The advent of immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1) transformed the treatment landscape in a variety of human cancers. However, responses to currently approved ICI agents occur in small subsets of patients with immunogenic tumors, and resistance to ICI therapy continues to be a limiting factor to achieving optimal clinical benefits. AGEN1181 is a Fc-enhanced, clinical-stage anti-CTLA-4 antibody designed to expand therapeutic benefit to a broader patient population, including tumor types that are refractory to conventional ICI approaches. Here we show that AGEN1181 exploits a novel Fcy receptor-related mechanism of action to promote T cell-mediated antitumor immunity. In primary in vitro T cell and antigen presenting cell (APC) co-culture stimulation assays, AGEN1181 demonstrated superior T cell priming and activation that was independent of Treg depletion, and across all CD16 allele variants - in contrast to conventional IgG1 agents that showed limited activity. In PD-1 refractory tumor-bearing mouse models, a murine AGEN1181 surrogate demonstrated superior antitumor activity compared to an Fc-unmodified anti-CTLA-4 antibody. This enhanced activity was associated with improved T cell priming, intratumoral Treg depletion, increased frequency of CD8 effector memory precursor T cells, enhanced peripheral TCR clonality, and expansion of tumor-associated T cell clones. Next we evaluated the combination potential of the AGEN1181 surrogate with targeted therapies, cell therapy or checkpoint blockade in a series of treatment-resistant preclinical tumor models. Notably, this antibody induced robust tumor control and antitumor immunity when administered alongside anti-PD-1 and focal radiation, adoptive T cell therapy, or iNKT-activating therapy in the refractory B16F10 or B16F1.OVA melanoma models. In treatment-resistant KPC pancreatic ductal tumor-bearing mice, curative responses were seen in combination with chemotherapy (gemcitabine, nab-paclitaxel and cisplatin). Moreover, combinations with other ICI (e.g. anti-PD-1 or anti-TIGIT antibodies) deepened responsiveness and overcame limited activity seen with conventional ICI therapy. Importantly, antitumor immune responses could be further improved with optimal sequencing of combination therapies with AGEN1181. Together, these data demonstrate that the novel Fcy receptor-related mechanism of action employed by AGEN1181 enhances antitumor immunity and confers the potential to expand therapeutic benefit to tumors refractory to ICI therapy. Clinical responses support these findings and a phase II trial is underway in patients with a range of solid tumor types, including angiosarcoma and microsatellite stable tumors.
Citation Format: Antoine J. Tanne, Claire Galand, Abdo Abou-Slaybi, Margaret Wilkens, Marilyn Marques, Serina Ng, Haiyong Han, Sylvia Dietrich, Jeremy Waight, Bishnu Joshi, Burcu Yigit, Xavier Michelet, Daniel Levey, David Savitsky, Jennifer Buell, Dhan Chand. Fc-enhanced anti-CTLA-4 antibody, AGEN1181: new mechanistic insights for potent antitumor immunity and combination potential in treatment-resistant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1878.