A Novel FOLR1 and TRAIL-R2 targeting bispecific antibody to treat ovarian cancer

We report a first-in-class tumor antigen dependent apoptotic inducing bispecific antibody, TRAILBody™, that co-targets FOLR1 and TRAIL-R2, selectively inducing TRAIL-R2 mediated apoptotic cell death with superior selectivity and efficacy. In a head-to-head comparison with the recently approved ADC drug, Elahere, FOLR1 TRAILBody showed superior activity. Extensive in vitro and in vivo analyses across ovarian cancer cell lines, patient-derived xenografts (PDX), and murine models demonstrate that FOLR1 TRAILBody drive high-level tumor-specific apoptosis independent of ADCC, significantly overcoming limitations of FcgammaR-mediated TRAIL-R2 clustering. Mechanistically, FOLR1 functions as a clustering anchor for TRAIL-R2, yielding enhanced receptor oligomerization, rapid caspase-3 activation, and robust cell death in FOLR1+ ovarian cancer models. Preclinical models confirm optimal stability, avidity, and selective tumor localization with minimized off-target toxicity. Notably, FOLR1 TRAILBody show superior regression of cisplatin-resistant PDX tumors and improved safety profile compared to clinically tested monospecific TRAIL-R2 antibody agonists, including minimized liver accumulation and hepatotoxicity with reduced levels of AST/ALT in blood. This study reveals a previously unappreciated mechanism in antibody therapeutics: the use of a tumor-enriched anchor (FOLR1) to optimize death receptor clustering and activation, enabling a quantum leap in apoptotic signaling and therapeutic index for ovarian cancer. The TRAILBody platform thus offers a foundation for next-generation immuno-oncology agents and revives hope for the clinical translation of death receptor agonism, particularly in solid tumors marked by immune exclusion and therapeutic resistance.