An international research group directed by UMC Utrecht has developed and characterized two first-in-class antibodies that specifically block the high-affinity IgG receptor Fc?RI. Their findings open new perspectives for therapeutic modulation of Fc?RI-driven inflammation in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and immune thrombocytopenia (ITP).
The work has been published in Nature Communications.
Fc?RI, also known as CD64, is a high-affinity receptor on myeloid cells that binds to the Fc region of immunoglobulin G (IgG) antibodies. It plays a key role in the immune defense by triggering cellular functions such as phagocytosis and cytokine production.
In a normal immune response, Fc?RI is activated by immune complexes—clusters of antibodies bound to pathogens, which mark them for clearance. In autoimmune diseases, however, the immune system mistakenly targets the body’s own tissues (such as joint proteins in RA, nuclear antigens in SLE, or platelets in ITP), which results in the production of autoantibodies that form immune complexes.
These misdirected complexes activate Fc?RI unnecessarily, driving chronic inflammation and subsequent tissue damage.
The study, led by Prof. Jeanette Leusen, Ph.D. from the Antibody Therapy research group at the Center for Translational Immunology (UMC Utrecht) and carried out by Ph.D. candidate Tosca Holtrop MSc, was a true team effort, in collaboration with experts from Kiel University (Germany), Leiden University Medical Center, Utrecht University, and Friedrich-Alexander University Erlangen-Nürnberg (Germany).
Discovery of first-in-class antibodies
For over 30 years, scientists have tried to generate antibodies against the IgG-binding domain of CD64, but the receptor’s extremely high affinity for IgG made this impossible with earlier technologies. Combining the UMAB unique immunization method with novel phage display antibody libraries, the team bypassed this challenge by excluding the Fc region of the antibodies.
This allowed them to discover two unique Fc-silent antibodies, C01 and C04, that bind purely via their Fab domains to Fc?RI. Crystal structural analysis confirmed that C01 binds precisely within the IgG-binding site on EC2, making binding mutually exclusive.
High affinity for Fc?RI
Quantitative binding studies revealed that both antibodies have higher affinity for Fc?RI than human IgG, allowing them to efficiently displace IgG or pathogenic immune complexes up to 60% and block binding up to 90%. Importantly, neither antibody triggered Fc?RI activation, a critical distinction from earlier anti-Fc?RI antibodies, which could inadvertently trigger receptor clustering and cytokine release.
Subsequently, an in vitro model for immune thrombocytopenia was set-up, where C01 and C04 effectively inhibited opsonized platelets from binding to immune cells from ITP patients. In a preclinical in vivo ITP model, the antibodies significantly reduced IgG-dependent platelet depletion.
The antibodies were also tested in an in vitro rheumatoid arthritis models, where they effectively inhibited patient-derived autoantibody–immune complex binding to monocytes, macrophages, and neutrophils from healthy donors.
Promising therapeutic candidate drugs
The study demonstrates that direct Fab-mediated inhibition of Fc?RI is feasible and effective, opening a new avenue for treating autoimmune diseases characterized by IgG-autoantibody complexes.
By preventing immune complex–driven activation without triggering the receptor, C01 and C04 represent a promising next step toward targeted, inflammation-sparing immunotherapy.
“I think we found the needle in the haystack, after searching for over a decade and thanks to a true team effort,” says Jeanette Leusen, principal investigator of the study.
“Each research partner contributed a critical piece, from antibody discovery and structure determination to patient sample testing and preclinical models. Only together could we bring this to fruition. These antibodies not only provide a unique tool for studying Fc?RI biology, but also hold promise as therapeutic candidates in autoimmune and infectious diseases.”
Next steps include affinity maturation of the antibodies to further enhance blocking and displacement, as well as humanization of the initially mouse-derived antibodies to reduce immunogenicity and enable future clinical development. The new antibodies have already been patented by Utrecht Holdings, and efforts are being made to find partners for clinical development.
More information:
Holtrop T, et al. Preclinical assessment of two Fc?RI-specific antibodies that competitively inhibit immune complex-Fc?RI binding to suppress autoimmune responses, Nature Communications (2025). DOI: 10.1038/s41467-025-65133-z
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