Antibodies to PMEL17 and conjugates thereof

Abstract

This application discloses anti-PMEL17 antibodies, antigen binding fragments thereof, and antibody drug conjugates of said antibodies or antigen binding fragments conjugated to a GNAQ / GNA11 inhibitor. The invention also relates to methods of treating or preventing cancer using the antibodies, antigen binding fragments, and antibody drug conjugates. Also disclosed herein are methods of making the antibodies, antigen binding fragments, and antibody drug conjugates, and methods of using the antibodies and antigen binding fragments as diagnostic reagents.

Description

Sequence Listing

[0000] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 6, 2019, is named PAT058359-WO-PCT_SL.txt and is 285,253 bytes in size Field of the Invention

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

[0002] PMEL17 (also referred to as gp100 and SILV) is a single-pass Type I transmembrane protein produced by melanocytes and involved in melanin synthesis. Along its maturation, PMEL17 is transiently expressed at the cell surface before trafficked to melanosomes where PMEL17 is degraded into various domains that multimerizes to form fibrillar sheets. Such pattern then serves as a support for trapping melanin. The melanosomes PMEL17 expression is regulated by MITF, a lineage oncogene, and was found to be up-regulated in a variety of primary and metastatic subcutaneous and uveal melanomas. The transient cell surface expression and subsequent internalization of PMEL17 makes it a suitable target for developing antibody drug conjugate (ADC) for the treatment of melanoma. PMEL17 and Cancer

[0003] Along its maturation, PMEL17 is heavily processed by pro-protein convertases. The protein is cleaved between V467 / K468 forming two subdomains, Ma at the N-term and Mp at the C-term, supposedly maintained via a disulphide bridge. After leaving the golgi apparatus, some PMEL17 molecules are transiently expressed at the cell surface. Most PMEL17 is then redirected to a melanocyte for further maturation while some PMEL17 appears to be shed. Following additional enzymatic cleavages, PMEL17 is degraded into various domains which reorganize and form fibrillar sheets where melanin polymerizes (Valencia JC, et al. Sorting of Pmel17 to melanosomes through the plasma membrane byAP1 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 constitutes a potential therapeutic target for the treatment of melanoma. PMEL17 is a direct transcriptional target of MITF, a lineage oncogene in melanoma, as observed 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 the melanocyte lineage which includes skin melanocytes, hair bulb melanocytes, retinal pigment epithelium, pigmented cilliary epithelium, and possibly the choroid melanocytes in the retina. PMEL17 is also highly expressed in melanocyte lineage tumors such as subcutaneous and uveal melanoma. In contrast, mRNA studies have demonstrated that PMEL17 expression is limited on 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). Besides, ADC and ImmTAC compounds targeting PMEL17 have previously been described to specifically induce killing of melanoma in vivo and in vitro and are currently evaluated in clinical trials (Chen Y, et al. The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma. J Biol Chern. 2012 Jul 13;287(29):24082-91. doi:10.1074 / jbc.M112.361485. Epub 2012 May 21). GNAQ / GNA11 and Cancer

[0005] GNAQ and GNA11 genes encode for the alpha subunit of the heterotrimeric G proteins Gq / 11, which are almost 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 Gaq and Ga11 activate p-isoforms of phospholipase C, which triggers a number of signal transduction pathways through the generation of second messengers IP3 and DAG. Signaling termination is triggered by GTP hydrolysis mediated by intrinsic GTPase activity of these Ga proteins. Gq and G11 have been shown to be involved in a vast array of physiological functions including platelet activation, myocardial hypertrophy, and smooth muscle tone.

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

[0007] Antibody drug conjugates (“ADCs”) have been used for the local delivery of cytotoxic agents in the treatment of cancer (see, e.g., Lambert, Curr. Opinion In Pharmacology 5:543-549, 2005). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal toxicity may be achieved. ADCs include an antibody selected for its ability to bind to a cell targeted for therapeutic intervention, linked to a drug selected for its cytostatic or cytotoxic activity. Binding of the antibody to the targeted cell thereby delivers the drug to the site where its therapeutic effect is needed.

[0008] Many antibodies that recognize and selectively bind to targeted cells, e.g., cancer cells, have been disclosed for use in ADCs. In spite of the extensive work on ADCs, antibody binding to a particular target of interest is not sufficient to predict success in ADC applications. Examples of factors that can effect therapeutic effectiveness of ADCs (besides target-intrinsic features) include various aspects that need customized fine-tuning, such as the optimal antibody affinity as a balance between target-mediated disposition (TMDD) and efficacy-driving exposure, evaluation of Fc-mediated functions (antibody-dependent cell-mediated cytotoxicity, ADCC), method of conjugation (site-specific or not), the ratio of the drug / payload molecules that conjugate to each antibody (“DAR” or “drug antibody ratio”), the cleavability or stability of the linker, stability of the ADC, and the tendency of an ADC to aggregate.

[0009] There remains a need for antibodies, attachment methods, and cytotoxic payloads with improved properties for use as effective ADC therapeutic compositions and methods. Summary of the invention

[0010] In one embodiment, the present application discloses an antibody or antigen binding fragment thereof that binds PMEL17 comprising: a. a heavy chain variable region that comprises 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 that comprises 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; b. a heavy chain variable region that comprises 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; c. a heavy chain variable region that comprises 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 NQ:70 or 73; d. a heavy chain variable region that comprises a heavy chain CDR1 of SEQ ID NO:79, 82, 83 or 85, a heavy chain CDR2 of SEQ ID NQ: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; e. a heavy chain variable region that comprises 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; f. a heavy chain variable region that comprises 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; g. a heavy chain variable region that comprises 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 NQ:50 or 154; and a light chain CDR3 of SEQIDNO:155 or 157; h. a heavy chain variable region that comprises 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 SEQIDNO:169 or 170; i. a heavy chain variable region that comprises 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 SEQIDNO:188 or 189; j. a heavy chain variable region that comprises 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 NQ:200 or 201; k. a heavy chain variable region that comprises a heavy chain CDR1 of SEQ ID NQ:206, 209, 210 or 212, a heavy chain CDR2 of SEQ ID NQ:207, 211 or 213; a heavy chain CDR3 of SEQ ID NQ:208 or 214; a light chain CDR1 of SEQ ID NO:153, 156 or 158; a light chain CDR2 of SEQ ID NQ:50 or 154; and a light chain CDR3 of SEQ ID NO:219or 220; I. a heavy chain variable region that comprises 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; m. a heavy chain variable region that comprises a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, 209, 210 or 212, an HCDR2 of SEQ ID NO: 207, 211 or 213, and an HCDR3 of SEQ ID NO:237 or 238; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, 245 or 247, an LCDR2 of SEQ ID NO:47 or 50, and an LCDR3 of SEQ ID NO:244 or 246; n. a heavy chain variable region that comprises a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, 209, 210 or 212, an HCDR2 of SEQ ID NO: 207, 211 or 213, and an HCDR3 of SEQ ID NO:252 or 253; and a light chain variable region that comprises an LCDR1 of SEQ ID NO: 153, 156 or 158, an LCDR2 of SEQ ID NQ:50 or 154, and an LCDR3 of SEQ ID NO:258 or 259; o. a heavy chain CDR1 of SEQ ID NO:1, a heavy chain CDR2 of SEQ ID NO:2, a heavy chain CDR3 of SEQ ID NO:3, 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; p. a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO:2, a heavy chain CDR3 of SEQ ID NO:3, 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; q. a heavy chain CDR1 of SEQ ID NO:5, a heavy chain CDR2 of SEQ ID NO:6, a heavy chain CDR3 of SEQ ID NO:3, 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; r. 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, a light chain CDR1 of SEQ ID NQ:20, a light chain CDR2 of SEQ ID NO:18, and a light chain CDR3 of SEQ ID NO:16; s. a heavy chain CDR1 of SEQ ID NO:33, a heavy chain CDR2 of SEQ ID NO:34, a heavy chain CDR3 of SEQ ID NO:35, 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; t. a heavy chain CDR1 of SEQ ID NO:36, a heavy chain CDR2 of SEQ ID NO:34, a heavy chain CDR3 of SEQ ID NO:35, 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; u. a heavy chain CDR1 of SEQ ID NO:37, a heavy chain CDR2 of SEQ ID NO:38, a heavy chain CDR3 of SEQ ID NO:35, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:51; v. a heavy chain CDR1 of SEQ ID NO: 39, a heavy chain CDR2 of SEQ ID NQ:40, a heavy chain CDR3 of SEQ ID NO:41, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:48; w. a heavy chain CDR1 of SEQ ID NO:57, a heavy chain CDR2 of SEQ ID NO:58, a heavy chain CDR3 of SEQ ID NO:59, 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 NQ:70; x. a heavy chain CDR1 of SEQ ID NQ:60, a heavy chain CDR2 of SEQ ID NO:58, a heavy chain CDR3 of SEQ ID NO:59, 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 NQ:70; y. a heavy chain CDR1 of SEQ ID NO:5, a heavy chain CDR2 of SEQ ID NO:61, a heavy chain CDR3 of SEQ ID NO:59, 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; z. a heavy chain CDR1 of SEQ ID NO:7, a heavy chain CDR2 of SEQ ID NO:62, a heavy chain CDR3 of SEQ ID NO:63, 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 NQ:70; aa. a heavy chain CDR1 of SEQ ID NO:79, , a heavy chain CDR2 of SEQ ID NQ:80, a heavy chain CDR3 of SEQ ID NO:81, 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; bb. a heavy chain CDR1 of SEQ ID NO:82, a heavy chain CDR2 of SEQ ID NQ:80, a heavy chain CDR3 of SEQ ID NO:81, 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; cc. a heavy chain CDR1 of SEQ ID NO:83, a heavy chain CDR2 of SEQ ID NO:84, a heavy chain CDR3 of SEQ ID NO:81, 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; dd. a heavy chain CDR1 of SEQ ID NO: 85, a heavy chain CDR2 of SEQ ID NO:86, a heavy chain CDR3 of SEQ ID NO:87, 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; ee. a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NQ:105, 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; ff. a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NQ:105, 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; gg. a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, a heavy chain CDR3 of SEQ ID NQ:105, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:118; hh. a heavy chain CDR1 of SEQ ID NQ:109, a heavy chain CDR2 of SEQ ID NO:110, a heavy chain CDR3 of SEQ ID NO:111, a light chain CDR1 of SEQ ID NO:52 a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:117; ii. a heavy chain CDR1 of SEQ ID NO:123, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:125, 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; jj. a heavy chain CDR1 of SEQ ID NO:126, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:125, 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; kk. a heavy chain CDR1 of SEQ ID NO:127, a heavy chain CDR2 of SEQ ID NO:128, a heavy chain CDR3 of SEQ ID NO:125, a light chain CDR1 of SEQ ID NO:139, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO: 141; II. a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NO:130, a heavy chain CDR3 of SEQ ID NO:131, a light chain CDR1 of SEQ ID NO:142, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO:138; mm. a heavy chain CDR1 of SEQ ID NO:123, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:147, 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; nn. a heavy chain CDR1 of SEQ ID NO:126, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:147, 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; oo. a heavy chain CDR1 of SEQ ID NO:127, a heavy chain CDR2 of SEQ ID NO:128, a heavy chain CDR3 of SEQ ID NO:147, a light chain CDR1 of SEQ ID NO:156, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:157; pp. a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NQ:130, a heavy chain CDR3 of SEQ ID NO:148, a light chain CDR1 of SEQ ID NO:158, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:155; qq. a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NO:163, 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; rr. a heavy chain CDR1 of SEQ ID NQ:106, a heavy chain CDR2 of SEQ ID NQ:104, a heavy chain CDR3 of SEQ ID NO:163, 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; ss. a heavy chain CDR1 of SEQ ID NQ:107, a heavy chain CDR2 of SEQ ID NQ:108, a heavy chain CDR3 of SEQ ID NO:163, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NQ:170; tt. a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110, a heavy chain CDR3 of SEQ ID NO:164, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:169; uu. a heavy chain CDR1 of SEQ ID NO:175, a heavy chain CDR2 of SEQ ID NO:176, a heavy chain CDR3 of SEQ ID NO:177, 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; vv. a heavy chain CDR1 of SEQ ID NO:178, a heavy chain CDR2 of SEQ ID NO:176, a heavy chain CDR3 of SEQ ID NO:177, 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; ww. a heavy chain CDR1 of SEQ ID NO:179, a heavy chain CDR2 of SEQ ID NQ:180, a heavy chain CDR3 of SEQ ID NO:177, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:189; xx. a heavy chain CDR1 of SEQ ID NO: 181, a heavy chain CDR2 of SEQ ID NO: 182; a heavy chain CDR3 of SEQ ID NO:183, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:188; yy. a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NO:194, 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 NQ:200; zz. a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NO:194, 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 NQ:200; aaa. a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, a heavy chain CDR3 of SEQ ID NO:194, 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; bbb. a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110, a heavy chain CDR3 of SEQ ID NO:195, 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 NQ:200; ccc. a heavy chain CDR1 of SEQ ID NQ:206, a heavy chain CDR2 of SEQ ID NQ:207, a heavy chain CDR3 of SEQ ID NQ:208, 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; ddd. a heavy chain CDR1 of SEQ ID NO:209, a heavy chain CDR2 of SEQ ID NO:207, a heavy chain CDR3 of SEQ ID NO:208, 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; eee. a heavy chain CDR1 of SEQ ID NQ:210, a heavy chain CDR2 of SEQ ID NO:211, a heavy chain CDR3 of SEQ ID NO:208, a light chain CDR1 of SEQ ID NO:156, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NQ:220; fff. a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO:213, a heavy chain CDR3 of SEQ ID NO:214, a light chain CDR1 of SEQ ID NO:158, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:219; ggg. a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207, a heavy chain CDR3 of SEQ ID NO:225, 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; hhh. a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207, a heavy chain CDR3 of SEQ ID NO:225, 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; iii. a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211, a heavy chain CDR3 of SEQ ID NO:225, a light chain CDR1 of SEQ ID NO:139, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO: 232; jjj. a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, a heavy chain CDR3 of SEQ ID NO: 226, 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; kkk. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:237,and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, an LCDR2 of SEQ ID NO:47, and an LCDR3 of SEQ ID NO:244; III. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 209, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:237, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, an LCDR2 of SEQ ID NO:47, and an LCDR3 of SEQ ID NO:244; mmm. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 210, an HCDR2 of SEQ ID NO: 211, and an HCDR3 of SEQ ID NO:237, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:245, an LCDR2 of SEQ ID NO:50, and an LCDR3 of SEQ ID NO:246; nnn. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 212, an HCDR2 of SEQ ID NO: 213, and an HCDR3 of SEQ ID NO:238; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:247, an LCDR2 of SEQ ID NO: 50, and an LCDR3 of SEQ ID NO:244; ooo. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:252,and a light chain variable region that comprises an LCDR1 of SEQ ID NO:153, an LCDR2 of SEQ ID NO: 154, and an LCDR3 of SEQ ID NO:258; ppp. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 209, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:252, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:153, an LCDR2 of SEQ ID NO:154, and an LCDR3 of SEQ ID NO:258; qqq. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 210, an HCDR2 of SEQ ID NO: 211, and an HCDR3 of SEQ ID NO:252, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:156, an LCDR2 of SEQ ID NQ:50, and an LCDR3 of SEQ ID NO:259; or rrr. a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 212, an HCDR2 of SEQ ID NO: 213, and an HCDR3 of SEQ ID NO: 253; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:158, an LCDR2 of SEQ ID NQ:50, and an LCDR3 of SEQ ID NO:258.

[0011] An antibody or antigen binding fragment thereof that binds PMEL17 of the present application may also comprise: 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 NQ:190; I. 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 NQ: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 NQ:260.

[0012] In another embodiment, the antibody or antigen binding fragment thereof that binds PMEL17 comprises: 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 NQ:90, and a light chain comprising the amino acid sequence of SEQ ID NQ: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; I. 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 NQ: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 NQ: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.

[0013] The antibody or antigen binding fragment thereof as 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 of the heavy chain of the antibody or antigen binding fragment thereof, wherein the position is numbered according to the Ell system. An antibody as disclosed herein can be a monoclonal antibody.

[0014] In one aspect, the Antibody Drug Conjugate of the invention is a conjugate of Formula (C): Ab-(LA-(D)n)y                 (C) wherein: 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 human PMEL17 protein; La is a linker; n is 1,2, 3 or 4, and y is 1, 2, 3 or 4, where the Linker-Drug moiety -(LA-(D)n) is covalently attached to the antibody or antigen binding fragment thereof.

[0015] In another aspect of the Antibody Drug Conjugates of Formula (C), La is a cleavable linker comprising one or more linker components selected from a self-immolative 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): I Ab< L2 X2 D i '                          (C-1) wherein: 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 human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; *          1                           1 / 'XX     * 0 O or X 0 , where the * of Y1 indicates the point of attachment to X2 and the ** of Y1 indicates the point of attachment to D; Li is a bivalent peptide linker; L2 is a bond or a 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 as 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 the pharmaceutical compositions disclosed herein, wherein the cancer expresses PMEL17, contains a mutation of the GNAQ or GNA11 gene, or the cancer expresses PMEL17 and contains a mutation of GNAQ, GNA11, or both.

[0019] In some embodiments of the methods of treatment or preventing cancer, the antibody drug conjugate or pharmaceutical composition are administered to the patient in combination with one or more additional therapeutic compounds. In one embodiment, the one or more additional therapeutic compounds is selected from a standard of care chemotherapeutic, an MDM2 inhibitor, an MRC2 inhibitor, a PKC inhibitor, a MAPK inhibitor, a costimulatory molecule, or a 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 ligand. In another embodiment, the 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] The present application also discloses the antibody drug conjugates or the pharmaceutical compositions disclosed herein, for use as a medicament. In one embodiment, the antibody drug conjugates or the pharmaceutical compositions disclosed herein, are for use in the treatment or prevention of a PMEL17 expressing cancer or a cancer that contains a mutation of the GNAQ or GNA11 gene in a patient in need thereof.

[0021] In one embodiment, the application discloses use of the antibodies or antigen binding fragments thereof, the antibody drug conjugates, or the pharmaceutical composition as disclosed herein, to treat or prevent a PMEL17 expressing cancer in a patient in need thereof.

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

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

[0024] The present application also discloses nucleic acids that encodes the antibodies or antigen binding fragments as disclosed herein. In one embodiment, the nucleic acid comprises the nucleotide sequence of SEQ ID NOs: 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. This application also discloses vectors comprising the nucleic acids, and host cells comprising the vectors or nucleic acids. This application also discloses a process for producing the antibodies or antigen binding fragments disclosed herein comprising cultivating the host cell and recovering the antibody from cell culture. In one embodiment, the process of recovering the antibody from cell culture comprises the steps of: a) removing cells and filtering the culture; b) purifying the culture by affinity chromatography ; c) inactivating 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) purifying the culture by cation exchange chromatography and performing on-column reduction of the culture; e) performing anion exchange chromatography on the culture; f) removing viruses by nanofiltration; g) filtering the culture containing the antibody; and h) obtaining purified antibody.

[0025] The present application also discloses a process for producing an anti-PMEL17 antibody drug conjugate comprising: (a) pre-forming a linker-drug moiety of the following Formula (B): R8-LB-(D)n                     (B) wherein: D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11; R8 is a reactive group; Lb is a cleavable or non-cleavable linker, and n is 1,2, 3 or 4; (b) conjugating said linker-drug moiety to the antibody recovered from the cell culture using the process for producing an antibody or antigen binding fragment disclosed herein to produce an antibody drug conjugate; and (c) purifying the antibody drug conjugate.

[0026] The present application also discloses a diagnostic reagent comprising an antibody or antigen binding fragment thereof as 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 the Drawings

[0027] FIGs. 1A-1B show exemplary data on in vitro anti-UM activity of GNAQ / 11 inhibitors Compound (A1) and Compound (A2).

[0028] FIG. 2 shows exemplary data on activity of GNAQ / 11 inhibitors Compound (A1) and Compound (A2) to induce apoptosis in uveal melanoma cells.

[0029] FIGs. 3A-3C show exemplary data on GNAQ / 11 inhibition by Compound (A1) and Compound (A2). Compound (A1) and Compound (A2) reduced IP1 levels (FIG. 3A) and relative proliferation (FIG. 3B) in 92.1 cells. Immunoblots of 92.1 cells treated with Compound (A1) and Compound (A2) showed reduced ERK signaling (FIG. 3C).

[0030] FIGs. 4A-4D show exemplary data on metabolic stability and PK properties of Compound (A1). Both disappearance of Compound (A1) (FIG. 4A) as well as appearance of the ring-opened form Compound (A8) (FIG. 4B) was monitored over 24h. With the exception of the rat, adding the % remaining Compound (A1) and % formed Compound (A8) shows stoichiometry over 24h (FIG. 4C). The PK of Compound (A1) after intravenous dosing in mouse is characterized by a very high clearance and moderate to high volume of distribution (FIG. 4D).

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

[0032] FIGs. 6A-6B show exemplary data on in vitro anti-uveal melanoma activity of anti-PMEL17-(B1) ADCs. Data presented as mean of 3 independent replicates and relative to PBS-treated cells (control).

[0033] FIG. 7 shows exemplary data on anti-PMEL17-(B1) ADCs inducing apoptosis in uveal melanoma cells. Data presented as mean of 3 independent replicates.

[0034] FIGs. 8A-8B show exemplary data on in vitro anti-uveal melanoma activity of anti-PMEL17-(B2) ADCs and anti-PMEL17 mAbs. Data presented as mean of 3 independent replicates and relative to PBS-treated cells (control).

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

[0036] FIGs. 10A-10D show exemplary data on binding activity of anti-PMEL17 antibodies to intact platelets and uveal melanoma cells.

[0037] FIGs. 11A-11C show exemplary data on impact of Compound (A1) and anti-PMEL17-(B1) ADCs on human platelet aggregation.

[0038] FIGs. 12A-12E show exemplary data on in vivo anti-tumor activity of anti-PMEL17-(B1) ADCs. G1-(B1) inhibited tumor growth in a dose-dependent manner (Fig. 12A). Values are mean ± SEM; sample size, (n=5-12 mice per group). Initial tumor volume at day 0 was approximately 200-250 mm3. No body weight loss was observed for up to 14 days after treatment (Fig. 12B). Values are mean ± SEM; sample size, (n=4 mice per group). G1-(B1) treatment resulted in GNAQ signaling inhibition and inhibition of tumor cell proliferation as indicated by reduced levels of pERK and Ki67, respectively (Fig. 12C). In addition, G1-(B1) induced cell apoptosis compared to vehicle- and isotype control 3207-(B1)-treated mice, which correlated with tumor cell accumulation of G1-(B1) ADC as detected by IgG staining (Fig. 12C). No changes were observed in MITF and PMEL17 levels following GNAQ inhibition (Fig. 12C). No platelet aggregation inhibition was observed in G1-(B1) treated mice for up to 7 days (Figs. 12D & E).

[0039] FIGs. 13A-13C show exemplary data on effect of G1-(B1) ADC on a liver and lung metastasis mouse model of uveal melanoma. Individual pictures from each mice are presented at day 45 following i.v. injection of 92.1-luciferase cells (just before the initiation of treatment) and 12 days post treatment (Figs. 13A and 13B); sample size, (n=6 mice per group). Initial BLI for liver metastasis at day 0 was approximately 2.8 *109 p / sec / cm2. Lung tumors (bioluminescence signal) in Fig. 13B are indicated by a black arrow. Corresponding body weight modulation (% vs day 15) was assessed 2-3 times per week prior and post treatment with G1-(B1) 20 mg / kg (grey 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] FIGs. 14A-14E show exemplary data on PK properties of G1-(B1) ADCs. The pharmacokinetic profile (total IgG levels) of G1-(B1) showed a slightly over-proportional increase of exposure with dose between 7.5 and 30 mg / kg in nude mice (Fig. 14A). In tumor bearing mice, free payload concentrations were measured after dosing either target binding G1-(B1) or isotype control 3207-(B1). A clear (>4-fold) increase in tumor delivery of Compound (A1) payload could be observed using the targeted ADC (Fig. 14B). The conversion of Compound (A1) (open circles) into its ring-opened form Compound (A8) (filled circles) while being conjugated to the antibody was shown in vivo in mice (Fig. 14C). The exposures in an in vivo efficacy study, comparing two different DAR2 formats with the DAR4 format of G1-(B1) and with the DAR4 Fc-silent format, showed lowest clearance for the DAR2 (E152C) and the DAR4 Fc-silent ADCs, whereas the DAR2 (S375C) exposure decreases faster (Fig. 14D). Fig. 14E shows the concentration of 3207 (isotype control antibody)-(BI) DAR4 (E152C, S375C) and 3207 (isotype control antibody)-(BI) DAR4 Fc-silent conjugates over time.

