Preclinical characterization and first-in-human phase I dose-escalation results with JYB1907, a novel anti-GARP-TGF-β1 complex monoclonal antibody in patients with advanced solid tumors

Transforming growth factor-β1 (TGF-β1) promotes immunosuppression in the tumor microenvironment via the GARP-latent TGF-β1 complex on regulatory T cells. JYB1907 is a humanized IgG4 monoclonal antibody targeting this complex. Preclinically, JYB1907 bound GARP-latent TGF-β1 complex with high affinity and specificity, inhibited the release of TGF-β1, and showed monotherapy antitumor activity and enhanced anti-PD-1 combination activity in humanized mouse models. Despite binding to platelets that constitutively express the GARP-latent TGF-β1 complex, it did not induce activation. In a first-in-human phase I dose-escalation trial (ClinicalTrials.gov identifier: NCT05821595; registered 20 April 2023 under the title “JYB1907 in Subjects With Advanced Solid Tumors”), patients with advanced solid tumors received intravenous JYB1907 (0.5-30 mg/kg every 3 weeks). No dose-limiting toxicities occurred; the maximum tolerated dose was not reached. The most common treatment-emergent adverse events were grade 1-2 elevated D-dimer (50.0%), anemia (35.7%), and increased C-reactive protein (28.6%). Pharmacokinetics were dose-proportional with a long half-life (8-16 days). No anti-drug antibodies were detected. Disease control (stable disease) was achieved in 27.3% of evaluable patients; median progression-free survival was 42 days. JYB1907 demonstrated a manageable safety profile and favorable pharmacokinetics, supporting its further development in combination therapies.