Nature communications · 2025
Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses.
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Holtrop Tosca, Brandsma Arianne M, Feitsma Louris J, Krohn Steffen, Moerer Petra, van den Haak Frederique, Versnel Anouk, Voss Leonie, Passchier Elsemieke M, Nederend Maaike, Jansen J H Marco, van Mourik Anouk G, Urbanus Rolf T, van der Woude Diane, Schutgens Roger E G, Toes Rene E M, Janssen Bert J C, Lux Anja, Budding Kevin, Peipp Matthias, Leusen Jeanette H W
Аннотация
Overactivation of FcγRI by immune complexes (IC) is implicated in various autoimmune disorders and neuropathies. Currently, no effective FcγRI-specific blocking antibodies are available. Here we report preclinical data revealing two anti-FcγRI antibodies, C01 and C04, with high affinity, Fab-mediated binding within the IgG binding site on extracellular domain 2 of FcγRI. Both C01 and C04 block 90% of IgG and IC binding, and displace ~60% of pre-bound ICs without activating FcγRI, thereby minimizing the risk of aggravating inflammation. In the context of autoimmunity, C01 and C04 inhibit RA patient-derived autoantibody-IC binding to monocytes, macrophages and activated neutrophils, meanwhile they also inhibit the binding of opsonized platelets to monocytes from patients with immune thrombocytopenia. In vivo, C01 and C04 reduce IgG-dependent platelet depletion in humanized immunodeficient FcRγ-/- mice. Structural studies confirm that C01 and C04 achieve their blocking effects through Fab-mediated binding to FcγRI. Our data thus suggest that C01 and C04 may offer therapeutic potential for autoimmune disorders.