Abstract 2390: FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses

T-cell immunoreceptor with Ig and ITIM domains (TIGIT) has emerged as an important regulator of the cancer-immunity cycle. Preclinical studies have demonstrated that TIGIT antibodies can enhance T and NK cell anti-tumor immunity, and therapeutic antibodies targeting TIGIT are advancing in the clinic. Nonetheless, questions on the optimal format for TIGIT therapeutics remain unresolved. Preclinical studies have demonstrated that anti-TIGIT antibodies enhance anti-tumor immunity by (1) blocking inhibitory signaling downstream of TIGIT/PVR and TIGIT/PVRL2 receptor-ligand interactions and (2) redirecting PVR/PVRL2 ligand binding to the co-stimulatory receptor CD226. Here we describe a novel and unanticipated mechanism of action of anti-TIGIT antibodies in which interactions between the antibody Fc domain and select FcγRs, particularly FcγRIIIA, dramatically improve T cell activation and effector function. In mouse tumor models, TIGIT antibodies that promote FcγR interactions enhance anti-tumor responses, whereas Fc-inert TIGIT antibodies show no such benefit. Moreover, TIGIT antibodies that enhance binding to human FcγRIIIA or mouse FcγRIV promote superior single agent activity and combination activity with other checkpoint modulators in antigen-stimulation assays and mouse tumor models respectively. Notably, this mechanism of action is independent of regulatory T cell depletion. Our findings support a dependence on Fc-FcγR interaction for promoting T cell responsiveness and effector function upon TIGIT antagonism. We further demonstrate that this novel mechanism also extends to anti-CTLA-4, but not anti-PD-1 or anti-LAG-3 antibodies. Altogether, our data describe a novel FcγR-dependent mechanism of action that may enhance the therapeutic activity of anti-TIGIT antibodies, deepen our understanding of this class of therapies, and inform on the optimal design for a new class of Fc-engineered antibodies that could be leveraged to potentially enhance antitumor immune responses. Citation Format: Dhan Chand, Jeremy D. Waight, Elena Paltrinieri, Sylvia Dietrich, Mark Bushell, Mathew Costa, Randi Gombos, Nicholas S. Wilson, Jennifer S. Buell, Robert B. Stein, Alexander Duncan, David A. Savitsky. FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses [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 2390.