Antibodies to pmel17 and conjugates thereof

Abstract

This application discloses an anti-PMEL17 antibody, its antigen-binding fragment, and its conjugation to... The present invention relates to antibody-drug conjugates of the antibodies or antigen-binding fragments of GNAQ / GNA11 inhibitors. The invention also relates to methods for treating or preventing cancer using the antibody, antigen-binding fragment, and antibody-drug conjugate. Furthermore, the present invention discloses methods for preparing the antibody, antigen-binding fragment, and antibody-drug conjugate, as well as methods for using the antibody and antigen-binding fragment as diagnostic reagents.

Description

[Technical Field] sequence list This application contains a sequence list, which has been electronically submitted in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on December 6, 2019, and is named PAT058359-WO-PCT_SL.txt, with a size of 285,253 bytes. This invention relates generally to anti-PMEL17 antibodies or fragments thereof, their conjugates (including their GNAQ / GNA11 inhibitor conjugates), and their use in the treatment or prevention of cancer. [Previous Technology] PMEL17 (also known as gp100 and SILV) is a single-pathway type I transmembrane protein produced by melanocytes and involved in melanin synthesis. Upon maturation, PMEL17 transiently manifests on the cell surface before being transported to the melanosome, where it degrades into multiple domains that polymerize to form fibrous sheets. This pattern then serves as a support for melanin capture. The expression of PMEL17 on the melanosome is regulated by the lineage-specific oncogene MITF and has been found to be upregulated in various primary and metastatic subcutaneous and uveal melanomas. The transient cell surface manifestation and subsequent internalization of PMEL17 make it a suitable target for developing antibody-drug conjugates (ADCs) for the treatment of melanoma. PMEL17 and Cancer As it matures, PMEL17 is extensively processed by pro-protein convertases. The protein cleaves between V467 and K468, forming two subdomains: Mα at the N-terminus and Mβ at the C-terminus, presumably maintained by disulfide bridges. After leaving the Golgi apparatus, some PMEL17 molecules transiently appear on the cell surface. Most PMEL17 are then redirected to melanocytes for further maturation, while some appear to detach. Following further enzymatic cleavage, PMEL17 degrades into multiple domains, which recombine to form fibrous sheets that undergo melanin polymerization (Valencia JC et al. Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes). J Cell Sci. 2006, March 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. [Research on Pigment Cells] 2005, 18(5): 322-36. PMEL17 constitutes a potential therapeutic target for melanoma. As observed in mRNA expression studies, PMEL17 is a direct transcriptional target of MITF, a lineage-specific oncogene in melanoma (Du J et al. MLANA / MART1 and SILV / PMEL17 / GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. [MLANA / MART1 and SILV / PMEL17 / GP100 are transcriptionally regulated by MITF in melanocytes and melanoma] Am J Pathol. [American Journal of Pathology] July 2003; 163(1): 333-43). PMEL17 expression is limited to the melanocyte lineage, including cutaneous melanocytes, hair bulb melanocytes, retinal pigment epithelial cells, pigmented ciliary epithelial cells, and possibly choroidal melanocytes in the retina. PMEL17 is also highly expressed in melanocyte lineage tumors such as subcutaneous and uveal melanomas. In contrast, mRNA studies have shown that PMEL17 expression is limited in 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. June 1997; 44(4): 239-47). In addition, ADCs and ImmTACs targeting PMEL17 have previously been described as specifically inducing melanoma killing in vivo and in vitro, and are currently being evaluated in clinical trials (Chen Y et al. The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma. J Biol Chem. 2012 July 13; 287(29): 24082-91. doi: 10.1074 / jbc.M112.361485. Epub 2012 May 21). GNAQ / GNA11 and Cancer The GNAQ and GNA11 genes encode the α subunit of the heterotrimeric G protein Gq / 11, which is almost universally expressed and acts as a bistate molecular switch cycling between an activated guanosine triphosphate (GTP)-bound state and an inactivated guanosine diphosphate (GDP)-bound state. GTP-bound Gαq and Gα11 activate the β-isoform of phospholipase C, thereby triggering multiple signal transduction pathways by generating the second messengers IP3 and DAG. The intrinsic GTPase activity of these Gα proteins mediates GTP hydrolysis, triggering signal transduction termination. Gq and G11 have been shown to participate in various physiological functions, including platelet activation, cardiac hypertrophy, and smooth muscle tone. Oncogene mutations in GNAQ or GNA11 occur in up to 90% of uveal melanomas (UM) and approximately 2-3% of cutaneous melanomas. About 95% of these mutations affect codon 209 (Q209) in the Ras-like domain, resulting in complete or partial loss of GTPase activity, thereby locking GNAQ / 11 into its active state. Q209 GNAQ / 11 is a major functional oncogene that can transform melanocytes by triggering activation of multiple pathways, including PKC / MAPK, Rho / Rac, β-catenin, and YAP. Although the PKC / MAPK pathway has been shown to be a contributing factor to GNAQ-mediated tumorigenesis, multiple pieces of evidence suggest that mutant GNAQ / 11 controls other pathways (i.e., YAP and β-catenin) that may also play a role in UM tumorigenesis. Interestingly, the etiology of another somatic activation mutation in GNAQ (R183Q), Sturge-Weber syndrome (SWS), was recently described. SWS is a neurocutaneous disorder characterized by capillary malformations (port-wine stains) and choroidal and meningeal vascular malformations. Therefore, GNAQ and GNA11 constitute potential therapeutic targets for uveal and cutaneous melanomas. Antibody-drug conjugates Antibody-drug conjugates (“ADCs”) have been used in the local delivery of cytotoxic agents in cancer treatment (see, for example, Lambert, Curr. Opinion in Pharmacology 5: 543-549, 2005). ADCs allow for targeted delivery of drug portions, where maximum efficacy with minimal toxicity can be achieved. An ADC comprises an antibody selected for its ability to bind to cells targeted for a therapeutic intervention, linked to a drug selected for its cellular inhibitory or cytotoxic activity. Thus, the binding of the antibody to the target cell delivers the drug to the site where its therapeutic effect is desired. Numerous antibodies that recognize and selectively bind to target cells (e.g., cancer cells) have been identified for use in ADCs. Despite extensive work on ADCs, the specific antibody binding to a particular target is insufficient to predict the success of ADC applications. Examples of factors that can influence the