Abstract 4552: Preclinical characterization of BMS-986218, a novel nonfucosylated anti–CTLA-4 antibody designed to enhance antitumor activity
Authors: Engelhardt John , Akter Rahima , Loffredo John , So Paula , Bezman Natalie , Price Karen 
Published: September 2020

Abstract
Background: Blockade of the CTLA-4 pathway with ipilimumab (IPI) as monotherapy or in combination with nivolumab (anti–PD-1) is an effective treatment for a variety of cancers. Antibody-dependent cellular cytotoxicity (ADCC) is a cellular process through which effector immune cells that express an Fc receptor (FcR) recognize and eliminate antibody-bound targets. Anti–CTLA-4 has been shown to mediate the ADCC depletion of tumor-infiltrating regulatory T cells (Tregs), which play an important role in suppressing antitumor immune response in the tumor microenvironment. A version of IPI that is nonfucosylated (NF) in the Fc region (BMS-986218; anti–CTLA-4 NF) was created to increase binding affinity to activating Fcγ receptors (FcγR, CD16) and improve ADCC, thus increasing intratumoral Treg depletion.
Methods: Antibody binding to CD16 was studied by surface plasmon resonance. IL-2 release from staphylococcal enterotoxin B (SEB)–stimulated normal human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells was measured; ADCC function was evaluated by IL-2–activated NK cell–induced lysis of CD4+ T cells or activated CD4+Foxp3+ Tregs. Tumor growth was measured in transgenic (human CD16) mice implanted with MC38 tumors. Peripheral pharmacodynamics (PD) was evaluated in cynomolgus (CYNO) macaques after administration of customized adenovirus-5 vector vaccines.
Results: Binding affinity to human CD16 was enhanced by BMS-986218 compared with IPI. BMS-986218 induced greater NK cell–mediated lysis of CD4+ T cells (37%) and Tregs (100%) compared with that induced by IPI (7% and 58%, respectively). Anti–CTLA-4 NF was also more effective than IPI in enhancing IL-2 release from SEB-stimulated PBMCs. Addition of an anti-CD16 antibody blocked the IL-2 response, supporting the concept that CD16 was necessary for anti–CTLA-4 NF activity. In mice, anti–CTLA-4 NF produced greater dose-dependent tumor growth inhibition (99%) than anti–CTLA-4 (61%). Tumors from anti–CTLA-4 NF–treated mice compared with anti–CTLA-4–treated mice had a greater decrease in Treg levels (70% vs 30%, respectively) and a larger increase in CD8+ T-cell levels (82% vs 62%, respectively) and no changes in Treg or CD8+ cell levels in the spleen. A more pronounced vaccine-induced T-cell response in anti–CTLA-4 NF–treated vs anti–CTLA-4–treated CYNO macaques was observed over a 3-week period.
Conclusions: Nonfucosylation of an anti–CTLA-4 antibody increased binding affinity to CD16, induced depletion of Tregs while increasing T-effector cells in mouse tumors, and enhanced tumor growth inhibition in a dose-dependent manner, thus demonstrating improved ADCC compared with IPI. An ongoing phase 1/2 study is evaluating the safety and antitumor activity of anti–CTLA-4 NF alone and in combination with nivolumab (NCT03110107) in patients with advanced solid cancers.
Citation Format: John Engelhardt, Rahima Akter, John Loffredo, Paula So, Natalie Bezman, Karen Price. Preclinical characterization of BMS-986218, a novel nonfucosylated anti–CTLA-4 antibody designed to enhance antitumor activity [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 4552.