcc gtgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatctct tcttggctgg cctggtatca gcagaagcct 120

ggcaaggccc ctaagctgct gatctatgcc gcttccagtc tgcagagcgg cgtgccaagc 180

agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcca 240

gaggacttcg ccacctacta ctgccagcag tacatcttct accctctgac cttcggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 252

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 252

Val Ala Ser Pro Ser Ala Pro Gly Gly Phe Asp Tyr

1 5 10

<210> 253

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 253

Ala Arg Val Ala Ser Pro Ser Ala Pro Gly Gly Phe Asp Tyr

1 5 10

<210> 254

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 254

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Val Ala Ser Pro Ser Ala Pro Gly Gly Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 255

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 255

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gtggcttctc cttctgctcc cggcggattc gattattggg gccagggaac actggtcacc 360

gtgtctagt 369

<210> 256

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 256

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Asp Ala Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Val Ala Ser Pro Ser Ala Pro Gly Gly Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Cys Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cys Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 257

<211> 1359

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 257

gaagtgcagc tggtggaatc tggcggcgga cttgtgaaac ctggcggctc tctgagactg 60

agctgtgccg cttccggctt caccttcagc aatgcctgga tgagctgggt ccgacaggcc 120

cctggaaaag gccttgagtg ggtcggacgg atcaagagca agaccgatgc cggcaccacc 180

gattatgctg cccctgtgaa gggcagattc accatcagca gggacgacag caagaacacc 240

ctgtacctgc agatgaacag cctgaaaacc gaggacaccg ccgtgtacta ctgcgccaga 300

gtggcttctc cttctgctcc cggcggattc gattattggg gccagggaac actggtcacc 360

gtgtctagtg ctagcaccaa gggcccaagt gtgtttcccc tggcccccag cagcaagtct 420

acttccggcg gaactgctgc cctgggttgc ctggtgaagg actacttccc ctgtcccgtg 480

acagtgtcct ggaactctgg ggctctgact tccggcgtgc acaccttccc cgccgtgctg 540

cagagcagcg gcctgtacag cctgagcagc gtggtgacag tgccctccag ctctctggga 600

acccagacct atatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga 660

gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc tccagaactg 720

ctgggaggc cttccgtgtt cctgttcccc cccaagccca aggacaccct gatgatcagc 780

aggacccccg aggtgacctg cgtggtggtg gacgtgtccc acgaggaccc agaggtgaag 840

ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc cagagaggag 900

cagtacaaca gcacctacag ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg 960

aacggcaaag aatacaagtg caaagtctcc aacaaggccc tgccagcccc aatcgaaaag 1020

acaatcagca aggccaaggg ccagccacgg gagccccagg tgtacaccct gccccccagc 1080

cgggaggaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaggg cttctacccc 1140

tgtgatatcg ccgtggagtg ggagagcaac ggccagcccg agaacaacta caagaccacc 1200

cccccagtgc tggacagcga cggcagcttc ttcctgtaca gcaagctgac cgtggacaag 1260

tccaggtggc agcagggcaa cgtgttcagc tgcagcgtga tgcacgaggc cctgcacaac 1320

cactacaccc agaagtccct gagcctgagc cccggcaag 1359

<210> 258

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 258

Gln Gln Ser Leu Phe Ala Pro Phe Thr

1 5

<210> 259

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 259

Ser Leu Phe Ala Pro Phe

1 5

<210> 260

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 260

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Phe Ala Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 261

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 261

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ctgtcagcag agcctgttcg cccctttcac ctttggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 262

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 262

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Phe Ala Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 263

<211> 642

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polynucleotide"

<400> 263

gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60

atcacctgta gagccagcca gggcatcagc aactacctgg cctggtatca gcagaaaccc 120

ggcaaggtgc ccaagctgct gatctacgct gccagcacac tgcagagcgg agtgcctagc 180

agattttctg gcagcggctc cggcaccgat ttcaccctga ccatatctag cctgcagcca 240

gaggacgtgg ccacctacta ctgtcagcag agcctgttcg cccctttcac ctttggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag tggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 264

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic oligonucleotide"

<400> 264

ctctagcgcc accatgaaac a 21

<210> 265

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic oligonucleotide"

<400> 265

agcccagcaa caccaagg 18

<210> 266

<211> 20

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic oligonucleotide"

<400> 266

taatacgact cactataggg 20

<210> 267

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic 6xHis tag"

