An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma.
OBJECTIVE
To identify and evaluate targets amenable to antibody therapy in melanoma.


METHODS
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.


CONCLUSIONS
An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma.
Genentech, Inc., South San Francisco, California 94080, USA.
Jyoti
J
Asundi
Chae
C
Reed
Jennifer
J
Arca
Krista
K
McCutcheon
Ronald
R
Ferrando
Suzanna
S
Clark
Elizabeth
E
Luis
Janet
J
Tien
Ron
R
Firestein
Paul
P
Polakis
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D065131:Endothelin B Receptor Antagonists; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044023:Receptor, Endothelin B / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D065131:Endothelin B Receptor Antagonists; D018796:Immunoconjugates; D051739:Microphthalmia-Associated Transcription Factor; D009842:Oligopeptides; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; C495575:monomethyl auristatin E