Abstract 3654: AGEN1884, an IgG1 anti-CTLA-4 antibody, combines effectively with PD-1 blockade in primary human T cell assays and in a non-human primate pharmacodynamic (PD) model

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) play important non-redundant roles in negatively regulating T cell immune responses. Therapeutic blockade of CTLA-4 or PD-1 pathways has been demonstrated to enhance T cell reactivity to tumor-specific antigens, translating to a significant improvement in overall survival. This anti-tumor effect can be further augmented when PD-1 and CTLA-4 antagonist antibodies are co-administered. The therapeutic impact of this combination is exemplified by the approval of this combination for advanced melanoma, as well as clinical benefit of the combination observed in NSCLC, mRCC, and most recently, mUC. AGEN1884, a human IgG1 antibody directed against CTLA-4, potently inhibits CTLA-4 binding to CD80 and CD86, resulting in enhanced T cell responsiveness in vitro, as well as in a vaccination model in non-human primates. A Phase 1 clinical study (NCT02694822) is currently ongoing to evaluate the safety and pharmacokinetic (PK)/pharmacodynamic (PD) relationships in patients with advanced solid tumors. AGEN2034 is a human IgG4 antibody that binds selectively to PD-1 with high affinity and potentiates T cell responsiveness via the blockade of PD-L1 and PD-L2 binding to PD-1. Here we evaluated the pharmacologic effect of combining AGEN1884 with AGEN2034, and other molecules targeting the PD-1/PD-L1 pathway, on primary human T cell immune responses. AGEN1884 combined effectively with AGEN2034, and other antibodies targeting the PD1/PD-L1 pathway, to promote superior T cell immune responses compared to monotherapies. Consistent with these in vitro findings, the co-administration of AGEN1884 with an anti-PD-1 antibody in cynomolgus monkeys (Macaca fascicularis) induced a dynamic PD effect, including a proliferative T cell response in peripheral blood, as compared to animals receiving either antibody alone. Finally, co-administration of an anti-mouse CTLA-4 antibody together with Agenus’ tumor-specific neo-epitope-based vaccine (AutoSynVax™) in mice induced effective amplification of vaccine-driven T cell responses, compared to animals that received the vaccine alone. These data further exemplify the versatility of harnessing antibody-mediated CTLA-4 blockade to influence apical events involved in T cell priming by antigen presenting cells. Taken together, these in vitro and in vivo findings demonstrate that the combination of AGEN1884 with PD-1 pathway blockade or with neo-epitope-ba