IPH4301, an antibody targeting MICA and MICB exhibits potent cytotoxic activity and immunomodulatory properties for the treatment of cancer

MICA and MICB, and ULPB1-6, are ligands for NKG2D, an activating receptor expressed on NK cells and subsets of T cells. Expression of MICA and MICB is induced by cellular stress in transformed tumor cells, upon infections or at sites of chronic inflammation. Their expression is tightly regulated by complex mechanisms both at the mRNA and protein levels. As markers of cellular stress and tumorigenesis, MICA and MICB proteins are attractive candidates for targeting by a cytotoxic antibody. Moreover, ionizing radiation and various chemotherapies that cause cellular stress have been shown to induce expression of NKG2D ligands, opening interesting options for combination therapies. MICA and MICB are also compelling targets for immunomodulation. MICA and -B cause internalization of NKG2D, leading to reduced cell surface NKG2D levels and desensitization of cytotoxic effector cells in cancer patients. It was recently reported that blockade of the interactions between NKG2D and its ligands could lead to significant anti-tumor responses in mouse models. Moreover, NKG2D ligand expression was induced on immunosuppressive macrophages in cancer patients and in mouse tumor models, raising the possibility that anti-MICA/B antibodies may be used to counter local immunosuppression by targeting myeloid derived suppressor cells. We have selected the IPH4301 antibody for its ability to bind to all allotypes of MICA and MICB, and for its dual action as an immunomodulatory agent, as well as direct cytotoxicity towards MICA/B-expressing tumor cells. First, IPH4301 induces killing of MICA/B expressing tumor cells through antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) measured towards MICA expressing cells in vitro. In vivo ADCC/ADCP efficacy was demonstrated in several preventive and curative settings using MICA expressing cell lines or endogenous tumors. Second, IPH4301 blocks the binding of MICA/B to NKG2D. In a tumor context of chronic triggering, NKG2D downmodulation has been described in several studies of cancer patients. This modulation is mainly induced by expression of MICA/B, and less by the ULBPs. By blocking the MICA/NKG2D interaction, IPH4301 effectively restored NKG2D expression and function in vitro on primary NK and T cells. Third, we show that IPH4301 can override immunosuppression induced by suppressive myeloid cells. In vitro differentiated M2 macrophages, but not M1 macrophages, have the capacity to impair cytotoxic functions of autologous NK cells towards MICA expressing tumor cell lines. This suppression could be overcome by IPH4301, which triggered ADCC by these otherwise impaired NK cells. Altogether, IPH4301 is a novel, first-in-class anti-MICA/B mAb with both cytotoxic and immunomodulatory properties. Ongoing work aims to perform regulatory toxicology studies and manufacture a clinical grade product for testing in a clinical trial. Citation Format: Ariane Morel, Nicolas Viaud, Cecile Bonnafous, Sylvia Trichard, Alix Joulin-Giet, Samia Mizari, Gwendoline Grondin, Nadia Anceriz, J. Zhang, J. Jarzen, J. Wu, Gwendoline Grondin, Laetitia Cohen-Tannoudji, Yannis Morel, Benjamin Rossi, Carine Paturel, Renaud Buffet, Laurent Gauthier, Nicolai Wagtmann, Mathieu Blery. IPH4301, an antibody targeting MICA and MICB exhibits potent cytotoxic activity and immunomodulatory properties for the treatment of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1491.