Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners.

Abstract

Anti-tumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment including recruitment of arginase (ARG) expressing myeloid cells which deplete L-arginine essential for optimal T cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing anti-tumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition (TGI) in various syngeneic models. Anti-tumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1 and anti-NKG2A, and combination benefits with type I interferon (IFN) inducers including polyI:C and radiation. Our pre-clinical data demonstrates AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and anti-tumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.