A phase Ia first-in-human study of BPB-101, a novel trifunctional antibody targeting the GARP/TGF-β complex and PD-L1, in patients with locally advanced or metastatic solid tumors

BPB-101 is a first-in-class, humanized trifunctional bispecific IgG1 antibody targeting the GARP/TGF-β complex, active TGF-β, and PD-L1, with preclinical evidence of immunomodulatory and antitumor activity. This phase Ia study aimed to assess the safety, tolerability, pharmacology, and preliminary antitumor activity of BPB-101. A modified accelerated titration design (6, 20, and 60 mg) was followed by a 3 + 3 escalation (200–1800 mg), with intravenous dosing every 3 weeks (Q3W). Eligible patients with advanced or metastatic solid tumors who had received prior standard systemic treatment were enrolled. The primary objectives were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity. At the data cutoff of January 26, 2025, 19 patients with advanced tumors were enrolled. Treatment-related adverse events (TRAEs) occurred in 15 patients (78.9%), with the most common TRAEs being infusion-related reactions (26.3%), anemia (26.3%), and asthenia (21.1%). Grade ≥ 3 TRAEs were reported in two patients (10.5%), both of whom had anemia, with one patient each in the 400 mg and 800 mg groups. No DLTs or treatment-related deaths occurred, and the MTD was not reached. One patient in the 1800 mg cohort permanently discontinued treatment due to an immune-related TRAE (myalgia). BPB-101 exposure increased approximately dose-proportionately at doses ≥ 800 mg. Peripheral PD assessments showed high receptor occupancy (RO) and reductions in circulating TGF-β1 levels in the 1200 mg and 1800 mg cohorts. The 1200 mg and 1800 mg Q3W doses were selected as RP2Ds for further evaluation. Among 17 patients in the efficacy analysis set (EAS), one achieved confirmed immune partial response (iPR) and seven achieved immune stable disease (iSD). The overall immune objective response rate (iORR) was 5.9% (95% CI, 0.1–28.7), and the immune disease control rate (iDCR) was 47.1% (95% CI, 23.0–72.2). BPB-101 showed a manageable safety profile, peripheral PD activity, and preliminary antitumor activity, supporting further evaluation in expansion cohorts. This study was registered with ClinicalTrials.gov (NCT05869240); part of the study was reported at ESMO ASIA 2025 as an oral presentation. Abstract No: 158O.