therapeutic efficacy of ADCs (besides intrinsic target characteristics) include aspects requiring tailored fine-tuning, such as optimal antibody affinity as a balance between target-mediated disposition (TMDD) and efficacy-driven exposure, evaluation of Fc-mediated function (antibody-dependent cell-mediated cytotoxicity, ADCC), conjugation method (site specificity or non-specificity), drug / payload molecule ratio conjugated to each antibody (“DAR” or “drug-antibody ratio”), linker cleavability or stability, ADC stability, and the tendency of ADC aggregation. There is still a need for antibodies, attachment methods, and cytotoxic payloads with improved properties to serve as effective ADC therapeutic components and methods. [Summary of the Invention] In one embodiment, this application discloses an antibody or antigen-binding fragment thereof that binds to PMEL17, the antibody or antigen-binding fragment thereof comprising: a. A heavy chain variable region comprising heavy chain CDR1 (complementarity determining region 1) of SEQ ID NO: 1, 4, 5 or 7, heavy chain CDR2 (complementarity determining region 2) of SEQ ID NO: 2, 6 or 8, and heavy chain CDR3 (complementarity determining region 3) of SEQ ID NO: 3 or 9; and a light chain variable region comprising light chain CDR1 (complementarity determining region 1) of SEQ ID NO: 14, 17 or 20, light chain CDR2 (complementarity determining region 2) of SEQ ID NO: 15 or 18, and light chain CDR3 (complementarity determining region 3) of SEQ ID NO: 16 or 19; b. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 33, 36, 37 or 39, heavy chain CDR2 of SEQ ID NO: 34, 38 or 40, heavy chain CDR3 of SEQ ID NO: 35 or 41; light chain CDR1 of SEQ ID NO: 46, 49 or 52, light chain CDR2 of SEQ ID NO: 47 or 50, and light chain CDR3 of SEQ ID NO: 48 or 51; c. Heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 5, 7, 57 or 60, heavy chain CDR2 of SEQ ID NO: 58, 61 or 62, heavy chain CDR3 of SEQ ID NO: 59 or 63; light chain CDR1 of SEQ ID NO: 68, 71 or 74, light chain CDR2 of SEQ ID NO: 69 or 72, and light chain CDR3 of SEQ ID NO: 70 or 73; d. Heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 79, 82, 83 or 85, heavy chain CDR2 of SEQ ID NO: 80, 84 or 86, heavy chain CDR3 of SEQ ID NO: 81 or 87; light chain CDR1 of SEQ ID NO: 92, 95 or 98, light chain CDR2 of SEQ ID NO: 93 or 96, and light chain CDR3 of SEQ ID NO: 94 or 97; e. Heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, heavy chain CDR2 of SEQ ID NO: 104, 108 or 110, heavy chain CDR3 of SEQ ID NO: 105 or 111; light chain CDR1 of SEQ ID NO: 49, 52 or 116, light chain CDR2 of SEQ ID NO: 47 or 50, and light chain CDR3 of SEQ ID NO: 117 or 118; f. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 123, 126, 127 or 129, heavy chain CDR2 of SEQ ID NO: 124, 128 or 130, heavy chain CDR3 of SEQ ID NO: 125 or 131; light chain CDR1 of SEQ ID NO: 136, 139 or 142, light chain CDR2 of SEQ ID NO: 137 or 140, and light chain CDR3 of SEQ ID NO: 138 or 141; g. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 123, 126, 127 or 129, heavy chain CDR2 of SEQ ID NO: 124, 128 or 130, heavy chain CDR3 of SEQ ID NO: 147 or 148; light chain CDR1 of SEQ ID NO: 153, 156 or 158, light chain CDR2 of SEQ ID NO: 50 or 154, and light chain CDR3 of SEQ ID NO: 155 or 157; h. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, heavy chain CDR2 of SEQ ID NO: 104, 108 or 110, heavy chain CDR3 of SEQ ID NO: 163 or 164; light chain CDR1 of SEQ ID NO: 49, 52 or 116, light chain CDR2 of SEQ ID NO: 47 or 50, and light chain CDR3 of SEQ ID NO: 169 or 170; i. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 175, 178, 179 or 181, heavy chain CDR2 of SEQ ID NO: 176, 180 or 182, heavy chain CDR3 of SEQ ID NO: 177 or 183; light chain CDR1 of SEQ ID NO: 49, 52 or 116, light chain CDR2 of SEQ ID NO: 47 or 50, and light chain CDR3 of SEQ ID NO: 188 or 189; j. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 103, 106, 107 or 109, heavy chain CDR2 of SEQ ID NO: 104, 108 or 110, heavy chain CDR3 of SEQ ID NO: 194 or 195; light chain CDR1 of SEQ ID NO: 49, 52 or 116, light chain CDR2 of SEQ ID NO: 47 or 50, and light chain CDR3 of SEQ ID NO: 200 or 201; k. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 206, 209, 210 or 212, heavy chain CDR2 of SEQ ID NO: 207, 211 or 213, heavy chain CDR3 of SEQ ID NO: 208 or 214; light chain CDR1 of SEQ ID NO: 153, 156 or 158, light chain CDR2 of SEQ ID NO: 50 or 154, and light chain CDR3 of SEQ ID NO: 219 or 220; 1. A heavy chain variable region comprising heavy chain CDR1 of SEQ ID NO: 206, 209, 210 or 212, heavy chain CDR2 of SEQ ID NO: 207, 211 or 213, heavy chain CDR3 of SEQ ID NO: 225 or 226; light chain CDR1 of SEQ ID NO: 136, 139 or 142, light chain CDR2 of SEQ ID NO: 137 or 140, and light chain CDR3 of SEQ ID NO: 231 or 232; m. A heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, 209, 210 or 212, HCDR2 of SEQ ID NO: 207, 211 or 213, and HCDR3 of SEQ ID NO: 237 or 238; and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, 245 or 247, LCDR2 of SEQ ID NO: 47 or 50, and LCDR3 of SEQ ID NO: 244 or 246; n. A heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, 209, 210 or 212, HCDR2 of SEQ ID NO: 207, 211 or 213, and HCDR3 of SEQ ID NO: 252 or 253; and a light chain variable region comprising LCDR1 of SEQ ID NO: 153, 156 or 158, LCDR2 of SEQ ID NO: 50 or 154, and LCDR3 of SEQ ID NO: 258 or 259; o. Heavy chain CDR1 of SEQ ID NO: 1, heavy chain CDR2 of SEQ ID NO: 2, heavy chain CDR3 of SEQ ID NO: 3, light chain CDR1 of SEQ ID NO: 14, light chain CDR2 of SEQ ID NO: 15, and light chain CDR3 of SEQ ID NO: 16; p. Heavy chain CDR1 of SEQ ID NO: 4, heavy chain CDR2 of SEQ ID NO: 2, heavy chain CDR3 of SEQ ID NO: 3, light chain CDR1 of SEQ ID NO: 14, light chain CDR2 of SEQ ID NO: 15, and light chain CDR3 of SEQ ID NO: 16; q. CDR1 of heavy chain SEQ ID NO: 5, CDR2 of heavy chain SEQ ID NO: 6, CDR3 of heavy chain SEQ ID NO: 3, CDR1 of light chain SEQ ID NO: 17, CDR2 of light chain SEQ ID NO: 18, and CDR3 of light chain SEQ ID NO: 19; r. SEQ ID NO: 7 heavy chain CDR1, SEQ ID NO: 8 heavy chain CDR2, SEQ ID NO: 9 heavy chain CDR3, SEQ ID NO: 20 light chain CDR1, SEQ ID NO: 18 light chain CDR2, and SEQ ID NO: 16 light chain CDR3; s. Heavy chain CDR1 of SEQ ID NO: 33, heavy chain CDR2 of SEQ ID NO: 34, heavy chain CDR3 of SEQ ID NO: 35, light chain CDR1 of SEQ ID NO: 46, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 48; t. SEQ ID NO: 36 heavy chain CDR1, SEQ ID NO: 34 heavy chain CDR2, SEQ ID NO: 35 heavy chain CDR3, SEQ ID NO: 46 light chain CDR1, SEQ ID NO: 47 light chain CDR2, and SEQ ID NO: 48 light chain CDR3; u. SEQ ID NO: 37 heavy chain CDR1, SEQ ID NO: 38 heavy chain CDR2, SEQ ID NO: 35 heavy chain CDR3, SEQ ID NO: 49 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 51 light chain CDR3; v. Heavy chain CDR1 of SEQ ID NO: 39, heavy chain CDR2 of SEQ ID NO: 40, heavy chain CDR3 of SEQ ID NO: 41, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 