An international research team led by UMC Utrecht has developed two pioneering antibodies that specifically inhibit the high-affinity IgG receptor FcγRI. This breakthrough, published in Nature Communications, provides new therapeutic avenues for treating autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and immune thrombocytopenia (ITP).
FcγRI, also known as CD64, is a receptor found on myeloid cells, integral to the immune system’s function. It binds to the Fc region of immunoglobulin G (IgG) antibodies, triggering vital processes like phagocytosis and cytokine production. In a healthy immune response, FcγRI is activated by immune complexes—clusters of antibodies that bind to pathogens for clearance. However, in autoimmune diseases, the immune system mistakenly targets the body’s own tissues, leading to the production of autoantibodies that form harmful immune complexes. These complexes can activate FcγRI excessively, resulting in chronic inflammation and tissue damage.
The study, led by Prof. Jeanette Leusen, Ph.D., from the Antibody Therapy research group at the Center for Translational Immunology, involved collaboration with experts from Kiel University, Leiden University Medical Center, Utrecht University, and Friedrich-Alexander University Erlangen-Nürnberg.
Innovative Antibody Discovery
For over three decades, scientists have struggled to create antibodies against the IgG-binding domain of CD64, due to its high affinity for IgG. The research team utilized a unique immunization method developed by UMC alongside novel phage display antibody libraries to overcome this challenge. By excluding the Fc region of antibodies, they successfully identified two unique “Fc-silent” antibodies, designated C01 and C04.
Crystal structural analysis demonstrated that C01 binds precisely within the IgG-binding site on the second extracellular domain (EC2) of FcγRI, ensuring that its binding is mutually exclusive with IgG. Quantitative binding studies revealed that both antibodies exhibit a higher affinity for FcγRI than human IgG, effectively displacing IgG or pathogenic immune complexes by up to 60% and blocking binding by up to 90%. Crucially, neither antibody activated FcγRI, distinguishing them from previous anti-FcγRI antibodies that could inadvertently trigger receptor clustering and cytokine release.
In vitro models were established for ITP, where C01 and C04 effectively prevented opsonized platelets from binding to immune cells from patients. In a preclinical model for ITP, the antibodies significantly reduced IgG-dependent platelet depletion. Furthermore, in models for rheumatoid arthritis, they effectively inhibited binding of patient-derived autoantibody-immune complexes to monocytes, macrophages, and neutrophils from healthy donors.
Promising Therapeutic Potential
The findings illustrate that direct Fab-mediated inhibition of FcγRI is both feasible and effective. This opens new possibilities for treating autoimmune diseases characterized by IgG-autoantibody complexes. By preventing immune complex-driven activation without triggering the receptor, C01 and C04 signify a promising advancement toward targeted, inflammation-sparing immunotherapy.
“I think we found the needle in the haystack after searching for over a decade, thanks to a true team effort,” stated Jeanette Leusen. “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 FcγRI biology but also hold promise as therapeutic candidates in autoimmune and infectious diseases.”
Future steps involve affinity maturation of the antibodies to enhance blocking and displacement capabilities, as well as humanization of the initially mouse-derived antibodies to reduce immunogenicity and facilitate clinical development. The new antibodies have already been patented by Utrecht Holdings, and efforts are underway to secure partnerships for their clinical advancement.
For further details, refer to the study by Holtrop T, et al., titled “Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses,” published in Nature Communications in March 2025.