title: The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma.
abstract: Melanocytes uniquely express specialized genes required for pigment formation, some of which are maintained following their transformation to melanoma. Here we exploit this property to selectively target melanoma with an antibody drug conjugate (ADC) specific to PMEL17, the product of the SILV pigment-forming gene. We describe new PMEL17 antibodies that detect the endogenous protein. These antibodies help define the secretory fate of PMEL17 and demonstrate its utility as an ADC target. Although newly synthesized PMEL17 is ultimately routed to the melanosome, we find substantial amounts accessible to our antibodies at the cell surface that undergo internalization and routing to a LAMP1-enriched, lysosome-related organelle. Accordingly, an ADC reactive with PMEL17 exhibits target-dependent tumor cell killing in vitro and in vivo.
authors.affiliation: Department of Research Oncology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Chen
authors.forename: Cecile
authors.initials: C
authors.lastname: Chalouni
authors.forename: Christine
authors.initials: C
authors.lastname: Tan
authors.forename: Robyn
authors.initials: R
authors.lastname: Clark
authors.forename: Rayna
authors.initials: R
authors.lastname: Venook
authors.forename: Rachana
authors.initials: R
authors.lastname: Ohri
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.forename: William
authors.initials: W
authors.lastname: Mallet
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy*; D020460:Melanosomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D009842:Oligopeptides; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen; C495575:monomethyl auristatin E