Modulating FcγRI with novel therapeutic antibodies in autoimmunity and cancer

Summary

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Our immune system protects us from infections with the help of antibodies. These antibodies bind to pathogens and activate immune cells through special receptors on their surface, known as Fc receptors. One of these receptors, FcγRI (CD64), was long considered unimportant as it is continuously occupied by circulating IgG antibodies. As a result, it appeared “silent” and it did not receive a lot of attention.

Our research shows that this assumption is incorrect. FcγRI is in fact a silent gatekeeper: a receptor that seems passive but can transmit powerful activating or inhibitory signals depending on the type of antibody or immune complex that binds to it. This means that FcγRI plays a much larger role in both autoimmune diseases and cancer than previously recognized.

In collaboration with researchers in Kiel, we developed a panel of seven new antibodies that each bind FcγRI in a unique way. Two of these antibodies are first-in-class: they fully block FcγRI and prevent activation in autoimmune models of rheumatoid arthritis and immune thrombocytopenia. The remaining antibodies were designed as bispecific cancer therapies, directing immune cells toward tumor cells and showing effectiveness comparable to clinical antibodies. These innovations resulted in two patent applications.

This research also further demonstrates that FcγRI works closely together with FcγRII (CD32) and FcγRIII (CD16). Each receptor has distinct expression patterns, IgG subclass affinities, and polymorphisms that influence function and disease susceptibility. These receptors can reinforce or compensate one another, and together they determine IgG-dependent immune responses. Our identification of a true blocking antibody for FcγRI now enables precise dissection of individual FcγR contributions in disease models.

Overall, this work provides new tools and insights to more precisely steer the immune system and lays the groundwork for future IgG-mediated therapies for autoimmune diseases and cancer.