<400> 267

His His His His His

1 5

<210> 268

<211> 359

<212> PROTEIN

<213> Homo sapiens

<400> 268

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr

115 120 125

Val Asp Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

<210> 269

<211> 6343

<212> DNA

<213> Homo sapiens

<400> 269

agactatccg ctcccaccgc gcccccggcc cacctggtgg ccccggccct ggccgccgcc 60

cccgcggcgg ttcccggagc tcgtcccgga cgcgcgcccg ggcggcgggg gctcggcggc 120

caccgctgcc tcgggggagc gagggcggga gggtgtgtgt gcgcgctgtg agcaggggt 180

gccggcgggg ctgcagcgga ggcactttgg aagaatgact ctggagtcca tcatggcgtg 240

ctgcctgagc gaggaggcca aggaagcccg gcggatcaac gacgagatcg agcggcagct 300

ccgcagggac aagcgggacg cccgccggga gctcaagctg ctgctgctcg ggacaggaga 360

gagtggcaag agtacgttta tcaagcagat gagaatcatc catgggtcag gatactctga 420

tgaagataaa aggggcttca ccaagctggt gtatcagaac atcttcacgg ccatgcaggc 480

catgatcaga gccatggaca cactcaagat cccatacaag tatgagcaca ataaggctca 540

tgcacaatta gttcgagaag ttgatgtgga gaaggtgtct gcttttgaga atccatatgt 600

agatgcaata aagagtttat ggaatgatcc tggaatccag gaatgctatg atagacgacg 660

agaatatcaa ttatctgact ctaccaaata ctatcttaat gacttggacc gcgtagctga 720

ccctgcctac ctgcctacgc aacaagatgt gcttagagtt cgagtcccca ccacagggat 780

catcgaatac ccctttgact tacaaagtgt cattttcaga atggtcgatg tagggggcca 840

aaggtcagag agaagaaaat ggatacactg ctttgaaaat gtcacctcta tcatgtttct 900

agtagcgctt agtgaatatg atcaagttct cgtggagtca gacaatgaga accgaatgga 960

ggaaagcaag gctctcttta gaacaattat cacatacccc tggttccaga actcctcggt 1020

tattctgttc ttaaacaaga aagatcttct agaggagaaa atcatgtatt cccatctagt 1080

cgactacttc ccagaatatg atggacccca gagagatgcc caggcagccc gagaattcat 1140

tctgaagatg ttcgtggacc tgaacccaga cagtgacaaa attatctact cccacttcac 1200

gtgcgccaca gacaccgaga atatccgctt tgtctttgct gccgtcaagg acaccatcct 1260

ccagttgaac ctgaaggagt acaatctggt ctaattgtgc ctcctagaca cccgccctgc 1320

ccttccctgg tgggctattg aagatacaca agagggactg tatttctgtg gaaaacaatt 1380

tgcataatac taatttattg ccgtcctgga ctctgtgtga gcgtgtccac agagtttgta 1440

gtaaatatta tgattttatt taaactattc agaggaaaaa cagaggatgc tgaagtacag 1500

tcccagcaca tttcctctct atcttttttt taggcaaaac cttgtgactc agtgtatttt 1560

aaattctcag tcatgcactc acaaagataa gacttgtttc tttctgtctc tctctctttt 1620

tcttttctat ggagcaaaac aaagctgatt tccctttttt cttcccccgc taattcatac 1680

ctccctcctg atgtttttcc caggttacaa tggcctttat cctagttcca ttcttggtca 1740

agtttttctc tcaaatgata cagtcaggac acatcgttcg atttaagcca tcatcagctt 1800

aatttaagtt tgtagttttt gctgaaggat tatatgtatt aatacttacg gttttaaatg 1860

tgttgctttg gatacacaca tagtttcttt tttaatagaa tatactgtct tgtctcactt 1920

tggactggga cagtggatgc ccatctaaaa gttaagtgtc atttctttta gatgtttacc 1980

ttcagccata gcttgattgc tcagagaaat atgcagaagg caggatcaaa gacacacagg 2040

agtcctttct tttgaaatgc cacgtgccat tgtctttcct cccttctttg cttctttttc 2100

ttaccctctc tttcaattgc agatgccaaa aaagatgcca acagacacta cattacccta 2160

atggctgcta cccagaacct ttttataggt tgttcttaat ttttttgttg ttgttgttca 2220

agcttttcct ttcttttttt tcttggtgtt tgggccacga ttttaaaatg acttttatta 2280

tgggtatgtg ttgccaaagc tggctttttg tcaaataaaa tgaatacgaa cttaaaaaat 2340

aaaagctggt atcttaaaat gtaagagagt aagactgtga agcctaaaat gactggctga 2400

gaatgaacca gaaatgccat ttgccaaaca gttgtaacta gaaatttgat tctcacggtc 2460

cattcttttc tttgtcctta agatgacatt gttagtgttc acgtcccatg ttcagtgtcc 2520

aaaccggcaa tgtaaaaagt atcctgtgtg gtttaacagg aaatctgttt atgtctcttt 2580

atttgaaacc agttttactc tcagtggttc tttaagttca atgaagtctg ccaggaacat 2640

tggttggtag tattattccg acacctttaa tttccaaaat ctgaagttcc tgctagttta 2700

ccaccttcat gatcttcttg aactggtaac tgattaggtt gaacttatgg aagatttgtg 2760

gacttaactc aaaagtaacc tctcagtgtt ctatagaaca tgtatttgtg taactgaacc 2820

taccaggaga aatgtttgga attctatatg tgcaattttt caacaaatgc aaaaaaaata 2880

cagcacatgt attgacaagc ttctgtcaag cagcttgagt tgaaatttga tttaagaaaa 2940

taaatcatga ttgttcaaag ctgctgggac gttagaatta ggccatgata ctggtctcat 3000

tttaactaca gtggtatttg gcactagtgt aaacttccat ataaatcact cttttggaac 3060

aacaaagggg gagggagaaa aatcacggcc tgttaaatga gtaccaaagc cgcccaacag 3120

taatgagatg ttctcatcct tgattctccc agcctcaaac aacacagctt actttttttt 3180

tcccttgctc agaaagtacc tgtaatttaa caaacagact gcctgtaggt atagtgcaat 3240

tacaaatgct ctaatcattg tacatacatc tctcttgata ttgcagcatc catactggct 3300

ttgtaatcat taattttttg gcagattgaa tgtgctgtat tgatatgtat ctatgtaatt 3360

gtattgtatg tctatagcta attcacgttt tgaataatgt tattttattt acttttttaa 3420

gagaggagaa tgtaaatttg tcagtttatt tctgactagg gatattttct ttccattag 3480

aaaagaagaa aaaaaaaaaa ccttactgtc atacagagcg gtactagcgt cgtgctgtat 3540

aaaatcattt gcacattcct gagtagaggt atactgatta taagacccaa aggtaatttc 3600

atagcaaaat acataaaatc agtcggagct tttatacaaa catggaaacc aactttgtag 3660

aacttttgcc atttgatcta ggattggaat atgagctttt atacaattca tattcttatt 3720

tggcaaatgc acagtttagt attacctctc tgatggcctt tactagaaag gcagttttag 3780

aagctattgt gatccactaa ggaaatgttt taacagctag agaccactgc ttgcctgaaa 3840

gggcgttctt aaatttggtg cagcaaaaaa aaaaaaaaaa aaaaaaaaaa ttaaacaaca 3900

acatttgaag gcctacagtg tgtatagaga aaacctcatc acaagatcat aagtgttaca 3960

gttttaggga atcaagatat tctatttaat agagctatag taaatgtagt caattaaacc 4020

tgatctcaaa gcttgaagaa gctgagcaaa acagggaaag attgttatat ttgtctttat 4080

gaaattggga tggaatttgc tatgcagaat tgaggtttgt ggcttcgctg ttcctgtagg 4140

gtgcatgaca agatcccttc tcttgagaaa ggaaaaaatt gatcacccta gcagcagtga 4200

tgcatagaaa cctaatttta gccacaccag tcaatcgaag ctaaaggatt ttcttttttg 4260

tttcttcggg gttttattga aggggctagg ggcgggacgg gattcttttc agttttgtat 4320

aaaaacaaag tttactcatg ctttatatta tattgtgatt gcaagcgtta taagcgtgtg 4380

ccactggcct cctattgttg atgcttaggt aatggaggcc tgtggtgagt tttatggtga 4440

cttgggcatg tcttattcaa aaacaaaaac ataaaacaca gaaacctttc ttcagcatac 4500

caaggcaagc agccatttca tgactcactt aacacattgc agtgtaccag tttacagatg 4560

atttttccct ttttgcgtga catggcagtt ctaaccccca gagaattcct tatttgtaaa 4620

ttggaagttt ctactatgcc ttacagagct taaattcaga agtttgtgcc tcatatctga 4680

aacaaaggga aataacacac ccattcaaaa gtaaataaat ctcctagaag tttttgtttt 4740

taacatttcc atataaagag ctctgttgaa tgtcatgaat agactggaaa aaaaaatttt 4800

aagaacctgc atatgttgtt tactagcaga tgacaactac aaaaggaatc tgaagaacac 4860

gtaaaacttg tatttttttt tttttggtag attaactagc aggcctattt taaaaaggta 4920

attcagctaa agggcaattt acttttttgt acttcagact atcttgattg tcaaagtgta 4980

cgaactgtaa ttttaaaatt tatactgcca catgattgta aattttagtt gtcttaagtt 5040

aggaattggt gaaaagctat ttatgctgga tttggggtcaa aatgacttat ttgcaaaaaa 5100

ataaataatg ggaagaaagg gctgtataat gaaatactgc aagactcaca tattggttgg 5160

aaatttccct caaatcacct accgattacc cttgatttcc ctttgttttc agtttctcaa 5220

aacgaatgaa atgaaatata gcagaatgtt aacccatata aaaataaagt gtacccaaat 5280

attgtaatgt atattgctgc tcttcttcaa attaaataag ggtttaaaac cacttaattg 5340

gtaatcaaca tctcaattga tacaaataag gtgtgcttgg tatacattaa tattttcttc 5400

caaagatata tctttggtta gaaacacaaa aaaataaaac tagtaatatt gtatgtttat 5460

ctatctctac atatttccag catatgtagc gttaatagat ctgtcctggt aactgtgtct 5520

ttgggatttc attttggttc catcaaatta ggaaaagaaa tggcttagtt gtatatgatt 5580

agctagagat ttttggagcc agacacctgc tgtttagtag ataacttagt acagacccta 5640

aacttgtcat ttgtttttct cacagaatag ccatttcctg ctgtcttccc aatgatcact 5700

gccctttcaa taacactctt gcctctagaa tcatatgttc aaagtatgaa tacacaccta 5760

gcacatagta ggtgctcaaa tattaatttc ctccttgcct tccttatcta ccctgtgtcc 5820

tccatttccc cgtatgattc caacccaata tagcaaatga catttacatg ttatgaaaac 5880

atctattggg taaaatcaga tcttggataa agaaattctg acttttatat aagcttttgg 5940

tagacagaaa aaacagaaag gtattcgttg gtagaacatt tttaagttca ggaaagaaag 6000

ctggaataat actacgtaac tttgtccagg ttactttgac tgaaacacgt ttttggtgga 6060

tttcttttcc tcaaagaact ctctaaatgc aactccttgc tggattcctc acccatcatc 6120

ctgttggaaa cccttactag acctatgtat ttagggagtt ttgtcagaaa acatttttaa 6180

cttgcagtat ttaaaagaat atttactgtt cctaaaatgt cattcaaatg catgtactgt 6240

ctattgtttg gggatgggaa ctagttttgc aaaaaacacc taatgttgta taataatgcc 6300

ccaatgatct tgctggttaa aaatacagta tttttggcca taa 6343

<210> 270

<211> 359

<212> PROTEIN

<213> Homo sapiens

<400> 270

Met Thr Leu Glu Ser Met Ala Cys Cys Leu Ser Asp Glu Val Lys

1 5 10 15

Glu Ser Lys Arg Ile Asn Ala Glu Ile Glu Lys Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ala Gly Tyr Ser Glu Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Glu Thr

85 90 95

Leu Lys Ile Leu Tyr Lys Tyr Glu Gln Asn Lys Ala Asn Ala Leu Leu

100 105 110

Ile Arg Glu Val Asp Val Glu Lys Val Thr Thr Phe Glu His Gln Tyr

115 120 125

Val Ser Ala Ile Lys Thr Leu Trp Glu Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Ala Lys Tyr Tyr

145 150 155 160

Leu Thr Asp Val Asp Arg Ile Ala Thr Leu Gly Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Glu Asn Ile Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Asp Lys Ile Leu Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Phe Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

