Potent Conditionally Active Biologic (CAB) PD-1 antibodies to reduce systemic toxicities associated with single agent and combination therapies

Abstract PD-1 is an immune checkpoint inhibitor that limits T cell activity. The use of anti-PD-1 antagonist antibodies has demonstrated anti-tumor efficacy in mouse models and in a subset of human patients. However, blockade of PD-1 as a single agent and in combination with chemotherapy, targeted, and other immunomodulatory therapies has been limited clinically in part due to toxicities related to systemic immune-response related adverse events. In addition, there is increasing concern that systemic immune activation may lead to autoimmune-related adverse events in survivors. The Conditionally Active Biologics (CAB) technology is a patented, proprietary platform that selects antibodies that reversibly bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of glycolytic tumor metabolism including the Warburg effect. Using our CAB technology, we have identified anti-PD-1 Abs that reversibly bind human PD-1, and enhance T cell response to bacterial super-antigen under in vitro conditions that are present in the tumor microenvironment but not in normal tissues. CAB-PD-1 Abs demonstrated anti-tumor efficacy, including tumor regression, against MC38 colorectal tumor in human PD-1 knock-in mouse model in which the mouse PD-1 gene has been replaced with human PD-1. The anti-tumor activity of CAB-PD-1 Abs was similar to a reference PD-1 Ab. In conclusion, our data is consistent with our work on CAB-EGFR-ADC, CAB-AXL and CAB-ROR2-ADC antibodies, and suggests that anti-PD-1 Abs generated using the CAB technology provide potent, effective biologics with potential for increased therapeutic index. Specifically, the CAB-PD-1 is an excellent candidate for evaluation as a treatment for human cancers as a single agent or in combination with other anti-cancer therapies including immuno-oncology agents. Citation Format: Cathy Chang, Gerhard Frey, Leslie L. Sharp, Haizhen Liu, Jing Wang, Charles Xing, Safak Yalcin, Yong Ben, William J. Boyle, Jay M. Short. Potent Conditionally Active Biologic (CAB) PD-1 antibodies to reduce systemic toxicities associated with single agent and combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4555.