About this program
IPH4301 is a program to develop a first-in-class anti-MICA/B therapeutic antibody in oncology. MICA/B is a highly polymorphic ligand of the NK cell activating receptor NKG2D.
MICA/B expression is specifically induced in several highly prevalent solid tumors and with a high frequency (Colon, kidney, endometrium, melanoma, lung, liver, ovarian, breast).
Chronic exposure to MICA/B down-regulates NKG2D at the surface of NK and CD8 T cells, suppressing NKG2D+ NK and CD8 T cell activity. Furthermore, MICA/B expression can be induced on tumor associated, immuno-suppressive macrophages. Hence, targeting MICA/B with an antibody that is both ADCC-inducing and blocking NKG2D binding to MICA/B can act by a dual mechanism of action: tumor antigen targeting and immunomodulation.
IPH4301 is currently in IND-enabling studies.
Mechanism of action of anti-MICA/B
Mathieu Bléry and Eric Vivier et al, 2018. NKG2D-MICA interaction: a paradigm shift in innate recognition The Journal of Immunology Eric Vivier et al, 2018. Dr. Eric Vivier discusses a 1999 paper by Thomas Spies that revealed a new mode of immune recognition via NKG2A on NK cells. The Journal of Immunology ImmunoCasts Deng et al, 2015. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection Science Xiao et al, 2015. Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype J Hematol Oncol. Ames et al, 2015. Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells Oncoimmunology Crane et al, 2014. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients Proc Natl Acad Sci Molfetta et al, 2014. c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells Eur J Immunol. Liu et al, 2013. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis J Clin Invest. Raulet et al, 2013. Regulation of ligands for the NKG2D activating receptor Annu Rev Immunol. Pahl et al, 2013. Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity Cancer Immunol Immunother. Champsaur et al, 2010. Effect of NKG2D ligand expression on host immune responses Immunol Rev. von Lilienfeld-Toal et al, 2010. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked Cancer Immunol Immunother. Jinushi et al, 2006. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity Proc Natl Acad Sci Holdenrieder et al, 2006. Soluble MICA in malignant diseases Int J Cancer Steinle et al, 2001. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family Immunogenetics Bauer et al, 1999. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA Science