A Single Agent Dual Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor specific antibody-dependent cellular cytotoxicity (ADCC). Here we report a symbiotic approach that is highly selective and superior compared to investigational clinical antibodies. This Bispecific-Anchored Cytotoxicity-Activator (BaCa) 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 FcγRIIB 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 strategically makes use of a tumor-cell enriched anchor receptor for agonist death-receptor targeting to potentially generate a clinically viable strategy for OvCa.