48; w. Heavy chain CDR1 of SEQ ID NO: 57, heavy chain CDR2 of SEQ ID NO: 58, heavy chain CDR3 of SEQ ID NO: 59, light chain CDR1 of SEQ ID NO: 68, light chain CDR2 of SEQ ID NO: 69, and light chain CDR3 of SEQ ID NO: 70; x. Heavy chain CDR1 of SEQ ID NO: 60, heavy chain CDR2 of SEQ ID NO: 58, heavy chain CDR3 of SEQ ID NO: 59, light chain CDR1 of SEQ ID NO: 68, light chain CDR2 of SEQ ID NO: 69, and light chain CDR3 of SEQ ID NO: 70; y. SEQ ID NO: 5 heavy chain CDR1, SEQ ID NO: 61 heavy chain CDR2, SEQ ID NO: 59 heavy chain CDR3, SEQ ID NO: 71 light chain CDR1, SEQ ID NO: 72 light chain CDR2, and SEQ ID NO: 73 light chain CDR3; z. Heavy chain CDR1 of SEQ ID NO: 7, heavy chain CDR2 of SEQ ID NO: 62, heavy chain CDR3 of SEQ ID NO: 63, light chain CDR1 of SEQ ID NO: 74, light chain CDR2 of SEQ ID NO: 72, and light chain CDR3 of SEQ ID NO: 70; aa. Heavy chain CDR1 of SEQ ID NO: 79, heavy chain CDR2 of SEQ ID NO: 80, heavy chain CDR3 of SEQ ID NO: 81, light chain CDR1 of SEQ ID NO: 92, light chain CDR2 of SEQ ID NO: 93, and light chain CDR3 of SEQ ID NO: 94; bb. Heavy chain CDR1 of SEQ ID NO: 82, heavy chain CDR2 of SEQ ID NO: 80, heavy chain CDR3 of SEQ ID NO: 81, light chain CDR1 of SEQ ID NO: 92, light chain CDR2 of SEQ ID NO: 93, and light chain CDR3 of SEQ ID NO: 94; cc. SEQ ID NO: 83 heavy chain CDR1, SEQ ID NO: 84 heavy chain CDR2, SEQ ID NO: 81 heavy chain CDR3, SEQ ID NO: 95 light chain CDR1, SEQ ID NO: 96 light chain CDR2, and SEQ ID NO: 97 light chain CDR3; dd. SEQ ID NO: 85 heavy chain CDR1, SEQ ID NO: 86 heavy chain CDR2, SEQ ID NO: 87 heavy chain CDR3, SEQ ID NO: 98 light chain CDR1, SEQ ID NO: 96 light chain CDR2, and SEQ ID NO: 94 light chain CDR3; ee. Heavy chain CDR1 of SEQ ID NO: 103, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 105, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 117; ff. Heavy chain CDR1 of SEQ ID NO: 106, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 105, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 117; gg. Heavy chain CDR1 of SEQ ID NO: 107, heavy chain CDR2 of SEQ ID NO: 108, heavy chain CDR3 of SEQ ID NO: 105, light chain CDR1 of SEQ ID NO: 49, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 118; hh. SEQ ID NO: 109 heavy chain CDR1, SEQ ID NO: 110 heavy chain CDR2, SEQ ID NO: 111 heavy chain CDR3, SEQ ID NO: 52 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 117 light chain CDR3; ii. Heavy chain CDR1 of SEQ ID NO: 123, heavy chain CDR2 of SEQ ID NO: 124, heavy chain CDR3 of SEQ ID NO: 125, light chain CDR1 of SEQ ID NO: 136, light chain CDR2 of SEQ ID NO: 137, and light chain CDR3 of SEQ ID NO: 138; jj. Heavy chain CDR1 of SEQ ID NO: 126, heavy chain CDR2 of SEQ ID NO: 124, heavy chain CDR3 of SEQ ID NO: 125, light chain CDR1 of SEQ ID NO: 136, light chain CDR2 of SEQ ID NO: 137, and light chain CDR3 of SEQ ID NO: 138; kk. Heavy chain CDR1 of SEQ ID NO: 127, heavy chain CDR2 of SEQ ID NO: 128, heavy chain CDR3 of SEQ ID NO: 125, light chain CDR1 of SEQ ID NO: 139, light chain CDR2 of SEQ ID NO: 140, and light chain CDR3 of SEQ ID NO: 141; 11. Heavy chain CDR1 of SEQ ID NO: 129, heavy chain CDR2 of SEQ ID NO: 130, heavy chain CDR3 of SEQ ID NO: 131, light chain CDR1 of SEQ ID NO: 142, light chain CDR2 of SEQ ID NO: 140, and light chain CDR3 of SEQ ID NO: 138; mm. SEQ ID NO: 123 heavy chain CDR1, SEQ ID NO: 124 heavy chain CDR2, SEQ ID NO: 147 heavy chain CDR3, SEQ ID NO: 153 light chain CDR1, SEQ ID NO: 154 light chain CDR2, and SEQ ID NO: 155 light chain CDR3; nn. Heavy chain CDR1 of SEQ ID NO: 126, heavy chain CDR2 of SEQ ID NO: 124, heavy chain CDR3 of SEQ ID NO: 147, light chain CDR1 of SEQ ID NO: 153, light chain CDR2 of SEQ ID NO: 154, and light chain CDR3 of SEQ ID NO: 155; oo. SEQ ID NO: 127 heavy chain CDR1, SEQ ID NO: 128 heavy chain CDR2, SEQ ID NO: 147 heavy chain CDR3, SEQ ID NO: 156 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 157 light chain CDR3; pp. heavy chain CDR1 of SEQ ID NO: 129, heavy chain CDR2 of SEQ ID NO: 130, heavy chain CDR3 of SEQ ID NO: 148, light chain CDR1 of SEQ ID NO: 158, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 155; qq. Heavy chain CDR1 of SEQ ID NO: 103, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 163, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 169; rr. Heavy chain CDR1 of SEQ ID NO: 106, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 163, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 169; ss. SEQ ID NO: 107 heavy chain CDR1, SEQ ID NO: 108 heavy chain CDR2, SEQ ID NO: 163 heavy chain CDR3, SEQ ID NO: 49 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 170 light chain CDR3; tt. Heavy chain CDR1 of SEQ ID NO: 109, heavy chain CDR2 of SEQ ID NO: 110, heavy chain CDR3 of SEQ ID NO: 164, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 169; uu. SEQ ID NO: 175 heavy chain CDR1, SEQ ID NO: 176 heavy chain CDR2, SEQ ID NO: 177 heavy chain CDR3, SEQ ID NO: 116 light chain CDR1, SEQ ID NO: 47 light chain CDR2, and SEQ ID NO: 188 light chain CDR3; vv. Heavy chain CDR1 of SEQ ID NO: 178, heavy chain CDR2 of SEQ ID NO: 176, heavy chain CDR3 of SEQ ID NO: 177, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 188; www. SEQ ID NO: 179 heavy chain CDR1, SEQ ID NO: 180 heavy chain CDR2, SEQ ID NO: 177 heavy chain CDR3, SEQ ID NO: 49 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 189 light chain CDR3; xx. Heavy chain CDR1 of SEQ ID NO: 181, heavy chain CDR2 of SEQ ID NO: 182, heavy chain CDR3 of SEQ ID NO: 183, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 188; yy. Heavy chain CDR1 of SEQ ID NO: 103, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 200; zz. Heavy chain CDR1 of SEQ ID NO: 106, heavy chain CDR2 of SEQ ID NO: 104, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 116, light chain CDR2 of SEQ ID NO: 47, and light chain CDR3 of SEQ ID NO: 200; aaa. Heavy chain CDR1 of SEQ ID NO: 107, heavy chain CDR2 of SEQ ID NO: 108, heavy chain CDR3 of SEQ ID NO: 194, light chain CDR1 of SEQ ID NO: 49, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 201; bbb. Heavy chain CDR1 of SEQ ID NO: 109, heavy chain CDR2 of SEQ ID NO: 110, heavy chain CDR3 of SEQ ID NO: 195, light chain CDR1 of SEQ ID NO: 52, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 200; ccc. SEQ ID NO: 206 heavy chain CDR1, SEQ ID NO: 207 heavy chain CDR2, SEQ ID NO: 208 heavy chain CDR3, SEQ ID NO: 153 light chain CDR1, SEQ ID NO: 154 light chain CDR2, and SEQ ID NO: 219 light chain CDR3; ddd. Heavy chain CDR1 of SEQ ID NO: 209, heavy chain CDR2 of SEQ ID NO: 207, heavy chain CDR3 of SEQ ID NO: 208, light chain CDR1 of SEQ ID NO: 153, light chain CDR2 of SEQ ID NO: 154, and light chain CDR3 of SEQ ID NO: 219; eee. SEQ ID NO: 210 heavy chain CDR1, SEQ ID NO: 211 heavy chain CDR2, SEQ ID NO: 208 heavy chain CDR3, SEQ ID NO: 156 light chain CDR1, SEQ ID NO: 50 light chain CDR2, and SEQ ID NO: 220 light chain CDR3; fff. Heavy chain CDR1 of SEQ ID NO: 