The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to serious on-target drug-related toxicities, restricting the development of bispecific T cell engagers to targets that have limited expression in normal tissues. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates antibodies which have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed CD3/target bispecific antibodies that bind to recombinant CD3 and to CD3 expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions (CAB CD3). CAB CD3 bispecific antibodies were generated against various well-established tumor associated antigens (TAA), including EpCAM, B7-H3, HER-2 and EGFR. All of these molecules play important roles in cancer biology and are attractive targets for the development of therapeutic bispecific antibodies. In addition, we have also developed CAB TAA / CAB CD3 bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for CAB-T cell engagers will be presented. Our data demonstrates that CAB bispecific antibodies are efficacious in vivo and have lower toxicity comparing to non-CAB bispecific antibodies. The CAB technology will allow the generation of a new class of T-cell engagers with increased safety margin and therapeutic index in the clinic.
Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific T cell engagers targeting solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5698.