MacroGenics presents data on PD-L1 x CD137 DART program at symposium
MacroGenics announced that it had presented a poster at the EORTC-NCI-AACR Symposium. PD-1/PD-L1 blockade is a clinically proven cancer therapeutic strategy that releases an inhibitory brake on T-cell activation. Co-stimulation by CD137, also known as 4-1BB, has been shown to synergistically increase the activity of PD-1/PD-L1 axis blockade. Clinical application of such a combination approach, however, may be limited by toxicity associated with the systemic administration of CD137 agonists. Bispecific antibody targeting strategies afford the feasibility of localizing CD137 co-stimulation to the tumor microenvironment through simultaneous engagement of a tumor-expressed antigen and CD137 expressed on tumor infiltrating lymphocytes. In this poster, MacroGenics demonstrated that bispecific DART or TRIDENT proteins constructed using a proprietary PD-L1 blocking monoclonal antibody, or mAb, and a CD137-engaging mAb can further extend immune cell activation observed by concomitant PD-1/PD-L1 axis blockade and CD137 co-stimulation beyond that achieved by the combination of individual mAbs. The preclinical data presented show that PD-L1 x CD137 bispecific DART and TRIDENT molecules can switch on CD137 co-stimulation strictly in a PD-L1-dependent fashion, limiting the probability of systemic activation where PD-L1 is not expressed. Although tumor adaptive resistance via PD-L1 induction promotes immune escape, PD-L1 x CD137 bispecific molecules can exploit the upregulation of the checkpoint ligand to provide a co-stimulatory signal and further amplify concomitant checkpoint blockade. Additional investigations as a potential therapeutic approach to overcome limitations of existing PD-1/PD-L1-targeting strategies are ongoing.