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

Holtrop T, Brandsma AM, Feitsma LJ, Krohn S, Moerer P, van den Haak F, Versnel A, Voß L, Passchier EM, Nederend M, Jansen JH, van Mourik AG, Urbanus RT, van der Woude D, Schutgens RE, Toes RE, Janssen BJ, Lux A, Budding K, Peipp M, Leusen JH (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 10068

Journal Issue: 1

DOI: 10.1038/s41467-025-65133-z

Abstract

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.

Authors with CRIS profile

Leonie Voß Lehrstuhl für Genetik Anja Lux Lehrstuhl für Genetik

Involved external institutions

University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Bijvoet Center for Biomolecular Research NL Netherlands (NL) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Leiden University Medical Center NL Netherlands (NL)

How to cite

APA:

Holtrop, T., Brandsma, A.M., Feitsma, L.J., Krohn, S., Moerer, P., van den Haak, F.,... Leusen, J.H. (2025). Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-65133-z

MLA:

Holtrop, Tosca, et al. "Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses." Nature Communications 16.1 (2025).

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