[0041] FIGs. 15A-15C show exemplary data on in vitro stability of anti-PMEL17-GNAQ / 11i ADCs in buffer, mouse, rat, and human plasma and in vivo stability of anti-PMEL17-GNAQ / 11i ADCs in mouse.

[0042] FIGs. 16A-16B show exemplary data on in vivo efficacy of G1-E152C-DAR2-(B1), G1-S375C-DAR2-(B1), Fc-silent G1 -(B1) in a xenograft model of uveal melanoma. Values represent mean ± SEM; sample size, (n=5-6 mice per group). Initial tumor volume at day 0 was approximately 300-325 mm3.

[0043] FIGs. 17A-17B show exemplary data on in vitro anti-uveal melanoma activity of anti-PMEL17-(B1) ADCs. Data presented as mean of 3 independent replicates and relative to PBS-treated cells (control).

[0044] FIG. 18 shows exemplary data show exemplary data on in vivo anti-tumor activity of anti-PMEL17-(B1) ADCs.

[0045] FIG. 19A-19B shows exemplary data on an immunohistochemical analysis of tumor biopsies from metastatic uveal melanoma patients.

[0046] FIGs. 20A-20C shows exemplary sensorgram data to assess epitope binning of anti-PMEL antibodies. FIG. 20A illustrates the binding steps. FIG. 20B shows the sensorgram when antibody G1 3J LC is immobilized first and 17A9 is flowed over. FIG. 20C shows the sensorgram when 17A9 is immobilized first and G1 3J LC is flowed over. In both cases, binding is observed when the second antibody is flowed over, suggesting that G1 3J LC and 17A9 bind to different epitopes of human PM EL. Detailed Description of the Invention Definitions

[0047] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

[0048] The term “alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, Ci-Cealkyl refers to an alkyl group having from 1 to 6 carbon atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have 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 t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0049] “Cleavable” as used herein refers to a linking group or linker component that connects two moieties by covalent connections, but breaks down to sever the covalent connection between the moieties under physiologically relevant conditions, typically a cleavable linking group is severed in vivo more rapidly in an intracellular environment than when outside a cell, causing release of the payload to preferentially occur inside a targeted cell. Cleavage may be enzymatic or non-enzymatic, but generally releases a payload from an antibody without degrading the antibody. Cleavage may leave some portion of a linking group or linker component attached to the payload, or it may release the payload without any residue of the linking group.

[0050] “Non-cleavable” as used herein refers to a linking group or linker component that is not especially susceptible to breaking down under physiological conditions, e.g., it is at least as stable as the antibody or antigen binding fragment portion of the conjugate. Such linking groups are sometimes referred to as ‘stable’, meaning they are sufficiently resistant to degradation to keep the payload connected to antibody or antigen binding fragment until the antibody or antigen binding fragment is itself at least partially degraded, i.e., the degradation of the antibody or antigen binding fragment precedes cleavage of the linking group in vivo. Degradation of the antibody portion of an ADC having a stable or non-cleavable linking group may leave some or all of the linking group, e.g., one or more amino acid groups from an antibody, attached to the payload or drug moiety that is delivered in vivo.

[0051] The term “antibody” as used herein refers to a polypeptide of the immunoglobulin family that is capable of binding a corresponding antigen non-covalently, reversibly, and in a specific manner. For example, a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected 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, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed 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 a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including 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, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention). The antibodies can be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA and IgY), or subclass (e.g., lgG1, lgG2, lgG3, lgG4, lgA1 and lgA2).

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

[0054] The positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT) (on the worldwide web at www.imgt.org / ), and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia etal., Nature, 342:877-883 (1989); Chothia etal., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J.Mol.Biol., 273:927-748 (1997)). Definitions of antigen combining sites are also described in the following: Ruiz et al., Nucleic Acids Res., 28:219-221 (2000); and Lefranc, M.P., Nucleic Acids Res., 29:207-209 (2001); MacCallum etal., J. Mol. Biol., 262:732-745 (1996); and Martin etal., Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989); Martin etal., 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 divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally. In this regard, it will be appreciated that the variable domains of both the light (VL) and heavy (VH) chain portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and the heavy chain (CH1, CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention, the numbering of the constant region domains increases as they become more distal from the antigen binding site or amino-terminus of the antibody. The N-terminus is a variable region and at the C-terminus is a constant region; the CH3 and CL domains actually comprise the carboxy-terminal domains of the heavy and light chain, respectively.

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

[0057] Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (“scFv”); see, e.g., Bird et al., Science 242:423-426, 1988; and Huston etal., Proc. Natl. Acad. Sci. 85:5879-5883, 1988). Such single chain antibodies are also intended to be encompassed within the term “antigen binding fragment.” These antigen binding fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0058] Antigen binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, single domain antibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can be grafted into scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).

[0059] Antigen binding fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, 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. Pat. No. 5,641,870).

[0060] The term “monoclonal antibody” or “monoclonal antibody composition” as used herein refers to polypeptides, including antibodies and antigen binding fragments that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0061] The term “human antibody”, as used herein, includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., J. Mol. Biol. 296:57-86, 2000). Also included are antibodies derived from human sequences wherein one or more CDRs has been mutated for affinity maturation or for manufacturing / payload conjugation purposes. See Kilpatrick et al., “Rapid development of affinity matured monoclonal antibodies using RIMMS,” Hybridoma. 1997 Aug; 16(4):381-9.

[0062] The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing).

[0063] The term “recognize” as used herein refers to an antibody or antigen binding fragment thereof that finds and interacts (e.g., binds) with its epitope, whether that 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 invention specifically binds. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include techniques in the art, for example, x-ray crystallography and 2dimensional nuclear magnetic resonance (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G. E. Morris, Ed. (1996)).

[0064] The term “affinity” as used herein refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.

[0065] The term “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities. An isolated antibody that specifically binds to one antigen may, however, have cross-reactivity to other antigens. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0066] The term “corresponding human germline sequence” refers to the nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that shares the highest determined amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other all other known variable region amino acid sequences encoded by human germline immunoglobulin variable region sequences. The corresponding human germline sequence can also refer to the human variable region amino acid sequence or subsequence with the highest amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other evaluated variable region amino acid sequences. The corresponding human germline sequence can 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 can be determined using the methods described herein, for example, aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art. The corresponding human germline nucleic acid or amino acid sequence can have at least about 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference variable region nucleic acid or amino acid sequence. Corresponding human germline sequences can be determined, for example, through the publicly available international ImMunoGeneTics database (IMGT) (on the worldwide web atwww.imgt.org / ) and V-base (on the worldwide 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., a protein) and an antibody, antibody fragment, or antibody-derived binding agent, refers to a binding reaction that is determinative of the presence of the antigen in a heterogeneous population of proteins and other biologies, e.g., in a biological sample, e.g., a blood, serum, plasma or tissue sample. Thus, under certain designated immunoassay conditions, the antibodies or binding agents with a particular binding specificity bind to a particular antigen at least two times the background and do not substantially bind in a significant amount to other antigens present in the sample. In one embodiment, under designated immunoassay conditions, the antibody or binding agent with a particular binding specificity binds to a particular antigen at least ten (10) times the background and does not substantially bind in a significant amount to other antigens present in the sample. Specific binding to an antibody or binding agent under such conditions may require the antibody or agent to have been selected for its specificity for a particular protein. As desired or appropriate, this selection may be achieved by subtracting out antibodies that cross-react with molecules from other species {e.g., mouse or rat) or other subtypes. Alternatively, in some embodiments, antibodies or antibody fragments are selected that cross-react with certain desired molecules.

[0068] A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). Typically a specific or selective binding reaction will produce a signal at least twice over the background signal and more typically at least 10 to 100 times over the background.

[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 known method in the art. The antibodies of the present invention generally will have an equilibrium dissociation constant of less than about 10-7 or 10-8 M, for example, less than about 10-9 M or 10-10 M, in some embodiments, less than about 10-11 M, 10-12 M or 1013 M.

[0070] The term “bioavailability” refers to the systemic availability ( / .e., blood / plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.

[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 inactive 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 an antibody drug conjugate of the invention. In some embodiments, the phrase “consisting essentially of” expressly excludes the inclusion of one or more additional active agents other than an antibody drug conjugate of the invention and a second co-administered agent.

[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 in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

[0073] The term “conservatively modified variant” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence.

[0074] For polypeptide sequences, “conservatively modified variants” include individual substitutions, deletions or additions to a polypeptide sequence which result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention. The following eight groups contain amino acids that are conservative substitutions for one another: 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, e.g., Creighton, Proteins (1984)). In some embodiments, the term “conservative sequence modifications” are used to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence.

[0075] The term “optimized” as used herein refers to a nucleotide sequence that has been altered to encode an amino acid sequence using codons that are preferred in the production cell or organism, generally a eukaryotic cell, for example, a yeast cell, a Pichia cell, a fungal cell, a Trichoderma cell, a Chinese Hamster Ovary cell (CHO) or a human cell. The optimized nucleotide sequence is engineered to retain completely or as much as possible the amino acid sequence originally encoded by the starting nucleotide sequence, which is also known as the “parental” sequence.

[0076] The terms “percent identical” or “percent identity,” in the context of two or more nucleic acids or polypeptide sequences, refers to the extent to which two or more sequences or subsequences that 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 two sequences have a specified percentage of amino acid residues or nucleotides that are the same ( / .e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated 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 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

[0077] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0078] A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482c (1970), by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wl), or by manual alignment and visual inspection (see, e.g., Brent et 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 Altschul etal., Nuc. Acids Res. 25:3389-3402, 1977; and Altschul etal., J. Mol. Biol. 215:403410, 1990, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring 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 a comparison of both strands.

[0080] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:58735787, 1993). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of 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 of E. Meyers and W. Miller, Comput. Appl. Biosci. 4:11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch, J. Mol. Biol. 48:444-453 (1970) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a BLOSUM62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0082] Other than percentage of sequence identity noted above, another indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where 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 complements hybridize to each other under stringent conditions, as described below. Yet 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 either 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 similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).

[0084] Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, as detailed below, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer etal., (1991) Nucleic Acid Res. 19:5081; Ohtsuka et al., (1985) J. Biol. Chern. 260:2605-2608; and Rossolini etal., (1994) Mol. Cell. Probes 8:91-98).

[0085] The term “operably linked” in the context of nucleic acids refers to a functional relationship between two or more polynucleotide (e.g., DNA) segments. 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 the transcription of the coding sequence in an appropriate host cell or other expression system. Generally, promoter transcriptional regulatory sequences that are operably linked to a transcribed sequence are physically contiguous to the transcribed sequence, i.e., they are cis-acting. However, some transcriptional regulatory sequences, such as enhancers, need not be physically contiguous or located 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 amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0087] The term “antibody drug conjugate” or “immunoconjugate” as used herein refers to the linkage of an antibody or an antigen binding fragment thereof with another agent, such as a chemotherapeutic agent, a toxin, an immunotherapeutic agent, an imaging probe, and the like. The linkage can be covalent bonds, or non-covalent interactions such as through electrostatic forces. Various linkers, known in the art, can be employed in order to form the antibody drug conjugate. Additionally, the antibody drug conjugate can be provided in the form of a fusion protein that may be expressed from a polynucleotide encoding the immunoconjugate. As used herein, “fusion protein” refers to proteins created through the joining of two or more genes or gene fragments which originally coded for 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 human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, and reptiles. Except when noted, the terms “patient” or “subject” are used herein interchangeably.

[0089] The term “cytotoxin”, or “cytotoxic agent” as used herein, refers to any agent that is detrimental to the growth and proliferation of cells and may act to reduce, inhibit, or destroy a cell or malignancy.

[0090] The term “anti-cancer agent” as used herein 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, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0091] The term “drug moiety” or “payload” as used herein refers to a chemical moiety that is conjugated to an antibody or antigen binding fragment of the invention, and can include any therapeutic or diagnostic agent, for example, an anti-cancer, anti-inflammatory, anti-infective (e.g., anti-fungal, antibacterial, anti-parasitic, anti-viral), or an anesthetic agent. For example, the drug moiety can be an anti-cancer agent, such as a cytotoxin. In certain embodiments, a drug moiety is a target inhibitor compound. In addition, a payload can be a biophysical probe, a fluorophore, a spin label, an infrared probe, an affinity probe, a chelator, a spectroscopic probe, a radioactive probe, a lipid molecule, a polyethylene glycol, a polymer, a spin label, DNA, RNA, a protein, a peptide, a surface, an antibody, an antibody fragment, a nanoparticle, a quantum dot, a liposome, a PLGA particle, a saccharide ora polysaccharide.

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

[0093] GNAQ (Guanine nucleotide-binding protein G(q) subunit alpha, also known as CMC1, G-ALPHA-q, GAQ, SWS, and G protein subunit alpha q) and GNA11 (Guanine nucleotide-binding protein subunit alpha-11, also known as FBH, FBH2, FHH2, GNA-11, HHC2, HYPOC2, and G protein subunit alpha 11) are closely related GTPases that constitute a subunits of heterotrimeric G proteins acting downstream of G protein-coupled receptors (GPCRs). The a subunits act as a switch for activation of G proteins by exchanging the guanosine diphosphate (GDP) for guanosine triphosphate (GTP), leading to the activation of distinct downstream effectors. The activation is terminated by the intrinsic GTPase activity, as GTP is hydrolyzed to GDP (Van Raamsdonk et al., 2010, N Engl J Med.; 363(23):2191-9). The classical activation of Gq protein cascade occurs via phospholipase C-p (PLC-P), which hydrolyses phospholipid phosphatidylinositol 4,5-biphosphate to release two potent second messengers: D-myo-inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Following the transient increase of intracellular Ca2+, IP3 is rapidly transformed into IP2, IP1, and myo-inositol. On the other hand, DAG activates protein kinase C (PKC), leading to a cascade of phosphorylation of RAF, MEK, and ERK, which translocates 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 with the following Accession Nos.:

[0095] NP_002063 (SEQ ID NO:268) 1 mtlesimacc Iseeakearr indeierqlr rdkrdarrel kllllgtges gkstfikqmr 61 iihgsgysde dkrgftklvy qniftamqam iramdtlkip ykyehnkaha qlvrevdvek 121 vsafenpyvd aikslwndpg iqecydrrre yqlsdstkyy Indldrvadp aylptqqdvl 181 rvrvpttgii eypfdlqsvi frmvdvggqr serrkwihcf envtsimflv alseydqvlv 241 esdnenrmee skalfrtiit ypwfqnssvi Iflnkkdlle ekimyshlvd yfpeydgpqr 301 daqaarefil kmfvdlnpds dkiiyshftc atdtenirfv faavkdtilq Inlkeynlv

[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 agcagggggt 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 tcttttctat ggagcaaaac aaagctgatt tccctttttt cttcccccgc taattcatac ctccctcctg atgtttttcc caggttacaa tggcctttat cctagttcca ttcttggtca agtttttctc tcaaatgata cagtcaggac acatcgttcg atttaagcca tcatcagctt aatttaagtt tgtagttttt gctgaaggat tatatgtatt aatacttacg gttttaaatg tgttgctttg gatacacaca tagtttcttt tttaatagaa tatactgtct tgtctcactt tggactggga cagtggatgc ccatctaaaa gttaagtgtc atttctttta gatgtttacc ttcagccata gcttgattgc tcagagaaat atgcagaagg caggatcaaa gacacacagg agtcctttct tttgaaatgc cacgtgccat tgtctttcct cccttctttg cttctttttc ttaccctctc tttcaattgc agatgccaaa aaagatgcca acagacacta cattacccta atggctgcta cccagaacct ttttataggt tgttcttaat ttttttgttg ttgttgttca agcttttcct ttcttttttt tcttggtgtt tgggccacga ttttaaaatg acttttatta tgggtatgtg ttgccaaagc tggctttttg tcaaataaaa tgaatacgaa cttaaaaaat aaaagctggt atcttaaaat gtaagagagt aagactgtga agcctaaaat gactggctga gaatgaacca gaaatgccat ttgccaaaca gttgtaacta gaaatttgat tctcacggtc cattcttttc tttgtcctta agatgacatt gttagtgttc acgtcccatg ttcagtgtcc aaaccggcaa tgtaaaaagt atcctgtgtg gtttaacagg aaatctgttt atgtctcttt atttgaaacc agttttactc tcagtggttc tttaagttca atgaagtctg ccaggaacat tggttggtag tattattccg acacctttaa tttccaaaat ctgaagttcc tgctagttta ccaccttcat gatcttcttg aactggtaac tgattaggtt gaacttatgg aagatttgtg gacttaactc aaaagtaacc tctcagtgtt ctatagaaca tgtatttgtg taactgaacc taccaggaga aatgtttgga attctatatg tgcaattttt caacaaatgc aaaaaaaata cagcacatgt attgacaagc ttctgtcaag cagcttgagt tgaaatttga tttaagaaaa taaatcatga ttgttcaaag ctgctgggac gttagaatta ggccatgata ctggtctcat tttaactaca gtggtatttg gcactagtgt aaacttccat ataaatcact cttttggaac aacaaagggg gagggagaaa aatcacggcc tgttaaatga gtaccaaagc cgcccaacag taatgagatg ttctcatcct tgattctccc agcctcaaac aacacagctt actttttttt tcccttgctc agaaagtacc tgtaatttaa caaacagact gcctgtaggt atagtgcaat tacaaatgct ctaatcattg tacatacatc tctcttgata ttgcagcatc catactggct ttgtaatcat taattttttg gcagattgaa tgtgctgtat tgatatgtat ctatgtaatt gtattgtatg tctatagcta attcacgttt tgaataatgt tattttattt acttttttaa gagaggagaa tgtaaatttg tcagtttatt tctgactagg gatattttct ttccatttag aaaagaagaa aaaaaaaaaa ccttactgtc atacagagcg gtactagcgt cgtgctgtat aaaatcattt gcacattcct gagtagaggt atactgatta taagacccaa aggtaatttc atagcaaaat acataaaatc agtcggagct tttatacaaa catggaaacc aactttgtag aacttttgcc atttgatcta ggattggaat atgagctttt atacaattca tattcttatt tggcaaatgc acagtttagt attacctctc tgatggcctt tactagaaag gcagttttag aagctattgt gatccactaa ggaaatgttt taacagctag agaccactgc ttgcctgaaa gggcgttctt aaatttggtg cagcaaaaaa aaaaaaaaaa aaaaaaaaaa ttaaacaaca acatttgaag gcctacagtg tgtatagaga aaacctcatc acaagatcat aagtgttaca gttttaggga atcaagatat tctatttaat agagctatag taaatgtagt caattaaacc tgatctcaaa gcttgaagaa gctgagcaaa acagggaaag attgttatat ttgtctttat gaaattggga tggaatttgc tatgcagaat tgaggtttgt ggcttcgctg ttcctgtagg gtgcatgaca agatcccttc tcttgagaaa ggaaaaaatt gatcacccta gcagcagtga tgcatagaaa cctaatttta gccacaccag tcaatcgaag ctaaaggatt ttcttttttg tttcttcggg gttttattga aggggctagg ggcgggacgg gattcttttc agttttgtat aaaaacaaag tttactcatg ctttatatta tattgtgatt gcaagcgtta taagcgtgtg ccactggcct cctattgttg atgcttaggt aatggaggcc tgtggtgagt tttatggtga cttgggcatg tcttattcaa aaacaaaaac ataaaacaca gaaacctttc ttcagcatac caaggcaagc agccatttca tgactcactt aacacattgc agtgtaccag tttacagatg atttttccct ttttgcgtga catggcagtt ctaaccccca gagaattcct tatttgtaaa 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 tttgggtcaa 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 gtatgtttat 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 have been published in GenBank with the following Accession Nos.:

[0098] NP_002058 (SEQ ID NO:270) 1 mtlesmmacc Isdevkeskr inaeiekqlr 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 Iflnkkdlle dkilyshlvd yfpefdgpqr 301 daqaarefil kmfvdlnpds dkiiyshftc atdtenirfv faavkdtilq Inlkeynlv

[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 atccgggcca 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 ccacccagca 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 ccagggagac gggatggaga cacggggcag gaccttcctt ccacggagcc tgcggctgcc 1441 gggcgggtgg 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 cgggggcttc 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 cgagggtggg 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 neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[00101] The term “anti-tumor activity” means a reduction in the rate of tumor cell proliferation, viability, or metastatic activity. For example, anti-tumor activity can be shown by a decline in growth rate of abnormal cells that arises during therapy or tumor size stability or reduction, or longer survival due to therapy as compared to control without therapy. Such activity can be assessed using accepted in vitro or in vivo tumor models, including but not limited to xenograft models, allograft models, MMTV models, and other known models known in the art to investigate anti-tumor activity.

[00102] The term “malignancy” refers to a non-benign tumor or a cancer. As used herein, the term “cancer” includes a malignancy characterized by deregulated or uncontrolled cell growth. Exemplary cancers include: carcinomas, sarcomas, leukemias, and lymphomas.

[00103] The term “cancer” includes primary malignant tumors (e.g., those 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., those arising from metastasis, the migration of tumor cells to secondary sites that are different from the site of the original tumor).

[00104] The term “PMEL17” (also referred to as premelanosome protein (PMEL), D12S53E, ME20, ME20-M, ME20M, P1, P100, gp100, SI, SIL, and silver locus protein homolog (SILV)) refers to a single-pass Type I transmembrane protein produced by melanocytes and involved in melanin synthesis. The nucleic acid and amino acid sequence of human PMEL17 have been published in GenBank with the following Accession Nos.: 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 PMEL17 protein, or a variant thereof.

[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 Ipipepegpd 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 Idcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk 481 eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla dtnslavvst 541 qlimpvpgil Itgqeaglgq vplivgillv Imavvlasli yrrrlmkqdf svpqlphsss 601 hwlrlprifc scpigenspl Isgqqv

[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 Idcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk 481 eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla dtnslavvst 541 qlimpgqeag Igqvplivgi 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 Idivqgiesa eilqavpsge 421 gdafeltvsc qgglpkeacm eisspgcqpp aqrlcqpvlp spacqlvlhq ilkggsgtyc 481 Invsladtns 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 Ipipepegpd assimstesi tgslgplldg tatlrlvkrq vpldcvlyry 481 gsfsvtldiv qgiesaeilq avpsgegdaf eltvscqggl pkeacmeiss pgcqppaqrl 541 cqpvlpspac qlvlhqilkg gsgtyclnvs ladtnslavv stqlimpvpg illtgqeagl 601 gqvplivgil Ivlmavvlas 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 gccttgggca 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_O01200053 (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_O01200054 (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 gggggcccag 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 cagcacccag 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 gggggcccag 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 cttttccgtc 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 gggggcccag 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 cttttccgtc 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 ccttgggcag 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 is capable of having one or more activities of the reference polypeptide. For example, a variant can have about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity to a reference polypeptide, while retain one or more activities of the reference polypeptide.

[00116] As used herein, the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

[00117] As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder

[00118] The term “therapeutically acceptable amount” or “therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., a reduction in tumor size, inhibition of tumor growth, prevention of metastasis, inhibition or prevention of viral, bacterial, fungal or parasitic infection). In some embodiments, a therapeutically acceptable amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically acceptable amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient’s condition. A therapeutically acceptable amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved. A “prophylactically effective dosage,” and a “therapeutically effective dosage,” of the molecules of the invention can prevent the onset of, or result in a decrease in severity of, respectively, disease symptoms, including symptoms associated with cancer.

