Unlocking the potential of agonist antibodies for treating cancer using antibody engineering

Agonist antibodies that target immune checkpoints, such as those in the tumor necrosis factor receptor (TNFR) superfamily, are an important class of emerging therapeutics due to their ability to regulate immune cell activity, especially for treating cancer. Despite their potential, to date, they have shown limited clinical utility and further antibody optimization is urgently needed to improve their therapeutic potential. Here, we discuss key antibody engineering approaches for improving the activity of antibody agonists by optimizing their valency, specificity for different receptors (e.g., bispecific antibodies) and epitopes (e.g., biepitopic or biparatopic antibodies), and Fc affinity for Fcγ receptors (FcγRs). These powerful approaches are being used to develop the next generation of cancer immunotherapeutics with improved efficacy and safety. Agonist antibodies that activate the tumor necrosis factor receptor (TNFR) superfamily on T cells are being broadly pursued for cancer therapy. However, clinical translation is stymied by poor safety and efficacy.Clustering of TNFRs is critical for mediating potent receptor activation and bivalent antibodies have shown limited capacity to mediate receptor clustering on the cell surface. Thus, antibody engineering approaches for improving certain properties (i.e., multivalency and/or biepitopic targeting) are needed to enhance receptor clustering and agonist function.Beyond antigen-binding fragment (Fab) engineering, antibody isotype selection and improving Fcγ receptor interactions are influential in improving antitumor immunity in preclinical studies and clinical trials.Receptor binding epitopes and occupancy levels must also be considered to mediate optimal receptor signaling and antitumor immunity.