Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology
Punit Upadhyaya, Julia Kristensson, Johanna Lahdenranta, Elizabeth Repash, Jun Ma, Jessica Kublin, Gemma Mudd, Lia Luus, Phil Jeffrey, Kristen E. Hurov, Kevin McDonnell, Nicholas Keen
Abstract
tumor-targeted immune cell agonists by exploring the impact of chemical configuration, binding affinity, and pharmacokinetics on CD137 agonism and antitumor activity. This effort resulted in the discovery of BT7480, which elicited robust CD137 agonism and maximum antitumor activity in syngeneic mouse models. A tumor-targeted approach to CD137 agonism using low-molecular-weight, short-acting molecules with high tumor penetration is a yet unexplored path in the clinic, where emerging data suggest that persistent target engagement, characteristic of biologics, may lead to suboptimal immune response.