[00119] The term “co-administer” refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered.

[00120] The present invention provides antibodies, antibody fragments (e.g., antigen binding fragments), and drug conjugates thereof, 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 internalize upon such binding. The antibodies and antibody fragments (e.g., antigen binding fragments) of the present invention can be used for producing antibody drug conjugates. Furthermore, the present invention provides antibody drug conjugates that have desirable pharmacokinetic characteristics and other desirable attributes, and thus can be used for treating or preventing a cancer expressing PMEL17. The present invention further provides pharmaceutical compositions comprising the antibody drug conjugates of the invention, and methods of making and using such pharmaceutical compositions for the treatment or prevention of cancer. Drug Moiety (D)

[00121] In one aspect, the Drug moiety (D) of the Antibody Drug Conjugate of the 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 invention is a GNAQ inhibitor.

[00123] In another aspect, the Drug moiety (D) of the Antibody Drug Conjugate of the invention is a GNA11 inhibitor.

[00124] In another aspect, the Drug moiety (D) of the Antibody Drug Conjugate of the 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 invention is a compound having the structure of Formula (A): wherein Ro is methyl or ethyl, Ri is methyl or i-propyl, and R2 is methyl or ethyl.

[00126] In another aspect, Drug moiety of the Antibody Drug Conjugate of the invention is compound (A1) having the following structure: (A1).

[00127] In another aspect, Drug moiety of the Antibody Drug Conjugate of the invention is compound (A2) having the following structure:

[00128] In another aspect, Drug moiety of the Antibody Drug Conjugate of the invention is compound (A3) having the following structure: (A3). Table 1 gives the inhibitory activity of compounds (A1), (A2) and (A3) obtained using the assay described in Example 5. Table 1 Compound GI50 (nM) 92.1GNAQ Q209L A1 0.467 A2 22.1 Compound GI50 (nM) 92.1GNAQ Q209L A3 9.3 Linker-Drug Moiety (LA-(D)n)

[00129] In a second aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the one or more Drug moieties are each independently selected from a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor).

[00130] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the one or more Drug moieties are each independently selected from a GNAQ inhibitor.

[00131] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties attached to a linker (LA), wherein the one or more Drug moieties are each independently selected from a GNA11 inhibitor.

[00132] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the one or more Drug moieties are each independently selected from an inhibitor of GNAQ andGNAH (GNAQ / GNA11 inhibitor).

[00133] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a cleavable linker and the one or more Drug moieties are each independently selected from a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor).

[00134] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a cleavable linker and the one or more Drug moieties are each independently selected from a GNAQ inhibitor.

[00135] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a cleavable linker and the one or more Drug moieties are each independently selected from a GNA11 inhibitor.

[00136] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a cleavable linker and the one or more Drug moieties are each independently selected from an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor).

[00137] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (LA) is a non-cleavable linker and the one or more Drug moieties are each independently selected from a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ andGNAH (GNAQ / GNA11 inhibitor).

[00138] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a non-cleavable linker and the one or more Drug moieties are each independently selected from a GNAQ inhibitor.

[00139] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a non-cleavable linker and the one or more Drug moieties are each independently selected from a GNA11 inhibitor.

[00140] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention comprises one or more Drug moieties covalently attached to a linker (La), wherein the linker (La) is a non-cleavable linker and the one or more Drug moieties are each independently selected from an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor).

[00141] In another aspect, the linker (La) of the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention has the following formula: A l2 x2 A wherein: Xi is a bivalent coupling group; X2 is a self-immolative spacer; or , where the * of Yi indicates the point of attachment to X2 and the ** of Yi indicates the other point of attachment; Li is a bivalent peptide linker, and L2 is a bond or a linker.

[00142] In another aspect, the Linker-Drug moiety, ((LA-(D)n))), of the Antibody Drug Conjugate of the invention has the following formula: wherein: D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11; Xi is a bivalent coupling group; X2 is a self-immolative spacer; I ** s / WVWV' I Yi is OH OH OH , where the * of Yi indicates the point of attachment to X2 and the ** of Yi indicates the point of attachment to D; Li is a bivalent peptide linker, and L2 is a bond or a linker. Linker-Drug Compounds (LB-(D)n)

[00143] In one aspect the Linker-Drug of the invention is a compound having the structure of Formula (B), or stereoisomers or pharmaceutically acceptable salts thereof, R8-LB-(D)n (B) wherein: D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11; R8 is a reactive group; Lb is a cleavable linker or non-cleavable linker, and n is 1,2, 3 or 4.

[00144] In one aspect the Linker-Drug of the invention having the structure of Formula (B), or stereoisomers or pharmaceutically acceptable salts thereof, wherein D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11; R8 is a reactive group; Lb is a cleavable linker comprising one or more linker components selected from a self-immolative spacer, a phosphate group, a carbonate group and a bivalent peptide linker, and n is 1,2, 3 or 4.

[00145] In one aspect the Linker-Drug of the invention is a compound having the structure of Formula (B-1), or stereoisomers or pharmaceutically acceptable salts thereof, l2 x2 D (B-1) wherein: D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11; R8 is a reactive group; X2 is a self-immolative spacer; I                              I A 0 O or O , where the * of Y1 indicates the point of attachment to X2 and the ** of Y1 indicates the point of attachment to D; Li is a bivalent peptide linker, and L2 is a bond or a linker.

[00146] Certain aspects and examples of the Linker-Drug compounds of the invention are provided in the following listing of additional, enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

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

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

[00149] Embodiment 3. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, wherein D is an inhibitor of GNAQ and GNA11.

[00150] Embodiment 4. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, wherein D is wherein R° is methyl or ethyl, R1 is methyl or isopropyl, R2 is methyl or ethyl, and the *** indicates the point of attachment to LB or Yi.

[00151] Embodiment 5. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, wherein D is *** i where the *** indicates the point of attachment to Lb or Yi.

[00152] Embodiment 6. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, wherein D is *** i where the *** indicates the point of attachment to Lb or Yi.

[00153] Embodiment 7. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, wherein D is *** । where the *** indicates the point of attachment to LB or Yi.

[00154] Embodiment 8. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-2), or a pharmaceutically acceptable salt thereof: wherein: R° is methyl or ethyl,; R1 is methyl or isopropyl; R2 is methyl or ethyl, and X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00155] Embodiment 9. The compound of Formula (B), Formula (B-1) or Formula (B-2), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-2a), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00156] Embodiment 10. The compound of Formula (B), Formula (B-1) or Formula (B-2), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-2b), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00157] Embodiment 11. The compound of Formula (B), Formula (B-1) or Formula (B-2), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-2c), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00158] Embodiment 12. The compound of Formula (B) or Formula (B-1), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-3), or a pharmaceutically acceptable salt thereof: wherein: R° is methyl or ethyl,; R1 is methyl or isopropyl; R2 is methyl or ethyl, and X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00159] Embodiment 13. The compound of Formula (B), Formula (B-1) or Formula (B-3), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-3a), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00160] Embodiment 14. The compound of Formula (B), Formula (B-1) or Formula (B-3), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-3b), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00161] Embodiment 15. The compound of Formula (B), Formula (B-1) or Formula (B-3), or stereoisomers or a pharmaceutically acceptable salt thereof, having the structure of Formula (B-3c), or a pharmaceutically acceptable salt thereof: wherein: X2, Li, L2 and R8 are as define in compounds of Formula (B-1) above.

[00162] Embodiment 16. The compound of Formula (B-2) of Embodiment 8, Formula (B- 3) of Embodiment 12, or a pharmaceutically acceptable salt thereof: wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; of attachment to Li and the ** of X2 indicates the point of attachment to the group or the point of attachment to Li is a bivalent peptide linker comprising 2 to 4 amino acid residues; L2 is a linker, O -|-N R8 is selected from O , -N3, -ONH2, -NR4C(=O)CH=CH2, SH, -SSR13, - S(=O)2(CH=CH2), -NR4S(=O)2(CH=CH2), -NR4C(=O)CH2Br, -NR4C(=O)CH2I, - R4 i N x. T NHC(=O)CH2Br, -NHC(=O)CH2I, -C(=O)NHNH2, O , -CO2H, -NH2, wherein: each R4 is independently selected from H and Ci-Cealkyl; each R5 is independently selected from H, Ci-Cealkyl, F, Cl, and -OH; each R6 is independently selected from H, Ci-Cealkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH, and each R7 is independently selected from H, Ci-ealkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, Ci.4alkoxy substituted with -C(=O)OH and Ci.4alkyl substituted with -C(=O)OH.

[00163] Embodiment 17. The compound of any one of Embodiments 1 to 16, wherein X2 * is a self-immolative spacer selected from F * H *            oVH ho^Voh H                    ,        OH Il I ** * [j T u 1 , H , u                   * H          s j^Ny'K / y**     A X|    O 0^    0^ O^XOH        o^yoh 0H     no^^y^OH , O OH           ,        OH and o oh             , where the * of X2 indicates the point of attachment to Li and the ** O' of X2 indicates the point of attachment to Yi, the point of attachment to the OH group or O' the point of attachment to O group.

[00164] Embodiment 18. The compound of any one of Embodiments 1 to 17, wherein X2 e N is H , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to Yi, the point of attachment to the o* OH group or the point of attachment to

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

[00166] Embodiment 20. The compound of any one of Embodiments 1 to 18, wherein Li is a 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 to 18, wherein Li is a bivalent peptide linker comprising at least one valine (Vai) or citrulline (Cit) residue.

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

[00169] Embodiment 23. The compound of any one of Embodiments 1 to 18, wherein Li (PheLys), nh2 (ValLys) and (LeuCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2.

[00170] Embodiment 24. The compound of any one of Embodiments 1 to 18, wherein Li is ValCit.

[00171] Embodiment 25. The compound of any one of Embodiments 1 to 18, wherein NH Li is           0 nh2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2.

[00172] Embodiment 26. The compound of any one of Embodiments 1 to 25, wherein L2 is a linker.

[00173] Embodiment 27. The compound of any one of Embodiments 1 to 25, wherein L2 is a linker selected from: -*C(=O)((CH2)mO)p(CH2)m**-, -*C(=O)(CH2)m**-, -*C(=O)(CH2)nNHC(=O)(CH2)m**-, -*C(=O)(CH2)mNHC(=O)((CH2)mO)p(CH2)m**-, -* ((CH2)mO)p(CH2)m**-, -* ((CH2)mO)p(CH2)m**-, -(CH2)m-, -*(CH2)mNHC(=O)(CH2)m**-, -* (CH2)mNHC(=O)(CH2)mC(=O)NH(CH2)m**-, -* ((CH2)mO)p(CH2)mNHC(=O)(CH2)m**-, -* *((CH2)mO)pCH2)mC(=O)NH(CH2)m**-, -* (CH2)mC(R3)2**-, and -* (CH2)mC(R3)2SS(CH2)mNHC(=O)(CH2)m**-, where the * of L2 indicates the attachment point to Li and the ** of L2 indicates the point of attachment to R8; and wherein: each R3 is independently selected from H and Ci-Csalkyl; 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 to 25, wherein L2 is -*C(=O)((CH2)mO)p(CH2)m**- or -*C(=O)(CH2)m**-, where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs, and wherein 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 to 25, wherein L2 is where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs.

[00176] Embodiment 30. The compound of any one of Embodiments 1 to 29, wherein R8 O +N is o , -N3, -ONH2, -NR4C(=O)CH=CH2, SH, -SSR13, -S(=O)2(CH=CH2), - NR4S(=O)2(CH=CH2), -NR4C(=O)CH2Br, -NR4C(=O)CH2I, -NHC(=O)CH2Br, -NHC(=O)CH2I, - -co2h, -nh2 C(=O)NHNH2 each R4 is independently selected from H and Ci-Csalkyl; each R5 is independently selected from H, Ci-Cealkyl, F, Cl, and -OH; each R6 is independently selected from H, Ci-Cealkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH, and each R7 is independently selected from H, Ci-ealkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, Ci.4alkoxy substituted with -C(=O)OH and Ci.4alkyl substituted with -C(=O)OH.

[00177] Embodiment 31. The compound of any one of Embodiments 1 to 29, wherein R8 O

[00178] Embodiment 32. The compound of any one of Embodiments 1 to 29, wherein R8 O is O

[00179] Embodiment 33. The compound of Formula (B-2) of Embodiment 8, or a pharmaceutically acceptable salt thereof: wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; X2 is h                  , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to the OH group; Li is           0 nh2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2; L2 is O                   or O          , where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs, and O R8 is O .

[00180] Embodiment 34. The compound of Formula (B-3) of Embodiment 12, or a pharmaceutically acceptable salt thereof: wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; X2 is h                  , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to the Li is            0 nh2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2; L2 is O                   or O          , where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs, and O -|-N R8 is O .

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

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

[00183] Embodiment 37. The compound of Formula (B), Formula (B-1) or Formula (B-2),

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

[00185] Embodiment 39. The compound of Formula (B), Formula (B-1) or Formula (B-2),

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

[00187] Embodiment 41. The compound of Formula (B), Formula (B-1) or Formula (B-3), wherein the compound is H2N (B7).

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

[00189] H N H2N (B8). Embodiment 43. The compound of Formula (B), Formula (B-1) or Formula (B-3), wherein the compound is

[00190] (B9). Embodiment 44. The compound of Formula (B), Formula (B-1) or Formula (B-3), wherein the compound is

[00191] Embodiment 45. The compound of Formula (B), Formula (B-1) or Formula (B-3),

[00192] Embodiment 46. The compound of Formula (B), Formula (B-1) or Formula (B-3), wherein the compound is Antibody Drug Conjugates

[00193] In one aspect, the Antibody Drug Conjugate of the invention is a conjugate of Formula (C): Ab-(LA-(D)n)y                 (C) wherein: D is a drug moiety; Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; La is a linker; n is 1,2, 3 or 4, and y is 1, 2, 3 or 4, where the Linker-Drug moiety (LA-(D)n) is covalently attached to the antibody or antigen binding fragment thereof.

[00194] In one aspect, the Antibody Drug Conjugate of the invention having the structure of Formula (C), wherein: 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 human PMEL17 protein; La is a cleavable linker comprising one or more linker components selected from a self-immolative 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, where the Linker-Drug moiety (LA-(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): ,L1x / Yk I Ab^ L2         DI '                          (C-1) wherein: 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 human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; and the ** of Y1 indicates the point of attachment to D; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00196] In the conjugates of Formula (C), one or more Linker-Drug moiety (LB-(D)n) can be covalently attached to the antibody or antigen binding fragment thereof, Ab, thereby covalently attaching one or more drug moieties, D, to the antibody or antigen binding fragment thereof, Ab, through linker, LA. LA is any chemical moiety that is capable of linking the antibody or antigen binding fragment thereof, Ab, to one or more drug moieties, D. The conjugates of Formula (C), wherein one or more drug moieties, D, are covalently linked to an antibody or antigen binding fragment thereof, Ab, can 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 or antigen binding fragment thereof, Ab, by way of example, a thiol or an amine (e.g. a cysteine, an N-terminus or amino acid side chain such as lysine) to form a covalent linkage with one end of the linker La. Such reactive functional groups of the bifunctional or multifunctional linker reagent include, but are not limited to, a maleimide, a thiol and an NHS ester. The other reactive functional group or groups of the bifunctional or multifunctional linker reagent are used to covalently attached one or more drug moieties, D, to linker La.

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

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

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

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

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

[00202] In another aspect, the linker (La) has the following formula: wherein: Xi is a bivalent coupling group; X2 is a self-immolative spacer; Y1 is OH , OH 0 , where the * of Y1 indicates the point of attachment to X2, and the ** of Y1 indicates the other point of attachment; Li is a bivalent peptide linker, and L2 is a bond or a linker.

[00203] In another aspect, the linker (La) has the following formula: A l2 x2 A wherein: Xi is a bivalent coupling group; X2 is a self-immolative spacer; । ** , ** ** ** » / VWW'              s / WV*       JL                               I *V=° Vt=o 4-r0 Y1 is OH , OH , OH or OH , where the * of Y1 indicates the point of attachment to X2; Li is a bivalent peptide linker, and L2 is a bond or a linker.

[00204] In another aspect, the linker (La) has the following formula: l2 x2 A wherein: Xi is a bivalent coupling group; X2 is a self-immolative spacer; point of attachment to X2; Li is a bivalent peptide linker, and L2 is a bond or a linker.

[00205] While the drug to antibody ratio has an exact integer value for a specific conjugate molecule (e.g., the product of n and y in Formula (C), it is understood that the value will often be an average value when used to describe a sample containing many molecules, due to some degree of heterogeneity, typically associated with the conjugation step. The average loading for a sample of a conjugate is referred to herein as the drug to antibody ratio, or “DAR.” In some aspects, the DAR is between about 1 and about 5, and typically is about 1,2,3, or 4. In some aspects, at least 50% of a sample by weight is compound having the average DAR plus or minus 2, and preferably at least 50% of the sample is a conjugate that contains the average DAR plus or minus 1. Other aspects include conjugates wherein the DAR is about 2. In some aspects, a DAR of ‘about y’ means the measured value for DAR is within 20% of the product of n and y in Formula (I). In some aspects, a DAR of ‘about n’ means the measured value for DAR is within 20% of n in Formula (II).

[00206] In one aspect, the average molar ratio of the drug to the antibody in the conjugates of Formula (C) ( / .e., average value of the product of n and y, also known as drug to antibody ratio (DAR)) is about 1 to about 10, 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), about 1 to about 5, about 1.5 to about 4.5, or about 2 to about 4.

[00207] In one aspect provided by the disclosure, the conjugate has substantially high 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 conjugate species are monomeric, (b) unconjugated linker level in the conjugate 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 total linker), (c) less than 10% of conjugate species are crosslinked (e.g., less than or equal to about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0%), (d) free drug (ADP-induced platelet aggregation inhibitor, e.g., a GNAQ inhibitor, a GNA11 inhibitor, or a GNAQ and a GNA11 inhibitor) level in the conjugate preparation is less than about 2% (e.g., less than or equal to about 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 total drug).

[00208] Certain aspects and examples of the Antibody Drug Conjugates of the invention are provided in the following listing of additional, enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[00209] Embodiment 47. GNAQ inhibitor.

[00210] Embodiment 48. GNA11 inhibitor.

[00211] Embodiment 49. an inhibitor of GNAQ and GNA1

[00212] Embodiment 50. The conjugate of Formula (C) The conjugate of Formula (C) The conjugate of Formula (C) 1. The conjugate of Formula (C) or Formula (C-1), wherein D is a or Formula (C-1), wherein D is a or Formula (C-1), wherein D is or Formula (C-1), wherein D is wherein R° is methyl or ethyl, Ri is methyl or isopropyl, R2 is methyl or ethyl, and the *** indicates the point of attachment to LA or Yi.

[00213] Embodiment 51. The conjugate of Formula (C) or Formula (C-1), wherein D is *** i where the *** indicates the point of attachment to La or Yi.

[00214] Embodiment 52. The conjugate of Formula (C) or Formula (C-1), wherein D is *** I where the *** indicates the point of attachment to La or Yi.

[00215] Embodiment 53. The conjugate of Formula (C) or Formula (C-1), wherein D is *** I where the *** indicates the point of attachment to LA or Yi.

[00216] Embodiment 54. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-2): wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00217] Embodiment 55. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-2a): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00218] Embodiment 56. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-2b): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00219] Embodiment 57. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-2c): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00220] Embodiment 58. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-3): wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00221] Embodiment 59. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-3a): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00222] Embodiment 60. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-3b): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00223] Embodiment 61. The conjugate of Formula (C) or Formula (C-1), having the structure of Formula (C-3c): wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; Xi is a bivalent coupling group; X2 is a self-immolative spacer; Li is a bivalent peptide linker; L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00224] Embodiment 62. The conjugate of Formula (C-2) of Embodiment 54 or the conjugate of Formula (C-3) of Embodiment 58: wherein: R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; and o oh             , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to the OH group or the point of attachment to Li is a bivalent peptide linker comprising 2 to 4 amino acid residues; L2 is a linker; 0 **    0 Xi is a bivalent coupling group selected from 0     ,     0 । JWWW\ A .                   *        । * a n,6 HO—^    **            JxL. o ,           ,,   -*NR4C(=O)CH2* *S(=O)2CH2CH2**-, -* (CH2)2S(=O)2CH2CH2**-, -*NR4C(=O)CH2CH2**-, -NH-, -C(=O)-, -*NHC(=O) * r6r5 V < / / tCvn^** **   —4    T jT zn , -*nhch2ch2**-, -s-,                , \— / n R6                                  R6 -aTT ’^n—n-n * /                1 z—\\ Ji                /              -t- । / >• \      I X / N T                  1     I Z irv rYu IH" rS^X^J -^ / **         0 ' ** R6 , r6 , , r- / " -PAi. * ,       0            , -*NHC(=O)CH2**-, - -*NR4S(=O)2CH2CH2**-, -*CH2NHCH2CH2**- * n'n\_j iT xn<Y R6    ** ^-(R6)l-2 —N | ** * 0 k N x----\ II VN x ** , **-, where the * of Xi indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab; and wherein: each R4 is independently selected from H and Ci-Cealkyl; each R5 is independently selected from H, Ci-Cealkyl, F, Cl, and -OH; each R6 is independently selected from H, Ci-Cealkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH, and each R7 is independently selected from H, Ci-ealkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, Ci.4alkoxy substituted with -C(=O)OH and Ci.4alkyl substituted with -C(=O)OH, and y is 1, 2, 3 or 4.

[00225] Embodiment 63. The conjugate of any one of Embodiments 54 to 62, wherein X2 and 0 oh             , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to Y1 or the point of attachment to the the point of attachment to OH group or

[00226] Embodiment 64. The conjugate of any one of Embodiments 54 to 63, wherein X2 is H              , where the * of X2 indicates the point of attachment to Li and the ** of X2 A indicates the point of attachment to Y1 or the point of attachment to the OH group or the o'V point of attachment to V^b group.

[00227] Embodiment 65. The conjugate of any one of Embodiments 54 to 64, wherein Li is a bivalent peptide linker comprising 2 to 4 amino acid residues.

[00228] Embodiment 66. The conjugate of any one of Embodiments 54 to 65, wherein Li is a 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 Li is a bivalent peptide linker comprising at least one valine (Vai) or citrulline (Cit) residue.

[00230] Embodiment 68. The conjugate of any one of Embodiments 54 to 64, wherein Li is a bivalent dipeptide linker selected from ValCit, PheLys, ValAla and ValLys.

[00231] Embodiment 69. The conjugate of any one of Embodiments 54 to 64, wherein Li u U ** HO** "               H J = ^Xr^**      \          y (PheLys), H O - (ValAla),             NH2 (ValLys) and            ° NH2 (LeuCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2.

[00232] Embodiment 70. The conjugate of any one of Embodiments 54 to 64, wherein Li is ValCit.

[00233] Embodiment 71. The conjugate of any one of Embodiments 54 to 64, wherein H 0 k kNH Li is            0 NH2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2.

[00234] Embodiment 72. The conjugate of any one of Embodiments 54 to 71, wherein L2 is a linker.

[00235] Embodiment 73. The conjugate of any one of Embodiments 54 to 71, wherein L2 is a linker selected from: -*C(=O)((CH2)mO)p(CH2)m**-, -*C(=O)(CH2)m**-, -*C(=O)(CH2)nNHC(=O)(CH2)m**-, -*C(=O)(CH2)mNHC(=O)((CH2)mO)p(CH2)m**-, -* ((CH2)mO)p(CH2)m**-, -* ((CH2)mO)p(CH2)m**-, -(CH2)m-, -*(CH2)mNHC(=O)(CH2)m**-, -* (CH2)mNHC(=O)(CH2)mC(=O)NH(CH2)m**-, -* ((CH2)mO)p(CH2)mNHC(=O)(CH2)m**-, -* *((CH2)mO)pCH2)mC(=O)NH(CH2)m**-, -* (CH2)mC(R3)2**-, and -* (CH2)mC(R3)2SS(CH2)mNHC(=O)(CH2)m**-, where the * of L2 indicates the attachment point to Li and the ** of L2 indicates the point of attachment to Xi; and wherein: each R3 is independently selected from H and Ci-Cealkyl; 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 to 71, wherein L2 is -*C(=O)((CH2)mO)p(CH2)m**- or -*C(=O)(CH2)m**-, where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Xi, and wherein 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 to 71, wherein L2 is O                   , O                   or O          , where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Xi.