212, heavy chain CDR2 of SEQ ID NO: 213, heavy chain CDR3 of SEQ ID NO: 214, light chain CDR1 of SEQ ID NO: 158, light chain CDR2 of SEQ ID NO: 50, and light chain CDR3 of SEQ ID NO: 219; ggg. SEQ ID NO: 206 heavy chain CDR1, SEQ ID NO: 207 heavy chain CDR2, SEQ ID NO: 225 heavy chain CDR3, SEQ ID NO: 136 light chain CDR1, SEQ ID NO: 137 light chain CDR2, and SEQ ID NO: 231 light chain CDR3; hhh. SEQ ID NO: 209 heavy chain CDR1, SEQ ID NO: 207 heavy chain CDR2, SEQ ID NO: 225 heavy chain CDR3, SEQ ID NO: 136 light chain CDR1, SEQ ID NO: 137 light chain CDR2, and SEQ ID NO: 231 light chain CDR3; iii. Heavy chain CDR1 of SEQ ID NO: 210, heavy chain CDR2 of SEQ ID NO: 211, heavy chain CDR3 of SEQ ID NO: 225, light chain CDR1 of SEQ ID NO: 139, light chain CDR2 of SEQ ID NO: 140, and light chain CDR3 of SEQ ID NO: 232; jjj. Heavy chain CDR1 of SEQ ID NO: 212, heavy chain CDR2 of SEQ ID NO: 213, heavy chain CDR3 of SEQ ID NO: 226, light chain CDR1 of SEQ ID NO: 142, light chain CDR2 of SEQ ID NO: 140, and light chain CDR3 of SEQ ID NO: 231; kkk. Heavy chain variable region comprising HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207, and HCDR3 of SEQ ID NO: 237; and light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 244; lll. A heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207, and HCDR3 of SEQ ID NO: 237; and a light chain variable region comprising LCDR1 of SEQ ID NO: 243, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 244; mmm. Heavy chain variable region comprising HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211, and HCDR3 of SEQ ID NO: 237; and light chain variable region comprising LCDR1 of SEQ ID NO: 245, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 246; nnn. Heavy chain variable region comprising HCDR1 of SEQ ID NO: 212, HCDR2 of SEQ ID NO: 213, and HCDR3 of SEQ ID NO: 238; and light chain variable region comprising LCDR1 of SEQ ID NO: 247, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 244; ooo. Heavy chain variable region, which includes HCDR1 of SEQ ID NO: 206, HCDR2 of SEQ ID NO: 207, and HCDR3 of SEQ ID NO: 252; and light chain variable region, which includes LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154, and LCDR3 of SEQ ID NO: 258; ppp. Heavy chain variable region comprising HCDR1 of SEQ ID NO: 209, HCDR2 of SEQ ID NO: 207, and HCDR3 of SEQ ID NO: 252; and light chain variable region comprising LCDR1 of SEQ ID NO: 153, LCDR2 of SEQ ID NO: 154, and LCDR3 of SEQ ID NO: 258; qqq. Heavy chain variable region, comprising HCDR1 of SEQ ID NO: 210, HCDR2 of SEQ ID NO: 211, and HCDR3 of SEQ ID NO: 252; and light chain variable region, comprising LCDR1 of SEQ ID NO: 156, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 259; or rrr. Heavy chain variable region comprising HCDR1 of SEQ ID NO: 212, HCDR2 of SEQ ID NO: 213, and HCDR3 of SEQ ID NO: 253; and light chain variable region comprising LCDR1 of SEQ ID NO: 158, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 258. The antibody or antigen-binding fragment thereof binding to PMEL17 may also include: a. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 21; b. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 25; c. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 29; d. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 42 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 53; e. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 64 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 75; f. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 88 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 99; g. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 112 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 119; h. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 132 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 143; i. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 149 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 159; j. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 165 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 171; k. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 184 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 190; l. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 196 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 202; m. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 215 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 221; n. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 227 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 233; o. A heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 239 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 248; or p. The heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 254 and the light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 260. In another embodiment, the antibody or antigen-binding fragment of PMEL17 comprises: a. A heavy chain containing the amino acid sequence of SEQ ID NO: 12, and a light chain containing the amino acid sequence of SEQ ID NO: 23; b. A heavy chain containing the amino acid sequence of SEQ ID NO: 12, and a light chain containing the amino acid sequence of SEQ ID NO: 27; c. A heavy chain containing the amino acid sequence of SEQ ID NO: 12, and a light chain containing the amino acid sequence of SEQ ID NO: 31; d. A heavy chain containing the amino acid sequence of SEQ ID NO: 44, and a light chain containing the amino acid sequence of SEQ ID NO: 55; e. A heavy chain containing the amino acid sequence of SEQ ID NO: 66, and a light chain containing the amino acid sequence of SEQ ID NO: 77; f. A heavy chain containing the amino acid sequence of SEQ ID NO: 90, and a light chain containing the amino acid sequence of SEQ ID NO: 101; g. A heavy chain containing the amino acid sequence of SEQ ID NO: 114, and a light chain containing the amino acid sequence of SEQ ID NO: 121; h. A heavy chain containing the amino acid sequence of SEQ ID NO: 134, and a light chain containing the amino acid sequence of SEQ ID NO: 145; i. A heavy chain containing the amino acid sequence of SEQ ID NO: 151, and a light chain containing the amino acid sequence of SEQ ID NO: 161; j. A heavy chain containing the amino acid sequence of SEQ ID NO: 167, and a light chain containing the amino acid sequence of SEQ ID NO: 173; k. A heavy chain containing the amino acid sequence of SEQ ID NO: 186, and a light chain containing the amino acid sequence of SEQ ID NO: 192; l. A heavy chain containing the amino acid sequence of SEQ ID NO: 198, and a light chain containing the amino acid sequence of SEQ ID NO: 204; m. A heavy chain containing the amino acid sequence of SEQ ID NO: 217, and a light chain containing the amino acid sequence of SEQ ID NO: 223; n. A heavy chain containing the amino acid sequence of SEQ ID NO: 229, and a light chain containing the amino acid sequence of SEQ ID NO: 235; o. A heavy chain containing the amino acid sequence of