Modulating FcγRI with novel therapeutic antibodies in autoimmunity and cancer: The Silent Gatekeeper

Abstract

Our immune system protects us from infections with the help of antibodies, which bind to pathogens and activate immune cells through special receptors on their surface, known as Fc receptors. Upon binding, they induce effector functions such as phagocytosis, antibody‑dependent cellular cytotoxicity, cytokine release, immune complex clearance, and antigen presentation. Among these receptors, FcγRI (CD64) is the only high‑affinity human IgG receptor. Despite this unique property, FcγRI has historically received limited attention in the context of autoimmune disease and cancer, as it is continuously occupied by circulating monomeric IgG. This led to the long‑standing assumption that it is functionally inert under physiological and pathological conditions. This thesis demonstrates that this assumption is incorrect and shows that FcγRI functions as 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. These findings highlight a broader and previously underappreciated role for FcγRI in inflammatory pathology. In collaboration with researchers in Kiel, we developed seven monoclonal antibodies with distinct Fab‑mediated binding specificities using cellular immunization and phage display. Two of these antibodies are first-in-class: fully blocking FcγRI by binding directly within the IgG‑binding domain and effectively inhibiting IC engagement. These antibodies consistently outperformed the widely used clone 10.1. Using patient‑derived in vitro systems and a humanized in vivo model, we demonstrate that FcγRI blockade prevents binding and pathogenic activation in rheumatoid arthritis and immune thrombocytopenia, establishing FcγRI as a therapeutically relevant driver of autoimmunity. This research also demonstrates that FcγRI works closely with FcγRII (CD32) and FcγRIII (CD16), which differ in expression patterns, IgG subclass affinities, and polymorphisms that influence immune function and disease susceptibility. These receptors can reinforce or compensate one another and together shape IgG-dependent immune responses. The availability of a true FcγRI blocking antibody now enables precise dissection of individual FcγR contributions in autoimmune disease models. Beyond autoimmunity, FcγRI’s cytotoxic potential can be exploited for cancer immunotherapy, so we engineered the remaining 5 monoclonal antibodies as next-generation FcγRI‑targeting bispecific antibodies (bsAbs) that redirect monocytes and neutrophils toward tumor cells. These bsAbs demonstrated potent in vitro cytotoxicity and in vivo tumor clearance comparable to clinical benchmark antibodies. Furthermore, we introduced pH‑dependent binding into the C09×HER2 bsAb to reduce antigen sink effects caused by circulating monocytes to improve tumor selectivity. These innovations resulted in two patent applications. Lastly, we investigated how tumor acidosis shapes Fc receptor–mediated immunity. Acidic conditions significantly enhanced antibody‑dependent cytotoxicity by neutrophils and PBMCs while simultaneously suppressing tumor‑promoting functions such as reactive oxygen species production and NETosis. These findings reveal that the tumor microenvironment critically modulates FcγR‑driven effector responses and may be leveraged to improve therapeutic efficacy. Overall, this work provides new molecular tools, mechanistic insights and potential therapeutic strategies that redefine the role of FcγRI in immunity, allow for more precise steering of the immune system and lays the groundwork for future IgG-mediated therapies for autoimmune diseases and cancer.