Immunoglobulin G Fc–Fc and Immunoglobulin G–C1q protein–protein interfaces (IgG Fc–Fc/C1q PPI)

The Immunoglobulin G (IgG) Fc–Fc and IgG–C1q protein–protein interfaces are structural domains essential for the initiation of the classical complement pathway. When IgG antibodies bind to antigens on a cell surface, they can organize into hexameric clusters through specific Fc–Fc interactions (Diebolder et al., 2014, Science). These hexamers provide a high-affinity docking site for C1q, the initiating protein of the complement cascade, which leads to complement-dependent cytotoxicity (CDC) and target cell lysis (Ugurlar et al., 2020, Nature Communications). In drug development, these interfaces are primary targets for engineering therapeutic antibodies with enhanced effector functions. For example, the HexaBody platform utilizes mutations like E430G to stabilize hexamer formation and increase potency against tumor cells (de Jong et al., 2016, PLOS Biology). Conversely, inhibiting these interactions is a therapeutic strategy for autoimmune diseases where inappropriate complement activation causes tissue damage. The precise modulation of these interfaces allows for the fine-tuning of an antibody's ability to recruit the immune system against pathogens or malignant cells.

Other names

IgG hexamerization interfaceC1q binding siteFc-mediated complement activation interfaceIgG Fc-Fc interface

Modulation of IgG hexamerization and C1q recruitment to regulate the classical complement pathway.