SEQ ID NO: 241, and a light chain containing the amino acid sequence of SEQ ID NO: 250; or p. The heavy chain containing the amino acid sequence of SEQ ID NO: 256, and the light chain containing the amino acid sequence of SEQ ID NO: 262. The antibody or antigen-binding fragment thereof described herein may contain one or more cysteine ​​substitutions. In one embodiment, the antibody or antigen-binding fragment thereof contains 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 designated according to the EU system number. The antibody disclosed herein may be a monoclonal antibody. In one aspect, the antibody-drug conjugates of the present invention are conjugates of formula (C): Ab-(LA-(D)n)y(C) where: D-series GNAQ inhibitors, GNA11 inhibitors, or inhibitors of both GNAQ and GNA11; Ab is an antibody or antigen-binding fragment that binds to human PMEL17 protein; LA series connectors; n is 1, 2, 3 or 4, and y is 1, 2, 3 or 4, wherein the linker-drug moiety-(LA-(D)n) is covalently attached to the antibody or its antigen-binding fragment. In another aspect of the antibody-drug conjugate having formula (C), the LA-based cleavable linker comprises one or more linker components selected from self-immolative spacers, phosphate groups, carbonate groups, and divalent peptide linkers. On the other hand, the antibody-drug conjugate having formula (C) is a conjugate having formula (C-1): [Figure] Wherein: D-series GNAQ inhibitors, GNA11 inhibitors, or inhibitors of both GNAQ and GNA11; Ab is an antibody or antigen-binding fragment that binds to human PMEL17 protein; X1 series divalent coupling groups; X2 series suicide spacer; Y1 is a series of diagrams, where the * indicator of Y1 is attached to the attachment point of X2 and the ** indicator of Y1 is attached to the attachment point of D. L1 series divalent peptide linkers; L2 series keys or connectors, and The y series is 1, 2, 3, or 4. This application also discloses pharmaceutical compositions comprising the antibodies or antigen-binding fragments thereof disclosed herein, and pharmaceutically acceptable carriers. This application further discloses pharmaceutical compositions comprising the antibody-drug conjugates disclosed herein, and pharmaceutically acceptable carriers. This application also discloses a method for treating or preventing cancer in a patient in need, the method comprising administering to the patient an antibody-drug conjugate or drug composition disclosed herein, wherein the cancer manifests PMEL17 and contains a GNAQ or GNA11 gene mutation, or the cancer manifests PMEL17 and contains a GNAQ mutation, a GNA11 mutation, or a mutation of both. In some embodiments of this method of treating or preventing cancer, the antibody-drug conjugate or pharmaceutical composition is administered to the patient in combination with one or more additional therapeutic compounds. In one embodiment, the one or more additional therapeutic compounds are selected from standard care chemotherapy agents, MDM2 inhibitors, MRC2 inhibitors, PKC inhibitors, MAPK inhibitors, co-stimulatory molecules, or checkpoint inhibitors. In one embodiment, the co-stimulatory molecule is selected from agonists 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 ligands. In another embodiment, the checkpoint inhibitor is selected from inhibitors of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ. This application also discloses the antibody-drug conjugates or pharmaceutical compositions disclosed herein for use as medicines. In one embodiment, the antibody-drug conjugates or pharmaceutical compositions disclosed herein are used in patients in need to treat or prevent cancers expressing PMEL17 or cancers containing mutations in the GNAQ or GNA11 genes. In one embodiment, this application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions as disclosed herein for the treatment or prevention of cancers presenting PMEL17 in patients of need. In one embodiment, this application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions as disclosed herein for the treatment or prevention of cancers expressing PMEL17 or containing GNAQ or GNA11 gene mutations in patients of need. In one embodiment, this application discloses the use of antibodies or antigen-binding fragments thereof, antibody-drug conjugates, or pharmaceutical compositions as disclosed herein in the manufacture of a medicament. In one embodiment, the cancer exhibits PMEL17 or contains mutations in the GNAQ or GNA11 genes. In one embodiment, the cancer is uveal melanoma, subcutaneous melanoma, hepatocellular carcinoma, or metastatic cancer thereof. This application also discloses a nucleic acid encoding an antibody or antigen-binding fragment as disclosed herein. In one embodiment, the nucleic acid comprises a nucleotide sequence of SEQ ID NO: 13, 24, 28, 32, 45, 56, 67, 78, 91, 102, 115, 122, 135, 146, 152, 162, 168, 174, 187, 193, 199, 205, 218, 224, 230, 236, 242, 251, 257, or 26. This application also discloses a vector containing the nucleic acid and a host cell containing the vector or nucleic acid. This application also discloses a method for generating an antibody or antigen-binding fragment disclosed herein, the method comprising culturing the host cell and recovering the antibody from the cell culture. In one embodiment, the method for recovering the antibody from the cell culture includes the following steps: a) Recover the cells and filter the culture; b) Purify the culture by affinity chromatography; c) Inactivate any viruses in the culture by adjusting the pH to 3.4-3.6, then readjust the pH to 5.8-6.2 and filter the culture; d) The culture was purified by cation exchange chromatography and then reduced on column. e) Perform anion exchange chromatography on the culture; f) Remove viruses through nanofiltration; g) Filter the culture containing the antibody; and h) Obtain purified antibodies. This application also discloses a method for generating anti-PMEL17 antibody drug conjugates, the method comprising: (a) Pre-form the linker-drug portion having the following formula (B): R8-LB-(D)n(B) in: D-series GNAQ inhibitors, GNA11 inhibitors, or inhibitors of both GNAQ and GNA11; R8 is a reactive group; LB-based splittable or non-splittable linkers, and n is 1, 2, 3, or 4; (b) Using the methods disclosed herein for generating antibody or antigen-binding fragments, the linker-drug moiety is conjugated with an antibody recovered from the cell culture to generate an antibody-drug conjugate; and (c) Purify the antibody-drug conjugate. This application also discloses a diagnostic reagent comprising an antibody or an 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. [Simplified Explanation of the Diagram] [Figures 1A-1B] show exemplary data on the in vitro anti-UM activity of GNAQ / 11 inhibitor compounds (A1) and (A2). [Figure 2] shows exemplary data on the activity of GNAQ / 11 inhibitor compounds (A1) and (A2) in inducing