The high-affinity Fc gamma receptor I (FcγRI) plays a crucial role in the immune system. Also known as CD64, FcγRI is a high-affinity receptor on myeloid cells that bind to the Fc region of IgG antibodies and trigger cellular functions such as phagocytosis and cytokine production. In a normal immune response, FcγRI is activated by immune complexes—clusters of antibodies bound to pathogens, which mark them for clearance.

However, overactivation of FcγRI by immune complexes is implicated in various autoimmune disorders and neuropathies. Currently, no effective FcγRI-specific blocking antibodies are available.

Now, researchers at UMC Utrecht have developed and characterized two first-in-class antibodies that specifically block the high-affinity IgG receptor FcγRI. Their findings open new perspectives for therapeutic modulation of FcγRI-driven inflammation in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and immune thrombocytopenia.

This work is published in Nature Communications in the paper, “Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses.”

For over 30 years, scientists have tried to generate antibodies against the IgG-binding domain of CD64, but the receptor’s high affinity for IgG presented a challenge. Now, by combining a unique immunization method with novel phage display antibody libraries, the team was able to exclude the Fc region of the antibodies, allowing them to discover two unique Fc-silent antibodies, C01 and C04, that bind purely via their Fab domains to FcγRI. Crystal structure analysis confirmed that C01 binds precisely within the IgG-binding site on EC2, making binding mutually exclusive.

Quantitative binding studies revealed that both antibodies have higher affinity for FcγRI than human IgG, allowing them to efficiently displace IgG or pathogenic immune complexes up to 60% and block binding up to 90%. Specifically, the authors note that “both C01 and C04 block 90% of IgG and IC binding, and displace ~60% of pre-bound ICs.” In addition, neither antibody triggered FcγRI activation, a critical distinction from earlier anti-FcγRI antibodies, which could inadvertently trigger receptor clustering and cytokine release.

In a preclinical in vivo immune thrombocytopenia mouse model (humanized immunodeficient FcRγ^-/- mice) the antibodies significantly reduced IgG-dependent platelet depletion. When tested in in vitro rheumatoid arthritis models, the antibodies effectively inhibited patient-derived autoantibody–immune complex binding to monocytes, macrophages, and neutrophils from healthy donors.

The study opens 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 over a decade and thanks to a true team effort,” says Jeanette Leusen, PhD, professor at UMC Utrecht. “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.”