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

Tosca Holtrop, Arianne M. Brandsma, Louris J. Feitsma, Steffen Krohn, Petra Moerer, Frederique van den Haak, Anouk Versnel, Leonie Voss, Elsemieke M. Passchier, Maaike Nederend, J. H. Marco Jansen, Anouk G. van Mourik, Rolf T. Urbanus, Diane van der Woude, Roger E. G. Schutgens, Rene E. M. Toes, Bert J. C. Janssen, Anja Lux, Kevin Budding, Matthias Peipp and Jeanette H. W. Leusen ()
Additional contact information
Tosca Holtrop: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Arianne M. Brandsma: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Louris J. Feitsma: Utrecht University, Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science
Steffen Krohn: University Medical Center Schleswig-Holstein and Christian-Albrechts-University Kiel, Division of Antibody-Based Immunotherapy, Department of Internal Medicine II
Petra Moerer: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Frederique van den Haak: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Anouk Versnel: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Leonie Voss: Friedrich-Alexander-Universität Erlangen-Nürnberg, Division of Genetics, Department of Biology
Elsemieke M. Passchier: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Maaike Nederend: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
J. H. Marco Jansen: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Anouk G. van Mourik: Leiden University Medical Center, Department of Rheumatology
Rolf T. Urbanus: Utrecht University, Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht
Diane van der Woude: Leiden University Medical Center, Department of Rheumatology
Roger E. G. Schutgens: Utrecht University, Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht
Rene E. M. Toes: Leiden University Medical Center, Department of Rheumatology
Bert J. C. Janssen: Utrecht University, Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science
Anja Lux: Friedrich-Alexander-Universität Erlangen-Nürnberg, Division of Genetics, Department of Biology
Kevin Budding: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology
Matthias Peipp: Utrecht University, Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science
Jeanette H. W. Leusen: University Medical Center Utrecht, Immunotherapy Laboratory, Center for Translational Immunology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65133-z

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