Researchers led by UMC Utrecht have developed pioneering antibodies that inhibit inflammation in autoimmune diseases by targeting specific immune receptor sites. This breakthrough opens promising avenues for novel treatments.
An international team of researchers led by UMC Utrecht has announced a breakthrough in the fight against autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and immune thrombocytopenia (ITP). The team has developed and characterized two first-in-class antibodies, C01 and C04, which specifically block the high-affinity IgG receptor FcγRI, also known as CD64. This groundbreaking discovery could pave the way for new treatments aimed at reducing inflammation and tissue damage in various autoimmune conditions.
The research, published today in Nature Communications, was spearheaded by Jeanette Leusen, a full professor in the Antibody Therapy research group at UMC Utrecht’s Center for Translational Immunology, and carried out by doctoral candidate Tosca Holtrop. The project was a collaborative effort involving experts from Kiel University in Germany, Leiden University Medical Center, Utrecht University and Friedrich-Alexander University Erlangen-Nürnberg in Germany.
In autoimmune diseases, the immune system mistakenly targets the body’s own tissues, leading to chronic inflammation. FcγRI plays a significant role in this process by binding to immunoglobulin G (IgG) antibodies and triggering cellular functions like phagocytosis and cytokine production.
Normally, FcγRI is activated by immune complexes — clusters of antibodies bound to pathogens. In autoimmune diseases, however, the production of autoantibodies leads to the formation of immune complexes that activate FcγRI unnecessarily, resulting in persistent inflammation and tissue damage.
For over three decades, scientists have attempted to generate antibodies against the IgG-binding domain of CD64, but the receptor’s high affinity for IgG made this challenging.
The researchers overcame this hurdle by using the UMAB immunization method combined with novel phage display antibody libraries. This approach enabled them to discover the unique Fc-silent antibodies C01 and C04, which bind exclusively via their Fab domains to FcγRI.
Quantitative binding studies revealed that both antibodies have a higher affinity for FcγRI than human IgG, allowing them to displace IgG or pathogenic immune complexes efficiently. Critically, neither antibody triggered FcγRI activation, which distinguishes them from earlier attempts that inadvertently caused further inflammation.
In laboratory models, C01 and C04 effectively inhibited the binding of opsonized platelets to immune cells in ITP patients, and significantly reduced IgG-dependent platelet depletion in preclinical models. Additionally, in models for rheumatoid arthritis, the antibodies inhibited the binding of patient-derived autoantibody-immune complexes to monocytes, macrophages and neutrophils.
“I think we found the needle in the haystack, after searching over a decade and thanks to a true team effort,” Leusen added. “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.”
The next steps for the research team include enhancing the antibodies’ affinity, humanizing the initially mouse-derived antibodies to reduce immunogenicity, and seeking partners for clinical development.
The antibodies have already been patented by the Utrecht Holdings, highlighting the significant potential of this discovery.
Source: University Medical Center Utrecht