apoptosis in uveal melanoma cells. [Figures 3A-3C] show exemplary data on the inhibition of GNAQ / 11 by compounds (A1) and (A2). Compounds (A1) and (A2) reduced IP1 levels (Figure 3A) and relative proliferation (Figure 3B) in 92.1 cells. Immunoblots of 92.1 cells treated with compounds (A1) and (A2) showed reduced ERK signaling (Figure 3C). [Figures 4A-4D] show exemplary data on the metabolic stability and PK properties of compound (A1). The disappearance of compound (A1) and the appearance of the open-ring form of compound (A8) were monitored over a 24-hour period (Figure 4A) (Figure 4B). The stoichiometry over 24 hours is shown by adding % of the remaining compound (A1) and % of the formed compound (A8), excluding rats (Figure 4C). In mice, after intravenous administration, the PK of compound (A1) is characterized by very high clearance and medium to high volume of distribution (Figure 4D). [Figures 5A-5D] show exemplary data on the metabolic stability and PK properties of compounds (A1) and (A2). The in vitro stability of compound (A2) was tested in plasma and blood from different species (Figure 5A). Compound (A2) showed good chemical stability in three different systems (Figure 5B). In female balb / c mice, compound (A2) exhibited high PK clearance and a short elimination half-life (Figure 5C). Compounds (A1) and (A2) were stable in buffer at pH 5.6 and in lysosomes over a period of 4 hours (Figure 5D). [Figures 6A-6B] show exemplary data on the in vitro anti-uveal melanoma activity of anti-PMEL17-(B1)ADC. Data are presented as the mean of three independent replicates, relative to PBS-treated cells (control). [Figure 7] shows exemplary data on the induction of apoptosis in uveal melanoma cells by anti-PMEL17-(B1)ADC. Data are presented as the mean of three independent replicates. [Figures 8A-8B] show exemplary data on the in vitro anti-uveal melanoma activity of anti-PMEL17-(B2)ADC and anti-PMEL17 mAb. Data are presented as the mean of three independent replicates, relative to PBS-treated cells (control). [Figure 9] shows exemplary data on the inhibition of GNAQ / 11 by anti-PMEL17-(B1) and anti-PMEL17-(B2) ADCs in uveal melanoma cells. IP1 levels (nM) are expressed as the mean of three independent replicates. [Figures 10A-10D] show exemplary data on the binding activity of anti-PMEL17 antibody with intact platelets and uveal melanoma cells. [Figures 11A-11C] show exemplary data on the effects of compound (A1) and anti-PMEL17-(B1) ADC on human platelet aggregation. [Figures 12A-12E] show exemplary data on the in vivo antitumor activity of G1-(B1)ADC. G1-(B1) inhibited tumor growth in a dose-dependent manner (Figure 12A). Values ​​are mean ± SEM; sample size (n = 5-12 mice / group). The initial tumor volume on day 0 was approximately 200-250 mm3. No weight loss was observed up to 14 days after treatment (Figure 12B). Values ​​are mean ± SEM; sample size (n = 4 mice / group). G1-(B1) treatment resulted in inhibition of GNAQ signaling and tumor cell proliferation, as indicated by decreased pERK and Ki67 levels (Figure 12C). Furthermore, compared with mice treated with the vector and those treated with the isotype control 3207-(B1), G1-(B1) induced apoptosis, which was associated with tumor cell accumulation of G1-(B1)ADC detected by IgG staining (Figure 12C). No changes in MITF and PMEL17 levels were observed after GNAQ inhibition (Fig. 12C). No inhibition of platelet aggregation was observed in G1-(B1) treated mice over a period of up to 7 days (Fig. 12D and E). [Figures 13A-13C] show exemplary data on the effects of G1-(B1) ADC on a mouse model of liver and lung metastases from uveal melanoma. Individual images of each mouse are presented on day 45 after intravenous injection of 92.1-luciferase cells (just before treatment) and day 12 after treatment (Figures 13A and 13B); sample size (n=6 mice / group). The initial BLI of liver metastases on day 0 was approximately 2.8 * 10⁹ p / sec / cm². Black arrows indicate lung tumors (bioluminescent signals) in Figure 13B. The corresponding weight adjustment (%) relative to day 15 was assessed 2–3 times weekly before and after treatment with 20 mg / kg G1-(B1) (grey circles). Values ​​in Figure 13C are mean ± SEM; sample size (n=5–6 mice / group). The initial body weight on day 15 was approximately 21 g. [Figures 14A-14E] show exemplary data on the pharmacokinetic properties of the G1-(B1) ADC. Pharmacokinetic curves (total IgG levels) for G1-(B1) show a slight overproportional increase in exposure in nude mice at doses between 7.5 and 30 mg / kg (Figure 14A). In tumor-bearing mice, the free effective load concentration was measured after administration of G1-(B1) or the isotype control 3207-(B1). A significant increase (>4-fold) in tumor delivery of the compound (A1) effective load was observed using the targeted ADC (Figure 14B). In vivo, the conversion of compound (A1) (hollow circle) to its open-ring form (A8) (solid circle) was shown to occur simultaneously with antibody conjugation (Figure 14C). Comparisons of two different DAR2 formulations with the G1-(B1) DAR4 formulation and with the DAR4 Fc-silenced formulation in in vivo efficacy studies showed that the DAR2 (E152C) and DAR4 Fc-silenced ADCs had the lowest clearance rates, while the DAR2 (S375C) exposure decreased more rapidly (Figure 14D). Figure 14E shows the concentrations of the 3207 (isotype control antibody)-(B1)DAR4 (E152C, S375C) and 3207 (isotype control antibody)-(B1)DAR4 Fc-silenced conjugates over time. [Figures 15A-15C] show exemplary data on the in vitro stability of anti-PMEL17-GNAQ / 11i ADC in buffer, mouse, rat and human plasma, as well as the in vivo stability of anti-PMEL17-GNAQ / 11i ADC in mice. [Figures 16A-16B] show exemplary data on the in vivo efficacy of G1-E152C-DAR2-(B1), G1-S375C-DAR2-(B1), and Fc-silenced G1-(B1) in a xenograft model of uveal melanoma. Values ​​represent mean ± SEM; sample size (n = 5-6 mice / group). Initial tumor volume on day 0 was approximately 300-325 mm3. [Figures 17A-17B] show exemplary data on the in vitro anti-uveal melanoma activity of anti-PMEL17-(B1)ADC. Data are presented as the mean of three independent replicates, relative to PBS-treated cells (control). [Figure 18] shows exemplary data on the in vivo antitumor activity of the anti-PMEL17-(B1)ADC. [Figures 19A-19B] show exemplary data of immunohistochemical analysis of tumor biopsies from patients with metastatic uveal melanoma. [Figures 20A-20C] illustrate exemplary sensor data for evaluating epitope binning of anti-PMEL antibodies. Figure 20A shows the binding process. Figure 20B shows the sensor data when antibody G1 3J LC is first immobilized and 17A9 flows through. Figure 20C shows the sensor data when 17A9 is first immobilized and G1 3J LC flows through. In both cases, binding was observed when the second antibody flowed through, indicating that G1 3J LC and 17A9 bind to different epitopes of human PMEL.

