RESUMO
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.
Assuntos
5'-Nucleotidase/imunologia , Anticorpos Bloqueadores/imunologia , Antígenos CD/imunologia , Apirase/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Anticorpos Bloqueadores/uso terapêutico , Antígenos CD/genética , Antineoplásicos/uso terapêutico , Apirase/deficiência , Apirase/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxaliplatina/uso terapêutico , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
Advanced cutaneous T-cell lymphoma (CTCL) remains an unmet medical need, which lacks effective targeted therapies. In this study, we report the development of IPH4102, a humanized monoclonal antibody that targets the immune receptor KIR3DL2, which is widely expressed on CTCL cells but few normal immune cells. Potent antitumor properties of IPH4102 were documented in allogeneic human CTCL cells and a mouse model of KIR3DL2(+) disease. IPH4102 antitumor activity was mediated by antibody-dependent cell cytotoxicity and phagocytosis. IPH4102 improved survival and reduced tumor growth in mice inoculated with KIR3DL2(+) tumors. Ex vivo efficacy was further evaluated in primary Sézary patient cells, sorted natural killer-based autologous assays, and direct spiking into Sézary patient peripheral blood mononuclear cells. In these settings, IPH4102 selectively and efficiently killed primary Sézary cells, including at unfavorable effector-to-target ratios characteristic of unsorted PBMC. Together, our results offer preclinical proof of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.