Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses
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<sup>-/-</sup> 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
- Elsemieke M. Passchier (ORCID: https://orcid.org/0000-0003-0655-3231)
- Matthias Peipp (ORCID: https://orcid.org/0000-0002-5088-3804)
- Rolf T. Urbanus (ORCID: https://orcid.org/0000-0002-1601-9393)
- Jeanette H.W. Leusen (ORCID: https://orcid.org/0000-0003-4982-6914)
- Tosca Holtrop (ORCID: https://orcid.org/0000-0003-0016-2475)
- Steffen Krohn
- Diane van der Woude (ORCID: https://orcid.org/0000-0001-8121-5879)
- Anja Lux (ORCID: https://orcid.org/0000-0001-9475-2147)
- B.J.C. Janssen (ORCID: https://orcid.org/0000-0002-8101-8370)
- L.J. Feitsma (ORCID: https://orcid.org/0000-0002-8403-1108)
- Petra Moerer
- Kevin Budding (ORCID: https://orcid.org/0000-0002-3827-7131)
- Anouk Versnel (ORCID: https://orcid.org/0009-0002-1529-7137)
- René E. M. Toes (ORCID: https://orcid.org/0000-0002-9618-6414)
- Maaike Nederend (ORCID: https://orcid.org/0000-0001-5918-4682)
- Roger E. G. Schutgens (ORCID: https://orcid.org/0000-0002-2762-6033)
- Leonie Voss (ORCID: https://orcid.org/0009-0005-7557-8688)
- Arianne M. Brandsma (ORCID: https://orcid.org/0000-0002-7969-4046)
- Anouk G. van Mourik (ORCID: https://orcid.org/0000-0002-3811-7373)
- Frederique van den Haak (ORCID: https://orcid.org/0009-0002-4362-6444)
- J.H. Marco Jansen
Institutions
- University of Applied Sciences Utrecht (NL)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Utrecht University (NL)
- Leiden University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Christian-Albrechts-Universität zu Kiel (DE)
- Immunomedics (Germany) (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-19
- DOI
- https://doi.org/10.1038/s41467-025-65133-z
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Leids Universitair Medisch Centrum