Implementation Method

Claims

1. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the antibody or antigen-binding fragment comprising: a. the heavy chain CDR1 (complementarity-determining region 1) of SEQ ID NO: 1, the heavy chain CDR2 (complementarity-determining region 2) of SEQ ID NO: 2, the heavy chain CDR3 (complementarity-determining region 3) of SEQ ID NO: 3, the light chain CDR1 of SEQ ID NO: 14, the light chain CDR2 of SEQ ID NO: 15, and the light chain CDR3 of SEQ ID NO: 16; b. the heavy chain CDR1 of SEQ ID NO: 4, the heavy chain CDR2 of SEQ ID NO: 2, the heavy chain CDR3 of SEQ ID NO: 3, the light chain CDR1 of SEQ ID NO: 14, the light chain CDR2 of SEQ ID NO: 15, and the light chain CDR3 of SEQ ID NO: 16; c. the heavy chain CDR1 of SEQ ID NO: 5, the heavy chain CDR2 of SEQ ID NO: 6, the heavy chain CDR3 of SEQ ID NO: 3, and the light chain CDR3 of SEQ ID NO:

16. Light chain CDR1 of SEQ ID NO: 17, light chain CDR2 of SEQ ID NO: 18, and light chain CDR3 of SEQ ID NO: 19; or d. heavy chain CDR1 of SEQ ID NO: 7, heavy chain CDR2 of SEQ ID NO: 8, heavy chain CDR3 of SEQ ID NO: 9, light chain CDR1 of SEQ ID NO: 20, light chain CDR2 of SEQ ID NO: 18, and light chain CDR3 of SEQ ID NO:

16.

2. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the antibody or antigen-binding fragment comprising: a. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 21; b. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 25; or c. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:

29.

3. An antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the antibody or antigen-binding fragment comprising: a. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 23; b. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 27; or c. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO:

31.

4. An antibody or antigen-binding fragment thereof, as claimed in any of claims 1 to 3, wherein the antibody or antigen-binding fragment thereof contains one or more cysteine ​​substitutions in a constant region of the antibody or antigen-binding fragment thereof.

5. An antibody or antigen-binding fragment thereof as claimed in any of claims 1 to 3, 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 assigned according to the EU system number.

6. An antibody or antigen-binding fragment thereof as claimed in any of claims 1 to 3, wherein the anti-system monoclonal antibody is described.

7. An antibody-drug conjugate comprising the formula (C)Ab-(LA-(D)n)y (C) wherein: D refers to an inhibitor of GNAQ, an inhibitor of GNA11, or an inhibitor of both GNAQ and GNA11; Ab refers to an antibody or antigen-binding fragment thereof as claimed in any of items 1 to 6; LA refers to a linker; n refers to 1, 2, 3, or 4, and y refers to 1, 2, 3, or 4.

8. The antibody-drug conjugate as requested in item 7, wherein n is 1.

9. The antibody-drug conjugate as requested in item 7 or 8, wherein y is a 2.

10. The antibody-drug conjugate of claim 7 or 8, wherein the linker is a cleavable linker or a non-cleavable linker.

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

12. The antibody-drug conjugate as requested in item 7 or 8, wherein D is an inhibitor of GNAQ and GNA11.

13. Antibody-drug conjugates as requested in item 7 or 8, wherein D series 14. Antibody-drug conjugates as requested in item 7 or 8, wherein D series 15. The antibody-drug conjugate of claim 7 or 8, wherein the antibody-drug conjugate comprises the following structure, 16. The antibody-drug conjugate of claim 7 or 8, wherein the antibody-drug conjugate comprises the following structure, 17. An antibody-drug conjugate comprising the following formula (C-2):

17. Among them: R0 is methyl or ethyl; R1 is methyl or isopropyl; R2 is methyl or ethyl; Ab is an antibody or antigen-binding fragment thereof as claimed in any of claims 1 to 6; X1 is a divalent coupling group; X2 is a suicide spacer; L1 is a divalent peptide linker; L2 is a bond or linker, and y is 1, 2, 3 or 4.

18. An antibody-drug conjugate comprising the following formula:

18. Wherein Ab is an antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the Ab comprising: a. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 21; b. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 25; or c. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 29; and wherein y is 2.

19. The antibody-drug conjugate of claim 18, wherein the antibody or its antigen-binding fragment comprises: a. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 23; b. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 27; or c. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO:

31.

