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

Abstract

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.

Keywords: 4-1BB; CD137; CD40; OX40; immunotherapy; monoclonal antibody.

Figure 1.

Summary of antibody engineering approaches for optimizing agonist activity for therapeutic applications. Agonist activity can be optimized via engineering the Fab, hinge and Fc regions to enhance receptor clustering and activation.

Figure 2.

Multivalent Fc-fusion protein potently activates GITR receptor. Schematic illustration of a hexavalent Fc-fusion protein, which is composed of a trimeric form of the human GITR ligand ectodomain fused on the Fc region of each heavy chain, shows potent receptor clustering and enhanced T cell activation. Adapted from [12].

Figure 3.

DR5-FAP bispecific antibodies promote Fc-independent DR5 receptor clustering and activation. Schematic illustration of tumor-specific antibodies targeting (left) only the DR5 receptor and (right) also the fibroblast activation protein (FAP) expressed on surrounding stromal cells to enhance DR5 receptor clustering and activation. Adapted from [18].

Figure 4.

Inverse relationship between hinge region flexibility and receptor activation for anti-mouse CD40 agonist antibodies with human constant domains. Schematic illustration of the negative correlation between CD40 agonist activity and hinge flexibility of human IgG isotypes. Adapted from [27].

Figure 5.

Selective FcγR engagement is required for optimal human CD40 antibody agonism and anti-tumor activity. Schematic illustration of the impact of activating and inhibitory FcγRs on CD40 receptor agonism. Selective antibody binding to the inhibitory receptor FcγRIIB is positively correlated with receptor activation. Adapted from [35].

Figure 6.

CD137 epitope strongly influences the activity of agonist antibodies. Schematic illustration of the impact of CD137 receptor epitopes on the activity of two agonist antibodies, namely urelumab and utomilumab. The non-ligand blocking antibody (urelumab) targets membrane-distal cysteine-rich domain 1 (CRD1) and displays enhanced agonist activity. In contrast, the ligand-blocking antibody (utomilumab) binds to CRDs 3 and 4 and displays reduced agonist function. Adapted from [46].