Abstract
Immune checkpoint inhibitors have revolutionizedcancer treatment. However, many cancers are resis-tant to ICIs, and the targeting of additional inhibitorysignals is crucial for limiting tumor evasion. The pro-duction of adenosine via the sequential activity ofCD39 and CD73 ectoenzymes participates to thegeneration of an immunosuppressive tumor micro-environment. In order to disrupt the adenosinepathway, we generated two antibodies, IPH5201and IPH5301, targeting human membrane-associ-ated and soluble forms of CD39 and CD73, respec-tively, and efficiently blocking the hydrolysis ofimmunogenic ATP into immunosuppressive adeno-sine. These antibodies promoted antitumor immunityby stimulating dendritic cells and macrophages andby restoring the activation of T cells isolated fromcancer patients. In a human CD39 knockin mousepreclinical model, IPH5201 increased the anti-tumoractivity of the ATP-inducing chemotherapeutic drugoxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies andtheir combination with immune checkpoint inhibitorsand chemotherapies in cancer