Abstract 2708: Potent CAB CTLA4 antibody to reduce immune side effects and toxicities associated with single-agent and combination cancer immuno therapies
Authors: Sharp Leslie , Chang Cathy , Frey Gerhard , Liu Haizhen , Xing Charles , Wang Jing , Walls Marlena , Wheeler Christina , Ben Yong , Boyle William J. , Short Jay M. 
Published: August 2019

Abstract
CTLA4 is a receptor on T cells that acts as a brake on their activation during immune responses, and when blocked can stimulate cancer immune-surveillance. The use of anti-CTLA4 antibodies to unleash T cells has demonstrable anti-tumor efficacy in animal models and in certain patients in the clinic. However, blockade of CTLA4 as a single agent and in combination with chemotherapy, targeted, and other immunomodulatory therapies has been limited clinically in part due to systemic immune-response related toxicities. In addition, there is increasing concern that systemic immune activation may lead to sustained autoimmune-related disease in survivors. The Conditionally Active Biologics (CAB) technology generates 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 because of glycolytic tumor metabolism including the Warburg effect. Using our CAB technology, we have identified anti-CTLA4 Abs that reversibly bind human CTLA4 and enhance T cell response to bacterial super-antigen under in vitro tumor microenvironment, but not in normal tissue conditions. CAB-CTLA4 Abs have anti-tumor efficacy equal to that of ipilimumab analog, including tumor regression, against MC38 colorectal tumor in a syngeneic human CTLA4 knock-in mouse model. Interestingly, CAB CTLA4 antibodies modulate the activity and numbers of infiltrating T cell subsets within the tumor microenvironment, but unlike ipilimumab analog, the CAB CTLA antibodies do not increase CD4 effector T Cells in periphery, suggesting less systemic immune toxicities impacting normal tissues. Repeated co-administration of either CAB CTLA4 or ipilimumab analog in combination with an anti-PD-1 (nivolumab analog) into monkeys for four weeks was performed to access the peripheral systemic and normal tissue effects of combination treatments. Combination treatment with ipilimumab and nivolumab analogs (I+N) resulted in increases in T cell proliferation markers in peripheral blood cells, while the CAB CTLA4 plus nivolumab analog had normal immunophenotypic patterns. All animals in the I+N treated groups had significant gastrointestinal symptoms (diarrhea, loose stools) that presented early, were sustained throughout the treatment period and were associated with substantial mononuclear infiltration within the intestinal wall. In sharp contrast, the CAB-CTLA4 plus nivolumab treated groups showed no significant GI symptomology nor histopathology. These data indicate that our CAB CTLA4 molecule may have a superior safety profile when used in combination with PD-1 inhibitors and allow increased dosing levels to achieve superior efficacy to current anti CTLA4 therapy as a single agent or in combination with other anti-cancer therapies including immuno-oncology agents.
Citation Format: Leslie Sharp, Cathy Chang, Gerhard Frey, Haizhen Liu, Charles Xing, Jing Wang, Marlena Walls, Christina Wheeler, Yong Ben, William J. Boyle, Jay M. Short. Potent CAB CTLA4 antibody to reduce immune side effects and toxicities associated with single-agent and combination cancer immuno therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2708.