Harnessing the Dual Power of IPH4301: Unleashing Cytotoxic and Immunomodulatory Effects in Cancer Therapy

The abstract discusses the role of MICA and MICB, along with ULPB1-6, as ligands for NKG2D, a receptor found on natural killer (NK) cells and certain T cells. These ligands are expressed in response to cellular stress, such as in tumors or during infections and chronic inflammation, and are regulated at multiple levels. They are considered promising targets for cancer therapy due to their association with cellular stress and tumor development. The induction of NKG2D ligands by radiation and chemotherapy suggests potential for combined treatment strategies. Furthermore, MICA and MICB are implicated in immunomodulation, as they can lead to the internalization of NKG2D, affecting the function of cytotoxic cells in cancer patients. Recent findings indicate that disrupting NKG2D-ligand interactions can enhance anti-tumor responses, and the expression of NKG2D ligands on immunosuppressive macrophages in cancer suggests a potential therapeutic role for anti-MICA/B antibodies in targeting myeloid-derived suppressor cells.

The IPH4301 antibody has been identified for its ability to bind to all MICA and MICB allotypes and its dual action as an immunomodulatory agent and a direct cytotoxic agent against MICA/B-expressing tumor cells. In vitro and in vivo studies have demonstrated its efficacy in inducing the killing of tumor cells through antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). Additionally, IPH4301 has been shown to block the binding of MICA/B to NKG2D, restoring NKG2D expression and function on primary NK and T cells. The antibody also has the capacity to counteract immunosuppression induced by suppressive myeloid cells, as evidenced by its ability to trigger ADCC by NK cells that were otherwise impaired.

IPH4301 is a novel monoclonal antibody with both cytotoxic and immunomodulatory properties, representing a first-in-class approach to anti-MICA/B therapy. Current efforts are focused on conducting regulatory toxicology studies and preparing a clinical-grade product for clinical trials. The research was presented at the 107th Annual Meeting of the American Association for Cancer Research.