[00238] Embodiment 76. The conjugate of any one of Embodiments 54 to 75, wherein Xi is is a bivalent coupling group selected from 0     , O । .AA / WWX / /          0               > A *       . * H0-4( s * X-X                   -vlJ? * [J                     **              '"iT ** 0     , O ,             ,,    -*NR4C(=O)CH2**-, ■ *NHC(=O)CH2**-, -*S(=O)2CH2CH2**-, -* (CH2)2S(=O)2CH2CH2**-, *NR4S(=O)2CH2CH2**-, -*NR4C(=O)CH2CH2**-, -NH-, -C(=O)-, -*NHC(=O) indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab; and wherein: each R4 is independently selected from H and Ci-Cealkyl; each R5 is independently selected from H, Ci-Cealkyl, F, Cl, and -OH; each R6 is independently selected from H, Ci-Cealkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH, and each R7 is independently selected from H, C^alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, Ci^alkoxy substituted with -C(=O)OH and Ci^alkyl substituted with -C(=O)OH.

[00239] Embodiment 77. The conjugate of any one of Embodiments 54 to 75, wherein Xi is is a bivalent coupling group selected from JWWWX •"W"- ** and , where the * of Xi indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab.

[00240] Embodiment 78. The conjugate of any one of Embodiments 54 to 75, wherein Xi is is a bivalent coupling group selected from and 0    , where the * of Xi indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab.

[00241] Embodiment 79. The conjugate of Formula (C-2) of Embodiment 54 wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Xi is is a bivalent coupling group selected from where the * of Xi indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab X2 is H                  , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to the OH group; Li is            O nh2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2; L2 is O                   or O          , where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs, and y is 1, 2, 3 or 4.

[00242] Embodiment 80. The conjugate of Formula (C-3) of Embodiment 58 wherein: Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein; R° is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Xi is is a bivalent coupling group selected from where the * of Xi indicates the point of attachment to L2 and the ** of Xi indicates the point of attachment to Ab X2 is ** , where the * of X2 indicates the point of attachment to Li and the ** of X2 indicates the point of attachment to the Li is            0 nh2 (ValCit), where the * of Li indicates the attachment point to L2 and the ** of Li indicates the attachment point to X2; L2 is O                   or O          , where the * of L2 indicates the point of attachment to Li and the ** of L2 indicates the point of attachment to Rs, and y is 1, 2, 3 or 4.

[00243] Embodiment 81. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00244] Embodiment 82. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00245] Embodiment 83. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00246] Embodiment 84. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00247] Embodiment 85. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00248] Embodiment 86. The conjugate of Formula (C), Formula (C-1) or Formula (C-2) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00249] Embodiment 87. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00250] Embodiment 88. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00251] Embodiment 89. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00252] Embodiment 90. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00253] Embodiment 91. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00254] Embodiment 92. The conjugate of Formula (C), Formula (C-1) or Formula (C-3) having the structure: wherein: y is 2 or 4 and Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein.

[00255] Further, the antibodies, antibody fragments (e.g., antigen binding fragments) or functional equivalents of the present invention may be conjugated to a drug moiety that modifies a given biological response. Drug moieties are not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein, peptide, or polypeptide possessing 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, a-interferon, p-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, a cytokine, an apoptotic agent, an anti-angiogenic agent, or, a biological response modifier such as, for example, a lymphokine.

[00256] In one embodiment, the antibodies, antibody fragments (e.g., antigen binding fragments) or functional equivalents of the present invention are conjugated to a drug moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin. Examples of cytotoxins include but are not limited to, taxanes (see, e.g., International (PCT) Patent Application Nos. WO 01 / 38318 and PCT / US03 / 02675), DNA-alkylating agents (e.g., CC-1065 analogs), anthracyclines, tubulysin analogs, duocarmycin analogs, auristatin E, auristatin F, maytansinoids, pyrrolobenzodiazipines (PBDs), and cytotoxic agents comprising a reactive polyethylene glycol moiety (see, e.g., Sasse etal., J. Antibiot. (Tokyo), 53, 879-85 (2000), Suzawa et al., Bioorg. Med. Chern., 8, 2175-84 (2000), Ichimura etal., J. Antibiot. (Tokyo), 44, 1045-53 (1991), Francisco et al., Blood (2003) (electronic publication prior to print publication), U.S. Pat. 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 Ser. 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, tenoposide, vincristine, vinblastine, t. colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents also include, for example, anti-metabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), ablating agents (e.g., mechlorethamine, thiotepa chlorambucil, meiphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cisdichlorodiamine platinum (II) (DDP) cisplatin, anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine). (See e.g., Seattle Genetics US20090304721).

[00257] Other examples of cytotoxins that can be conjugated to the antibodies, antibody fragments (antigen binding fragments) or functional equivalents of the 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, e.g., Saito et 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; Senterand Springer, (2001) Adv. Drug Deliv. Rev. 53:247-264.

[00259] The antibodies, antibody fragments (e.g., antigen binding fragments) or functional equivalents of the present invention can also be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, referred to as radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine-131, indium-111, yttrium-90, and lutetium-177. Methods for preparing radioimmunoconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including Zevalin™ (DEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention. In certain 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 commonly known in the art and described in Denardo et al., (1998) Clin Cancer Res. 4(10):2483-90; Peterson et al., (1999) Bioconjug. Chern. 10(4):553-7; and Zimmerman etal., (1999) Nucl. Med. Biol. 26(8):943-50, each incorporated by reference in their entireties.

[00260] The antibodies, antibody fragments (e.g., antigen binding fragments) or functional equivalents of the present invention can also conjugated to a heterologous protein or polypeptide (or fragment thereof, preferably to 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 generate fusion proteins. In particular, the invention provides fusion proteins comprising an antibody fragment (e.g., antigen binding fragment) described herein (e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, a VH domain, a VH CDR, a VL domain or a VL CDR) and a heterologous protein, polypeptide, or peptide.

[00261] Additional fusion proteins may be generated through the techniques of geneshuffling, motif-shuffling, exon-shuffling, and / or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to alter the activities of antibodies of the invention or fragments thereof {e.g., antibodies or fragments thereof with higher affinities and lower dissociation rates). See, generally, U.S. Patent Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten et al., (1997) Curr. Opinion Biotechnol. 8:724-33; Harayama, (1998) Trends Biotechnol. 16(2):76-82; Hansson eta!., (1999) J. Mol. Biol. 287:265-76; and Lorenzo and Blasco, (1998) Biotechniques 24(2):308- 313 (each of these patents and publications are hereby incorporated by reference in its entirety). Antibodies or fragments thereof, or the encoded antibodies or fragments thereof, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. A polynucleotide encoding an antibody or fragment thereof that specifically binds to an antigen may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[00262] Moreover, the antibodies, antibody fragments {e.g., antigen binding fragments) or functional equivalents of the present invention can be conjugated to marker sequences, such as a peptide, to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide (SEQ ID NO: 267), such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available. As described in Gentz et al., (1989) Proc. Natl. Acad. Sci. USA 86:821824, for instance, hexa-histidine (SEQ ID NO: 267) provides 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 influenza hemagglutinin protein (Wilson et al., (1984) Cell 37:767), and the “FLAG” tag (A. Einhauer et al., J. Biochem. Biophys. Methods 49: 455-465, 2001). According to the present invention, antibodies or antigen binding fragments can also be conjugated to tumor-penetrating peptides in order to enhance their efficacy.

[00263] In other embodiments, the antibodies, antibody fragments {e.g., antigen binding fragments) or functional equivalents of the present invention are conjugated to a diagnostic or detectable agent. Such immunoconjugates can be useful for monitoring or prognosing the onset, 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 diagnosis and detection can be accomplished by coupling 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 materials, 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, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; luminescent materials, such as, but not limited to, luminol; bioluminescent materials, such as but not limited to, luciferase, luciferin, and aequorin; radioactive materials, such as, but not limited to, iodine (131l, 125l, 123l, and 121l,), carbon (14C), sulfur (35S), tritium (3H), indium (115ln, 113ln, 112ln, and 111 In,), technetium ("Tc), 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, and 117Sn; and positron emitting metals using various positron emission tomographies, and non-radioactive paramagnetic metal ions.

[00264] The antibodies, antibody fragments (e.g., antigen binding fragments) or functional equivalents of the 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 Preparation of ADCs Processes for Making Antibody conjugates of Formula (C), Formula (C-1) and Formula (C-2)

[00265] A general reaction scheme for the formation of conjugates of Formula (C) is shown in Scheme 1 below: Scheme 1 Ab—(RG^y + y^R8—LB-(D)n)-------Ab-(LA-(D)n)y (B)                     (C) where: RGi is a reactive group on the antibody or antigen binding fragment thereof, Ab, by way of example only a thiol, amine or ketone, which reacts with a compatible reactive group, R8, attached to the linker-drug compound thereby covalently linking antibody or antigen binding fragment thereof, Ab, to one or more linker-drug moieties. Nonlimiting examples of such reactions of RGi and R8 groups are a maleimide (R8) reacting with a thiol (RGi) to give a succinimide ring, or a hydroxylamine (R8) reacting with a ketone (RGi) to give an oxime. In one embodiment, D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor), La is a linker further comprising a bivalent coupling group formed when RGi and R8 react, n is 1,2, 3 or 4, and y is 1,2, 3 or 4.

[00266] A general reaction scheme for the formation of conjugates of Formula (C-1) is shown in Scheme 2 below: Scheme 2 Ab-(RG,)y + »(R\AXAD) ------Ab^X,'LfL’'XrY,-D) (B-1)                                (C-1)        7 where: RG1 is a reactive group on the antibody or antigen binding fragment thereof, Ab, by way of example only a thiol, amine or ketone, which reacts with a compatible reactive group, R8, attached to the linker-drug moiety thereby covalently linking antibody or antigen binding fragment thereof, Ab, to one or more linker-drug moieties. Nonlimiting examples of such reactions of RG1 and R8 groups are a maleimide (R8) reacting with a thiol (RG1) to give a succinimide ring, or a hydroxylamine (R8) reacting with a ketone (RG1) to give an oxime. In one embodiment, D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of GNAQ and GNA11 (GNAQ / GNA11 inhibitor), Xi is a bivalent coupling group formed when RG1 and R8 react (e.g. a succinimide ring or an oxime), Y1 is a phosphate group, X2 is a self-immolative spacer, Li is a bivalent peptide linker, L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00267] A general reaction scheme for the formation of conjugates of Formula (C-2) is shown in Scheme 3 below: Scheme 3 where: RGi is a reactive group on the antibody or antigen binding fragment thereof, Ab, by way of example only a thiol, amine or ketone, which reacts with a compatible reactive group, R8, attached to the linker-drug moiety thereby covalently linking antibody or antigen binding fragment thereof, Ab, to one or more linker-drug moieties. Nonlimiting examples of such reactions of RGi and R8 groups are a maleimide (R8) reacting with a thiol (RGi) to give a succinimide ring, or a hydroxylamine (R8) reacting with a ketone (RGi) to give an oxime. Here R° is methyl or ethyl, R1 is methyl or isopropyl, R2 is methyl or ethyl, Xi is a bivalent coupling group formed when RGi and R8 react (e.g. a succinimide ring or an oxime), X2 is a self-immolative spacer, Li is a bivalent peptide linker, L2 is a bond or a linker, and y is 1, 2, 3 or 4.

[00268] A general reaction scheme for the formation of conjugates of Formula (C-2) is shown in Scheme 4 below: Scheme 4 where: RGi is a reactive group on the antibody or antigen binding fragment thereof, Ab, by way of example only a thiol, amine or ketone, which reacts with a compatible reactive group, R8, attached to the linker-drug moiety thereby covalently linking antibody or antigen binding fragment thereof, Ab, to one or more linker-drug moieties. Nonlimiting examples of such reactions of RGi and R8 groups are a maleimide (R8) reacting with a thiol (RGi) to give a succinimide ring, or a hydroxylamine (R8) reacting with a ketone (RGi) to give an oxime. Here R° is methyl or ethyl, R1 is methyl or isopropyl, R2 is methyl or ethyl, Xi is a bivalent coupling group formed when RGi and R8 react (e.g. a succinimide ring or an oxime), X2 is a self-immolative spacer, Li is a bivalent peptide linker, L2 is a bond or a linker, and y is 1, 2, 3 or 4. Process For Conjugation to Engineered Cysteine Antibody Residues

[00269] Conjugates of the invention can be prepared using cysteine residues engineered into an antibody by, for example, site-directed mutagenesis. Such site-specific conjugates are homogenous 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 their biosynthesis (Chen etal. 2009), the engineered cysteine residues in the product as initially expressed are unreactive to thiol reactive reagents such as maleimido or bromo-or iodoacetamide groups. To conjugate payload to an engineered cysteine after expression, glutathione or cysteine adducts need to be removed by reducing these disulfide adducts, which generally entails also reducing native disulfides in the expressed protein. Deprotection of adducted engineered cysteines can be accomplished by first exposing antibody to a reducing agent, e.g., dithiothreitol (DTT), TCEP, or reduced cysteine, followed by a procedure that allows for re-oxidation of all native disulfide bonds of an antibody to restore and / or stabilize the functional antibody structure.

[00271] Several methods can be employed to reduce and re-oxidize antibodies with engineered cysteine residues for preparation of antibody drug conjugates. Attempts to follow re-oxidation protocols previously described in the literature using high concentration 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). We have successfully prepared and obtained antibody drug conjugates with several different methods for reduction and antibody re-oxidation.

[00272] The following is a method to reduce and re-oxidize antibodies with engineered cysteine residues for preparation of antibody drug conjugates: Freshly prepared DTT is added to purified Cys mutant antibodies to a final concentration of 10 mM. After incubation with DTT at room temperature for 1 hour, mixture is dialyzed at 4°C against PBS for three days with daily buffer exchange to remove DTT and re-oxidize native disulfide bonds of the antibody. An alternative method is to remove reducing reagents through a desalting column such as Sephadex G-25, equilibrated with PBS. Once protein is fully reduced, 1 mM oxidized ascorbate (dehydro-ascorbic acid) is optionally added to desalted samples and re-oxidation incubations are carried out for 20-24 hours.

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

[00274] After re-oxidation, the antibody is conjugated to a linker-drug compound of, by way of example, compounds of Formula (B), Formula (B-1), Formula (B-2) or Formula (B-3) (see schemes 1-4). By way of example, a compound of Formula (B), Formula (B-1), Formula (B-2) or Formula (B-3) is added to re-oxidized Cys mutant antibody at 5-10 molar equivalents relative to 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 is able to separate conjugated antibodies from non-conjugated ones. Conjugation reaction mixtures are analyzed on a PRLP-S column (4000 A, 50 mm x 2.1 mm, Agilent) heated to 80°C and elution of the column are carried out by a linear gradient of 30-60% acetonitrile in water containing 0.1% TFA at a flow rate of 1.5 ml / min. Elution of proteins from the column is monitored at 280 nm, 254 nm and 215 nm.

[00275] Alternatively, for antibodies bound to a Protein A resin, once the antibody is reoxidized, the resin is washed with 10 column volumes PBS and the resin is then resuspended in equal volume PBS and an 8x excess of a 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 1 M Tris pH 9.0 and buffer exchanged into appropriate buffer to perform preparative size exclusion chromatography (if needed).

[00276] Immunoconjugates are also characterized in terms of average loading of a drug moiety to antibody binding moiety, generally referred to as drug-to-antibody ratio (DAR). The DAR value is extrapolated, for example, from LC-MS data for reduced and deglycosylated samples. LC / MS allows quantitation of the average number of molecules of payload (drug moiety) attached to an antibody in an ADC. HPLC separates an antibody into light and heavy chains, and also separates heavy chain (HC) and light chain (LC) according to the number of Linker-Payload groups per chain. Mass spectral data enables identification of the component species in the mixture, e.g., LC, LC+1, LC+2, HC, HC+1, HC+2, etc. From average loading of LC and HC chains, the average DAR can be calculated for an ADC. The DAR for a given immunoconjugate sample represents the average number of drug (payload) molecules attached to a tetrameric antibody containing two light chains and two heavy chains.

