Targeting Tumor-Restricted T-Cell Costimulation with MP0310: A Novel 4-1BB/FAP Bispecific DARPin Approach

The abstract discusses the development of a novel 4-1BB agonist, MP0310, which is designed to target tumors more effectively and reduce systemic toxicity. MP0310 is a bispecific DARPin molecule that binds to both 4-1BB and fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts. Unlike traditional antibodies, MP0310 lacks an Fc domain, which may contribute to its reduced systemic side effects.

In vitro studies have shown that MP0310 is a potent T cell co-stimulator, but its activity is limited to the presence of FAP-positive cells. This feature was further confirmed in humanized mouse xenograft models, where MP0310 induced a strong co-stimulation of CD8 T cells leading to tumor growth inhibition without causing hepatotoxicity or exacerbating graft versus host disease.

In non-human primates, MP0310 did not induce systemic T cell proliferation in the absence of FAP-positive tumors, suggesting its potential for safe administration. The study concludes that MP0310's tumor-restricted T cell co-stimulation could prevent toxicities associated with systemic 4-1BB activation, offering a promising approach to enhance anti-tumor immune responses. This could enable higher dosing and better integration with checkpoint inhibitors and other immunotherapies. MP0310 is now being prepared for clinical trials.