Tumor-localized CD40 agonism with MP0317, a FAP x CD40 DARPin, reprograms the tumor microenvironment in patients with advanced solid tumors: an open-label, nonrandomized, dose-escalation phase 1 study.

This phase 1, open-label, nonrandomized, dose-escalation study evaluated MP0317 (FAP x CD40 DARPin) in adults with advanced solid tumors. Forty-six patients across nine cohorts received MP0317 at doses ranging from 0.03 to 10 mg kg-1 intravenously weekly or every 3 weeks. The primary outcome measure was safety; secondary and exploratory outcome measures included antitumor activity, pharmacokinetics and pharmacodynamics. Most treatment-related adverse events were of grades 1 and 2 (95%); a maximum tolerated dose was not reached. One patient achieved an unconfirmed partial response and 14 patients had stable disease. MP0317 serum pharmacokinetics confirmed extended half-life properties; terminal half-life estimates increased with dose and ranged from 21.8 to 120 h. Paired tumor biopsies confirmed colocalization of MP0317 with fibroblast activation protein and CD40. Activation of the CD40 pathway in the tumor microenvironment was shown by increased infiltration of antigen-presenting, plasma and follicular helper T cells, dendritic cell maturation, interferon-γ signaling and circulating immune markers. Collectively, these data confirm a favorable safety profile for MP0317 and support further clinical evaluation in combination with complementary immunotherapies. ClinicalTrials.gov registration: NCT05098405 .