Strength in Complementary Weaknesses: An Effective Dual Specificity Antibody Approach against Ovarian Cancer
Authors: Tushir‐Singh Jogender 
Published: June 2021

Ovarian cancer (OvCa) is the most lethal of gynecological diseases and is known for chemoresistance and frequent reoccurrence with no effective treatment available(1). Therefore, developing safe and efficacious therapies that improve long‐term progression free survival remains an urgent unmet medical need. Recent clinical data indicates that immune system activating antibodies (mono‐specific or bispecific) are highly effective in chemoresistant blood cancer and melanoma patients(2–5). However, in the solid tumors of epithelial origin, including high‐grade serous ovarian carcinomas, antibody‐based approaches have not produced similar clinical outcomes. One major roadblock to the success of therapeutic antibodies in solid cancers is the ineffective penetration of the immune effector cells into the sturdy tumor bed(6, 7), a requisite for the natural killer cell‐mediated antibody‐directed cell cytotoxicity (ADCC) and killer T‐cell‐mediated cytotoxicity (8–10). In support, various solid epithelial cancer approved antibodies targeted against receptor tyrosine kinases have also indicated that ADCC contribution is not a major part of their efficacy in breast(11–14), colorectal(15–17), renal(18), and lung cancers(19).Farletuzumab, an ADCC activating humanized antibody targeted against folate receptor alpha‐1 (FOLR1) improves survival for a very small subset of OvCa patients having low Cancer antigen‐125 levels (20–24). Thus we strongly argue that in larger OvCa populations, which highly overexpress Cancer antigen‐125, ADCC‐based targeting approaches are not clinically feasible options (25–27). Since FOLR1 levels are strikingly elevated in >80% of high‐grade serous tumors, we hypothesize that if farletuzumab's activity is significantly enhanced beyond the ADCC function, the potential to achieve effective clinical response is very high in a larger subset of OvCa patients. One such approach is epithelial cancer enriched death receptor 5 (DR5/TRAIL‐R2) activating antibodies (28, 29). TRAIL‐R2 is a major extrinsic apoptotic pathway receptor expressed in tumors of epithelial origin(30)and we have engineered a novel OvCa selective Bispecific‐anchored Cytotoxicity‐activator (BaCa) antibody that combines the specificities against the FOLR1 and TRAIL‐R2 and is highly superior to failed clinical antibodies both in vitro and in vivo. Importantly, the cytotoxic function of the BaCa antibody is self‐sufficient on readily available inhibitory Fc‐gamma receptor expressing tumor‐associated leukocytes(31), and does not require distinct infiltration of immune effector NK cells or T‐cells into the tumor microenvironment. Since extrinsic TRAIL‐R2 induced cell‐death is independent of intrinsic p53‐mediated apoptosis, the BaCa antibody reflects a tailored treatment strategy for the majority of serous ovarian carcinomas (>90%) harboring p53 loss‐of‐function mutations(29, 32). Therefore, if given opportunity to present this work (as a talk) in the meeting, I will show detailed data on BaCa antibody engineering, selectivity, safety and efficacy using relevant OvCa models.Support or Funding InformationUniversity of Virginia Cancer CenterThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.