Future Engineering Strategies
Monoclonal antibodies are potent therapeutics in a number of chronic or once incurable diseases. However, there is still extensive unmet clinical need as well as considerable room for improvement in many existing therapeutics.
Further understanding of how antibody structure affects FcγR function is essential for future development of more potent and effective mAbs. Already, engineering of the IgG Fc and its glycan has proved a potent and effective approach for increasing the clinical effectiveness, functional specificity and safety of therapeutic mAbs and is an emerging pathway to the development of the “next‐gen” therapeutics.
Future directions in the development and use of therapeutic antibodies should increasingly mimic normal protective antibody responses, which are polyclonal and elicited in the context of innate receptor engagement which includes the FcR as well as other powerfully responsive systems including the Toll‐like receptors and complement receptors. Furthermore, the mixed subclass nature of these normal antibody responses suggests that circumstances may arise in therapeutic strategies where there is value in having distinctly modified Fcs for the nuanced engagement of different FcγR family members. Treatments comprising multiple mAbs and immune stimulants are under investigation in infectious disease for neutralization coverage of variant strains. Indeed, such an approach may be most effective in emerging infectious disease such as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. The use of multiple mAbs tailored for distinct effector functions and targeting different epitopes will maximize the opportunity for cocktailing of effector functions in different types of diseases. Indeed, in a small but contemporary example outside of infectious disease, the FDA‐approved combination in adenocarcinoma therapy uses a cocktail of two mAbs, pertuzumab and trastuzumab, against Her2.123
Rather than one type of Fc to conquer all, the combined use of appropriately selected mAbs whose individual components are enhanced for the engagement of different FcγR members may utilize multiple components of the spectrum of effector responses on offer by the immune system. Such “next‐gen” biologics will begin to realize the full potential of FcγR‐mediated antibody immune therapeutics and offer transformational change for the treatment of intractable and incurable diseases.