[00277] Throughout the text of this application, should there be a discrepancy between the text of the specification and the sequence listing, the text of the specification shall prevail. Table 2. Examples of Anti-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 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGII PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCA SEQ ID NO: 12 Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGI I PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEQ ID NO: 13 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCAGCTAGCACCAAGGGCCCAAGT GTGTTTCCCCTGGCCCCCAGCAGCAAGTCTA CTTCCGGCGGAACTGCTGCCCTGGGTTGCC TGGTGAAGGACTACTTCCCCTGTCCCGTGAC AGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAG AGCAGCGGCCTGTACAGCCTGAGCAGCGTG GTGACAGTGCCCTCCAGCTCTCTGGGAACC CAGACCTATATCTGCAACGTGAACCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTGG AGCCCAAGAGCTGCGACAAGACCCACACCT GCCCCCCCTGCCCAGCTCCAGAACTGCTGG GAGGGCCTTCCGTGTTCCTGTTCCCCCCCAA GCCCAAGGACACCCTGATGATCAGCAGGAC CCCCGAGGTGACCTGCGTGGTGGTGGACGT GTCCCACGAGGACCCAGAGGTGAAGTTCAA CTGGTACGTGGACGGCGTGGAGGTGCACAA CGCCAAGACCAAGCCCAGAGAGGAGCAGTA CAACAGCACCTACAGGGTGGTGTCCGTGCT GACCGTGCTGCACCAGGACTGGCTGAACGG CAAAGAATACAAGTGCAAAGTCTCCAACAAG GCCCTGCCAGCCCCAATCGAAAAGACAATCA GCAAGGCCAAGGGCCAGCCACGGGAGCCC CAGGTGTACACCCTGCCCCCCAGCCGGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCT GTCTGGTGAAGGGCTTCTACCCCTGTGATAT CGCCGTGGAGTGGGAGAGCAACGGCCAGCC CGAGAACAACTACAAGACCACCCCCCCAGTG CTGGACAGCGACGGCAGCTTCTTCCTGTACA GCAAGCTGACCGTGGACAAGTCCAGGTGGC AGCAGGGCAACGTGTTCAGCTGCAGCGTGA TGCACGAGGCCCTGCACAACCACTACACCCA GAAGTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) DALRDKF SEQ ID NO: 18 LCDR2 (Chothia) DDN SEQ ID NO: 19 LCDR3 (Chothia) 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 DIELTQPPSVSVSPGQTASITCSGDALRDKFVY WYQQKPGQAPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISGTQAEDEADYYCQSWDHSYSLV VFGGGTKLTVL SEQ ID NO: 22 DNA VL GATATCGAACTGACCCAGCCGCCGAGCGTG AGCGTGAGCCCGGGCCAGACCGCGAGCATT ACCTGTAGCGGCGATGCTCTGCGTGACAAAT TCGTTTACTGGTACCAGCAGAAACCGGGCCA GGCGCCGGTGCTGGTGATCTACGACGACAA CAACCGTCCGAGCGGCATCCCGGAACGTTTT AGCGGATCCAACAGCGGCAACACCGCGACC CTGACCATTAGCGGCACCCAGGCGGAAGAC GAAGCGGATTATTACTGCCAGTCTTGGGACC ATTCTTACTCTCTGGTTGTGTTTGGCGGCGG CACGAAGTTAACTGTCCTG SEQ ID NO: 23 Light Chain DIELTQPPSVSVSPGQTASITCSGDALRDKFVY WYQQKPGQAPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISGTQAEDEADYYCQSWDHSYSLV VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSN N KYAASSYLSLTPEQWKSH RSY SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 24 DNA Light Chain GATATCGAACTGACCCAGCCGCCGAGCGTG AGCGTGAGCCCGGGCCAGACCGCGAGCATT ACCTGTAGCGGCGATGCTCTGCGTGACAAAT TCGTTTACTGGTACCAGCAGAAACCGGGCCA GGCGCCGGTGCTGGTGATCTACGACGACAA CAACCGTCCGAGCGGCATCCCGGAACGTTTT AGCGGATCCAACAGCGGCAACACCGCGACC CTGACCATTAGCGGCACCCAGGCGGAAGAC GAAGCGGATTATTACTGCCAGTCTTGGGACC ATTCTTACTCTCTGGTTGTGTTTGGCGGCGG CACGAAGTTAACTGTCCTGGGACAACCTAAG GCCGCTCCCTCCGTGACCCTGTTCCCCCCC AGCTCCGAGGAACTGCAGGCCAACAAGGCC ACCCTGGTGTGCCTGATCAGCGACTTCTACC CTGGCGCCGTGACCGTGGCCTGGAAGGCCG ACAGCAGCCCCGTGAAGGCCGGCGTGGAGA CAACCACCCCCAGCAAGCAGAGCAACAACAA GTACGCCGCCAGCAGCTACCTGAGCCTGAC CCCCGAGCAGTGGAAGAGCCACAGAAGCTA CAGCTGCCAGGTCACCCACGAGGGCAGCAC CGTGGAGAAAACCGTGGCCCCCACCGAGTG CAGC G1 E152C_S375C_3J 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(Ch othia) EGGLLTDISYSRYWFAY SEQ ID NO: 7 HCDR1 (IM GT) GGTFSDYA SEQ ID NO: 8 HCDR2 (IM GT) IIPIFGTA SEQ ID NO: 9 HCDR3 (IM GT) AREGGLLTDISYSRYWFAY SEQ ID NO: 10 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGI I PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCA SEQ ID NO: 12 Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGI I PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS WTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGN VFSCSVM H EALH N H YTQKSLS LSPGK SEQ ID NO: 13 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCAGCTAGCACCAAGGGCCCAAGT GTGTTTCCCCTGGCCCCCAGCAGCAAGTCTA CTTCCGGCGGAACTGCTGCCCTGGGTTGCC TGGTGAAGGACTACTTCCCCTGTCCCGTGAC AGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAG AGCAGCGGCCTGTACAGCCTGAGCAGCGTG GTGACAGTGCCCTCCAGCTCTCTGGGAACCC AGACCTATATCTGCAACGTGAACCACAAGCC CAGCAACACCAAGGTGGACAAGAGAGTGGA GCCCAAGAGCTGCGACAAGACCCACACCTG CCCCCCCTGCCCAGCTCCAGAACTGCTGGG AGGGCCTTCCGTGTTCCTGTTCCCCCCCAAG CCCAAGGACACCCTGATGATCAGCAGGACC CCCGAGGTGACCTGCGTGGTGGTGGACGTG TCCCACGAGGACCCAGAGGTGAAGTTCAACT GGTACGTGGACGGCGTGGAGGTGCACAACG CCAAGACCAAGCCCAGAGAGGAGCAGTACA ACAGCACCTACAGGGTGGTGTCCGTGCTGA CCGTGCTGCACCAGGACTGGCTGAACGGCA AAGAATACAAGTGCAAAGTCTCCAACAAGGC CCTGCCAGCCCCAATCGAAAAGACAATCAGC AAGGCCAAGGGCCAGCCACGGGAGCCCCAG GTGTACACCCTGCCCCCCAGCCGGGAGGAG ATGACCAAGAACCAGGTGTCCCTGACCTGTC TGGTGAAGGGCTTCTACCCCTGTGATATCGC CGTGGAGTGGGAGAGCAACGGCCAGCCCGA GAACAACTACAAGACCACCCCCCCAGTGCTG GACAGCGACGGCAGCTTCTTCCTGTACAGCA AGCTGACCGTGGACAAGTCCAGGTGGCAGC AGGGCAACGTGTTCAGCTGCAGCGTGATGC ACGAGGCCCTGCACAACCACTACACCCAGAA GTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) DALRDKF SEQ ID NO: 18 LCDR2 (Chothia) DDN SEQ ID NO: 19 LCDR3 (Chothia) WDHSYSLV SEQ ID NO: 20 LCDR1 (IM GT) ALRDKF SEQ ID NO: 18 LCDR2 (IM GT) DDN SEQ ID NO: 16 LCDR3 (IM GT) QSWDHSYSLVV SEQ ID NO: 25 VL SYELTQPLSVSVALGQTARITCSGDALRDKFVY WYQQKPGQAPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCQSWDHSYSLV VFGGGTKLTVL SEQ ID NO: 26 DNA VL AGCTACGAGCTGACCCAGCCGCTGTCGGTG TCAGTCGCCCTGGGACAAACTGCCAGGATCA CTTGTTCCGGGGACGCATTGCGGGACAAGTT CGTGTACTGGTACCAGCAGAAGCCGGGTCA AGCCCCAGTGCTCGTGATCTACGACGACAAC AACCGGCCTTCCGGTATCCCCGAACGCTTCT CCGGATCCAATAGCGGAAACACCGCCACCCT GACCATTTCGAGAGCTCAGGCCGGGGATGA AGCGGACTACTACTGCCAGTCATGGGATCAC TCGTACTCCCTCGTCGTGTTTGGAGGCGGCA CGAAGCTTACTGTGCTG SEQ ID NO: 27 Light Chain SYELTQPLSVSVALGQTARITCSGDALRDKFVY WYQQKPGQAPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCQSWDHSYSLV VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSNNKYAASSYLSLTPEQWKSHRSY SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 28 DNA Light Chain AGCTACGAGCTGACCCAGCCGCTGTCGGTG TCAGTCGCCCTGGGACAAACTGCCAGGATCA CTTGTTCCGGGGACGCATTGCGGGACAAGTT CGTGTACTGGTACCAGCAGAAGCCGGGTCA AGCCCCAGTGCTCGTGATCTACGACGACAAC AACCGGCCTTCCGGTATCCCCGAACGCTTCT CCGGATCCAATAGCGGAAACACCGCCACCCT GACCATTTCGAGAGCTCAGGCCGGGGATGA AGCGGACTACTACTGCCAGTCATGGGATCAC TCGTACTCCCTCGTCGTGTTTGGAGGCGGCA CGAAGCTTACTGTGCTGGGCCAGCCTAAGG CCGCTCCCTCCGTGACCCTGTTCCCCCCCAG CTCCGAGGAACTGCAGGCCAACAAGGCCAC CCTGGTGTGCCTGATCAGCGACTTCTACCCT GGCGCCGTGACCGTGGCCTGGAAGGCCGAC AGCAGCCCCGTGAAGGCCGGCGTGGAGACA ACCACCCCCAGCAAGCAGAGCAACAACAAGT ACGCCGCCAGCAGCTACCTGAGCCTGACCC CCGAGCAGTGGAAGAGCCACAGAAGCTACA GCTGCCAGGTCACCCACGAGGGCAGCACCG TGGAGAAAACCGTGGCCCCCACCGAGTGCA GC 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(Ch othia) EGGLLTDISYSRYWFAY SEQ ID NO: 7 HCDR1 (IM GT) GGTFSDYA SEQ ID NO: 8 HCDR2 (IM GT) IIPIFGTA SEQ ID NO: 9 HCDR3 (IM GT) AREGGLLTDISYSRYWFAY SEQ ID NO: 10 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGII PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSS SEQ ID NO: 11 DNA VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCA SEQ ID NO: 12 Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAITWVRQAPGQGLEWMGGII PI FGTANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REGGLLTDISYSRYWFAYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGN VFSCSVM H EALH N H YTQKSLS LSPGK SEQ ID NO: 13 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTGA CTACGCTATCACTTGGGTGCGCCAGGCCCC GGGCCAGGGCCTCGAGTGGATGGGCGGTAT CATCCCGATCTTCGGCACTGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGGTGGTCTG CTGACTGACATCTCTTACTCTCGTTACTGGTT CGCTTACTGGGGCCAAGGCACCCTGGTGAC TGTTAGCTCAGCTAGCACCAAGGGCCCAAGT GTGTTTCCCCTGGCCCCCAGCAGCAAGTCTA CTTCCGGCGGAACTGCTGCCCTGGGTTGCC TGGTGAAGGACTACTTCCCCTGTCCCGTGAC AGTGTCCTGGAACTCTGGGGCTCTGACTTCC GGCGTGCACACCTTCCCCGCCGTGCTGCAG AGCAGCGGCCTGTACAGCCTGAGCAGCGTG GTGACAGTGCCCTCCAGCTCTCTGGGAACCC AGACCTATATCTGCAACGTGAACCACAAGCC CAGCAACACCAAGGTGGACAAGAGAGTGGA GCCCAAGAGCTGCGACAAGACCCACACCTG CCCCCCCTGCCCAGCTCCAGAACTGCTGGG AGGGCCTTCCGTGTTCCTGTTCCCCCCCAAG CCCAAGGACACCCTGATGATCAGCAGGACC CCCGAGGTGACCTGCGTGGTGGTGGACGTG TCCCACGAGGACCCAGAGGTGAAGTTCAACT GGTACGTGGACGGCGTGGAGGTGCACAACG CCAAGACCAAGCCCAGAGAGGAGCAGTACA ACAGCACCTACAGGGTGGTGTCCGTGCTGA CCGTGCTGCACCAGGACTGGCTGAACGGCA AAGAATACAAGTGCAAAGTCTCCAACAAGGC CCTGCCAGCCCCAATCGAAAAGACAATCAGC AAGGCCAAGGGCCAGCCACGGGAGCCCCAG GTGTACACCCTGCCCCCCAGCCGGGAGGAG ATGACCAAGAACCAGGTGTCCCTGACCTGTC TGGTGAAGGGCTTCTACCCCTGTGATATCGC CGTGGAGTGGGAGAGCAACGGCCAGCCCGA GAACAACTACAAGACCACCCCCCCAGTGCTG GACAGCGACGGCAGCTTCTTCCTGTACAGCA AGCTGACCGTGGACAAGTCCAGGTGGCAGC AGGGCAACGTGTTCAGCTGCAGCGTGATGC ACGAGGCCCTGCACAACCACTACACCCAGAA GTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) DALRDKF SEQ ID NO: 18 LCDR2 (Chothia) DDN SEQ ID NO: 19 LCDR3 (Chothia) WDHSYSLV SEQ ID NO: 20 LCDR1 (IM GT) ALRDKF SEQ ID NO: 18 LCDR2 (IM GT) DDN SEQ ID NO: 16 LCDR3 (IM GT) QSWDHSYSLVV SEQ ID NO: 29 VL SYELTQPPSVSVSPGQTASITCSGDALRDKFVY WYQQKPGQSPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISGTQAMDEADYYCQSWDHSYSLV VFGGGTKLTVL SEQ ID NO: 30 DNA VL TCGTACGAGCTCACTCAACCGCCTTCTGTGT CCGTGTCACCCGGGCAGACTGCCTCCATTAC CTGTTCGGGAGATGCCCTGCGCGACAAGTTT GTGTACTGGTACCAGCAGAAGCCCGGACAG TCGCCAGTGCTCGTCATCTATGACGACAACA ACAGACCTTCCGGTATCCCGGAACGGTTCAG CGGAAGCAATTCCGGCAACACCGCTACCCTG ACCATTAGCGGCACTCAGGCCATGGACGAA GCGGATTACTACTGCCAATCCTGGGACCACT CATACTCCCTTGTGGTGTTCGGTGGCGGAAC GAAGCTGACCGTCCTG SEQ ID NO: 31 Light Chain SYELTQPPSVSVSPGQTASITCSGDALRDKFVY WYQQKPGQSPVLVIYDDNNRPSGIPERFSGSN SGNTATLTISGTQAMDEADYYCQSWDHSYSLV VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSNNKYAASSYLSLTPEQWKSHRSY SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 32 DNA Light Chain TCGTACGAGCTCACTCAACCGCCTTCTGTGT CCGTGTCACCCGGGCAGACTGCCTCCATTAC CTGTTCGGGAGATGCCCTGCGCGACAAGTTT GTGTACTGGTACCAGCAGAAGCCCGGACAG TCGCCAGTGCTCGTCATCTATGACGACAACA ACAGACCTTCCGGTATCCCGGAACGGTTCAG CGGAAGCAATTCCGGCAACACCGCTACCCTG ACCATTAGCGGCACTCAGGCCATGGACGAA GCGGATTACTACTGCCAATCCTGGGACCACT CATACTCCCTTGTGGTGTTCGGTGGCGGAAC GAAGCTGACCGTCCTGGGCCAGCCTAAGGC CGCTCCCTCCGTGACCCTGTTCCCCCCCAGC TCCGAGGAACTGCAGGCCAACAAGGCCACC CTGGTGTGCCTGATCAGCGACTTCTACCCTG GCGCCGTGACCGTGGCCTGGAAGGCCGACA GCAGCCCCGTGAAGGCCGGCGTGGAGACAA CCACCCCCAGCAAGCAGAGCAACAACAAGTA CGCCGCCAGCAGCTACCTGAGCCTGACCCC CGAGCAGTGGAAGAGCCACAGAAGCTACAG CTGCCAGGTCACCCACGAGGGCAGCACCGT GGAGAAAACCGTGGCCCCCACCGAGTGCAG C 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) GGTFSTY SEQ ID NO: 38 HCDR2 (Chothia) IPILGI SEQ ID NO: 35 HCDR3(Ch othia) 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 QVQLVQSGAEVKKPGSSVKVSCKASGGTFST YAISWVRQAPGQGLEWMGRIIPILGIANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REVRMIFDYWGQGTLVTVSS SEQ ID NO: 43 DNA VH CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG Illi CTAC TTACGCTATCTCTTGGGTGCGCCAGGCCCCG GGCCAGGGCCTCGAGTGGATGGGCCGTATC ATCCCGATCCTGGGCATCGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGTTCGTATG ATCTTCGATTACTGGGGCCAAGGCACCCTGG TGACTGTTAGCTCA SEQ ID NO: 44 Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFST YAISWVRQAPGQGLEWMGRIIPILGIANYAQKF QGRVTITADESTSTAYMELSSLRSEDTAVYYCA REVRMIFDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPCPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPCDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 45 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCCGAA GTGAAAAAACCGGGCAGCAGCGTGAAAGTTA GCTGCAAAGCATCCGGAGGGACG I I I ICI AC TTACGCTATCTCTTGGGTGCGCCAGGCCCCG GGCCAGGGCCTCGAGTGGATGGGCCGTATC ATCCCGATCCTGGGCATCGCGAACTACGCC CAGAAATTTCAGGGCCGGGTGACCATTACCG CCGATGAAAGCACCAGCACCGCCTATATGGA ACTGAGCAGCCTGCGCAGCGAAGATACGGC CGTGTATTATTGCGCGCGTGAAGTTCGTATG ATCTTCGATTACTGGGGCCAAGGCACCCTGG TGACTGTTAGCTCAGCCTCTACGAAAGGCCC AAGCGTATTTCCCCTGGCTCCTTCTAGTAAAT CAACCTCAGGTGGTACAGCAGCCCTTGGCT GCCTGGTCAAAGACTATTTCCCCTGTCCGGT GACCGTCTCATGGAACTCAGGTGCTTTGACA TCTGGTGTGCATACATTCCCAGCTGTGCTGC AAAGTAGTGGACTGTACAGCCTTTCCAGCGT GGTCACGGTGCCAAGTAGCTCCTTGGGTACT CAGACTTATATCTGCAATGTGAACCACAAGC CCTCTAACACGAAGGTGGACAAGCGCGTGG AGCCCAAATCTTGCGATAAGACGCATACTTG TCCCCCATGCCCTGCTCCTGAGCTGTTGGGA GGCCCGTCAGTGTTCTTGTTCCCTCCGAAGC CTAAGGACACTTTGATGATAAGTAGGACACC AGAGGTGACTTGCGTGGTGGTTGATGTGTCC CATGAAGATCCCGAGGTCAAATTTAATTGGT ACGTAGATGGTGTCGAAGTTCACAATGCTAA GACTAAGCCAAGGGAAGAGCAGTACAACAGT ACATATAGGGTAGTCTCCGTGCTGACAGTCC TCCACCAGGACTGGTTGAACGGCAAGGAATA CAAATGTAAGGTGTCAAACAAAGCTCTGCCT GCTCCCATTGAGAAAACAATCTCTAAAGCCA AAGGCCAGCCGAGAGAGCCCCAAGTCTACA CTTTGCCCCCGAGCAGGGAGGAAATGACCA AGAATCAGGTGAGTCTGACGTGCCTCGTCAA AGGA Illi ATCCATGCGATATTGCAGTTGAAT GGGAGAGCAATGGCCAGCCAGAGAACAACT ATAAAACCACACCACCCGTGCTCGACTCTGA TGGCAGCTTCTTCCTCTATAGCAAGCTGACA GTCGATAAATCTCGCTGGCAGCAAGGCAATG TGTTCTCCTGCTCCGTCATGCACGAGGCTTT GCATAACCATTATACTCAAAAATCTCTGTCCC TGTCACCTGGTAAA 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 (Chothia) SQSISSY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 51 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQSISSYL AWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQSYDYYTFG QGTKVEIK SEQ ID NO: 54 DNA VL GATATCCAGATGACCCAGAGCCCGAGCAGC CTGAGCGCCAGCGTGGGCGATCGCGTGACC ATTACCTGCAGAGCCAGCCAGTCTATTTCTT CTTACCTGGCTTGGTACCAGCAGAAACCGGG CAAAGCGCCGAAACTATTAATCTACGCTGCT TCTTCTCTGCAAAGCGGCGTGCCGAGCCGC TTTAGCGGCAGCGGATCCGGCACCGATTTCA CCCTGACCATTAGCTCTCTGCAACCGGAAGA CTTTGCGACCTATTATTGCCAGCAGTCTTAC GACTACTACACCTTTGGCCAGGGCACGAAAG TTGAAATTAAA SEQ ID NO: 55 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL AWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQSYDYYTFG QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC SEQ ID NO: 56 DNA Light Chain GATATCCAGATGACCCAGAGCCCGAGCAGC CTGAGCGCCAGCGTGGGCGATCGCGTGACC ATTACCTGCAGAGCCAGCCAGTCTATTTCTT CTTACCTGGCTTGGTACCAGCAGAAACCGGG CAAAGCGCCGAAACTATTAATCTACGCTGCT TCTTCTCTGCAAAGCGGCGTGCCGAGCCGC TTTAGCGGCAGCGGATCCGGCACCGATTTCA CCCTGACCATTAGCTCTCTGCAACCGGAAGA CTTTGCGACCTATTATTGCCAGCAGTCTTAC GACTACTACACCTTTGGCCAGGGCACGAAAG TTGAAATTAAACGTACGGTGGCAGCTCCGTC TG I I I I CATCTTTCCACCTAGCGACGAGCAA CTCAAAAGTGGTACAGCATCCGTGGTTTGTC TGCTGAACAA I I I I IACCCCAGGGAGGCTAA GGTCCAGTGGAAAGTCGATAACGCTCTTCAG TCTGGCAACAGTCAGGAGAGCGTCACAGAG CAGGACTCTAAGGATAGCACTTATAGTCTGT CCTCCACGCTGACACTGTCTAAAGCGGATTA TGAGAAGCACAAGGTTTACGCCTGTGAGGTA ACGCACCAAGGACTCTCCTCCCCAGTTACCA AATCTTTCAACAGAGGAGAATGT 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(Ch othia) 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 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAISWVRQAPGQGLEWMGGIIPIFGDANYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYC AREGSSYFYMAYWGQGTLVTVSS SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAACCTGGCAGCAGCGTGAAGGTG TCCTGCAAAGCAAGCGGCGGCACCTTCAGC GATTACGCCATCTCTTGGGTCCGACAGGCCC CTGGACAAGGCTTGGAATGGATGGGCGGCA TCATCCCCATCTTCGGCGACGCCAATTACGC CCAGAAATTCCAGGGCAGAGTGACCATCACC GCCGACGAGTCTACAAGCACCGCCTACATG GAACTGAGCAGCCTGAGAAGCGAGGACACC GCCGTGTACTACTGTGCCAGAGAGGGCAGC AGCTACTTCTACATGGCCTATTGGGGCCAGG GCACCCTGGTCACAGTTAGCTCT SEQ ID NO: 66 Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFSD YAISWVRQAPGQGLEWMGGIIPIFGDANYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYC AREGSSYFYMAYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPCPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPCDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK SEQ ID NO: 67 DNA Heavy Chain CAGGTTCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAACCTGGCAGCAGCGTGAAGGTG TCCTGCAAAGCAAGCGGCGGCACCTTCAGC GATTACGCCATCTCTTGGGTCCGACAGGCCC CTGGACAAGGCTTGGAATGGATGGGCGGCA TCATCCCCATCTTCGGCGACGCCAATTACGC CCAGAAATTCCAGGGCAGAGTGACCATCACC GCCGACGAGTCTACAAGCACCGCCTACATG GAACTGAGCAGCCTGAGAAGCGAGGACACC GCCGTGTACTACTGTGCCAGAGAGGGCAGC AGCTACTTCTACATGGCCTATTGGGGCCAGG GCACCCTGGTCACAGTTAGCTCTGCTAGCAC CAAGGGCCCAAGTGTGTTTCCCCTGGCCCC CAGCAGCAAGTCTACTTCCGGCGGAACTGCT GCCCTGGGTTGCCTGGTGAAGGACTACTTCC CCTGTCCCGTGACAGTGTCCTGGAACTCTGG GGCTCTGACTTCCGGCGTGCACACCTTCCCC GCCGTGCTGCAGAGCAGCGGCCTGTACAGC CTGAGCAGCGTGGTGACAGTGCCCTCCAGC TCTCTGGGAACCCAGACCTATATCTGCAACG TGAACCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCACACCTGCCCCCCCTGCCCAGCTC CAGAACTGCTGGGAGGGCCTTCCGTGTTCCT GTTCCCCCCCAAGCCCAAGGACACCCTGAT GATCAGCAGGACCCCCGAGGTGACCTGCGT GGTGGTGGACGTGTCCCACGAGGACCCAGA GGTGAAGTTCAACTGGTACGTGGACGGCGT GGAGGTGCACAACGCCAAGACCAAGCCCAG AGAGGAGCAGTACAACAGCACCTACAGGGT GGTGTCCGTGCTGACCGTGCTGCACCAGGA CTGGCTGAACGGCAAAGAATACAAGTGCAAA GTCTCCAACAAGGCCCTGCCAGCCCCAATC GAAAAGACAATCAGCAAGGCCAAGGGCCAG CCACGGGAGCCCCAGGTGTACACCCTGCCC CCCAGCCGGGAGGAGATGACCAAGAACCAG GTGTCCCTGACCTGTCTGGTGAAGGGCTTCT ACCCCTGTGATATCGCCGTGGAGTGGGAGA GCAACGGCCAGCCCGAGAACAACTACAAGA CCACCCCCCCAGTGCTGGACAGCGACGGCA GCTTCTTCCTGTACAGCAAGCTGACCGTGGA CAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATGCACGAGGCCCTGCA CAACCACTACACCCAGAAGTCCCTGAGCCTG AGCCCCGGCAAG 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 (Chothia) DNIGSKL SEQ ID NO: 72 LCDR2 (Chothia) DDS SEQ ID NO: 73 LCDR3 (Chothia) 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 SYELTQPLSVSVALGQTARITCSGDNIGSKLAS WYQQKPGQAPVLVIYDDSNRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCAATAGDRWAY VFGGGTKLTVL SEQ ID NO: 76 DNA VL AGCTATGAGCTGACACAGCCTCTGTCCGTGT CTGTGGCTCTGGGACAGACCGCCAGAATCA CCTGTAGCGGCGACAACATCGGCAGCAAGC TGGCCTCTTGGTATCAGCAGAAGCCTGGACA GGCCCCTGTGCTGGTCATCTACGACGACAG CAATAGACCCAGCGGCATCCCCGAGAGATTC AGCGGCAGCAATAGCGGCAATACCGCCACA CTGACCATCAGCAGAGCACAGGCTGGCGAC GAGGCCGATTACTATTGTGCTGCCACAGCCG GCGACAGATGGGCCTATGI I I I IGGCGGCG GAACAAAGCTGACCGTGCTG SEQ ID NO: 77 Light Chain SYELTQPLSVSVALGQTARITCSGDNIGSKLAS WYQQKPGQAPVLVIYDDSNRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCAATAGDRWAY VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSN N KYAASSYLSLTPEQWKSH RSY SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 78 DNA Light Chain AGCTATGAGCTGACACAGCCTCTGTCCGTGT CTGTGGCTCTGGGACAGACCGCCAGAATCA CCTGTAGCGGCGACAACATCGGCAGCAAGC TGGCCTCTTGGTATCAGCAGAAGCCTGGACA GGCCCCTGTGCTGGTCATCTACGACGACAG CAATAGACCCAGCGGCATCCCCGAGAGATTC AGCGGCAGCAATAGCGGCAATACCGCCACA CTGACCATCAGCAGAGCACAGGCTGGCGAC GAGGCCGATTACTATTGTGCTGCCACAGCCG GCGACAGATGGGCCTATGI I I I IGGCGGCG GAACAAAGCTGACCGTGCTGGGACAGCCTA AGGCCGCTCCCTCCGTGACCCTGTTCCCCC CCAGCTCCGAGGAACTGCAGGCCAACAAGG CCACCCTGGTGTGCCTGATCAGCGACTTCTA CCCTGGCGCCGTGACCGTGGCCTGGAAGGC CGACAGCAGCCCCGTGAAGGCCGGCGTGGA GACAACCACCCCCAGCAAGCAGAGCAACAA CAAGTACGCCGCCAGCAGCTACCTGAGCCT GACCCCCGAGCAGTGGAAGAGCCACAGAAG CTACAGCTGCCAGGTCACCCACGAGGGCAG CACCGTGGAGAAAACCGTGGCCCCCACCGA GTGCAGC 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(Ch othia) 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 QVQLLESGGGLVQPGGSLRLSCAASGFTFSSF GMSWVRQAPGKGLEWVSAISYSGSDTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARDVGVMDYWGQGTLVTVSS SEQ ID NO: 89 DNA VH CAGGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTCAGCAG CTTTGGCATGAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAATGGGTGTCCGCCATC AGCTACAGCGGCAGCGATACCTACTACGCC GACAGCGTGAAGGGCAGATTCACCATCTCCA GAGACAACAGCAAGAACACCCTGTACCTGCA GATGAACAGCCTGAGAGCCGAGGACACCGC CGTGTACTACTGTGCCAGAGATGTGGGCGT GATGGACTATTGGGGCCAGGGCACACTGGT CACCGTTAGCTCT SEQ ID NO: 90 Heavy Chain QVQLLESGGGLVQPGGSLRLSCAASGFTFSSF GMSWVRQAPGKGLEWVSAISYSGSDTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARDVGVMDYWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPCPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVWDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPCDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQG N VFSCSVM H EALH N H YTQKSLSLSPGK SEQ ID NO: 91 DNA Heavy Chain CAGGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTCAGCAG CTTTGGCATGAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAATGGGTGTCCGCCATC AGCTACAGCGGCAGCGATACCTACTACGCC GACAGCGTGAAGGGCAGATTCACCATCTCCA GAGACAACAGCAAGAACACCCTGTACCTGCA GATGAACAGCCTGAGAGCCGAGGACACCGC CGTGTACTACTGTGCCAGAGATGTGGGCGT GATGGACTATTGGGGCCAGGGCACACTGGT CACCGTTAGCTCTGCTAGCACCAAGGGCCCA AGTGTGTTTCCCCTGGCCCCCAGCAGCAAGT CTACTTCCGGCGGAACTGCTGCCCTGGGTT GCCTGGTGAAGGACTACTTCCCCTGTCCCGT GACAGTGTCCTGGAACTCTGGGGCTCTGACT TCCGGCGTGCACACCTTCCCCGCCGTGCTG CAGAGCAGCGGCCTGTACAGCCTGAGCAGC GTGGTGACAGTGCCCTCCAGCTCTCTGGGA ACCCAGACCTATATCTGCAACGTGAACCACA AGCCCAGCAACACCAAGGTGGACAAGAGAG TGGAGCCCAAGAGCTGCGACAAGACCCACA CCTGCCCCCCCTGCCCAGCTCCAGAACTGC TGGGAGGGCCTTCCGTGTTCCTGTTCCCCCC CAAGCCCAAGGACACCCTGATGATCAGCAG GACCCCCGAGGTGACCTGCGTGGTGGTGGA CGTGTCCCACGAGGACCCAGAGGTGAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCA CAACGCCAAGACCAAGCCCAGAGAGGAGCA GTACAACAGCACCTACAGGGTGGTGTCCGT GCTGACCGTGCTGCACCAGGACTGGCTGAA CGGCAAAGAATACAAGTGCAAAGTCTCCAAC AAGGCCCTGCCAGCCCCAATCGAAAAGACAA TCAGCAAGGCCAAGGGCCAGCCACGGGAGC CCCAGGTGTACACCCTGCCCCCCAGCCGGG AGGAGATGACCAAGAACCAGGTGTCCCTGA CCTGTCTGGTGAAGGGCTTCTACCCCTGTGA TATCGCCGTGGAGTGGGAGAGCAACGGCCA GCCCGAGAACAACTACAAGACCACCCCCCC AGTGCTGGACAGCGACGGCAGCTTCTTCCT GTACAGCAAGCTGACCGTGGACAAGTCCAG GTGGCAGCAGGGCAACGTGTTCAGCTGCAG CGTGATGCACGAGGCCCTGCACAACCACTA CACCCAGAAGTCCCTGAGCCTGAGCCCCGG CAAG 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 (Chothia) DNLGTYY SEQ ID NO: 96 LCDR2 (Chothia) SQS SEQ ID NO: 97 LCDR3 (Chothia) 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 SYELTQPLSVSVALGQTARITCSGDNLGTYYAH WYQQKPGQAPVLVIYSQSHRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCGAWDAPSPEL VFGGGTKLTVL SEQ ID NO: 100 DNA VL AGCTATGAGCTGACACAGCCTCTGTCCGTGT CTGTGGCTCTGGGACAGACCGCCAGAATCA CCTGTAGCGGCGATAACCTGGGCACCTACTA CGCCCACTGGTATCAGCAGAAGCCTGGACA GGCTCCCGTGCTGGTCATCTACAGCCAGTCT CACAGACCCAGCGGCATCCCCGAGAGATTC AGCGGCAGCAATAGCGGCAATACCGCCACA CTGACCATCAGCAGAGCACAGGCTGGCGAC GAGGCCGATTACTATTGTGGCGCTTGGGAC GCCCCATCTCCTGAGCTTG I I I I IGGCGGAG GCACCAAGCTGACAGTGCTG SEQ ID NO: 101 Light Chain SYELTQPLSVSVALGQTARITCSGDNLGTYYAH WYQQKPGQAPVLVIYSQSHRPSGIPERFSGSN SGNTATLTISRAQAGDEADYYCGAWDAPSPEL VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSN N KYAASSYLSLTPEQWKSH RSY SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 102 DNA Light Chain AGCTATGAGCTGACACAGCCTCTGTCCGTGT CTGTGGCTCTGGGACAGACCGCCAGAATCA CCTGTAGCGGCGATAACCTGGGCACCTACTA CGCCCACTGGTATCAGCAGAAGCCTGGACA GGCTCCCGTGCTGGTCATCTACAGCCAGTCT CACAGACCCAGCGGCATCCCCGAGAGATTC AGCGGCAGCAATAGCGGCAATACCGCCACA CTGACCATCAGCAGAGCACAGGCTGGCGAC GAGGCCGATTACTATTGTGGCGCTTGGGAC GCCCCATCTCCTGAGCTTG I I I I I GGCGGAG GCACCAAGCTGACAGTGCTGGGACAGCCTA AGGCCGCTCCCTCCGTGACCCTGTTCCCCC CCAGCTCCGAGGAACTGCAGGCCAACAAGG CCACCCTGGTGTGCCTGATCAGCGACTTCTA CCCTGGCGCCGTGACCGTGGCCTGGAAGGC CGACAGCAGCCCCGTGAAGGCCGGCGTGGA GACAACCACCCCCAGCAAGCAGAGCAACAA CAAGTACGCCGCCAGCAGCTACCTGAGCCT GACCCCCGAGCAGTGGAAGAGCCACAGAAG CTACAGCTGCCAGGTCACCCACGAGGGCAG CACCGTGGAGAAAACCGTGGCCCCCACCGA GTGCAGC 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(Ch othia) 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 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARAFRLYWLDVWGQGTLVTVSS SEQ ID NO: 113 DNA VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTATTGTGCCAGAGCCTTCCGGCTGT ACTGGCTGGATGTTTGGGGACAGGGCACCC TGGTCACAGTGTCATCT SEQ ID NO: 114 Heavy Chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARAFRLYWLDVWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPCPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPCDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK SEQ ID NO: 115 DNA Heavy Chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTATTGTGCCAGAGCCTTCCGGCTGT ACTGGCTGGATGTTTGGGGACAGGGCACCC TGGTCACAGTGTCATCTGCTAGCACCAAGGG CCCAAGTGTGTTTCCCCTGGCCCCCAGCAG CAAGTCTACTTCCGGCGGAACTGCTGCCCTG GGTTGCCTGGTGAAGGACTACTTCCCCTGTC CCGTGACAGTGTCCTGGAACTCTGGGGCTCT GACTTCCGGCGTGCACACCTTCCCCGCCGT GCTGCAGAGCAGCGGCCTGTACAGCCTGAG CAGCGTGGTGACAGTGCCCTCCAGCTCTCT GGGAACCCAGACCTATATCTGCAACGTGAAC CACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTGGAGCCCAAGAGCTGCGACAAGACC CACACCTGCCCCCCCTGCCCAGCTCCAGAA CTGCTGGGAGGGCCTTCCGTGTTCCTGTTCC CCCCCAAGCCCAAGGACACCCTGATGATCA GCAGGACCCCCGAGGTGACCTGCGTGGTGG TGGACGTGTCCCACGAGGACCCAGAGGTGA AGTTCAACTGGTACGTGGACGGCGTGGAGG TGCACAACGCCAAGACCAAGCCCAGAGAGG AGCAGTACAACAGCACCTACAGGGTGGTGTC CGTGCTGACCGTGCTGCACCAGGACTGGCT GAACGGCAAAGAATACAAGTGCAAAGTCTCC AACAAGGCCCTGCCAGCCCCAATCGAAAAGA CAATCAGCAAGGCCAAGGGCCAGCCACGGG AGCCCCAGGTGTACACCCTGCCCCCCAGCC GGGAGGAGATGACCAAGAACCAGGTGTCCC TGACCTGTCTGGTGAAGGGCTTCTACCCCTG TGATATCGCCGTGGAGTGGGAGAGCAACGG CCAGCCCGAGAACAACTACAAGACCACCCC CCCAGTGCTGGACAGCGACGGCAGCTTCTT CCTGTACAGCAAGCTGACCGTGGACAAGTCC AGGTGGCAGCAGGGCAACGTGTTCAGCTGC AGCGTGATGCACGAGGCCCTGCACAACCAC TACACCCAGAAGTCCCTGAGCCTGAGCCCC GGCAAG 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 (Chothia) SQSISSY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 118 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVYSAPVTF GQGTKVEIK SEQ ID NO: 120 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGTCTA CAGCGCCCCTGTGACATTTGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 121 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVYSAPVTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 122 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGTCTA CAGCGCCCCTGTGACATTTGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGC TCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGTGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGG AGGCCAAGGTGCAGTGGAAGGTGGACAACG CCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCT ACAGCCTGAGCAGCACCCTGACCCTGAGCA AGGCCGACTACGAGAAGCATAAGGTGTACG CCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCG AGTGC Y010355 E152C_S375C SEQ ID NO: 123 HCDR1 (Combined) GFTFSNYWIS SEQ ID NO: 124 HCDR2 (Combined) RI KSKTYGGTTDYAEPVKG SEQ ID NO: 125 HCDR3 (Combined) TSRRSYAFDY SEQ ID NO: 126 HCDR1 (Kabat) NYWIS SEQ ID NO: 124 HCDR2 (Kabat) RI KSKTYGGTTDYAEPVKG 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(Ch othia) 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 EVQLVESGGGLVKPGGSLRLSCAASGFTFSNY WISWVRQAPGKGLEWVGRIKSKTYGGTTDYA EPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARTSRRSYAFDYWGQGTLVTVSS SEQ ID NO: 133 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA CTACTGGATCAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCTACGGCGGCACCACCGA TTATGCCGAGCCTGTGAAGGGCAGATTCACC ATCAGCCGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAACCA GCAGAAGAAGCTACGCCTTCGACTACTGGG GCCAGGGCACACTGGTTACCGTTAGCTCT SEQ ID NO: 134 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNY WISWVRQAPGKGLEWVGRIKSKTYGGTTDYA EPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARTSRRSYAFDYWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPCDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGN VFSCSVM H EALH N HYTQKSLSL SPGK SEQ ID NO: 135 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA CTACTGGATCAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCTACGGCGGCACCACCGA TTATGCCGAGCCTGTGAAGGGCAGATTCACC ATCAGCCGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAACCA GCAGAAGAAGCTACGCCTTCGACTACTGGG GCCAGGGCACACTGGTTACCGTTAGCTCTGC TAGCACCAAGGGCCCAAGTGTGTTTCCCCTG GCCCCCAGCAGCAAGTCTACTTCCGGCGGA ACTGCTGCCCTGGGTTGCCTGGTGAAGGAC TACTTCCCCTGTCCCGTGACAGTGTCCTGGA ACTCTGGGGCTCTGACTTCCGGCGTGCACA CCTTCCCCGCCGTGCTGCAGAGCAGCGGCC TGTACAGCCTGAGCAGCGTGGTGACAGTGC CCTCCAGCTCTCTGGGAACCCAGACCTATAT CTGCAACGTGAACCACAAGCCCAGCAACACC AAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGC CCAGCTCCAGAACTGCTGGGAGGGCCTTCC GTGTTCCTGTTCCCCCCCAAGCCCAAGGACA CCCTGATGATCAGCAGGACCCCCGAGGTGA CCTGCGTGGTGGTGGACGTGTCCCACGAGG ACCCAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACCAA GCCCAGAGAGGAGCAGTACAACAGCACCTA CAGGGTGGTGTCCGTGCTGACCGTGCTGCA CCAGGACTGGCTGAACGGCAAAGAATACAA GTGCAAAGTCTCCAACAAGGCCCTGCCAGC CCCAATCGAAAAGACAATCAGCAAGGCCAAG GGCCAGCCACGGGAGCCCCAGGTGTACACC CTGCCCCCCAGCCGGGAGGAGATGACCAAG AACCAGGTGTCCCTGACCTGTCTGGTGAAGG GCTTCTACCCCTGTGATATCGCCGTGGAGTG GGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCCAGTGCTGGACAGCGA CGGCAGCTTCTTCCTGTACAGCAAGCTGACC GTGGACAAGTCCAGGTGGCAGCAGGGCAAC GTGTTCAGCTGCAGCGTGATGCACGAGGCC CTGCACAACCACTACACCCAGAAGTCCCTGA GCCTGAGCCCCGGCAAG 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 (Chothia) SQSISSW SEQ ID NO: 140 LCDR2 (Chothia) DAS SEQ ID NO: 141 LCDR3 (Chothia) 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 DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPEDFATYYCQQITRYPVTF GQGTKVEIK SEQ ID NO: 