Abstract 1677: Characterization of the pharmacodynamic activity of AGEN1181, an Fc-enhanced CTLA-4 antibody, alone and in combination with the PD-1 antibody balstilimab
Authors: Irina Shapiro, Min Lim, Simarjot Pabla, Steven J. O'Day, Anthony El-Khoueiry, Chethan Ramamurthy, Andrea J. Bullock, Michael S. Gordon, Jennifer Buell, Dhan Chand, Anna Wijatyk
Journal: Cancer Research (2021)

Abstract AGEN1181 is a novel, Fc-engineered monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with enhanced FcyR-dependent functionality designed to improve T cell priming and activation, deplete intratumoral regulatory T cells (Treg), and improve memory T cell response. AGEN1181 is currently undergoing Phase I clinical evaluation, both as a single agent and in combination with the anti-PD-1 antibody balstilimab, in patients with advanced solid tumors (NCT03860272). Encouraging signals of clinical benefit have emerged as part of this ongoing study, including complete and durable responses in patients that would traditionally be considered unresponsive to conventional CTLA-4/PD-1 therapy. Here we report on pharmacodynamic analyses associated with AGEN1181 exposure in patients on study in this trial. As monotherapy, AGEN1181 was administered on a once every 3 or once every 6 week cycle (doses escalated from 0.1 - 4 mg/kg). Alternatively, AGEN1181 was dosed once every six weeks in combination with balstilimab (3 mg/kg once every 2 weeks). Tumor mutational burden (TMB) and gene expression were assessed from pre-treatment and on-treatment biopsies by whole exome sequencing (WES) and RNASeq, respectively. Multiplex immunohistochemistry was used to assess Treg depletion and CD8 T-cell activation in response to AGEN1181. TCR repertoire was analyzed in PBMCs collected on-treatment with AGEN1181. FcγRIIIA genotyping was performed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry. Consistent with its proposed mechanism of action, dose-dependent pharmacodynamic effects have been observed in patients while on-treatment with AGEN1181. Peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T cells increased over baseline in response to monotherapy. This effect was further enhanced in subjects treated with AGEN1181 when given in combination with balstilimab. Responders expressed either the low affinity FcγRIIIA allele or were heterozygous - suggesting that AGEN1181 has the potential to expand clinical activity to patients with low affinity Fc binding, in contrast to conventional CTLA-4 inhibitors. Additionally, we show that AGEN1181 induced selective Treg depletion within the tumor microenvironment with concomitant increases in CD8 T cell infiltration. TCRSeq analysis demonstrated increased clonality and decreased downsampled diversity, providing further evidence that the Fc-enhanced activity of AGEN1181 can promote improved T cell priming and Treg depletion. In summary, the pharmacodynamic analyses presented here are consistent with the Fc-enhanced design of AGEN1181 and its potential to broaden the therapeutic reach of CTLA-4-based immunotherapy. Citation Format: Irina Shapiro, Min Lim, Simarjot Pabla, Steven J. O'Day, Anthony El-Khoueiry, Chethan Ramamurthy, Andrea J. Bullock, Michael S. Gordon, Jennifer Buell, Dhan Chand, Anna Wijatyk. Characterization of the pharmacodynamic activity of AGEN1181, an Fc-enhanced CTLA-4 antibody, alone and in combination with the PD-1 antibody balstilimab [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 1677.