Abstract A32: GIGA-564, a third generation anti-CTLA-4 with minimal ability to block CTLA-4 binding to B7 ligands, has enhanced efficacy but reduced toxicity compared to ipilimumab in pre-clinical models

Abstract Anti-CTLA-4 antibodies such as ipilimumab were among the first immuno-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. Here we present evidence that checkpoint inhibition may not be the primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy may be FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb), GIGA-564, that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, GIGA-564 has superior anti-tumor activity compared to ipilimumab in a murine model. GIGA-564 also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of GIGA-564 likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that GIGA-564 was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition. Citation Format: Erica L Stone, Kyle P Carter, Ellen K Wagner, Michael A Asensio, Emily Benzie, Yao Yuan Chiang, Garry L Coles, Chelsea Edgar, Bishal K Gautam, Ashley Gras, Jackson Leong, Renee Leong, Vishal A Manickam, Rena A Mizrahi, Ariel R Niedecken, Jasmeen Saini, Savreet K Sandhu, Jan Fredrick Simons, Kacy Stadtmiller, Brendan Tinsley, LaRee Tracy, Nicholas P Wayham, Yoong Wearn Lim, Adam S Adler, David S Johnson. GIGA-564, a third generation anti-CTLA-4 with minimal ability to block CTLA-4 binding to B7 ligands, has enhanced efficacy but reduced toxicity compared to ipilimumab in pre-clinical models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A32.