Eliciting or silencing complement activation: strategies for optimizing monoclonal antibodies functions

Tuning complement activity is essential to maximize therapeutic efficacy while minimizing off-target effects in monoclonal antibody (mAb) design. Complement-enhancing strategies are primarily applied to mAbs targeting pathogens, infected cells, tumors, or immunosuppressive cells within the tumor microenvironment. In contrast, complement-silencing strategies are more appropriate for mAbs used in autoimmune or inflammatory diseases, as well as in transplantation settings. This review highlights the symmetrical approaches available to either enhance or suppress complement activation: isotype or subtype selection, fragment crystallizable (Fc) region mutations, glycosylation engineering, and bispecific antibody design. These latter can either recruit C1q or block complement inhibitors to enhance activation or co-localize complement inhibitors. Additionally, Fc-deficient formats provide a straightforward way to eliminate complement-activating functions. As understanding of complement biology deepens and mAb engineering advances, especially with artificial intelligence-driven design, tailored modulation of complement activity will be central to next-generation mAb therapeutics.