144 DNA VL GACATCCAGATGACACAGAGCCCCAGCACA CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCTCCT CTTGGCTGGCCTGGTATCAGCAGAAGCCTG GCAAGGCCCCTAAGCTGCTGATCTACGATGC CAGCAGCCTGGAAAGCGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGAGTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGATCAC AAGATACCCCGTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 145 Light Chain DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPEDFATYYCQQITRYPVTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 146 DNA Light Chain GACATCCAGATGACACAGAGCCCCAGCACA CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCTCCT CTTGGCTGGCCTGGTATCAGCAGAAGCCTG GCAAGGCCCCTAAGCTGCTGATCTACGATGC CAGCAGCCTGGAAAGCGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGAGTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGATCAC AAGATACCCCGTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGC TCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGTGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGG AGGCCAAGGTGCAGTGGAAGGTGGACAACG CCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCT ACAGCCTGAGCAGCACCCTGACCCTGAGCA AGGCCGACTACGAGAAGCATAAGGTGTACG CCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCG AGTGC Y010356 E152C_S375C SEQ ID NO: 123 HCDR1 (Combined) GFTFSNYWIS SEQ ID NO: 124 HCDR2 (Combined) RI KSKTYGGTTDYAEPVKG SEQ ID NO: 147 HCDR3 (Combined) VSGYYSHSGGFDV SEQ ID NO: 126 HCDR1 (Kabat) NYWIS SEQ ID NO: 124 HCDR2 (Kabat) RI KSKTYGGTTDYAEPVKG 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(Ch othia) 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 EVQLVESGGGLVKPGGSLRLSCAASGFTFSNY WISWVRQAPGKGLEWVGRIKSKTYGGTTDYA EPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARVSGYYSHSGGFDVWGQGTLVTVSS SEQ ID NO: 150 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA CTACTGGATCAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCTACGGCGGCACCACCGA TTATGCCGAGCCTGTGAAGGGCAGATTCACC ATCAGCCGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGTGTC TGGCTACTACTCTCACAGCGGCGGCTTTGAT GTGTGGGGCCAGGGAACACTGGTCACCGTT AGTTCT SEQ ID NO: 151 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNY WISWVRQAPGKGLEWVGRIKSKTYGGTTDYA EPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARVSGYYSHSGGFDVWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPC PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPCDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEQ ID NO: 152 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA CTACTGGATCAGCTGGGTCCGACAGGCCCC TGGCAAAGGACTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCTACGGCGGCACCACCGA TTATGCCGAGCCTGTGAAGGGCAGATTCACC ATCAGCCGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGTGTC TGGCTACTACTCTCACAGCGGCGGCTTTGAT GTGTGGGGCCAGGGAACACTGGTCACCGTT AGTTCTGCTAGCACCAAGGGCCCAAGTGTGT TTCCCCTGGCCCCCAGCAGCAAGTCTACTTC CGGCGGAACTGCTGCCCTGGGTTGCCTGGT GAAGGACTACTTCCCCTGTCCCGTGACAGTG TCCTGGAACTCTGGGGCTCTGACTTCCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGCCTGTACAGCCTGAGCAGCGTGGTG ACAGTGCCCTCCAGCTCTCTGGGAACCCAGA CCTATATCTGCAACGTGAACCACAAGCCCAG CAACACCAAGGTGGACAAGAGAGTGGAGCC CAAGAGCTGCGACAAGACCCACACCTGCCC CCCCTGCCCAGCTCCAGAACTGCTGGGAGG GCCTTCCGTGTTCCTGTTCCCCCCCAAGCCC AAGGACACCCTGATGATCAGCAGGACCCCC GAGGTGACCTGCGTGGTGGTGGACGTGTCC CACGAGGACCCAGAGGTGAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCACAACGCC AAGACCAAGCCCAGAGAGGAGCAGTACAAC AGCACCTACAGGGTGGTGTCCGTGCTGACC GTGCTGCACCAGGACTGGCTGAACGGCAAA GAATACAAGTGCAAAGTCTCCAACAAGGCCC TGCCAGCCCCAATCGAAAAGACAATCAGCAA GGCCAAGGGCCAGCCACGGGAGCCCCAGG TGTACACCCTGCCCCCCAGCCGGGAGGAGA TGACCAAGAACCAGGTGTCCCTGACCTGTCT GGTGAAGGGCTTCTACCCCTGTGATATCGCC GTGGAGTGGGAGAGCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCCCCAGTGCTGG ACAGCGACGGCAGCTTCTTCCTGTACAGCAA GCTGACCGTGGACAAGTCCAGGTGGCAGCA GGGCAACGTGTTCAGCTGCAGCGTGATGCA CGAGGCCCTGCACAACCACTACACCCAGAA GTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) SQGISNY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 157 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQKTWRTPGT FGQGTKVEIK SEQ ID NO: 160 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I ICTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTACTGTCAGAAAACCT GGCGGACCCCTGGCACATTTGGCCAGGGAA CAAAGGTGGAAATCAAG SEQ ID NO: 161 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQKTWRTPGT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFN RGEC SEQ ID NO: 162 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I I CTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTACTGTCAGAAAACCT GGCGGACCCCTGGCACATTTGGCCAGGGAA CAAAGGTGGAAATCAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCCAGCGA CGAGCAGCTGAAGAGTGGCACCGCCAGCGT GGTGTGCCTGCTGAACAACTTCTACCCCCGG GAGGCCAAGGTGCAGTGGAAGGTGGACAAC GCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACC TACAGCCTGAGCAGCACCCTGACCCTGAGC AAGGCCGACTACGAGAAGCATAAGGTGTAC GCCTGCGAGGTGACCCACCAGGGCCTGTCC AGCCCCGTGACCAAGAGCTTCAACAGGGGC GAGTGC 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(Ch othia) 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 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARSRLIAPWLDYWGQGTLVTVSS SEQ ID NO: 166 DNA VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTACTGTGCCAGAAGCAGACTGATCG CCCCTTGGCTGGATTATTGGGGCCAGGGCA CACTGGTCACCGTGTCATCT SEQ ID NO: 167 Heavy Chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARSRLIAPWLDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPCPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPCDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK SEQ ID NO: 168 DNA Heavy Chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTACTGTGCCAGAAGCAGACTGATCG CCCCTTGGCTGGATTATTGGGGCCAGGGCA CACTGGTCACCGTGTCATCTGCTAGCACCAA GGGCCCAAGTGTGTTTCCCCTGGCCCCCAG CAGCAAGTCTACTTCCGGCGGAACTGCTGCC CTGGGTTGCCTGGTGAAGGACTACTTCCCCT GTCCCGTGACAGTGTCCTGGAACTCTGGGG CTCTGACTTCCGGCGTGCACACCTTCCCCGC CGTGCTGCAGAGCAGCGGCCTGTACAGCCT GAGCAGCGTGGTGACAGTGCCCTCCAGCTC TCTGGGAACCCAGACCTATATCTGCAACGTG AACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGCCCAAGAGCTGCGACAAG ACCCACACCTGCCCCCCCTGCCCAGCTCCA GAACTGCTGGGAGGGCCTTCCGTGTTCCTGT TCCCCCCCAAGCCCAAGGACACCCTGATGAT CAGCAGGACCCCCGAGGTGACCTGCGTGGT GGTGGACGTGTCCCACGAGGACCCAGAGGT GAAGTTCAACTGGTACGTGGACGGCGTGGA GGTGCACAACGCCAAGACCAAGCCCAGAGA GGAGCAGTACAACAGCACCTACAGGGTGGT GTCCGTGCTGACCGTGCTGCACCAGGACTG GCTGAACGGCAAAGAATACAAGTGCAAAGTC TCCAACAAGGCCCTGCCAGCCCCAATCGAAA AGACAATCAGCAAGGCCAAGGGCCAGCCAC GGGAGCCCCAGGTGTACACCCTGCCCCCCA GCCGGGAGGAGATGACCAAGAACCAGGTGT CCCTGACCTGTCTGGTGAAGGGCTTCTACCC CTGTGATATCGCCGTGGAGTGGGAGAGCAA CGGCCAGCCCGAGAACAACTACAAGACCAC CCCCCCAGTGCTGGACAGCGACGGCAGCTT CTTCCTGTACAGCAAGCTGACCGTGGACAAG TCCAGGTGGCAGCAGGGCAACGTGTTCAGC TGCAGCGTGATGCACGAGGCCCTGCACAAC CACTACACCCAGAAGTCCCTGAGCCTGAGCC CCGGCAAG 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 (Chothia) SQSISSY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 170 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVYGSPPTF GQGTKVEIK SEQ ID NO: 172 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGTCTA CGGCAGCCCTCCTACATTTGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 173 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVYGSPPTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 174 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGTCTA CGGCAGCCCTCCTACATTTGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGC TCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGTGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGG AGGCCAAGGTGCAGTGGAAGGTGGACAACG CCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCT ACAGCCTGAGCAGCACCCTGACCCTGAGCA AGGCCGACTACGAGAAGCATAAGGTGTACG CCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCG AGTGC 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(Ch othia) 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 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSY WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYYC ARGSSAASGLSGDLWGQGTLVTVSS SEQ ID NO: 185 DNA VH GAAGTTCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAGCCTGGCGAGAGCCTGAAGATC TCCTGCAAAGGCAGCGGCTACAGCTTCACCA GCTACTGGATCGGCTGGGTCCGACAGATGC CTGGCAAAGGCCTTGAGTGGATGGGCATCAT CTACCCCGGCGACAGCGACACCAGATACAG CCCTAGCTTTCAGGGCCAAGTGACCATCAGC GCCGACAAGAGCATCAGCACAGCCTACCTG CAGTGGTCCAGCCTGAAGGCCTCTGACACC GCCATGTACTACTGTGCCAGAGGAAGCTCTG CCGCCTCTGGACTGTCTGGCGATCTTTGGG GACAGGGCACACTGGTCACAGTGTCTAGT SEQ ID NO: 186 Heavy Chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSY WIGWVRQMPGKGLEWMGIIYPGDSDTRYSPS FQGQVTISADKSISTAYLQWSSLKASDTAMYYC ARGSSAASGLSGDLWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPCDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGN VFSCSVM H EALH N H YTQKSLSL SPGK SEQ ID NO: 187 DNA Heavy Chain GAAGTTCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAGCCTGGCGAGAGCCTGAAGATC TCCTGCAAAGGCAGCGGCTACAGCTTCACCA GCTACTGGATCGGCTGGGTCCGACAGATGC CTGGCAAAGGCCTTGAGTGGATGGGCATCAT CTACCCCGGCGACAGCGACACCAGATACAG CCCTAGCTTTCAGGGCCAAGTGACCATCAGC GCCGACAAGAGCATCAGCACAGCCTACCTG CAGTGGTCCAGCCTGAAGGCCTCTGACACC GCCATGTACTACTGTGCCAGAGGAAGCTCTG CCGCCTCTGGACTGTCTGGCGATCTTTGGG GACAGGGCACACTGGTCACAGTGTCTAGTG CTAGCACCAAGGGCCCAAGTGTGTTTCCCCT GGCCCCCAGCAGCAAGTCTACTTCCGGCGG AACTGCTGCCCTGGGTTGCCTGGTGAAGGA CTACTTCCCCTGTCCCGTGACAGTGTCCTGG AACTCTGGGGCTCTGACTTCCGGCGTGCACA CCTTCCCCGCCGTGCTGCAGAGCAGCGGCC TGTACAGCCTGAGCAGCGTGGTGACAGTGC CCTCCAGCTCTCTGGGAACCCAGACCTATAT CTGCAACGTGAACCACAAGCCCAGCAACACC AAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGC CCAGCTCCAGAACTGCTGGGAGGGCCTTCC GTGTTCCTGTTCCCCCCCAAGCCCAAGGACA CCCTGATGATCAGCAGGACCCCCGAGGTGA CCTGCGTGGTGGTGGACGTGTCCCACGAGG ACCCAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACCAA GCCCAGAGAGGAGCAGTACAACAGCACCTA CAGGGTGGTGTCCGTGCTGACCGTGCTGCA CCAGGACTGGCTGAACGGCAAAGAATACAA GTGCAAAGTCTCCAACAAGGCCCTGCCAGC CCCAATCGAAAAGACAATCAGCAAGGCCAAG GGCCAGCCACGGGAGCCCCAGGTGTACACC CTGCCCCCCAGCCGGGAGGAGATGACCAAG AACCAGGTGTCCCTGACCTGTCTGGTGAAGG GCTTCTACCCCTGTGATATCGCCGTGGAGTG GGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCCAGTGCTGGACAGCGA CGGCAGCTTCTTCCTGTACAGCAAGCTGACC GTGGACAAGTCCAGGTGGCAGCAGGGCAAC GTGTTCAGCTGCAGCGTGATGCACGAGGCC CTGCACAACCACTACACCCAGAAGTCCCTGA GCCTGAGCCCCGGCAAG 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 (Chothia) SQSISSY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 189 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQDYYSPFTF GQGTKVEIK SEQ ID NO: 191 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGACTA CTACAGCCCCTTCACCTTTGGCCAGGGCACC AAGGTGGAAATCAAG SEQ ID NO: 192 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQDYYSPFTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 193 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I I CTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAGGACTA CTACAGCCCCTTCACCTTTGGCCAGGGCACC AAGGTGGAAATCAAGCGTACGGTGGCCGCT CCCAGCGTGTTCATCTTCCCCCCCAGCGACG AGCAGCTGAAGAGTGGCACCGCCAGCGTGG TGTGCCTGCTGAACAACTTCTACCCCCGGGA GGCCAAGGTGCAGTGGAAGGTGGACAACGC CCTGCAGAGCGGCAACAGCCAGGAGAGCGT CACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAA GGCCGACTACGAGAAGCATAAGGTGTACGC CTGCGAGGTGACCCACCAGGGCCTGTCCAG CCCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC 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(Ch othia) 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 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARAYKLSWLDLWGQGTLVTVSS SEQ ID NO: 197 DNA VH GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTATTGTGCCAGAGCCTACAAGCTGA GCTGGCTGGATCTTTGGGGCCAGGGCACAC TGGTCACAGTGTCATCT SEQ ID NO: 198 Heavy Chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSY AMSWVRQAPGKGLEWVSAISGSGGSTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARAYKLSWLDLWGQGTLVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPCPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPCDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGN VFSCSVM H EALH N H YTQKSLSLSPG K SEQ ID NO: 199 DNA Heavy Chain GAAGTTCAGCTGCTGGAATCTGGCGGAGGA CTGGTTCAACCTGGCGGCTCTCTGAGACTGT CTTGTGCCGCCAGCGGCTTCACCTTTAGCAG CTACGCCATGAGCTGGGTCCGACAGGCTCC TGGCAAAGGCCTTGAATGGGTGTCCGCCATC TCTGGCTCTGGCGGCAGCACATATTACGCCG ACTCTGTGAAGGGCAGATTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAG ATGAACAGCCTGAGAGCCGAGGACACCGCC GTGTACTATTGTGCCAGAGCCTACAAGCTGA GCTGGCTGGATCTTTGGGGCCAGGGCACAC TGGTCACAGTGTCATCTGCTAGCACCAAGGG CCCAAGTGTGTTTCCCCTGGCCCCCAGCAG CAAGTCTACTTCCGGCGGAACTGCTGCCCTG GGTTGCCTGGTGAAGGACTACTTCCCCTGTC CCGTGACAGTGTCCTGGAACTCTGGGGCTCT GACTTCCGGCGTGCACACCTTCCCCGCCGT GCTGCAGAGCAGCGGCCTGTACAGCCTGAG CAGCGTGGTGACAGTGCCCTCCAGCTCTCT GGGAACCCAGACCTATATCTGCAACGTGAAC CACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTGGAGCCCAAGAGCTGCGACAAGACC CACACCTGCCCCCCCTGCCCAGCTCCAGAA CTGCTGGGAGGGCCTTCCGTGTTCCTGTTCC CCCCCAAGCCCAAGGACACCCTGATGATCA GCAGGACCCCCGAGGTGACCTGCGTGGTGG TGGACGTGTCCCACGAGGACCCAGAGGTGA AGTTCAACTGGTACGTGGACGGCGTGGAGG TGCACAACGCCAAGACCAAGCCCAGAGAGG AGCAGTACAACAGCACCTACAGGGTGGTGTC CGTGCTGACCGTGCTGCACCAGGACTGGCT GAACGGCAAAGAATACAAGTGCAAAGTCTCC AACAAGGCCCTGCCAGCCCCAATCGAAAAGA CAATCAGCAAGGCCAAGGGCCAGCCACGGG AGCCCCAGGTGTACACCCTGCCCCCCAGCC GGGAGGAGATGACCAAGAACCAGGTGTCCC TGACCTGTCTGGTGAAGGGCTTCTACCCCTG TGATATCGCCGTGGAGTGGGAGAGCAACGG CCAGCCCGAGAACAACTACAAGACCACCCC CCCAGTGCTGGACAGCGACGGCAGCTTCTT CCTGTACAGCAAGCTGACCGTGGACAAGTCC AGGTGGCAGCAGGGCAACGTGTTCAGCTGC AGCGTGATGCACGAGGCCCTGCACAACCAC TACACCCAGAAGTCCCTGAGCCTGAGCCCC GGCAAG 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 (Chothia) SQSISSY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 201 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVWYAPVT FGQGTKVEIK SEQ ID NO: 203 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAAGTTTG GTACGCCCCTGTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 204 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQVWYAPVT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFN RGEC SEQ ID NO: 205 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCAGCA GCTACCTGAACTGGTATCAGCAGAAGCCCG GCAAGGCCCCTAAACTGCTGATCTATGCCGC CAGCTCTCTGCAGTCTGGCGTGCCAAGCAG AI I I IC rGGCAGCGGCTCTGGCACCGACTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTACTGCCAGCAAGTTTG GTACGCCCCTGTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGC TCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGTGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGG AGGCCAAGGTGCAGTGGAAGGTGGACAACG CCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCT ACAGCCTGAGCAGCACCCTGACCCTGAGCA AGGCCGACTACGAGAAGCATAAGGTGTACG CCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCG AGTGC 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(Ch othia) TIYPSAPSSSLDY SEQ ID NO: 212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO: 213 HCDR2 (IMGT) IKSKTDAGTT SEQ ID NO: 214 HCDR3 (IMGT) ARTIYPSAPSSSLDY SEQ ID NO: 215 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARTIYPSAPSSSLDYWGQGTLVTVSS SEQ ID NO: 216 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAACAAT CTACCCCAGCGCTCCTAGCAGCAGCCTGGA TTATTGGGGCCAGGGCACACTGGTCACCGT GTCATCT SEQ ID NO: 217 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARTIYPSAPSSSLDYWGQGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPCP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK SEQ ID NO: 218 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAACAAT CTACCCCAGCGCTCCTAGCAGCAGCCTGGA TTATTGGGGCCAGGGCACACTGGTCACCGT GTCATCTGCTAGCACCAAGGGCCCAAGTGTG TTTCCCCTGGCCCCCAGCAGCAAGTCTACTT CCGGCGGAACTGCTGCCCTGGGTTGCCTGG TGAAGGACTACTTCCCCTGTCCCGTGACAGT GTCCTGGAACTCTGGGGCTCTGACTTCCGG CGTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGGT GACAGTGCCCTCCAGCTCTCTGGGAACCCA GACCTATATCTGCAACGTGAACCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTGGAG CCCAAGAGCTGCGACAAGACCCACACCTGC CCCCCCTGCCCAGCTCCAGAACTGCTGGGA GGGCCTTCCGTGTTCCTGTTCCCCCCCAAGC CCAAGGACACCCTGATGATCAGCAGGACCC CCGAGGTGACCTGCGTGGTGGTGGACGTGT CCCACGAGGACCCAGAGGTGAAGTTCAACT GGTACGTGGACGGCGTGGAGGTGCACAACG CCAAGACCAAGCCCAGAGAGGAGCAGTACA ACAGCACCTACAGGGTGGTGTCCGTGCTGA CCGTGCTGCACCAGGACTGGCTGAACGGCA AAGAATACAAGTGCAAAGTCTCCAACAAGGC CCTGCCAGCCCCAATCGAAAAGACAATCAGC AAGGCCAAGGGCCAGCCACGGGAGCCCCAG GTGTACACCCTGCCCCCCAGCCGGGAGGAG ATGACCAAGAACCAGGTGTCCCTGACCTGTC TGGTGAAGGGCTTCTACCCCTGTGATATCGC CGTGGAGTGGGAGAGCAACGGCCAGCCCGA GAACAACTACAAGACCACCCCCCCAGTGCTG GACAGCGACGGCAGCTTCTTCCTGTACAGCA AGCTGACCGTGGACAAGTCCAGGTGGCAGC AGGGCAACGTGTTCAGCTGCAGCGTGATGC ACGAGGCCCTGCACAACCACTACACCCAGAA GTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) SQGISNY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 220 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQQLIFFPLTFG QGTKVEIK SEQ ID NO: 222 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I ICTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTATTGCCAGCAGCTGA TCTTCTTCCCTCTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAG SEQ ID NO: 223 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQQLIFFPLTFG QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC SEQ ID NO: 224 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I I CTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTATTGCCAGCAGCTGA TCTTCTTCCCTCTGACCTTTGGCCAGGGCAC CAAGGTGGAAATCAAGCGTACGGTGGCCGC TCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGTGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGG AGGCCAAGGTGCAGTGGAAGGTGGACAACG CCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAGCAGGACAGCAAGGACTCCACCT ACAGCCTGAGCAGCACCCTGACCCTGAGCA AGGCCGACTACGAGAAGCATAAGGTGTACG CCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCG AGTGC 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(Ch othia) ASHRLHSLFDV SEQ ID NO: 212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO: 213 HCDR2 (IMGT) IKSKTDAGTT SEQ ID NO: 226 HCDR3 (IMGT) ARASHRLHSLFDV SEQ ID NO: 227 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARASHRLHSLFDVWGQGTLVTVSS SEQ ID NO: 228 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGTGCCAGAGCCTC TCACAGACTGCACAGCCTGTTTGACGTGTGG GGCCAGGGAACACTGGTCACCGTTAGTTCT SEQ ID NO: 229 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARASHRLHSLFDVWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPCPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPCDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGN VFSCSVM H EALH N H YTQKSLSL SPGK SEQ ID NO: 230 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGTGCCAGAGCCTC TCACAGACTGCACAGCCTGTTTGACGTGTGG GGCCAGGGAACACTGGTCACCGTTAGTTCTG CTAGCACCAAGGGCCCAAGTGTGTTTCCCCT GGCCCCCAGCAGCAAGTCTACTTCCGGCGG AACTGCTGCCCTGGGTTGCCTGGTGAAGGA CTACTTCCCCTGTCCCGTGACAGTGTCCTGG AACTCTGGGGCTCTGACTTCCGGCGTGCACA CCTTCCCCGCCGTGCTGCAGAGCAGCGGCC TGTACAGCCTGAGCAGCGTGGTGACAGTGC CCTCCAGCTCTCTGGGAACCCAGACCTATAT CTGCAACGTGAACCACAAGCCCAGCAACACC AAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGC CCAGCTCCAGAACTGCTGGGAGGGCCTTCC GTGTTCCTGTTCCCCCCCAAGCCCAAGGACA CCCTGATGATCAGCAGGACCCCCGAGGTGA CCTGCGTGGTGGTGGACGTGTCCCACGAGG ACCCAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACCAA GCCCAGAGAGGAGCAGTACAACAGCACCTA CAGGGTGGTGTCCGTGCTGACCGTGCTGCA CCAGGACTGGCTGAACGGCAAAGAATACAA GTGCAAAGTCTCCAACAAGGCCCTGCCAGC CCCAATCGAAAAGACAATCAGCAAGGCCAAG GGCCAGCCACGGGAGCCCCAGGTGTACACC CTGCCCCCCAGCCGGGAGGAGATGACCAAG AACCAGGTGTCCCTGACCTGTCTGGTGAAGG GCTTCTACCCCTGTGATATCGCCGTGGAGTG GGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCCAGTGCTGGACAGCGA CGGCAGCTTCTTCCTGTACAGCAAGCTGACC GTGGACAAGTCCAGGTGGCAGCAGGGCAAC GTGTTCAGCTGCAGCGTGATGCACGAGGCC CTGCACAACCACTACACCCAGAAGTCCCTGA GCCTGAGCCCCGGCAAG 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 (Chothia) SQSISSW SEQ ID NO: 140 LCDR2 (Chothia) DAS SEQ ID NO: 232 LCDR3 (Chothia) 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 DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPEDFATYYCQQGLFYPHTF GQGTKVEIK SEQ ID NO: 234 DNA VL GACATCCAGATGACACAGAGCCCCAGCACA CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCTCCT CTTGGCTGGCCTGGTATCAGCAGAAGCCTG GCAAGGCCCCTAAGCTGCTGATCTACGATGC CAGCAGCCTGGAAAGCGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGAGTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTATTGTCAGCAGGGCCT GTTCTACCCTCACACCTTTGGCCAGGGCACC AAGGTGGAAATCAAG SEQ ID NO: 235 Light Chain DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPEDFATYYCQQGLFYPHTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 236 DNA Light Chain GACATCCAGATGACACAGAGCCCCAGCACA CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGAGCATCTCCT CTTGGCTGGCCTGGTATCAGCAGAAGCCTG GCAAGGCCCCTAAGCTGCTGATCTACGATGC CAGCAGCCTGGAAAGCGGCGTGCCAAGCAG AI I I ICTGGCAGCGGCTCTGGCACCGAGTTC ACCCTGACCATATCTAGCCTGCAGCCAGAGG ACTTCGCCACCTACTATTGTCAGCAGGGCCT GTTCTACCCTCACACCTTTGGCCAGGGCACC AAGGTGGAAATCAAGCGTACGGTGGCCGCT CCCAGCGTGTTCATCTTCCCCCCCAGCGACG AGCAGCTGAAGAGTGGCACCGCCAGCGTGG TGTGCCTGCTGAACAACTTCTACCCCCGGGA GGCCAAGGTGCAGTGGAAGGTGGACAACGC CCTGCAGAGCGGCAACAGCCAGGAGAGCGT CACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAA GGCCGACTACGAGAAGCATAAGGTGTACGC CTGCGAGGTGACCCACCAGGGCCTGTCCAG CCCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC 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(Ch othia) DEYPWGWFDV SEQ ID NO: 212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO: 213 HCDR2 (IMGT) IKSKTDAGTT SEQ ID NO: 238 HCDR3 (IMGT) ARDEYPWGWFDV SEQ ID NO: 239 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARDEYPWGWFDVWGQGTLVTVSS SEQ ID NO: 240 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGATGA GTACCCCTGGGGATGGTTCGATGTGTGGGG ACAGGGAACCCTGGTCACCGTTAGTTCT SEQ ID NO: 241 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARDEYPWGWFDVWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPCPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPCDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGN VFSCSVM H EALH N H YTQKSLSL SPGK SEQ ID NO: 242 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGATGA GTACCCCTGGGGATGGTTCGATGTGTGGGG ACAGGGAACCCTGGTCACCGTTAGTTCTGCT AGCACCAAGGGCCCAAGTGTGTTTCCCCTG GCCCCCAGCAGCAAGTCTACTTCCGGCGGA ACTGCTGCCCTGGGTTGCCTGGTGAAGGAC TACTTCCCCTGTCCCGTGACAGTGTCCTGGA ACTCTGGGGCTCTGACTTCCGGCGTGCACA CCTTCCCCGCCGTGCTGCAGAGCAGCGGCC TGTACAGCCTGAGCAGCGTGGTGACAGTGC CCTCCAGCTCTCTGGGAACCCAGACCTATAT CTGCAACGTGAACCACAAGCCCAGCAACACC AAGGTGGACAAGAGAGTGGAGCCCAAGAGC TGCGACAAGACCCACACCTGCCCCCCCTGC CCAGCTCCAGAACTGCTGGGAGGGCCTTCC GTGTTCCTGTTCCCCCCCAAGCCCAAGGACA CCCTGATGATCAGCAGGACCCCCGAGGTGA CCTGCGTGGTGGTGGACGTGTCCCACGAGG ACCCAGAGGTGAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCACAACGCCAAGACCAA GCCCAGAGAGGAGCAGTACAACAGCACCTA CAGGGTGGTGTCCGTGCTGACCGTGCTGCA CCAGGACTGGCTGAACGGCAAAGAATACAA GTGCAAAGTCTCCAACAAGGCCCTGCCAGC CCCAATCGAAAAGACAATCAGCAAGGCCAAG GGCCAGCCACGGGAGCCCCAGGTGTACACC CTGCCCCCCAGCCGGGAGGAGATGACCAAG AACCAGGTGTCCCTGACCTGTCTGGTGAAGG GCTTCTACCCCTGTGATATCGCCGTGGAGTG GGAGAGCAACGGCCAGCCCGAGAACAACTA CAAGACCACCCCCCCAGTGCTGGACAGCGA CGGCAGCTTCTTCCTGTACAGCAAGCTGACC GTGGACAAGTCCAGGTGGCAGCAGGGCAAC GTGTTCAGCTGCAGCGTGATGCACGAGGCC CTGCACAACCACTACACCCAGAAGTCCCTGA GCCTGAGCCCCGGCAAG 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 (Chothia) SQGISSW SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 246 LCDR3 (Chothia) 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 DI QMTQSPSSVSASVG DRVTITC RASQGISSWL AWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYIFYPLTF GQGTKVEIK SEQ ID NO: 249 DNA VL GACATCCAGATGACACAGAGCCCTAGCTCCG TGTCTGCCAGCGTGGGAGACAGAGTGACCA TCACCTGTAGAGCCAGCCAGGGCATCTCTTC TTGGCTGGCCTGGTATCAGCAGAAGCCTGG CAAGGCCCCTAAGCTGCTGATCTATGCCGCT TCCAGTCTGCAGAGCGGCGTGCCAAGCAGA Illi CTGGCAGCGGCTCTGGCACCGACTTCA CCCTGACCATATCTAGCCTGCAGCCAGAGGA CTTCGCCACCTACTACTGCCAGCAGTACATC TTCTACCCTCTGACCTTCGGCCAGGGCACCA AGGTGGAAATCAAG SEQ ID NO: 250 Light Chain DIQMTQSPSSVSASVGDRVTITCRASQGISSWL AWYQQKPGKAPKLLIYAASSLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYIFYPLTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 251 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCTCCG TGTCTGCCAGCGTGGGAGACAGAGTGACCA TCACCTGTAGAGCCAGCCAGGGCATCTCTTC TTGGCTGGCCTGGTATCAGCAGAAGCCTGG CAAGGCCCCTAAGCTGCTGATCTATGCCGCT TCCAGTCTGCAGAGCGGCGTGCCAAGCAGA Illi CTGGCAGCGGCTCTGGCACCGACTTCA CCCTGACCATATCTAGCCTGCAGCCAGAGGA CTTCGCCACCTACTACTGCCAGCAGTACATC TTCTACCCTCTGACCTTCGGCCAGGGCACCA AGGTGGAAATCAAGCGTACGGTGGCCGCTC CCAGCGTGTTCATCTTCCCCCCCAGCGACGA GCAGCTGAAGAGTGGCACCGCCAGCGTGGT GTGCCTGCTGAACAACTTCTACCCCCGGGAG GCCAAGGTGCAGTGGAAGGTGGACAACGCC CTGCAGAGCGGCAACAGCCAGGAGAGCGTC ACCGAGCAGGACAGCAAGGACTCCACCTAC AGCCTGAGCAGCACCCTGACCCTGAGCAAG GCCGACTACGAGAAGCATAAGGTGTACGCCT GCGAGGTGACCCACCAGGGCCTGTCCAGCC CCGTGACCAAGAGCTTCAACAGGGGCGAGT GC 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(Ch othia) VASPSAPGGFDY SEQ ID NO: 212 HCDR1 (IMGT) GFTFSNAW SEQ ID NO: 213 HCDR2 (IMGT) IKSKTDAGTT SEQ ID NO: 253 HCDR3 (IMGT) ARVASPSAPGGFDY SEQ ID NO: 254 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARVASPSAPGGFDYWGQGTLVTVSS SEQ ID NO: 255 DNA VH GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGTGG CTTCTCCTTCTGCTCCCGGCGGATTCGATTA TTGGGGCCAGGGAACACTGGTCACCGTGTC TAGT SEQ ID NO: 256 Heavy Chain EVQLVESGGGLVKPGGSLRLSCAASGFTFSNA WMSWVRQAPGKGLEWVGRIKSKTDAGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVY YCARVASPSAPGGFDYWGQGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPCP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPCDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK SEQ ID NO: 257 DNA Heavy Chain GAAGTGCAGCTGGTGGAATCTGGCGGCGGA CTTGTGAAACCTGGCGGCTCTCTGAGACTGA GCTGTGCCGCTTCCGGCTTCACCTTCAGCAA TGCCTGGATGAGCTGGGTCCGACAGGCCCC TGGAAAAGGCCTTGAGTGGGTCGGACGGAT CAAGAGCAAGACCGATGCCGGCACCACCGA TTATGCTGCCCCTGTGAAGGGCAGATTCACC ATCAGCAGGGACGACAGCAAGAACACCCTG TACCTGCAGATGAACAGCCTGAAAACCGAGG ACACCGCCGTGTACTACTGCGCCAGAGTGG CTTCTCCTTCTGCTCCCGGCGGATTCGATTA TTGGGGCCAGGGAACACTGGTCACCGTGTC TAGTGCTAGCACCAAGGGCCCAAGTGTGTTT CCCCTGGCCCCCAGCAGCAAGTCTACTTCC GGCGGAACTGCTGCCCTGGGTTGCCTGGTG AAGGACTACTTCCCCTGTCCCGTGACAGTGT CCTGGAACTCTGGGGCTCTGACTTCCGGCG TGCACACCTTCCCCGCCGTGCTGCAGAGCA GCGGCCTGTACAGCCTGAGCAGCGTGGTGA CAGTGCCCTCCAGCTCTCTGGGAACCCAGA CCTATATCTGCAACGTGAACCACAAGCCCAG CAACACCAAGGTGGACAAGAGAGTGGAGCC CAAGAGCTGCGACAAGACCCACACCTGCCC CCCCTGCCCAGCTCCAGAACTGCTGGGAGG GCCTTCCGTGTTCCTGTTCCCCCCCAAGCCC AAGGACACCCTGATGATCAGCAGGACCCCC GAGGTGACCTGCGTGGTGGTGGACGTGTCC CACGAGGACCCAGAGGTGAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCACAACGCC AAGACCAAGCCCAGAGAGGAGCAGTACAAC AGCACCTACAGGGTGGTGTCCGTGCTGACC GTGCTGCACCAGGACTGGCTGAACGGCAAA GAATACAAGTGCAAAGTCTCCAACAAGGCCC TGCCAGCCCCAATCGAAAAGACAATCAGCAA GGCCAAGGGCCAGCCACGGGAGCCCCAGG TGTACACCCTGCCCCCCAGCCGGGAGGAGA TGACCAAGAACCAGGTGTCCCTGACCTGTCT GGTGAAGGGCTTCTACCCCTGTGATATCGCC GTGGAGTGGGAGAGCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCCCCAGTGCTGG ACAGCGACGGCAGCTTCTTCCTGTACAGCAA GCTGACCGTGGACAAGTCCAGGTGGCAGCA GGGCAACGTGTTCAGCTGCAGCGTGATGCA CGAGGCCCTGCACAACCACTACACCCAGAA GTCCCTGAGCCTGAGCCCCGGCAAG 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 (Chothia) SQGISNY SEQ ID NO: 50 LCDR2 (Chothia) AAS SEQ ID NO: 259 LCDR3 (Chothia) 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 DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQQSLFAPFTF GQGTKVEIK SEQ ID NO: 261 DNA VL GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I ICTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTACTGTCAGCAGAGC CTGTTCGCCCCTTTCACCTTTGGCCAGGGCA CCAAGGTGGAAATCAAG SEQ ID NO: 262 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISNYL AWYQQKPGKVPKLLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDVATYYCQQSLFAPFTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO: 263 DNA Light Chain GACATCCAGATGACACAGAGCCCTAGCAGC CTGTCTGCCAGCGTGGGAGACAGAGTGACC ATCACCTGTAGAGCCAGCCAGGGCATCAGC AACTACCTGGCCTGGTATCAGCAGAAACCCG GCAAGGTGCCCAAGCTGCTGATCTACGCTG CCAGCACACTGCAGAGCGGAGTGCCTAGCA GA I I I I CTGGCAGCGGCTCCGGCACCGATTT CACCCTGACCATATCTAGCCTGCAGCCAGAG GACGTGGCCACCTACTACTGTCAGCAGAGC CTGTTCGCCCCTTTCACCTTTGGCCAGGGCA CCAAGGTGGAAATCAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCCAGCGA CGAGCAGCTGAAGAGTGGCACCGCCAGCGT GGTGTGCCTGCTGAACAACTTCTACCCCCGG GAGGCCAAGGTGCAGTGGAAGGTGGACAAC GCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACC TACAGCCTGAGCAGCACCCTGACCCTGAGC AAGGCCGACTACGAGAAGCATAAGGTGTAC GCCTGCGAGGTGACCCACCAGGGCCTGTCC AGCCCCGTGACCAAGAGCTTCAACAGGGGC GAGTGC

