Perrot et al. identified two antibodies, IPH5201 and IPH5301 that inhibit membrane and soluble human CD39 and CD73 respectively – major ecto-enzymes regulating ATP levels and immunosuppressive adenosine production. Blocking CD39, which is frequently expressed on PD-1+ TILs, with IPH5201 inhibited ATP hydrolysis in vitro and synergized with chemotherapy to enhance antitumor immunity in a mouse model. Inhibiting CD73 with IPH5301 resulted in a dose-dependent increase in CD4+ and CD8+ T cells. Targeting both CD73 and CD39 resulted in a synergistic effect on T cell proliferation in PBMCs from breast cancer patients.
Contributed by Katherine Turner
Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
Author Info: (1) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (2) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut
Author Info: (1) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (2) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut regional du Cancer de Montpellier, 34298 Montpellier, France. (3) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (4) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (5) OREGA Biotech, 69130 Ecully, France. (6) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut regional du Cancer de Montpellier, 34298 Montpellier, France. (7) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (8) OREGA Biotech, 69130 Ecully, France. (9) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (10) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut regional du Cancer de Montpellier, 34298 Montpellier, France; Departement de Dermatologie, Centre Hospitalier Regional Universitaire de Montpellier et Faculte de Medecine, Universite de Montpellier, 34295 Montpellier, France. (11) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (12) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (13) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (14) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (15) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (16) CNRS, Aix Marseille Universite, AFMB, Architecture et Fonction des Macromolecules Biologiques, 13009 Marseille, France. (17) CNRS, Aix Marseille Universite, AFMB, Architecture et Fonction des Macromolecules Biologiques, 13009 Marseille, France. (18) Institut National de la Sante et de la Recherche Medicale (INSERM) UMR-S 976, Universite Paris Diderot, Sorbonne Paris Cite, Laboratory of Human Immunology, Pathophysiology and Immunotherapy, 75475 Paris, France. (19) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut regional du Cancer de Montpellier, 34298 Montpellier, France; Departement d'Immunologie, Centre Hospitalier Regional Universitaire de Montpellier et Faculte de Medecine, Universite de Montpellier, 34295 Montpellier, France. (20) OREGA Biotech, 69130 Ecully, France. (21) MI-mAbs, Aix Marseille Universite, 117 Avenue de Luminy, 13009 Marseille, France. (22) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. (23) Aix Marseille Universite, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France. (24) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France; Aix Marseille Universite, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France; Service d'Immunologie, Marseille Immunopole, Hopital de la Timone, Assistance Publique-Hopitaux de Marseille, 13005 Marseille, France. Electronic address: vivier@ciml.univ-mrs.fr. (25) Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. Electronic address: carine.paturel@innate-pharma.fr. (26) IRCM, Institut de Recherche en Cancerologie de Montpellier, INSERM U1194, Universite de Montpellier, Institut regional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address: nathalie.bonnefoy@inserm.fr.
