Journal
CANCER CELL
Volume 34, Issue 2, Pages 331-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.07.005
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Funding
- Institutional American Cancer Society (ACS) grant [88-001-30-IRG]
- Department of Defense (DoD) CDMRP Research Breakthrough Award [BC170197P1, BC170197]
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Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate cis'' and trans'' cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5). Whereas the in vivo agonist DR5 signaling requires Fc gamma RIIB interaction, the FOLR1 anchor functions as a primary clustering point to retain and maintain a high level of tumor-specific apoptosis. The presented proof of concept study strategicallymakes use of a tumor cell-enriched anchor receptor for agonist death receptor targeting to potentially generate a clinically viable strategy for OvCa.
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