An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma

Jyoti Asundi, Chae Reed, Jennifer Arca, Krista McCutcheon, Ronald Ferrando, Suzanna Clark, Elizabeth Luis, Janet Tien, Ron Firestein, Paul Polakis

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33 Citations (Scopus)

Abstract

Purpose: To identify and evaluate targets amenable to antibody therapy in melanoma. Experimental Design: We searched for mRNA transcripts coding for cell-surface proteins with expression patterns similar to that of the melanoma oncogene MITF. One such candidate, the endothelin B receptor (EDNBR), was first analyzed for a functional contribution to tumor growth by conditional induction of shRNA. Second, antibodies were raised to the receptor, conjugated with monomethyl auristatin E, and tested for efficacy against melanoma tumor models generated from cell lines. Results: Conditional knockdown of the receptor in tumor xenograft models resulted in only a modest impact on tumor growth. A monoclonal antibody reactive with the N-terminal tail of EDNBR was found to internalize rapidly into melanoma cells. When conjugated with monomethyl auristatin E, the antibody-drug conjugate (ADC) showed remarkable efficacy against human melanoma cell lines and xenograft tumor models that was commensurate with levels of receptor expression. Comparative immunohistochemistry revealed a range of EDNBR expression across a panel of human melanomas, with the majority expressing levels equivalent to or greater than that in the models responsive to the ADC. Conclusion: An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma.

Original languageEnglish
Pages (from-to)965-975
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number5
DOIs
Publication statusPublished - 1 Mar 2011
Externally publishedYes

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