[00278] Other antibodies of the invention include those where the amino acids or nucleic acids encoding the amino acids have been mutated, yet have 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 when compared with the variable regions depicted 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 to PMEL17, the VH, VL, full length light chain, and full length heavy chain sequences (amino acid sequences and the nucleotide sequences encoding the amino acid sequences) can be “mixed and matched” to create other PMEL17-binding antibodies of the invention. Such “mixed and matched” PMEL17-binding antibodies can be tested using the binding assays known in the art (e.g., ELISAs, and other assays described in the Example section). When these chains are mixed and matched, a VH sequence from a particular VH / VL pairing should be replaced with a structurally similar VH sequence. Likewise a full length heavy chain sequence from a particular full length heavy chain I full length light chain pairing should be replaced with a structurally similar full length heavy chain sequence. Likewise, a VL sequence from a particular VH / VL pairing should be replaced with a structurally similar VL sequence. Likewise a full length light chain sequence from a particular full length heavy chain I full length light chain pairing should be replaced with a structurally similar full length light chain sequence. Accordingly, in one aspect, the 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 invention provides (i) an isolated monoclonal antibody having: a full length heavy chain comprising an amino acid sequence that has been optimized for expression in the 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 that has been optimized for expression in the cell of a mammalian 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 CDR1s, CDR2s and CDR3s as described in Table 2, or combinations thereof. The amino acid sequences of the VH CDR1s of the antibodies are shown, for example, in 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 CDR2s of the antibodies and are shown, for example, in 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 CDR3s of the antibodies are shown, for example, in 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 CDR1s of the antibodies are shown, for example, in 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 VL CDR2s of the antibodies are shown, for example, in SEQ ID Nos: 15, 18, 47, 50, 69, 72, 93, 96, 137, 140, and 154. The amino acid sequences of the VL CDR3s of the antibodies are shown, for example, in 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 to PMEL17 and that antigen-binding specificity is provided primarily by the CDR1,2 and 3 regions, the VH CDR1, CDR2 and CDR3 sequences and VL CDR1, CDR2 and CDR3 sequences can be “mixed and matched” ( / .e., CDRs from different antibodies can be mixed and matched. Such “mixed and matched” PMEL17-binding antibodies can be tested using the binding assays known in the art and those described in the Examples (e.g., ELISAs). When VH CDR sequences are mixed and matched, the CDR1, CDR2 and / or CDR3 sequence from a particular VH sequence should be replaced with a 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 a structurally similar CDR sequence(s). It will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences can be created by substituting one or more VH and / or VL CDR region sequences with structurally similar sequences from the CDR sequences shown herein for 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 ofSEQ 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 ofSEQ 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 ofSEQ 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain CDR1 ofSEQ 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:70 or 73.

