Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses

Author(s):
Holtrop, T.; Brandsma, A.M.; Feitsma, L.J.; Krohn, S.; Moerer, P.; Haak, F. van den; Versnel, A.; Voss, L.; Passchier, E.M.; Nederend, M.; Jansen, J.H.M.; Mourik, A.G. van; Urbanus, R.T.; Woude, D. van der (0000-0001-8121-5879); Schutgens, R.E.G.; Toes, R.E.M. (0000-0002-9618-6414); Janssen, B.J.C.; Lux, A.; Budding, K.; Peipp, M.; Leusen, J.H.W.
Published
2025
Publication type
Article / Letter to editor

Abstract

Overactivation of Fc gamma RI by immune complexes (IC) is implicated in various autoimmune disorders and neuropathies. Currently, no effective Fc gamma RI-specific blocking antibodies are available. Here we report preclinical data revealing two anti-Fc gamma RI antibodies, C01 and C04, with high affinity, Fab-mediated binding within the IgG binding site on extracellular domain 2 of Fc gamma RI. Both C01 and C04 block 90% of IgG and IC binding, and displace similar to 60% of pre-bound ICs without activating Fc gamma RI, 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 FcR gamma(-/-) mice. Structural studies confirm that C01 and C04 achieve their blocking effects through Fab-mediated binding to Fc gamma RI. Our data thus suggest that C01 and C04 may offer therapeutic potential for autoimmune disorders.

Date issued
2025-11-19
Language
English
Publisher
NATURE PORTFOLIO
Is part of
Nature Communications (2025), No. 1
hdl
1887/4293865
doi
10.1038/s41467-025-65133-z