<210> 271

<211> 4190

<212> DNA

<213> Homo sapiens

<400> 271

aggttgtccg gcgctgtcgc tcggttgcgg cggctgcggt tggcggtggc tgcggcggcg 60

gcgcgggctg agtgcggccg cgcgggagtc cgcggctggc gcggcccgag cggggacccg 120

gcggctcgcc aggcggcggc cgaggcgggg cgggccggcc cggggccgag ggccggtggc 180

cgaggccgga gggccgcggc gggcggcggc cgaggcggct ccggccaggg ccgggccggg 240

ggccgggggg cggcggcggg caggcggccg cgtcggccgg ggccgggacg atgactctgg 300

agtccatgat ggcgtgttgc ctgagcgatg aggtgaagga gtccaagcgg atcaacgccg 360

agatcgagaa gcagctgcgg cgggacaagc gcgacgcccg gcgcgagctc aagctgctgc 420

tgctcggcac gggcgagagc gggaagagca cgttcatcaa gcagatgcgc atcatccacg 480

gcgccggcta ctcggaggag gacaagcgcg gcttcaccaa gctcgtctac cagaacatct 540

tcaccgccat gcaggccatg atccggggcca tggagacgct caagatcctc tacaagtacg 600

agcagaacaa ggccaatgcg ctcctgatcc gggaggtgga cgtggagaag gtgaccacct 660

tcgagcatca gtacgtcagt gccatcaaga ccctgtggga ggacccgggc atccaggaat 720

gctacgaccg caggcgcgag taccagctct ccgactctgc caagtactac ctgaccgacg 780

ttgaccgcat cgccaccttg ggctacctgc ccacccagca ggacgtgctg cgggtccgcg 840

tgcccaccac cggcatcatc gagtaccctt tcgacctgga gaacatcatc ttccggatgg 900

tggatgtggg gggccagcgg tcggagcgga ggaagtggat ccactgcttt gagaacgtga 960

catccatcat gtttctcgtc gccctcagcg aatacgacca agtcctggtg gagtcggaca 1020

acgagaaccg gatggaggag agcaaagccc tgttccggac catcatcacc tacccctggt 1080

tccagaactc ctccgtcatc ctcttcctca acaagaagga cctgctggag gacaagatcc 1140

tgtactcgca cctggtggac tacttccccg agttcgatgg tccccagcgg gacgcccagg 1200

cggcgcggga gttcatcctg aagatgttcg tggacctgaa ccccgacagc gacaagatca 1260

tctactcaca cttcacgtgt gccaccgaca cggagaacat ccgcttcgtg ttcgcggccg 1320

tgaaggacac catcctgcag ctcaacctca aggagtacaa cctggtctga gcgcccaggc 1380

ccaggggagac gggatggaga cacggggcag gaccttcctt ccacggagcc tgcggctgcc 1440

gggcgggtgg cgctgccgag tccgggccgg ggcctctgcc cgcgggagga gatttttttt 1500

tttcatattt ttaacaaatg gtttttattt cacagttatc aggggatgta catctctccc 1560

tccgtacact tcgcgcacct tctcaccttt tgtcaacggc aaaggcagcc tttttctggc 1620

cttgacttat ggctcgcttt tttctaaaaa aaaaaaaaaa agaaagaaag aaaaaaagca 1680

acgaaacata aaacacacaa gcgccccgtg cccccagtga ctctgggcct cacagagccc 1740

ccgccagcca gcatggggcc ccgccctgca gccagtcacg cgcccccaca ccgcagcccc 1800

ccgtggctgt ccttccaacc ccacgtgctt tttctttctc ctgcccgctt cttttcttca 1860

tcacaaaagg cgtggagact cggagacgga cgtttttccc cttttttaag ttattgacgc 1920

ccagcgcgcc tcgcctcttc acccatcaac gctgtgcttt gcccactgga ctcctgaaga 1980

gggggtgggg ggctccctcg gtcgcccacc ctgggaagtg cctaaccttt tattttattt 2040

tatttttttg aggaaaaaga acgcctgact cacaggttga agaaacaccc tgggccctct 2100

ctcatggccg ggttccccgt ccctctgcag aggctgggaa gggtccccgg gctggagcca 2160

cggggggcttc tctgggctgt gcctccgggg ccaacactgg ctgcttgggg ctgcccgggg 2220

actccagagg gctgcacggc caccctgccc tggctagagc gcaccccacc ggagcccacg 2280

tgggctgggc ggctggaggg atggtccccc ggtgacactg ggagaaaggc cacttggatg 2340

ggggcgtttc tgttttgttc cgctttgtga tgtcaccaat ttggaaacag cgaggtggg 2400

tggggacttt tacagaatat tctcaggtgt gtacccgaga ggcagagaga gggacgtggc 2460

cggcagctct gtgcgtggcc ttgtcccaag cacttgcgcc cgcccccgag cgccgccccc 2520

ggggagcggg aagccagcac tcgcactttg gccaggggcg cgtggaaggt ggtggcaggc 2580

accggcctgg gcagcttcca ggcctggctg gccacgacca cggcccgagg gggagcccgc 2640

caggccacgc cgcactgagc cacagccccg ggggccgcct cccggggccc cttgaggcac 2700

tgaggcaccg agactggttc tccccgagag actcggaagg tggggaacga ggggactgtg 2760

tttggggagg tggctttttc gtctgctgtt gactgaacac tacagcgccc tgtggttccg 2820

ggcttcgcac agctgtccca gggatggatc gcctgtgctg ccttcgcccg ccgccacacc 2880

gggaccctgc acggctgctt ctggcctcga cagatgacaa aagaaacagc cccaaaatac 2940

gaccactcca accagcagtt cccgcctgcc tgcccgccac tgtcaggcct gccctggcct 3000

cctcgtccgc agggctgtct gctggcttct gggggcagaa gagcggggag ccccgtggaa 3060

gggtcagggg agaccaggtc agggcagcta catttctggt gatcagcccc atggggagac 3120

ggggctggcg ggataccccc cccccggctt ccccacacca cttctgtctc acccggaagc 3180

gtcctttttt tgtgccaggt gtctacctaa gagggttggt gccagaagcc ccccatggcg 3240

agtgctgggg cccggcggtg ccctggggga gcagatgggg ccacccctgg cagggccgct 3300

acaacctttt ccagcagcgg agccctctgg ggggcctgtg cttgtggcat ctctgaggc 3360

ctagattgca caaggtgacc tggccgtggc ctgaggtgg agtcgcccag cacgcaggcc 3420

ggggcgctgc ggggctaagt attaggcctt cccagggagg gggcgtgcca agcatcccag 3480

agccgggctg ggaccgccaa aacgtcgtgg cctggatcct ctgggtctga gtgcctgatc 3540

ccctgccccc caaaaaagca gaggtaggtg ttgcaggccc agggcagggg tgcctgcccc 3600

aggagagtcc caggcagtgg ttctcgtgcc agtggcaccc aggggcaagg acagccaacc 3660

cccacccttg ccacgtgtgg ggccacgtgg gcatgtgggg tgtgtgtttt taccttggtg 3720

aatctcacct gccaacgatt tctcgtgagt gccgaccacc ttctccgacc atgttacgcc 3780

cgggcggcag cagcccccgg ccactgcaaa cccatgccct gggtcccccg gctcccccag 3840

ggaggcatcc ccgtgccaat gtcccccagt ggtggcagca gatcctgtgg ccggcctggc 3900

ggacgggacc cagtgatact tgtatattac acagtcctga tttcagacaa tttcaacctt 3960

aatctattta aaaaagaata ttctatacaa gctgttttta agccttttac catttgaaat 4020

gcatgtgttg tgcgcgttgg ggatgggagg aggggctgag gagcggctca gtgtcacctc 4080

ccacagccac cggccctgac ccttaatcca gacaccgatg gaagtcgact tttcatatct 4140

ttctcctgaa atgaactctg ttttaaattg gaataaattt tgttcctaaa 4190

<210> 272

<211> 661

<212> PROTEIN

<213> Homo sapiens

<400> 272

Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly

1 5 10 15

Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp

20 25 30

Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu

35 40 45

Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly

50 55 60

Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala

65 70 75 80

Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val

85 90 95

Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly

100 105 110

Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp

115 120 125

Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser

130 135 140

Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp

145 150 155 160

Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg

165 170 175

Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg

180 185 190

Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr

195 200 205

Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala

210 215 220

Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe

225 230 235 240

Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu

245 250 255

Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg

260 265 270

Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala

275 280 285

Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser

290 295 300

Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro

305 310 315 320

Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr

325 330 335

Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln

340 345 350

Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr

355 360 365

Ala Glu Ser Thr Gly Met Thr Pro Glu Lys Val Pro Val Ser Glu Val

370 375 380

Met Gly Thr Thr Leu Ala Glu Met Ser Thr Pro Glu Ala Thr Gly Met

385 390 395 400

Thr Pro Ala Glu Val Ser Ile Val Val Leu Ser Gly Thr Thr Ala Ala

405 410 415

Gln Val Thr Thr Thr Glu Trp Val Glu Thr Thr Ala Arg Glu Leu Pro

420 425 430

Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser Ser Ile Met Ser Thr Glu

435 440 445

Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu

450 455 460

Arg Leu Val Lys Arg Gln Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr

465 470 475 480

Gly Ser Phe Ser Val Thr Leu Asp Ile Val Gln Gly Ile Glu Ser Ala

485 490 495

Glu Ile Leu Gln Ala Val Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu

500 505 510

Thr Val Ser Cys Gln Gly Gly Leu Pro Lys Glu Ala Cys Met Glu Ile

515 520 525

Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln Arg Leu Cys Gln Pro Val

530 535 540

Leu Pro Ser Pro Ala Cys Gln Leu Val Leu His Gln Ile Leu Lys Gly

545 550 555 560

Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser Leu Ala Asp Thr Asn Ser

565 570 575

Leu Ala Val Val Ser Thr Gln Leu Ile Met Pro Gly Gln Glu Ala Gly

580 585 590

Leu Gly Gln Val Pro Leu Ile Val Gly Ile Leu Leu Val Leu Met Ala

595 600 605

Val Val Leu Ala Ser Leu Ile Tyr Arg Arg Arg Leu Met Lys Gln Asp

610 615 620

Phe Ser Val Pro Gln Leu Pro His Ser Ser Ser His Trp Leu Arg Leu

625 630 635 640

Pro Arg Ile Phe Cys Ser Cys Pro Ile Gly Glu Asn Ser Pro Leu Leu

645 650 655

Ser Gly Gln Gln Val

660

<210> 273

<211> 626

<212> PROTEIN

<213> Homo sapiens

<400> 273

Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly

1 5 10 15

Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp

20 25 30

Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu

35 40 45

Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly

50 55 60

Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala

65 70 75 80

Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val

85 90 95

Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly

100 105 110

Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp

115 120 125

Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser

130 135 140

Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp

145 150 155 160

Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg

165 170 175

Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg

180 185 190

Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr

195 200 205

Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala

210 215 220

Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe

225 230 235 240

Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu

245 250 255

Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg

260 265 270

Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala

275 280 285

Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser

290 295 300

Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro

305 310 315 320

Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr

325 330 335

Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln

340 345 350

Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr

355 360 365

Ala Glu Ser Thr Ala Ala Gln Val Thr Thr Thr Glu Trp Val Glu Thr

370 375 380

Thr Ala Arg Glu Leu Pro Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser

385 390 395 400

Ser Ile Met Ser Thr Glu Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu

405 410 415

Asp Gly Thr Ala Thr Leu Arg Leu Val Lys Arg Gln Val Pro Leu Asp

420 425 430

Cys Val Leu Tyr Arg Tyr Gly Ser Phe Ser Val Thr Leu Asp Ile Val

435 440 445

Gln Gly Ile Glu Ser Ala Glu Ile Leu Gln Ala Val Pro Ser Gly Glu

450 455 460

Gly Asp Ala Phe Glu Leu Thr Val Ser Cys Gln Gly Gly Leu Pro Lys

465 470 475 480

Glu Ala Cys Met Glu Ile Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln

485 490 495

Arg Leu Cys Gln Pro Val Leu Pro Ser Pro Ala Cys Gln Leu Val Leu

500 505 510

His Gln Ile Leu Lys Gly Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser

515 520 525

Leu Ala Asp Thr Asn Ser Leu Ala Val Val Ser Thr Gln Leu Ile Met

530 535 540

Pro Val Pro Gly Ile Leu Leu Thr Gly Gln Glu Ala Gly Leu Gly Gln

545 550 555 560

Val Pro Leu Ile Val Gly Ile Leu Leu Val Leu Met Ala Val Val Leu

565 570 575

Ala Ser Leu Ile Tyr Arg Arg Arg Leu Met Lys Gln Asp Phe Ser Val

580 585 590

Pro Gln Leu Pro His Ser Ser Ser His Trp Leu Arg Leu Pro Arg Ile

595 600 605

Phe Cys Ser Cys Pro Ile Gly Glu Asn Ser Pro Leu Leu Ser Gly Gln

610 615 620

Gln Val

625

<210> 274

<211> 619

<212> PROTEIN

<213> Homo sapiens

<400> 274

Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly

1 5 10 15

Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp

20 25 30

Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu

35 40 45

Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly

50 55 60

Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala

65 70 75 80

Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val

85 90 95

Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly

100 105 110

Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp

115 120 125

Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser

130 135 140

Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp

145 150 155 160

Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg

165 170 175

Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg

180 185 190

Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr

195 200 205

Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala

210 215 220

Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe

225 230 235 240

Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu

245 250 255

Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg

260 265 270

Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala

275 280 285

Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser

290 295 300

Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro

305 310 315 320

Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr

325 330 335

Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln

340 345 350

Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr

355 360 365

Ala Glu Ser Thr Ala Ala Gln Val Thr Thr Thr Glu Trp Val Glu Thr

370 375 380

Thr Ala Arg Glu Leu Pro Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser

385 390 395 400

Ser Ile Met Ser Thr Glu Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu

405 410 415

Asp Gly Thr Ala Thr Leu Arg Leu Val Lys Arg Gln Val Pro Leu Asp

420 425 430

Cys Val Leu Tyr Arg Tyr Gly Ser Phe Ser Val Thr Leu Asp Ile Val

435 440 445

Gln Gly Ile Glu Ser Ala Glu Ile Leu Gln Ala Val Pro Ser Gly Glu

450 455 460

Gly Asp Ala Phe Glu Leu Thr Val Ser Cys Gln Gly Gly Leu Pro Lys

465 470 475 480

Glu Ala Cys Met Glu Ile Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln

485 490 495

Arg Leu Cys Gln Pro Val Leu Pro Ser Pro Ala Cys Gln Leu Val Leu

500 505 510

His Gln Ile Leu Lys Gly Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser

515 520 525

Leu Ala Asp Thr Asn Ser Leu Ala Val Val Ser Thr Gln Leu Ile Met

530 535 540

Pro Gly Gln Glu Ala Gly Leu Gly Gln Val Pro Leu Ile Val Gly Ile

545 550 555 560

Leu Leu Val Leu Met Ala Val Val Leu Ala Ser Leu Ile Tyr Arg Arg

565 570 575

Arg Leu Met Lys Gln Asp Phe Ser Val Pro Gln Leu Pro His Ser Ser

580 585 590

Ser His Trp Leu Arg Leu Pro Arg Ile Phe Cys Ser Cys Pro Ile Gly

595 600 605

Glu Asn Ser Pro Leu Leu Ser Gly Gln Gln Val

610 615

<210> 275

<211> 575

<212> PROTEIN

<213> Homo sapiens

<400> 275

Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly

1 5 10 15

Ala Leu Leu Ala Val Gly Ala Thr Lys Gly Ser Gln Val Trp Gly Gly

20 25 30

Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp Ala Cys Ile Phe Pro Asp

35 40 45

Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser Gln Lys Arg Ser Phe Val

50 55 60

Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp Gln Val Leu Gly Gly Pro

65 70 75 80

Val Ser Gly Leu Ser Ile Gly Thr Gly Arg Ala Met Leu Gly Thr His

85 90 95

Thr Met Glu Val Thr Val Tyr His Arg Arg Gly Ser Arg Ser Tyr Val

100 105 110

Pro Leu Ala His Ser Ser Ser Ala Phe Thr Ile Thr Asp Gln Val Pro

115 120 125

Phe Ser Val Ser Val Ser Gln Leu Arg Ala Leu Asp Gly Gly Asn Lys

130 135 140

His Phe Leu Arg Asn Gln Pro Leu Thr Phe Ala Leu Gln Leu His Asp

145 150 155 160

Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu Ser Tyr Thr Trp Asp Phe

165 170 175

Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg Ala Leu Val Val Thr His

180 185 190

Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala Gln Val Val Leu Gln Ala

195 200 205

Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser Pro Val Pro Gly Thr Thr

210 215 220

Asp Gly His Arg Pro Thr Ala Glu Ala Pro Asn Thr Thr Ala Gly Gln

225 230 235 240

Val Pro Thr Thr Glu Val Val Gly Thr Thr Pro Gly Gln Ala Pro Thr

245 250 255

Ala Glu Pro Ser Gly Thr Thr Ser Val Gln Val Pro Thr Thr Glu Val

260 265 270

Ile Ser Thr Ala Pro Val Gln Met Pro Thr Ala Glu Ser Thr Gly Met

275 280 285

Thr Pro Glu Lys Val Pro Val Ser Glu Val Met Gly Thr Thr Leu Ala

290 295 300

Glu Met Ser Thr Pro Glu Ala Thr Gly Met Thr Pro Ala Glu Val Ser

305 310 315 320

Ile Val Val Leu Ser Gly Thr Thr Ala Ala Gln Val Thr Thr Thr Glu

325 330 335

Trp Val Glu Thr Thr Ala Arg Glu Leu Pro Ile Pro Glu Pro Glu Gly

340 345 350

Pro Asp Ala Ser Ser Ile Met Ser Thr Glu Ser Ile Thr Gly Ser Leu

355 360 365

Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu Arg Leu Val Lys Arg Gln

370 375 380

Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr Gly Ser Phe Ser Val Thr

385 390 395 400

Leu Asp Ile Val Gln Gly Ile Glu Ser Ala Glu Ile Leu Gln Ala Val

405 410 415

Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu Thr Val Ser Cys Gln Gly

420 425 430

Gly Leu Pro Lys Glu Ala Cys Met Glu Ile Ser Ser Pro Gly Cys Gln

435 440 445

