The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma

Youjun Chen, Cecile Chalouni, Christine Tan, Robyn Clark, Rayna Venook, Rachana Ohri, Helga Raab, Ron Firestein, William Mallet, Paul Polakis

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24082-24091
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number29
DOIs
Publication statusPublished - 13 Jul 2012
Externally publishedYes

Cite this

Chen, Y., Chalouni, C., Tan, C., Clark, R., Venook, R., Ohri, R., ... Polakis, P. (2012). The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma. Journal of Biological Chemistry, 287(29), 24082-24091. https://doi.org/10.1074/jbc.M112.361485