Abstract
To identify and evaluate targets amenable to antibody therapy in melanoma. 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. 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. An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma.
Highlights
Melanoma is an aggressive form of skin cancer that has recently undergone an alarming increase in incidence [1]
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 endothelin B receptor (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 antibody–drug conjugate (ADC)
Summary
Melanoma is an aggressive form of skin cancer that has recently undergone an alarming increase in incidence [1]. Cures can be achieved with surgical resection of localized lesions, the advanced stages of melanoma are only poorly responsive to currently approved therapies. The 5-year survival rate for stage IV metastatic melanoma is approximately 10% [1]. New therapeutic approaches, including antisense to Bcl, antibodies to CTLA4, small molecule RAF kinase inhibitors, and adoptive immunotherapy, are currently in clinical testing for metastatic melanoma [2]. The results from some of these recent studies seem to be encouraging, but a durable impact on overall survival will likely require therapeutic combinations including additional new agents. More than 20 years ago, endothelin-1 (ET-1) was isolated from aortic endothelial cells and found to have potent vasoconstrictive activity [3]. The receptors for endothelins were cloned shortly thereafter [4, 5] and their expression in Authors' Affiliation: Genentech, Inc., South San Francisco, California
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