Pro Pro Ala Gln Arg Leu Cys Gln Pro Val Leu Pro Ser Pro Ala Cys

450 455 460

Gln Leu Val Leu His Gln Ile Leu Lys Gly Gly Ser Gly Thr Tyr Cys

465 470 475 480

Leu Asn Val Ser Leu Ala Asp Thr Asn Ser Leu Ala Val Val Ser Thr

485 490 495

Gln Leu Ile Met Pro Gly Gln Glu Ala Gly Leu Gly Gln Val Pro Leu

500 505 510

Ile Val Gly Ile Leu Leu Val Leu Met Ala Val Val Leu Ala Ser Leu

515 520 525

Ile Tyr Arg Arg Arg Leu Met Lys Gln Asp Phe Ser Val Pro Gln Leu

530 535 540

Pro His Ser Ser Ser His Trp Leu Arg Leu Pro Arg Ile Phe Cys Ser

545 550 555 560

Cys Pro Ile Gly Glu Asn Ser Pro Leu Leu Ser Gly Gln Gln Val

565 570 575

<210> 276

<211> 668

<212> PROTEIN

<213> Homo sapiens

<400> 276

Met Asp Leu Val Leu Lys Arg Cys Leu Leu His Leu Ala Val Ile Gly

1 5 10 15

Ala Leu Leu Ala Val Gly Ala Thr Lys Val Pro Arg Asn Gln Asp Trp

20 25 30

Leu Gly Val Ser Arg Gln Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu

35 40 45

Tyr Pro Glu Trp Thr Glu Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly

50 55 60

Gln Val Ser Leu Lys Val Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala

65 70 75 80

Asn Ala Ser Phe Ser Ile Ala Leu Asn Phe Pro Gly Ser Gln Lys Val

85 90 95

Leu Pro Asp Gly Gln Val Ile Trp Val Asn Asn Thr Ile Ile Asn Gly

100 105 110

Ser Gln Val Trp Gly Gly Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp

115 120 125

Ala Cys Ile Phe Pro Asp Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser

130 135 140

Gln Lys Arg Ser Phe Val Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp

145 150 155 160

Gln Val Leu Gly Gly Pro Val Ser Gly Leu Ser Ile Gly Thr Gly Arg

165 170 175

Ala Met Leu Gly Thr His Thr Met Glu Val Thr Val Tyr His Arg Arg

180 185 190

Gly Ser Arg Ser Tyr Val Pro Leu Ala His Ser Ser Ser Ala Phe Thr

195 200 205

Ile Thr Asp Gln Val Pro Phe Ser Val Ser Val Ser Gln Leu Arg Ala

210 215 220

Leu Asp Gly Gly Asn Lys His Phe Leu Arg Asn Gln Pro Leu Thr Phe

225 230 235 240

Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala Glu Ala Asp Leu

245 250 255

Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr Leu Ile Ser Arg

260 265 270

Ala Leu Val Val Thr His Thr Tyr Leu Glu Pro Gly Pro Val Thr Ala

275 280 285

Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser Cys Gly Ser Ser

290 295 300

Pro Val Pro Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro

305 310 315 320

Asn Thr Thr Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr

325 330 335

Pro Gly Gln Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln

340 345 350

Val Pro Thr Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr

355 360 365

Ala Glu Ser Thr Gly Met Thr Pro Glu Lys Val Pro Val Ser Glu Val

370 375 380

Met Gly Thr Thr Leu Ala Glu Met Ser Thr Pro Glu Ala Thr Gly Met

385 390 395 400

Thr Pro Ala Glu Val Ser Ile Val Val Leu Ser Gly Thr Thr Ala Ala

405 410 415

Gln Val Thr Thr Thr Glu Trp Val Glu Thr Thr Ala Arg Glu Leu Pro

420 425 430

Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser Ser Ile Met Ser Thr Glu

435 440 445

Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu

450 455 460

Arg Leu Val Lys Arg Gln Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr

465 470 475 480

Gly Ser Phe Ser Val Thr Leu Asp Ile Val Gln Gly Ile Glu Ser Ala

485 490 495

Glu Ile Leu Gln Ala Val Pro Ser Gly Glu Gly Asp Ala Phe Glu Leu

500 505 510

Thr Val Ser Cys Gln Gly Gly Leu Pro Lys Glu Ala Cys Met Glu Ile

515 520 525

Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln Arg Leu Cys Gln Pro Val

530 535 540

Leu Pro Ser Pro Ala Cys Gln Leu Val Leu His Gln Ile Leu Lys Gly

545 550 555 560

Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser Leu Ala Asp Thr Asn Ser

565 570 575

Leu Ala Val Val Ser Thr Gln Leu Ile Met Pro Val Pro Gly Ile Leu

580 585 590

Leu Thr Gly Gln Glu Ala Gly Leu Gly Gln Val Pro Leu Ile Val Gly

595 600 605

Ile Leu Leu Val Leu Met Ala Val Val Leu Ala Ser Leu Ile Tyr Arg

610 615 620

Arg Arg Leu Met Lys Gln Asp Phe Ser Val Pro Gln Leu Pro His Ser

625 630 635 640

Ser Ser His Trp Leu Arg Leu Pro Arg Ile Phe Cys Ser Cys Pro Ile

645 650 655

Gly Glu Asn Ser Pro Leu Leu Ser Gly Gln Gln Val

660 665

<210> 277

<211> 2195

<212> DNA

<213> Homo sapiens

<400> 277

cccagcgctc ctccccgcaa atgatcccgc cccaggggcc tatcccagtc cccccagtgc 60

ctttggttgc tggagggaag aacacaatgg atctggtgct aaaaagatgc cttcttcatt 120

tggctgtgat aggtgctttg ctggctgtgg gggctacaaa agtacccaga aaccaggact 180

ggcttggtgt ctcaaggcaa ctcagaacca aagcctggaa caggcagctg tatccagagt 240

ggacagaagc ccagagactt gactgctgga gaggtggtca agtgtccctc aaggtcagta 300

atgatgggcc tacactgatt ggtgcaaatg cctccttctc tattgccttg aacttccctg 360

gaagccaaaa ggtattgcca gatgggcagg ttatctgggt caacaatacc atcatcaatg 420

ggagccaggt gtggggagga cagccagtgt atccccagga aactgacgat gcctgcatct 480

tccctgatgg tggaccttgc ccatctggct cttggtctca gaagagaagc tttgtttatg 540

tctggaagac ctggggccaa tactggcaag ttctaggggg cccagtgtct gggctgagca 600

ttgggacagg cagggcaatg ctgggcacac acaccatgga agtgactgtc taccatcgcc 660

ggggatcccg gagctatgtg cctcttgctc attccagctc agccttcacc attactgacc 720

aggtgccttt ctccgtgagc gtgtcccagt tgcgggcctt ggatggaggg aacaagcact 780

tcctgagaaa tcagcctctg acctttgccc tccagctcca tgaccccagt ggctatctgg 840

ctgaagctga cctctcctac acctgggact ttggagacag tagtggaacc ctgatctctc 900

gggcacttgt ggtcactcat acttacctgg agcctggccc agtcactgcc caggtggtcc 960

tgcaggctgc cattcctctc acctcctgtg gctcctcccc agttccaggc accacagatg 1020

ggcacaggcc aactgcagag gcccctaaca ccacagctgg ccaagtgcct actacagaag 1080

ttgtgggtac tacacctggt caggcgccaa ctgcagagcc ctctggaacc acatctgtgc 1140

aggtgccaac cactgaagtc ataagcactg cacctgtgca gatgccaact gcagagagca 1200

caggtatgac acctgagaag gtgccagttt cagaggtcat gggtaccaca ctggcagaga 1260

tgtcaactcc agaggctaca ggtatgacac ctgcagaggt atcaattgtg gtgctttctg 1320

gaaccacagc tgcacaggta acaactacag agtgggtgga gaccacagct agagagctac 1380

ctatccctga gcctgaaggt ccagatgcca gctcaatcat gtctacggaa agtattacag 1440

gttccctggg ccccctgctg gatggtacag ccaccttaag gctggtgaag agacaagtcc 1500

ccctggattg tgttctgtat cgatatggtt ccttttccgt caccctggac attgtccagg 1560

gtattgaaag tgccgagatc ctgcaggctg tgccgtccgg tgagggggat gcatttgagc 1620

tgactgtgtc ctgccaaggc gggctgccca aggaagcctg catggagatc tcatcgccag 1680

ggtgccagcc ccctgcccag cggctgtgcc agcctgtgct acccagccca gcctgccagc 1740

tggttctgca ccagatactg aagggtggct cggggacata ctgcctcaat gtgtctctgg 1800

ctgataccaa cagcctggca gtggtcagca cccagcttat catgcctggt caagaagcag 1860

gccttgggca ggttccgctg atcgtgggca tcttgctggt gttgatggct gtggtccttg 1920

catctctgat atataggcgc agacttatga agcaagactt ctccgtaccc cagttgccac 1980

atagcagcag tcactggctg cgtctacccc gcatcttctg ctcttgtccc attggtgaga 2040

acagccccct cctcagtggg cagcaggtct gagtactctc atatgatgct gtgattttcc 2100

tggagttgac agaaacacct atatttcccc cagtcttccc tgggagacta ctattaactg 2160

aaataaatac tcagagcctg aaaaaaaaaa aaaaa 2195

<210> 278

<211> 1902

<212> DNA

<213> Homo sapiens

<400> 278

gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg 60

gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct 120

acaaaaggga gccaggtgtg gggaggacag ccagtgtatc cccaggaaac tgacgatgcc 180

tgcatcttcc ctgatggtgg accttgccca tctggctctt ggtctcagaa gagaagcttt 240

gtttatgtct ggaagacctg gggccaatac tggcaagttc tagggggccc agtgtctggg 300

ctgagcattg ggacaggcag ggcaatgctg ggcacacaca ccatggaagt gactgtctac 360

catcgccggg gatcccggag ctatgtgcct cttgctcatt ccagctcagc cttcaccatt 420

actgaccagg tgcctttctc cgtgagcgtg tcccagttgc gggccttgga tggagggaac 480

aagcacttcc tgagaaatca gcctctgacc tttgccctcc agctccatga ccccagtggc 540

tatctggctg aagctgacct ctcctacacc tgggactttg gagacagtag tggaaccctg 600

atctctcggg cacttgtggt cactcatact tacctggagc ctggcccagt cactgcccag 660

gtggtcctgc aggctgccat tcctctcacc tcctgtggct cctccccagt tccaggcacc 720

acagatgggc acaggccaac tgcagaggcc cctaacacca cagctggcca agtgcctact 780

acagaagttg tgggtactac acctggtcag gcgccaactg cagagccctc tggaaccaca 840

tctgtgcagg tgccaaccac tgaagtcata agcactgcac ctgtgcagat gccaactgca 900

gagagcacag gtatgacacc tgagaaggtg ccagtttcag aggtcatggg taccacactg 960

gcagagatgt caactccaga ggctacaggt atgacacctg cagaggtatc aattgtggtg 1020

ctttctggaa ccacagctgc acaggtaaca actacagagt gggtggagac cacagctaga 1080

gagctaccta tccctgagcc tgaaggtcca gatgccagct caatcatgtc tacggaaagt 1140

attacaggtt ccctgggccc cctgctggat ggtacagcca ccttaaggct ggtgaagaga 1200

caagtccccc tggattgtgt tctgtatcga tatggttcct tttccgtcac cctggacatt 1260

