AGEN2373 is a Conditionally-Active Agonist Antibody Targeting the Costimulatory Receptor CD137 for the Treatment of Human Malignancies.

e14005 Background: Agonist antibodies targeting CD137 are potent inducers of tumor-reactive T cell proliferation, cytokine production, and cytotoxicity, and have been explored clinically for their ability to enhance immune cell-mediated destruction of tumor cells. Despite early signs of clinical activity, the development of first-generation anti-CD137 antibodies has been hampered by on-target dose-limiting hepatotoxicity or poor clinical activity. Subsequent CD137 therapies have therefore sought to localize CD137 agonism to the tumor microenvironment (TME) to potentially improve tolerability in patients. However, these approaches may also limit the potential benefit of CD137 signaling outside the TME that contributes to anti-tumor immunity, such as T cell priming in tumor draining lymph nodes. Here we describe the pharmacologic and non-clinical safety profile of a next-generation anti-CD137 monospecific antibody, AGEN2373. Methods: Flow cytometry and surface plasmon resonance-based binding, superantigen-driven immune cell activation, and luminescent reporter cell line assays were developed to test the ability of AGEN2373 to induce CD137 signaling. A non-clinical, multi-dose safety study was conducted wherein cynomolgus monkeys were injected intravenously with 100 mg/kg doses of AGEN2373. Results: AGEN2373 engages cell-expressed human and cynomolgus monkey CD137, and provides potent CD137 co-stimulation only in the presence of CD137 ligand and/or Fc gamma receptor-expressing antigen presenting cells. No changes in clinical parameters, importantly no sign of liver toxicity, were observed after administration of AGEN2373 in cynomolgus monkeys. Conclusions: AGEN2373, a novel conditionally-active anti-CD137 agonist antibody that is well-tolerated in non-human primates, is expected to have clinical activity in patients with human malignancies by its ability to selectively enhance tumor immunity in the context of immune co-stimulation.