[00287] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain CDR1 of SEQ ID NO:79, 82, 83 or 85, a heavy chain CDR2 of SEQ ID NQ: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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, a heavy chain CDR2 of SEQ IDNQ:104, 108or110;a heavy chain CDR3 of SEQ ID NQ:105 or 111; a light chain CDR1 of SEQ ID NO:49, 52 or 116; a light chain CDR2 ofSEQ ID NO:47 or 50; and a light chain CDR3 ofSEQ ID NO:117or118.

[00289] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:50 or 154; and a light chain CDR3 of SEQ ID NO:155 or 157.

[00291] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, a heavy chain CDR2 of SEQ IDNQ:104, 108or110;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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:200 or 201.

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

[00295] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, 209, 210 or 212, an HCDR2 of SEQ ID NO: 207, 211 or 213, and an HCDR3 of SEQ ID NO:237 or 238; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, 245 or 247, an LCDR2 of SEQ ID NO:47 or 50, and an LCDR3 of SEQ ID NO:244 or 246.

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

[00298] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:1, , a heavy chain CDR2 of SEQ ID NO:2, a heavy chain CDR3 of SEQ ID NO:3, 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 CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO:2, a heavy chain CDR3 of SEQ ID NO:3, 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 CDR1 of SEQ ID NO:5, a heavy chain CDR2 of SEQ ID NO:6, a heavy chain CDR3 of SEQ ID NO:3, 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; or d) 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, a light chain CDR1 of SEQ ID NQ:20, a light chain CDR2 of SEQ ID NO:18, and a light chain CDR3 of SEQ ID NO:16.

[00299] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:33, a heavy chain CDR2 of SEQ ID NO:34, a heavy chain CDR3 of SEQ ID NO:35, 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; b) a heavy chain CDR1 of SEQ ID NO:36, a heavy chain CDR2 of SEQ ID NO:34, a heavy chain CDR3 of SEQ ID NO:35, 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; c) a heavy chain CDR1 of SEQ ID NO:37, a heavy chain CDR2 of SEQ ID NO:38, a heavy chain CDR3 of SEQ ID NO:35, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:51; or d) a heavy chain CDR1 of SEQ ID NO: 39, a heavy chain CDR2 of SEQ ID NQ:40, a heavy chain CDR3 of SEQ ID NO:41, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:48.

[00300] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:57, a heavy chain CDR2 of SEQ ID NO:58, a heavy chain CDR3 of SEQ ID NO:59, 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 NQ:70; b) a heavy chain CDR1 of SEQ ID NQ:60, a heavy chain CDR2 of SEQ ID NO:58, a heavy chain CDR3 of SEQ ID NO:59, 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 NQ:70; c) a heavy chain CDR1 of SEQ ID NO:5, a heavy chain CDR2 of SEQ ID NO:61, a heavy chain CDR3 of SEQ ID NO:59, 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; or d) a heavy chain CDR1 of SEQ ID NO:7, a heavy chain CDR2 of SEQ ID NO:62, a heavy chain CDR3 of SEQ ID NO:63, 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 NQ:70.

[00301] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:79, , a heavy chain CDR2 of SEQ ID NQ:80, a heavy chain CDR3 of SEQ ID NO:81, 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; b) a heavy chain CDR1 of SEQ ID NO:82, a heavy chain CDR2 of SEQ ID NQ:80, a heavy chain CDR3 of SEQ ID NO:81, 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; c) a heavy chain CDR1 of SEQ ID NO:83, a heavy chain CDR2 of SEQ ID NO:84, a heavy chain CDR3 of SEQ ID NO:81, 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; or d) a heavy chain CDR1 of SEQ ID NO: 85, a heavy chain CDR2 of SEQ ID NO:86, a heavy chain CDR3 of SEQ ID NO:87, 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.

[00302] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:103, a heavy chain CDR2 of SEQ ID NO:104, a heavy chain CDR3 of SEQ ID NO:105, 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; b) a heavy chain CDR1 of SEQ ID NQ:106, a heavy chain CDR2 of SEQ ID NQ:104, a heavy chain CDR3 of SEQ ID NQ:105, 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; c) a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, a heavy chain CDR3 of SEQ ID NQ:105, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:118; or d) a heavy chain CDR1 of SEQ ID NQ:109, a heavy chain CDR2 of SEQ ID NQ:110, a heavy chain CDR3 of SEQ ID NO:111, a light chain CDR1 of SEQ ID NO:52 a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:117.

[00303] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:123, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:125, 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; b) a heavy chain CDR1 of SEQ ID NO:126, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:125, 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; c) a heavy chain CDR1 of SEQ ID NO:127, a heavy chain CDR2 of SEQ ID NO:128, a heavy chain CDR3 of SEQ ID NO:125, a light chain CDR1 of SEQ ID NO:139, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO: 141; or d) a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NO: 130, a heavy chain CDR3 of SEQ ID NO:131, a light chain CDR1 of SEQ ID NO:142, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO:138.

[00304] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO:123, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:147, 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; b) a heavy chain CDR1 of SEQ ID NO:126, a heavy chain CDR2 of SEQ ID NO:124, a heavy chain CDR3 of SEQ ID NO:147, 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; c) a heavy chain CDR1 of SEQ ID NO:127, a heavy chain CDR2 of SEQ ID NO:128, a heavy chain CDR3 of SEQ ID NO:147, a light chain CDR1 of SEQ ID NO:156, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:157; or d) a heavy chain CDR1 of SEQ ID NO: 129, a heavy chain CDR2 of SEQ ID NO: 130, a heavy chain CDR3 of SEQ ID NO:148, a light chain CDR1 of SEQ ID NO:158, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:155.

[00305] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NQ:103, a heavy chain CDR2 of SEQ ID NQ:104, a heavy chain CDR3 of SEQ ID NO:163, 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; b) a heavy chain CDR1 of SEQ ID NQ:106, a heavy chain CDR2 of SEQ ID NQ:104, a heavy chain CDR3 of SEQ ID NO:163, 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; c) a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, a heavy chain CDR3 of SEQ ID NO:163, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NQ:170; or d) a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO:110, a heavy chain CDR3 of SEQ ID NO:164, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:169.

[00306] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selection from: a) a heavy chain CDR1 of SEQ ID NO:175, a heavy chain CDR2 of SEQ ID NO:176, a heavy chain CDR3 of SEQ ID NO:177, 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; b) a heavy chain CDR1 of SEQ ID NO:178, a heavy chain CDR2 of SEQ ID NO:176, a heavy chain CDR3 of SEQ ID NO:177, 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; c) a heavy chain CDR1 of SEQ ID NO: 179, a heavy chain CDR2 of SEQ ID NO: 180, a heavy chain CDR3 of SEQ ID NO:177, a light chain CDR1 of SEQ ID NO:49, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:189; or d) a heavy chain CDR1 of SEQ ID NO: 181, a heavy chain CDR2 of SEQ ID NO: 182; a heavy chain CDR3 of SEQ ID NO:183, a light chain CDR1 of SEQ ID NO:52, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:188.

[00307] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO: 103, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NO:194, 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 NQ:200; b) a heavy chain CDR1 of SEQ ID NO: 106, a heavy chain CDR2 of SEQ ID NO: 104, a heavy chain CDR3 of SEQ ID NO:194, 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 NQ:200; c) a heavy chain CDR1 of SEQ ID NO: 107, a heavy chain CDR2 of SEQ ID NO: 108, a heavy chain CDR3 of SEQ ID NO:194, 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; or d) a heavy chain CDR1 of SEQ ID NO: 109, a heavy chain CDR2 of SEQ ID NO: 110, a heavy chain CDR3 of SEQ ID NO:195, 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 NQ:200.

[00308] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NQ:206, a heavy chain CDR2 of SEQ ID NQ:207, a heavy chain CDR3 of SEQ ID NQ:208, 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; b) a heavy chain CDR1 of SEQ ID NQ:209, a heavy chain CDR2 of SEQ ID NQ:207, a heavy chain CDR3 of SEQ ID NQ:208, 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; c) a heavy chain CDR1 of SEQ ID NQ:210, a heavy chain CDR2 of SEQ ID NO:211, a heavy chain CDR3 of SEQ ID NQ:208, a light chain CDR1 of SEQ ID NO:156, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NQ:220; or d) a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO:213, a heavy chain CDR3 of SEQ ID NO:214, a light chain CDR1 of SEQ ID NO:158, a light chain CDR2 of SEQ ID NQ:50, and a light chain CDR3 of SEQ ID NO:219.

[00309] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain CDR1 of SEQ ID NO: 206, a heavy chain CDR2 of SEQ ID NO: 207, a heavy chain CDR3 of SEQ ID NO:225, 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; b) a heavy chain CDR1 of SEQ ID NO: 209, a heavy chain CDR2 of SEQ ID NO: 207, a heavy chain CDR3 of SEQ ID NO:225, 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; c) a heavy chain CDR1 of SEQ ID NO: 210, a heavy chain CDR2 of SEQ ID NO: 211, a heavy chain CDR3 of SEQ ID NO:225, a light chain CDR1 of SEQ ID NO:139, a light chain CDR2 of SEQ ID NQ:140, and a light chain CDR3 of SEQ ID NO: 232; or d) a heavy chain CDR1 of SEQ ID NO: 212, a heavy chain CDR2 of SEQ ID NO: 213, a heavy chain CDR3 of SEQ ID NO: 226, 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.

[00310] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:237, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, an LCDR2 of SEQ ID NO:47, and an LCDR3 of SEQ ID NO:244; b) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 209, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:237, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:243, an LCDR2 of SEQ ID NO:47, and an LCDR3 of SEQ ID NO:244; c) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 210, an HCDR2 of SEQ ID NO: 211, and an HCDR3 of SEQ ID NO:237, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:245, an LCDR2 of SEQ ID NQ:50, and an LCDR3 of SEQ ID NO:246; or d) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 212, an HCDR2 of SEQ ID NO: 213, and an HCDR3 of SEQ ID NO:238; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:247, an LCDR2 of SEQ ID NO: 50, and an LCDR3 of SEQ ID NO:244.

[00311] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises CDR sequences selected from: a) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 206, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:252, and a light chain variable region that comprises an LCDR1 ofSEQ ID NO:153, an LCDR2 ofSEQ ID NO: 154, and an LCDR3 of SEQ ID NO:258; b) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 209, an HCDR2 of SEQ ID NO: 207, and an HCDR3 of SEQ ID NO:252, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:153, an LCDR2 of SEQ ID NO:154, and an LCDR3 of SEQ ID NO:258; c) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 210, an HCDR2 of SEQ ID NO: 211, and an HCDR3 of SEQ ID NO:252, and a light chain variable region that comprises an LCDR1 of SEQ ID NO:156, an LCDR2 of SEQ ID NQ:50, and an LCDR3 of SEQ ID NO:259; or d) a heavy chain variable region that comprises an HCDR1 of SEQ ID NO: 212, an HCDR2 of SEQ ID NO: 213, and an HCDR3 of SEQ ID NO: 253; and a light chain variable region that comprises an LCDR1 of SEQ ID NO:158, an LCDR2 of SEQ ID NQ:50, and an LCDR3 of SEQ ID NO:258.

[00312] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:202.

[00324] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:260.

[00328] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to 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.

[00329] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to 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:27.

[00330] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to 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:31.

[00331] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises a heavy chain comprising the amino acid sequence of SEQ ID NQ:90, and a light chain comprising the amino acid sequence of SEQ ID NO:101.

[00334] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically binds to PMEL17 comprises 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 NQ:204.

[00340] In a specific embodiment, an antibody or antibody fragment (e.g., antigen binding fragments) that specifically b...

Claims

1. An antibody or antigen binding fragment thereof that binds to human PMEL17 protein comprising:a. a heavy chain variable region that comprises a heavy chain complementarity determining region 1 (CDR1) of SEQ ID NO:1, a heavy chain complementarity determining region 2 (CDR2) of SEQ ID NO:2, and a heavy chain complementarity determining region 3 (CDR3) of SEQ ID NO:3; and a light chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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;2019409132   13 Jul 2026e. a heavy chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises a heavy chain CDR1 of SEQ ID NO:60, a heavy chain CDR2 of SEQ ID NO:58, and a heavy chain2019409132   13 Jul 2026CDR3 of SEQ ID NO:59; and a light chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises a2019409132   13 Jul 2026light 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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;2019409132   13 Jul 2026u. a heavy chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises a heavy chain CDR1 of SEQ ID NO:126, a heavy chain CDR2 of SEQ ID NO:124, and a heavy chain2019409132   13 Jul 2026CDR3 of SEQ ID NO:147; and a light chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises2019409132   13 Jul 2026a 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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;2019409132   13 Jul 2026kk. a heavy chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises a heavy chain CDR1 of SEQ ID NO:209, a heavy chain CDR2 of SEQ ID NO:207, and a heavy chain2019409132   13 Jul 2026CDR3 of SEQ ID NO:208; and a light chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises2019409132   13 Jul 2026a 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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;2019409132   13 Jul 2026aaa. a heavy chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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; orddd. a heavy chain variable region that comprises 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 that comprises 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;2019409132   13 Jul 2026b. 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;2019409132   13 Jul 2026j. 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; orp. 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;2019409132   13 Jul 2026b. 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;2019409132   13 Jul 2026n. 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; orp. 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. An antibody or antigen binding fragment thereof that binds to human PMEL17 protein comprising:a. a heavy chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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; ord. a heavy chain variable region that comprises a heavy chain CDR1 of SEQ ID NO:7, a heavy chain CDR2 of SEQ ID NO:8, and a heavy chain CDR32019409132   13 Jul 2026of SEQ ID NO:9; and a light chain variable region that comprises 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.

5. 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.

6. 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, wherein the position is numbered according to the EU system, and a light chain comprising the amino acid sequence of SEQ ID NO:27.

7. The antibody or antigen binding fragment thereof of any one of claims 1-2 or 4-5, wherein the antibody or antigen binding fragment thereof comprises one or more cysteine substitutions.

8. The antibody or antigen binding fragment thereof of claim 7, wherein the antibody or antigen binding fragment thereof comprises one or more cysteine substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or antigen binding fragment thereof, wherein the position is numbered according to the EU system.

9. The antibody or antigen binding fragment thereof of any one of claims 1-8, wherein said antibody is a monoclonal antibody.

10. An antibody drug conjugate comprising the formula (C)Ab-(LA-(D)n)y               (C)wherein:2019409132   13 Jul 2026D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11;Ab is the antibody or antigen binding fragment thereof that binds to human PMEL17 protein of any of claims 1-9;La is a linker;n is 1, 2, 3 or 4, andy is 1, 2, 3 or 4.

11. The antibody drug conjugate of claim 10, wherein:(a) said n is 1;(b) said y is 2; and / or(c) said linker is a cleavable linker or a non-cleavable linker.

12. The antibody drug conjugate of claim 10 or 11, wherein the linker comprises a ValCit peptide linker.

13. The antibody drug conjugate of any one of claims 10-12, wherein D is2019409132   13 Jul 2026or14. The antibody drug conjugate of any one of claims 10-13 having the following structure,; or2019409132   13 Jul 202615. An antibody drug conjugate having the following Formula (C-2):(C-2),wherein:R0 is methyl or ethyl;R1 is methyl or isopropyl;2019409132   13 Jul 2026R2 is methyl or ethyl;Ab is the antibody or antigen binding fragment thereof that binds to human PMEL17 protein of any of claims 1-9;X1 is a bivalent coupling group;X2 is a self-immolative spacer;L1 is a bivalent peptide linker;L2 is a bond or a linker, andy is 1, 2, 3 or 4.

16. An antibody drug conjugate comprising the following structure:wherein Ab is an antibody or antigen binding fragment thereof that binds to human PMEL17 protein comprising:a. a heavy chain variable region that comprises a heavy chain CDR1 of SEQ ID NO:1, a heavy chain CDR2 of SEQ ID NO:2, and a heavy chain CDR32019409132   13 Jul 2026of SEQ ID NO:3; and a light chain variable region that comprises 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 that comprises 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 that comprises 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 that comprises 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 that comprises 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; ord. a heavy chain variable region that comprises 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 that comprises 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; andwherein y is 2.

17. An antibody drug conjugate comprising the following structure:2019409132   13 Jul 2026wherein 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; andwherein y is 2.

18. An antibody drug conjugate comprising the following structure:2019409132   13 Jul 2026wherein 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, wherein the position is numbered according to the EU system, and a light chain comprising the amino acid sequence of SEQ ID NO:27; andwherein y is 2.

19. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-9 or the antibody drug conjugate of any one of claims 10-18 and a pharmaceutically acceptable carrier.

20. A method of treating or preventing a cancer in a patient in need thereof, comprising administering to said patient the antibody or antigen binding fragment thereof of any one of claims 1-9, antibody drug conjugate of any one of claims 10-18, or the pharmaceutical composition of claim 19, wherein the cancer expresses PMEL17, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene, the GNA11 gene, or both the GNAQ gene and the GNA11 gene.2019409132   13 Jul 202621. Use of the antibody or antigen binding fragment thereof of any one of claims 1-9, antibody drug conjugate of any one of claims 10-18, or the pharmaceutical composition of claim 19, in the manufacture of a medicament for treating or preventing a cancer in a patient, wherein the cancer expresses PMEL17, or the cancer expresses PMEL17 and contains a mutation of the GNAQ gene, the GNA11 gene, or both the GNAQ gene and the GNA11 gene.

22. The method of claim 20 or the use of claim 21, wherein the antibody or antigen binding fragment thereof, antibody drug conjugate, or pharmaceutical composition is administered to the patient in combination with one or more additional therapeutic compounds.

23. The method or use of claim 22, wherein the one or more additional therapeutic compounds is selected from a standard of care chemotherapeutic, an MDM2 inhibitor, an MRC2 inhibitor, a PKC inhibitor, a MAPK inhibitor, a costimulatory molecule, or a checkpoint inhibitor.

24. The method or use of claim 23, wherein:(a) 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 CD83 ligand; or(b) the 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.

25. Use of the antibody or antigen binding fragment thereof of any one of claims 1-9, the antibody drug conjugate of any one of claims 10-18, or the pharmaceutical composition of claim 19 in the manufacture of a medicament.2019409132   13 Jul 202626. The method of any of claims 20 or 22-24, or the use of any one of claims 21-24, wherein the cancer is uveal melanoma, subcutaneous melanoma, hepatocellular carcinoma, or a metastatic cancer thereof.27.A nucleic acid that encodes the antibody or antigen binding fragment of any one of claims 1-9.28.A nucleic acid that encodes the antibody or antigen binding fragment of any one of claims 1-3, wherein the nucleic acid comprises the nucleotide sequence of any one of SEQ ID NOs: 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.

29. A vector comprising the nucleic acid of claim 27 or 28.

30. A host cell comprising the vector of claim 29, or the nucleic acid of claim 27 or 28.

31. A process for producing an antibody or antigen binding fragment comprising cultivating the host cell of claim 30 and recovering the antibody or antigen binding fragment from cell culture.

32. The process of claim 31, wherein recovering the antibody or antigen binding fragment from cell culture comprises the steps of:a) removing cells and filtering the culture;b) purifying the culture by affinity chromatography ;c) inactivating 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) purifying the culture by cation exchange chromatography and performing on-column reduction of the culture;e) performing anion exchange chromatography on the culture;2019409132   13 Jul 2026f) removing viruses by nanofiltration;g) filtering the culture containing the antibody or antigen binding fragment; andh) obtaining purified antibody or antigen binding fragment.

33. A process for producing an anti-PMEL17 antibody drug conjugate comprising:(a) pre-forming a linker-drug moiety of the following Formula (B):R8-LB-(D)n                      (B)wherein:D is a GNAQ inhibitor, a GNA11 inhibitor or an inhibitor of GNAQ and GNA11;R8 is a reactive group;Lb is a cleavable or non-cleavable linker, andn is 1, 2, 3 or 4;(b) conjugating said linker-drug moiety to the antibody or antigen binding fragment recovered from the cell culture of claim 31 or 32 to produce an antibody drug conjugate; and(c) purifying the antibody drug conjugate.

34. A diagnostic reagent comprising the antibody or antigen binding fragment thereof of any one of claims 1-9, wherein the antibody or antigen binding fragment thereof is labelled with a radiolabel, a fluorophore, a chromophore, an imaging agent, or a metal ion.

Images