Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies

• Published in: Cell reports (Cambridge) Vol. 27; no. 8; pp. 2411 - 2425.e9
• Main Authors: Perrot, Ivan, Michaud, Henri-Alexandre, Giraudon-Paoli, Marc, Augier, Séverine, Docquier, Aurélie, Gros, Laurent, Courtois, Rachel, Déjou, Cécile, Jecko, Diana, Becquart, Ondine, Rispaud-Blanc, Hélène, Gauthier, Laurent, Rossi, Benjamin, Chanteux, Stéphanie, Gourdin, Nicolas, Amigues, Beatrice, Roussel, Alain, Bensussan, Armand, Eliaou, Jean-François, Bastid, Jérémy, Romagné, François, Morel, Yannis, Narni-Mancinelli, Emilie, Vivier, Eric, Paturel, Carine, Bonnefoy, Nathalie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2019; Elsevier
• Subjects: 5'-Nucleotidase - genetics; 5'-Nucleotidase - immunology; 5'-Nucleotidase - metabolism; Adenosine - metabolism; adenosine pathway; Adenosine Triphosphate - metabolism; Animals; Antibodies, Blocking - immunology; Antibodies, Blocking - therapeutic use; Antigens, CD - genetics; Antigens, CD - immunology; Antineoplastic Agents - therapeutic use; Apyrase - deficiency; Apyrase - genetics; Apyrase - immunology; Cancer; cancer immunotherapies; CD39; CD73; Cell Line, Tumor; Disease Models, Animal; Gene Knock-In Techniques; Humans; Immunology; immunosuppression; Immunotherapy; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Life Sciences; Melanoma - drug therapy; Melanoma - immunology; Melanoma - mortality; Melanoma - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxaliplatin - therapeutic use; Survival Rate; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; therapeutic antibodies; tumor micro-environment; Tumor Microenvironment; CD73; CD39; cancer immunotherapies; tumor micro-environment; immunosuppression; therapeutic antibodies; adenosine pathway
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.091

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. [Display omitted] •IPH5201 and IPH5301 block cell-borne and soluble CD39 and CD73, respectively•IPH5201 maintains immunogenic extracellular ATP•When used in combination with chemotherapy, IPH5201 promotes antitumor immunity•Targeting CD39 and CD73 synergistically promotes cancer patient T cell activation The production of adenosine via CD39 and CD73 ectoenzymes participates in an immunosuppressive tumor microenvironment. Perrot et al. generated two antibodies, IPH5201 and IPH5301, targeting human CD39 and CD73, respectively. In vitro and in vivo data support the use of anti-CD39 and anti-CD73 mAbs in combination cancer therapies.