Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology

CD137 (4-1BB) is a co-stimulatory receptor on immune
cells and
Nectin-4 is a cell adhesion molecule that is overexpressed in multiple
tumor types. Using a series of poly­(ethylene glycol) (PEG)-based linkers,
synthetic bicyclic peptides targeting CD137 were conjugated to Bicycles targeting Nectin-4. The resulting bispecific molecules
were potent CD137 agonists that require the presence of both Nectin-4-expressing
tumor cells and CD137-expressing immune cells for activity. A multipronged
approach was taken to optimize these Bicycle 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.