(Arcus) AB598, a Therapeutic Anti-Human CD39 Antibody, Binds and Inhibits CD39 Enzymatic Activity In Vivo to Promote Anti-Tumor Immunity

Introduction

AB598, which potently binds and inhibits CD39 enzymatic activity, is being developed as a cancer immunotherapy. CD39 catalyzes the conversion of extracellular adenosine triphosphate (ATP) into adenosine monophosphate (AMP), resulting in decreased amounts of immunostimulatory ATP and increased levels of immunosuppressive adenosine in the tumor microenvironment (TME). By blocking CD39 in the TME, local levels of ATP increase, leading to myeloid cell activation and improved tumor control.

AB598 is highly potent and specific, binding and inhibiting human CD39 with sub-nanomolar potency. AB598 does not bind or inhibit murine CD39, presenting a challenge for studying CD39 inhibition in an immunocompetent syngeneic tumor model. Human CD39 knock-in (hCD39KI) mice were employed to examine the preclinical anti-tumor efficacy of AB598 in animals with a fully competent immune system. The use of a murine model with natural expression and distribution of human CD39, targetable by AB598, allowed for a more physiological assessment of CD39 inhibition in solid tumors compared to the alternative use of human cancer cells growing in immunodeficient mice.