TY - JOUR
T1 - Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses
AU - Holtrop, Tosca
AU - Brandsma, Arianne M.
AU - Feitsma, Louris J.
AU - Krohn, Steffen
AU - Moerer, Petra
AU - van den Haak, Frederique
AU - Versnel, Anouk
AU - Voss, Leonie
AU - Passchier, Elsemieke M.
AU - Nederend, Maaike
AU - Jansen, J. H.Marco
AU - van Mourik, Anouk G.
AU - Urbanus, Rolf T.
AU - van der Woude, Diane
AU - Schutgens, Roger E.G.
AU - Toes, Rene E.M.
AU - Janssen, Bert J.C.
AU - Lux, Anja
AU - Budding, Kevin
AU - Peipp, Matthias
AU - Leusen, Jeanette H.W.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/11/19
Y1 - 2025/11/19
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105022220995
U2 - 10.1038/s41467-025-65133-z
DO - 10.1038/s41467-025-65133-z
M3 - Article
C2 - 41258113
AN - SCOPUS:105022220995
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10068
ER -