20. An antibody-drug conjugate comprising the following formula:

20. Wherein Ab is an antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the Ab comprising: a. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 21; b. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 25; or c. a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 29; and wherein y is 2.

21. The antibody-drug conjugate of claim 20, wherein the antibody or its antigen-binding fragment comprises: a. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 23; b. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO: 27; or c. a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and a light chain containing the amino acid sequence of SEQ ID NO:

31.

22. An antibody-drug conjugate as claimed in claim 18 or 20, wherein the antibody or its antigen-binding fragment comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or its antigen-binding fragment, wherein the position is based on the EU system number.

23. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising an antibody-drug conjugate as claimed in any one of claims 7 to 22, and a pharmaceutically acceptable carrier.

25. Use of an antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 6, an antibody-drug conjugate as claimed in any one of claims 7 to 22, or a pharmaceutical composition as claimed in claims 23 or 24, for the purpose of preparing a pharmaceutical product for the treatment or prevention in patients in need of cancer expressing PMEL17, cancer containing GNAQ gene mutation, GNA11 gene mutation, or both GNAQ gene mutation and GNA11 gene mutation, or cancer expressing PMEL17 and containing GNAQ gene mutation, GNA11 gene mutation, or both GNAQ gene mutation and GNA11 gene mutation.

26. As claimed in claim 25, wherein the cancer is uveal melanoma, subcutaneous melanoma, hepatocellular carcinoma, or metastatic cancer thereof.

27. As claimed in paragraphs 25 or 26, wherein the antibody or its antigen-binding fragment, the antibody-drug conjugate, or the drug composition is administered in combination with one or more other therapeutic compounds.

28. As claimed in claim 27, wherein the one or more additional therapeutic compounds are selected from standard care chemotherapeutic agents, MDM2 inhibitors, MRC2 inhibitors, PKC inhibitors, MAPK inhibitors, co-stimulatory molecules, or checkpoint inhibitors.

29. As claimed in claim 28, wherein the co-stimulatory molecule is selected from agonists 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 ligands.

30. As claimed in claim 28, wherein the checkpoint inhibitor is selected from inhibitors of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ.

31. A nucleic acid that encodes an antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 6.

32. The nucleic acid of claim 31, wherein the nucleic acid comprises the nucleotide sequence of any one of SEQ ID NO: 13, 24, 28 or 32.

33. A vector comprising a nucleic acid as claimed in claim 31 or 32.

34. A host cell comprising nucleic acid as claimed in claim 31 or 32 or a vector as claimed in claim 33.

35. A method for generating an antibody or an antigen-binding fragment thereof, the method comprising culturing a host cell as claimed in claim 34 and recovering the antibody or an antigen-binding fragment thereof from the cell culture.

36. The method of claim 35, wherein recovering the antibody or its antigen-binding fragment from a cell culture comprises the following steps: a) recovering cells and filtering the culture; b) purifying the culture by affinity chromatography; c) inactivating any virus 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 on the culture; e) performing anion exchange chromatography on the culture; f) removing the virus by nanofiltration; g) filtering the culture containing the antibody or its antigen-binding fragment; and h) obtaining the purified antibody or its antigen-binding fragment.

37. A method for generating an anti-PMEL17 antibody drug conjugate, the method comprising: (a) Pre-forming a linker-drug moiety having the following formula (B): R8-LB-(D)n (B) wherein: D is a GNAQ inhibitor, a GNA11 inhibitor, or an inhibitor of both 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 the linker-drug moiety with an antibody or an antigen-binding fragment thereof as claimed in any of claims 1 to 6 to produce an antibody-drug conjugate; and (c) purifying the antibody-drug conjugate.

38. A diagnostic reagent comprising an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 6.

39. The diagnostic reagent of claim 38, wherein the antibody or its antigen-binding fragment is labeled with a radiolabel, a fluorescent group, a chromophore, an imaging agent or a metal ion.

40. An antibody-drug conjugate comprising the following formula:

40. The Ab is an antibody or antigen-binding fragment of human PMEL17 protein, comprising: a. the heavy chain CDR1 of SEQ ID NO: 1, the heavy chain CDR2 of SEQ ID NO: 2, the heavy chain CDR3 of SEQ ID NO: 3, the light chain CDR1 of SEQ ID NO: 14, the light chain CDR2 of SEQ ID NO: 15, and the light chain CDR3 of SEQ ID NO: 16; b. the heavy chain CDR1 of SEQ ID NO: 4, the heavy chain CDR2 of SEQ ID NO: 2, the heavy chain CDR3 of SEQ ID NO: 3, the light chain CDR1 of SEQ ID NO: 14, the light chain CDR2 of SEQ ID NO: 15, and the light chain CDR3 of SEQ ID NO: 16; c. the heavy chain CDR1 of SEQ ID NO: 5, the heavy chain CDR2 of SEQ ID NO: 6, the heavy chain CDR3 of SEQ ID NO: 3, the light chain CDR1 of SEQ ID NO: 17, and the light chain CDR3 of SEQ ID NO:

16. Light chain CDR2 of SEQ ID NO: 18 and light chain CDR3 of SEQ ID NO: 19; or heavy chain CDR1 of SEQ ID NO: 7, heavy chain CDR2 of SEQ ID NO: 8, heavy chain CDR3 of SEQ ID NO: 9, light chain CDR1 of SEQ ID NO: 20, light chain CDR2 of SEQ ID NO: 18, and light chain CDR3 of SEQ ID NO: 16; and wherein y is a series 2.

41. An antibody-drug conjugate comprising the following formula:

41. Wherein Ab is an antibody or antigen-binding fragment of human PMEL17 protein, the Ab comprising a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 25; and wherein y is 2.

42. An antibody-drug conjugate comprising the following formula:

42. The Ab is an antibody or antigen-binding fragment thereof that binds to human PMEL17 protein, the Ab comprising: a heavy chain containing the amino acid sequence of SEQ ID NO: 12, except that the amino acid at position 375 is S, wherein the position is according to the EU system number, and a light chain containing the amino acid sequence of SEQ ID NO: 27; and wherein y is 2.

43. A pharmaceutical composition comprising an antibody-drug conjugate as claimed in any one of claims 40 to 42 and a pharmaceutically acceptable carrier.

44. Use of an antibody-drug conjugate as claimed in any one of claims 40 to 42 or a pharmaceutical composition as claimed in claim 43, for the purpose of preparing a pharmaceutical product for the treatment or prevention of cancer in patients in need, wherein the cancer manifests as PMEL17, the cancer contains a GNAQ gene mutation, a GNA11 gene mutation, or both a GNAQ gene mutation and a GNA11 gene mutation, or the cancer manifests as PMEL17 and contains a GNAQ gene mutation, a GNA11 gene mutation, or both a GNAQ gene mutation and a GNA11 gene mutation.

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