An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma
| Autor: | Ron Firestein, Mccutcheon Krista, Jennifer Arca, Elizabeth Luis, Chae Janeka Reed, Suzanna Clark, Janet Tien, Paul Polakis, Ronald E. Ferrando, Jyoti Asundi |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Antibody-drug conjugate Immunoconjugates medicine.drug_class Endothelin B Receptor Antagonists Receptor expression Blotting Western Melanoma Experimental Fluorescent Antibody Technique Gene Expression Antineoplastic Agents Monoclonal antibody chemistry.chemical_compound Mice Cell Line Tumor medicine Animals Humans RNA Messenger Melanoma Mice Inbred BALB C Microphthalmia-Associated Transcription Factor Oncogene business.industry Cancer Antibodies Monoclonal medicine.disease Flow Cytometry Receptor Endothelin B Xenograft Model Antitumor Assays Rats Macaca fascicularis Oncology Monomethyl auristatin E chemistry Gene Knockdown Techniques Immunology Cancer research business Oligopeptides |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(5) |
| ISSN: | 1557-3265 |
| Popis: | 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. Clin Cancer Res; 17(5); 965–75. ©2011 AACR. |
| Databáze: | OpenAIRE |
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