gtccagggta ttgaaagtgc cgagatcctg caggctgtgc cgtccggtga gggggatgca 1320

tttgagctga ctgtgtcctg ccaaggcggg ctgcccaagg aagcctgcat ggagatctca 1380

tcgccaggt gccagccccc tgcccagcgg ctgtgccagc ctgtgctacc cagcccagcc 1440

tgccagctgg ttctgcacca gatactgaag ggtggctcgg ggacatactg cctcaatgtg 1500

tctctggctg ataccaacag cctggcagtg gtcagcaccc agcttatcat gcctggtcaa 1560

gaagcaggcc ttgggcaggt tccgctgatc gtgggcatct tgctggtgtt gatggctgtg 1620

gtccttgcat ctctgatata taggcgcaga cttatgaagc aagacttctc cgtaccccag 1680

ttgccacata gcagcagtca ctggctgcgt ctaccccgca tcttctgctc ttgtcccatt 1740

ggtgagaaca gccccctcct cagtgggcag caggtctgag tactctcata tgatgctgtg 1800

attttcctgg agttgacaga aacacctata tttcccccag tcttccctgg gagactacta 1860

ttaactgaaa taaatactca gagcctgaaa aaaaaaaaaa aa 1902

<210> 279

<211> 2181

<212> DNA

<213> Homo sapiens

<400> 279

gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg 60

gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct 120

acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc 180

tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt 240

ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc 300

ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc 360

tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc 420

caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg 480

tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta 540

gggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc 600

atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc 660

agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg 720

gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag 780

ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga 840

gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct 900

ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc 960

tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca 1020

gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca 1080

gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct 1140

gtgcagatgc caactgcaga gagcacaggt atgacacctg agaaggtgcc agtttcagag 1200

gtcatgggta ccacactggc agagatgtca actccagagg ctacaggtat gacacctgca 1260

gaggtatcaa ttgtggtgct ttctggaacc acagctgcac aggtaacaac tacagagtgg 1320

gtggagacca cagctagaga gctacctatc cctgagcctg aaggtccaga tgccagctca 1380

atcatgtcta cggaaagtat tacaggttcc ctgggccccc tgctggatgg tacagccacc 1440

ttaaggctgg tgaagagaca agtccccctg gattgtgttc tgtatcgata tggttccttt 1500

tccgtcaccc tggacattgt cccaggtatt gaaagtgccg agatcctgca ggctgtgccg 1560

tccggtgagg gggatgcatt tgagctgact gtgtcctgcc aaggcgggct gcccaaggaa 1620

gcctgcatgg agatctcatc gccagggtgc cagccccctg cccagcggct gtgccagcct 1680

gtgctaccca gcccagcctg ccagctggtt ctgcaccaga tactgaaggg tggctcgggg 1740

acatactgcc tcaatgtgtc tctggctgat accaacagcc tggcagtggt cagcacccag 1800

cttatcatgc ctgtgcctgg gattcttctc acaggtcaag aagcaggcct tgggcaggtt 1860

ccgctgatcg tgggcatctt gctggtgttg atggctgtgg tccttgcatc tctgatatat 1920

aggcgcagac ttatgaagca agacttctcc gtaccccagt tgccacatag cagcagtcac 1980

tggctgcgtc taccccgcat cttctgctct tgtcccattg gtgagaacag ccccctcctc 2040

agtgggcagc aggtctgagt actctcatat gatgctgtga ttttcctgga gttgacagaa 2100

acacctatat ttcccccagt cttccctggg agactactat taactgaaat aaatactcag 2160

agcctgaaaa aaaaaaaaaa a 2181

<210> 280

<211> 2041

<212> DNA

<213> Homo sapiens

<400> 280

gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg 60

gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct 120

acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc 180

tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt 240

ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc 300

ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc 360

tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc 420

caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg 480

tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta 540

gggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc 600

atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc 660

agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg 720

gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag 780

ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga 840

gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct 900

ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc 960

tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca 1020

gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca 1080

gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct 1140

gtgcagatgc caactgcaga gagcacagct gcacaggtaa caactacaga gtgggtggag 1200

accacagcta gagagctacc tatccctgag cctgaaggtc cagatgccag ctcaatcatg 1260

tctacggaaa gtattacagg ttccctgggc cccctgctgg atggtacagc caccttaagg 1320

ctggtgaaga gacaagtccc cctggattgt gttctgtatc gatatggttc cttttccgtc 1380

accctggaca ttgtccaggg tattgaaagt gccgagatcc tgcaggctgt gccgtccggt 1440

gagggggatg catttgagct gactgtgtcc tgccaaggcg ggctgcccaa ggaagcctgc 1500

atggagatct catcgccagg gtgccagccc cctgcccagc ggctgtgcca gcctgtgcta 1560

cccagcccag cctgccagct ggttctgcac cagatactga agggtggctc ggggacatac 1620

tgcctcaatg tgtctctggc tgataccaac agcctggcag tggtcagcac ccagcttatc 1680

atgcctgtgc ctgggattct tctcacaggt caagaagcag gccttgggca ggttccgctg 1740

atcgtgggca tcttgctggt gttgatggct gtggtccttg catctctgat atataggcgc 1800

agacttatga agcaagactt ctccgtaccc cagttgccac atagcagcag tcactggctg 1860

cgtctacccc gcatcttctg ctcttgtccc attggtgaga acagccccct cctcagtggg 1920

cagcaggtct gagtactctc atatgatgct gtgattttcc tggagttgac agaaacacct 1980

atatttcccc cagtcttccc tgggagacta ctattaactg aaataaatac tcagagcctg 2040

a 2041

<210> 281

<211> 2020

<212> DNA

<213> Homo sapiens

<400> 281

gggcctatcc cagtcccccc agtgcctttg gttgctggag ggaagaacac aatggatctg 60

gtgctaaaaa gatgccttct tcatttggct gtgataggtg ctttgctggc tgtgggggct 120

acaaaagtac ccagaaacca ggactggctt ggtgtctcaa ggcaactcag aaccaaagcc 180

tggaacaggc agctgtatcc agagtggaca gaagcccaga gacttgactg ctggagaggt 240

ggtcaagtgt ccctcaaggt cagtaatgat gggcctacac tgattggtgc aaatgcctcc 300

ttctctattg ccttgaactt ccctggaagc caaaaggtat tgccagatgg gcaggttatc 360

tgggtcaaca ataccatcat caatgggagc caggtgtggg gaggacagcc agtgtatccc 420

caggaaactg acgatgcctg catcttccct gatggtggac cttgcccatc tggctcttgg 480

tctcagaaga gaagctttgt ttatgtctgg aagacctggg gccaatactg gcaagttcta 540

gggggcccag tgtctgggct gagcattggg acaggcaggg caatgctggg cacacacacc 600

atggaagtga ctgtctacca tcgccgggga tcccggagct atgtgcctct tgctcattcc 660

agctcagcct tcaccattac tgaccaggtg cctttctccg tgagcgtgtc ccagttgcgg 720

gccttggatg gagggaacaa gcacttcctg agaaatcagc ctctgacctt tgccctccag 780

ctccatgacc ccagtggcta tctggctgaa gctgacctct cctacacctg ggactttgga 840

gacagtagtg gaaccctgat ctctcgggca cttgtggtca ctcatactta cctggagcct 900

ggcccagtca ctgcccaggt ggtcctgcag gctgccattc ctctcacctc ctgtggctcc 960

tccccagttc caggcaccac agatgggcac aggccaactg cagaggcccc taacaccaca 1020

gctggccaag tgcctactac agaagttgtg ggtactacac ctggtcaggc gccaactgca 1080

gagccctctg gaaccacatc tgtgcaggtg ccaaccactg aagtcataag cactgcacct 1140

gtgcagatgc caactgcaga gagcacagct gcacaggtaa caactacaga gtgggtggag 1200

accacagcta gagagctacc tatccctgag cctgaaggtc cagatgccag ctcaatcatg 1260

tctacggaaa gtattacagg ttccctgggc cccctgctgg atggtacagc caccttaagg 1320

ctggtgaaga gacaagtccc cctggattgt gttctgtatc gatatggttc cttttccgtc 1380

accctggaca ttgtccaggg tattgaaagt gccgagatcc tgcaggctgt gccgtccggt 1440

gagggggatg catttgagct gactgtgtcc tgccaaggcg ggctgcccaa ggaagcctgc 1500

atggagatct catcgccagg gtgccagccc cctgcccagc ggctgtgcca gcctgtgcta 1560

cccagcccag cctgccagct ggttctgcac cagatactga agggtggctc ggggacatac 1620

tgcctcaatg tgtctctggc tgataccaac agcctggcag tggtcagcac ccagcttatc 1680

atgcctggtc aagaagcagg ccttgggcag gttccgctga tcgtgggcat cttgctggtg 1740

ttgatggctg tggtccttgc atctctgata tataggcgca gacttatgaa gcaagacttc 1800

tccgtacccc agttgccaca tagcagcagt cactggctgc gtctaccccg catcttctgc 1860

tcttgtccca ttggtgagaa cagccccctc ctcagtgggc agcaggtctg agtactctca 1920

tatgatgctg tgattttcct ggagttgaca gaaacaccta tatttccccc agtcttccct 1980

gggagactac tattaactga aataaatact cagagcctga 2020

<210> 282

<211> 22

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic peptide"

<400> 282

Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Leu Tyr Arg Ser Pro

1 5 10 15

Ala Met Pro Glu Asn Leu

20

<---

Claims (202)

1. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, comprising: a) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 14, a light chain CDR2 of SEQ ID NO: 15 and a light chain CDR3 of SEQ ID NO: 16; b) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 2 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 14, a light chain CDR2 of SEQ ID NO: 15 and a light chain CDR3 of SEQ ID NO: 16; c) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 5, a heavy chain CDR2 of SEQ ID NO: 6 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 17, a light chain CDR2 of SEQ ID NO: 18 and a light chain CDR3 of SEQ ID NO: 19; d) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8 and a heavy chain CDR3 of SEQ ID NO: 9; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 20, a light chain CDR2 of SEQ ID NO: 18 and a light chain CDR3 of SEQ ID NO: 16; e) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 33, a heavy chain CDR2 of SEQ ID NO: 34, and a heavy chain CDR3 of SEQ ID NO: 35; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 46, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 48; f) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 36, a heavy chain CDR2 of SEQ ID NO: 34 and a heavy chain CDR3 of SEQ ID NO: 35; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 46, a light chain CDR2 of SEQ ID NO: 47 and a light chain CDR3 of SEQ ID NO: 48; g) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 37, a heavy chain CDR2 of SEQ ID NO: 38, and a heavy chain CDR3 of SEQ ID NO: 35; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 49, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 51; h) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 39, a heavy chain CDR2 of SEQ ID NO: 40 and a heavy chain CDR3 of SEQ ID NO: 41; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 52, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 48; i) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 57, a heavy chain CDR2 of SEQ ID NO: 58, and a heavy chain CDR3 of SEQ ID NO: 59; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 68, a light chain CDR2 of SEQ ID NO: 69, and a light chain CDR3 of SEQ ID NO: 70; j) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 60, a heavy chain CDR2 of SEQ ID NO: 58, and a heavy chain CDR3 of SEQ ID NO: 59; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 68, a light chain CDR2 of SEQ ID NO: 69, and a light chain CDR3 of SEQ ID NO: 70; k) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 5, a heavy chain CDR2 of SEQ ID NO: 61 and a heavy chain CDR3 of SEQ ID NO: 59; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 71, a light chain CDR2 of SEQ ID NO: 72 and a light chain CDR3 of SEQ ID NO: 73; l) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 62 and a heavy chain CDR3 of SEQ ID NO: 63; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 74, a light chain CDR2 of SEQ ID NO: 72 and a light chain CDR3 of SEQ ID NO: 70; m) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 79, a heavy chain CDR2 of SEQ ID NO: 80 and a heavy chain CDR3 of SEQ ID NO: 81; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 92, a light chain CDR2 of SEQ ID NO: 93 and a light chain CDR3 of SEQ ID NO: 94; n) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 82, a heavy chain CDR2 of SEQ ID NO: 80, and a heavy chain CDR3 of SEQ ID NO: 81; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 92, a light chain CDR2 of SEQ ID NO: 93, and a light chain CDR3 of SEQ ID NO: 94; o) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 83, a heavy chain CDR2 of SEQ ID NO: 84 and a heavy chain CDR3 of SEQ ID NO: 81; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 95, a light chain CDR2 of SEQ ID NO: 96 and a light chain CDR3 of SEQ ID NO: 97; p) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 85, a heavy chain CDR2 of SEQ ID NO: 86 and a heavy chain CDR3 of SEQ ID NO: 87; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 98, a light chain CDR2 of SEQ ID NO: 96 and a light chain CDR3 of SEQ ID NO: 94; q) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, and a heavy chain CDR3 of SEQ ID NO: 105; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 117; r) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104 and a heavy chain CDR3 of SEQ ID NO: 105; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47 and a light chain CDR3 of SEQ ID NO: 117; s) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108 and a heavy chain CDR3 of SEQ ID NO: 105; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 49, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 118; t) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110 and a heavy chain CDR3 of SEQ ID NO: 111; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 52, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 117; u) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 123, a heavy chain CDR2 of SEQ ID NO: 124 and a heavy chain CDR3 of SEQ ID NO: 125; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 136, a light chain CDR2 of SEQ ID NO: 137 and a light chain CDR3 of SEQ ID NO: 138; v) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 126, a heavy chain CDR2 of SEQ ID NO: 124 and a heavy chain CDR3 of SEQ ID NO: 125; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 136, a light chain CDR2 of SEQ ID NO: 137 and a light chain CDR3 of SEQ ID NO: 138; w) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 127, a heavy chain CDR2 of SEQ ID NO: 128, and a heavy chain CDR3 of SEQ ID NO: 125; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 139, a light chain CDR2 of SEQ ID NO: 140, and a light chain CDR3 of SEQ ID NO: 141; x) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NO: 130, and a heavy chain CDR3 of SEQ ID NO: 131; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 142, a light chain CDR2 of SEQ ID NO: 140, and a light chain CDR3 of SEQ ID NO: 138; y) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 123, a heavy chain CDR2 of SEQ ID NO: 124, and a heavy chain CDR3 of SEQ ID NO: 147; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154, and a light chain CDR3 of SEQ ID NO: 155; z) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 126, a heavy chain CDR2 of SEQ ID NO: 124, and a heavy chain CDR3 of SEQ ID NO: 147; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154, and a light chain CDR3 of SEQ ID NO: 155; aa) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 127, a heavy chain CDR2 of SEQ ID NO: 128, and a heavy chain CDR3 of SEQ ID NO: 147; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 156, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 157; bb) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NO: 130, and a heavy chain CDR3 of SEQ ID NO: 148; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 158, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 155; cc) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, and a heavy chain CDR3 of SEQ ID NO: 163; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 169; dd) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104, and a heavy chain CDR3 of SEQ ID NO: 163; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 169; ee) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, and a heavy chain CDR3 of SEQ ID NO: 163; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 49, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 170; ff) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110 and a heavy chain CDR3 of SEQ ID NO: 164; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 52, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 169; gg) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 175, a heavy chain CDR2 of SEQ ID NO: 176, and a heavy chain CDR3 of SEQ ID NO: 177; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 188; hh) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 178, a heavy chain CDR2 of SEQ ID NO: 176, and a heavy chain CDR3 of SEQ ID NO: 177; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 188; ii) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 179, a heavy chain CDR2 of SEQ ID NO: 180 and a heavy chain CDR3 of SEQ ID NO: 177; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 49, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 189; jj) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 181, a heavy chain CDR2 of SEQ ID NO: 182, and a heavy chain CDR3 of SEQ ID NO: 183; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 52, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 188; kk) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, and a heavy chain CDR3 of SEQ ID NO: 194; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 200; ll) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104, and a heavy chain CDR3 of SEQ ID NO: 194; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 116, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 200; mm) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108 and a heavy chain CDR3 of SEQ ID NO: 194; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 49, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 201; nn) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110 and a heavy chain CDR3 of SEQ ID NO: 195; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 52, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 200; oo) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207 and a heavy chain CDR3 of SEQ ID NO: 208; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154 and a light chain CDR3 of SEQ ID NO: 219; pp) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 208; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154, and a light chain CDR3 of SEQ ID NO: 219; qq) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211, and a heavy chain CDR3 of SEQ ID NO: 208; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 156, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 220; rr) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, and a heavy chain CDR3 of SEQ ID NO: 214; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 158, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 219; ss) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 225; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 136, a light chain CDR2 of SEQ ID NO: 137, and a light chain CDR3 of SEQ ID NO: 231; tt) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207 and a heavy chain CDR3 of SEQ ID NO: 225; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 136, a light chain CDR2 of SEQ ID NO: 137 and a light chain CDR3 of SEQ ID NO: 231; uu) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211, and a heavy chain CDR3 of SEQ ID NO: 225; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 139, a light chain CDR2 of SEQ ID NO: 140, and a light chain CDR3 of SEQ ID NO: 232; vv) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, and a heavy chain CDR3 of SEQ ID NO: 226; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 142; a light chain CDR2 of SEQ ID NO: 140, and a light chain CDR3 of SEQ ID NO: 231; ww) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 237; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 243, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 244; xx) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 237; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 243, a light chain CDR2 of SEQ ID NO: 47, and a light chain CDR3 of SEQ ID NO: 244; yy) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211 and a heavy chain CDR3 of SEQ ID NO: 237; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 245, a light chain CDR2 of SEQ ID NO: 50 and a light chain CDR3 of SEQ ID NO: 246; zz) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, and a heavy chain CDR3 of SEQ ID NO: 238; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 247, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 244; aaa) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 252; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154, and a light chain CDR3 of SEQ ID NO: 258; bbb) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207, and a heavy chain CDR3 of SEQ ID NO: 252; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 153, a light chain CDR2 of SEQ ID NO: 154, and a light chain CDR3 of SEQ ID NO: 258; ccc) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211, and a heavy chain CDR3 of SEQ ID NO: 252; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 156, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 259; or ddd) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, and a heavy chain CDR3 of SEQ ID NO: 253; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 158, a light chain CDR2 of SEQ ID NO: 50, and a light chain CDR3 of SEQ ID NO: 258. 2. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, comprising: a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 21; b) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 25; c) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 29; d) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 42 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 53; e) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 64 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 75; f) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 88 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 99; g) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 112 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 119; h) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 132 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143; i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 149 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 159; j) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 165 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 171; k) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 184 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 190; l) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 196 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 202; m) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 215 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 221; n) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 227 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 233; o) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 239 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 248; or p) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 254 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 260. 3. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, comprising: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 27; c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 55; e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 and a light chain comprising the amino acid sequence of SEQ ID NO: 77; f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 and a light chain comprising the amino acid sequence of SEQ ID NO: 101; g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 114 and a light chain comprising the amino acid sequence of SEQ ID NO: 121; h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 134 and a light chain comprising the amino acid sequence of SEQ ID NO: 145; i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 151 and a light chain comprising the amino acid sequence of SEQ ID NO: 161; j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 167 and a light chain comprising the amino acid sequence of SEQ ID NO: 173; k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 186 and a light chain comprising the amino acid sequence of SEQ ID NO: 192; l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 198 and a light chain comprising the amino acid sequence of SEQ ID NO: 204; m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 217 and a light chain comprising the amino acid sequence of SEQ ID NO: 223; n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 229 and a light chain comprising the amino acid sequence of SEQ ID NO: 235; o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 241 and a light chain comprising the amino acid sequence of SEQ ID NO: 250; or p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 256 and a light chain comprising the amino acid sequence of SEQ ID NO: 262. 4. The antibody of any one of claims 1-3, wherein the antibody or antigen-binding fragment thereof comprises one or more cysteine substitutions. 5. The antibody of claim 4, wherein one or more cysteine substitutions are selected from E152C, S375C or both E152C and S375C in the heavy chain of the antibody or antigen-binding fragment thereof, wherein the position numbering corresponds to the EU system. 6. The antibody according to any one of claims 1-5, wherein said antibody is a monoclonal antibody. 7. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises formula (C): Ab-(L _A -(D) _n ) _y (C), where D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11; Ab is an antibody or antigen-binding fragment thereof that binds to the human PMEL17 protein according to any one of claims 1-6; L _A is a linker; n is 1, 2, 3 or 4 and y is 1, 2, 3, or 4. 8. A conjugate of an antibody and a drug according to claim 7, where n is equal to 1. 9. A conjugate of an antibody and a drug according to claim 7 or 8, wherein y is 2. 10. An antibody-drug conjugate according to any one of claims 7-9, wherein said linker is a cleavable linker or a non-cleavable linker. 11. The antibody-drug conjugate of claim 10, wherein the linker comprises a ValCit peptide linker. 12. An antibody-drug conjugate according to any one of claims 7-11, wherein D is an inhibitor of GNAQ and GNA11. 13. The antibody-drug conjugate of any one of claims 7-11, wherein D is . 14. The antibody-drug conjugate of any one of claims 7-11, wherein D is . 15. An antibody-drug conjugate according to any one of claims 7-13, comprising the following structure: . 16. An antibody-drug conjugate according to any one of claims 7-12 or 14, comprising the following structure: . 17. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the formula (C-2) (C-2), where R ⁰ is methyl or ethyl; R ¹ is methyl or isopropyl; R ² represents methyl or ethyl; Ab is an antibody or antigen-binding fragment thereof that binds to the human PMEL17 protein according to any one of claims 1-6; X ₁ is a bivalent linking group; X ₂ is a self-cleaving spacer; L ₁ is a bivalent peptide linker; L ₂ is a bond or linker and y is 1, 2, 3, or 4. 18. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the following structure: , where Ab is an antibody or antigen-binding fragment thereof that binds to the human PMEL17 protein, comprising: a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 21; b) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 25; c) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 29; d) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 23; e) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 27; or f) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 31; and where y equals 2. 19. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the following structure: , where Ab is an antibody or antigen-binding fragment thereof that binds to the human PMEL17 protein, comprising: a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 21; b) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 25; c) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 29; d) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 23; e) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 27; or f) a heavy chain that comprises the amino acid sequence of SEQ ID NO: 12 and a light chain that comprises the amino acid sequence of SEQ ID NO: 31; and where y equals 2. 20. A pharmaceutical composition for treating or preventing cancer in a patient in need thereof, wherein the composition comprises a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-6 and a pharmaceutically acceptable carrier, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 21. A pharmaceutical composition for treating or preventing cancer in a patient in need thereof, wherein the composition comprises a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 7-19 and a pharmaceutically acceptable carrier, wherein the cancer expresses PMEL17, the cancer comprises a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and comprises a mutation of the GNAQ gene and/or the GNA11 gene. 22. A method for treating or preventing cancer in a patient in need thereof, comprising administering to said patient a conjugate of an antibody and a drug according to any one of claims 7-19 or a pharmaceutical composition according to claim 20 or 21, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 23. The method of claim 22, wherein the antibody-drug conjugate or pharmaceutical composition is administered to the patient in combination with one or more additional therapeutic compounds. 24. The method of claim 23, wherein one or more additional therapeutic compounds are selected from a standard chemotherapeutic agent, an MDM2 inhibitor, an MRC2 inhibitor, a PKC inhibitor, a MAPK inhibitor, a costimulatory molecule, or an immune checkpoint inhibitor. 25. The method of claim 24, wherein the costimulatory molecule is selected from an agonist of OX40, CD2, CD27, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, STING or a CD83 ligand. 26. The method according to claim 24, wherein the immune checkpoint inhibitor is selected from an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR-beta. 27. A conjugate of an antibody and a drug according to any one of claims 7-19 or a pharmaceutical composition according to claim 20 or 21 for use in the treatment or prevention of cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 28. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-6, a conjugate of an antibody and a drug according to any one of claims 7-19 or a pharmaceutical composition according to claim 20 or 21 for the treatment or prevention of cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 29. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-6, a conjugate of an antibody and a drug according to any one of claims 7-19 or a pharmaceutical composition according to claim 20 or 21 in the manufacture of a medicinal product for the treatment or prevention of cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 30. The method according to any one of claims 22-26, the conjugate of an antibody and a drug or pharmaceutical composition according to claim 27, the use according to claim 28 or 29, wherein the cancer is uveal melanoma, subcutaneous melanoma, hepatocellular carcinoma or a metastatic form of these types of cancer. 31. A nucleic acid that encodes an antibody or antigen-binding fragment according to any one of claims 1-6. 32. The nucleic acid of claim 31, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 13, 24, 28, 32, 45, 56, 67, 78, 91, 102, 115, 122, 135, 146, 152, 162, 168, 174, 187, 193, 199, 205, 218, 224, 230, 236, 242, 251, 257 or 263. 33. An expression vector containing a nucleic acid according to claim 31 or 32. 34. A host cell for producing an antibody or antigen-binding fragment that binds to the human PMEL17 protein, wherein said host cell contains the nucleic acid of claim 31 or 32, the expression vector of claim 33. 35. A method for producing an antibody or antigen-binding fragment, comprising culturing a host cell according to claim 34 and extracting the antibody or antigen-binding fragment from the cell culture. 36. The method according to claim 35, wherein the extraction of the antibody or antigen-binding fragment from the cell culture comprises the following steps: a) removal of cells and filtration of the culture; b) purification of the culture by affinity chromatography; c) inactivation of any viruses in the culture by adjusting the pH to 3.4-3.6, then readjusting the pH to 5.8-6.2 and filtering the culture; d) carrying out purification of the culture by means of cation exchange chromatography and carrying out recovery of the culture on the column; e) performing anion exchange chromatography on the culture; f) removal of viruses by nanofiltration; g) filtering the culture containing the antibody or antigen-binding fragment, and h) obtaining a purified antibody or antigen-binding fragment. 37. A method for producing a conjugate of an antibody and a drug that binds to the human PMEL17 protein, according to any one of paragraphs 7-19, comprising: (a) preforming a linker-drug moiety of the following formula (B): R ⁸ -L _B -(D) _n (B), where D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11; R ⁸ is a reactive group; L _B is a cleavable or non-cleavable linker and n is 1, 2, 3, or 4; (b) conjugating said linker-drug moiety to an antibody recovered from the cell culture of claim 35 or 36 to form an antibody-drug conjugate; and (c) performing purification of the antibody-drug conjugate. 38. A diagnostic reagent for diagnosing a disease associated with PMEL17 expression, wherein said diagnostic reagent comprises an antibody or antigen-binding fragment thereof according to any one of claims 1-6. 39. The diagnostic reagent of claim 38, wherein the antibody or antigen-binding fragment thereof is labeled with a radioactive label, fluorophore, chromophore, imaging agent, or metal ion. 40. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the following structure where Ab is an antibody or antigen-binding fragment thereof that binds to the human PMEL17 protein, comprising: a) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 14, a light chain CDR2 of SEQ ID NO: 15 and a light chain CDR3 of SEQ ID NO: 16; b) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 2 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 14, a light chain CDR2 of SEQ ID NO: 15 and a light chain CDR3 of SEQ ID NO: 16; c) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 5, a heavy chain CDR2 of SEQ ID NO: 6 and a heavy chain CDR3 of SEQ ID NO: 3; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 17, a light chain CDR2 of SEQ ID NO: 18 and a light chain CDR3 of SEQ ID NO: 19; d) a heavy chain variable region comprising a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, a heavy chain CDR3 of SEQ ID NO: 9; and a light chain variable region comprising a light chain CDR1 of SEQ ID NO: 20, a light chain CDR2 of SEQ ID NO: 18, and a light chain CDR3 of SEQ ID NO: 16; and where y equals 2. 41. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the following structure: wherein Ab is an antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 25; and where y equals 2. 42. An antibody-drug conjugate that binds to human PMEL17 protein, wherein the antibody-drug conjugate comprises the following structure: wherein Ab is an antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 12, except that the amino acid at position 375 is S, where the position is numbered according to the EU system, and a light chain comprising the amino acid sequence of SEQ ID NO: 27; and where y equals 2. 43. A pharmaceutical composition for treating or preventing cancer in a patient in need thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 40-42 and a pharmaceutically acceptable carrier, and wherein the cancer expresses PMEL17, the cancer comprises a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and comprises a mutation of the GNAQ gene and/or the GNA11 gene. 44. A method for treating or preventing cancer in a patient in need thereof, comprising administering to said patient a conjugate of an antibody and a drug according to any one of claims 40-42 or a pharmaceutical composition according to claim 43, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 45. A conjugate of an antibody and a drug according to any one of claims 40-42 or a pharmaceutical composition according to claim 43 for use in a method of treating or preventing cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer comprises a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and comprises a mutation of the GNAQ gene and/or the GNA11 gene. 46. Use of a conjugate of an antibody and a drug according to any one of claims 40-42 or a pharmaceutical composition according to claim 43 in a method of treating cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene. 47. Use of a conjugate of an antibody and a drug according to any of claims 40-42 or a pharmaceutical composition according to claim 43 in the manufacture of a medicinal product for the treatment or prevention of cancer in a patient in need thereof, wherein the cancer expresses PMEL17, the cancer contains a mutation of the GNAQ gene and/or the GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene and/or the GNA11 gene.

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