The Melanosomal Protein PMEL17 as a Target for Antibody Drug Conjugate Therapy in Melanoma

Background: A search for cell surface proteins amenable to antibody drug conjugate (ADC) therapy was performed. Results: Expression of PMEL17 was highly restricted to melanoma cells, and an ADC directed against it was efficacious. Conclusion: PMEL17 is an attractive target for ADC therapy in melanoma. Significance: Intracellular transmembrane proteins that transit the cell surface represent a new class of targets for ADCs. 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.