Effect of MP0317, a FAP x CD40 DARPin, on safety profile and tumor-localized CD40 activation in a phase 1 study in patients with advanced solid tumors

Background: Major challenges of the clinical development of CD40 agonists are toxicity due to systemic CD40 activation and peripheral target-mediated drug disposition. MP0317, a CD40 agonist DARPin (designed ankyrin repeat protein), is exclusively activated by binding to fibroblast activation protein (FAP) on cancer-associated fibroblasts. This enables local CD40 activation in the tumor microenvironment (TME) and reduces systemic toxicity. Methods: This Phase 1, multicenter, open-label, dose-escalation study assessed safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 mono-therapy (NCT05098405; data cut-off 15 Jan 2024). Eligible adults with selected advanced solid tumors (based on predicted FAP expression) were enrolled into 9 dose-escalation cohorts of MP0317 0.03–10 mg/kg administered IV 3-weekly (Q3W) or weekly (Q1W) until disease progression or unacceptable toxicity. Blood biomarkers were analyzed by immuno-assays and flow cytometry, and paired tumor biopsies by RNA sequencing and immunofluorescence. Results: Dose-escalation enrolment is complete and 46 patients received $1 MP0317 dose, including 24 women (52%) and 22 men (48%). Median age at enrolment was 63 years (range 35–79). Patients received a median of 4 prior treatment lines (range 1–13). Colorectal cancer was the most frequent tumor type (12 patients, 26%). MP0317 maximum tolerated dose was not reached; only one patient experienced a dose-limiting toxicity (asymptomatic Grade 3 alanine and aspartate aminotransferases elevation), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade #2 fatigue was the most frequent adverse reaction (15 patients, 30%), followed by Grade #2 infusion-related reaction, nausea and anorexia in 8, 7, and 5 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 11 patients (24%). Serum PK data showed MP0317’s half-life extended properties and sustained exposure at higher doses. Paired tumor biopsies confirmed the colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies at doses $1.5 mg/kg was associated with an increase in antigen-presenting (dendritic and B cells), plasma and T follicular helper cell abundance, as well as enhanced dendritic cell maturation and IFNg production in the TME. CXCL10 serum level increases post MP0317 treatment supported these findings. Only minor changes were seen in pro-inflammatory cytokines. Conclusions: MP0317 had a favorable safety profile in 46 patients across all 9 dose-escalation cohorts exploring Q3W and Q1W regimens. Doses $1.5 mg/kg showed evidence of pharmacodynamic TME modulation, indicating tumor-localized CD40 activation. The data support further clinical evaluation of MP0317 including combination with complementary anticancer therapies. Clinical trial information: NCT05098405. Research Sponsor: Molecular Partners AG.