Phase I study of Y101D, a bispecific antibody targeting PD-L1 and TGF-β in patients with advanced solid tumors

Abstract Background Y101D is a novel bispecific antibody targeting PD-L1 and TGF-β. This multicenter phase I study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of Y101D in patients with metastatic or locally advanced solid tumors. Methods Patients who failed standard therapies were enrolled. In the dose-escalation and expansion phases, Y101D was administered intravenously every 2 weeks (Q2W) at 1, 3, 10, 20, and 30 mg/kg. Primary objectives were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in escalation, safety and objective response rate (ORR) in expansion. Secondary objectives included pharmacokinetics/pharmacodynamics parameters, and immunogenicity. Results Among 50 enrolled patients, the most common treatment-related adverse events (TRAEs) were aspartate aminotransferase elevation (20.0%), gingival bleeding (18.0%), alanine aminotransferase elevation (14.0%), rash (14.0%), and proteinuria (14.0%). Grade ≥3 TRAEs occurred in 10.0% of patients, with no grade 4/5 TRAEs. Immune-related adverse events (irAEs) occurred in 22.0%, predominantly grade 1–2. No DLTs were observed, and MTD was not reached. One extensive-stage small cell lung cancer (ES-SCLC) patient (20 mg/kg Q2W) achieved a confirmed partial response (ORR: 2.1%, 95% CI 0.1–11.3%). Median progression-free survival and overall survival were 1.3 months (95% CI 0.9–1.3) and 10.5 months (95% CI 6.6–12.7), respectively. The pharmacokinetic characteristics of single and multiple doses of 20 mg/kg Q3W and 1200 mg Q3W supported the administration schedule of once every 3 weeks. PD-L1 target occupancy exceeded 95% at 2 hours post-dose across all cohorts and remained sustained pre-dose. Conclusions Y101D monotherapy exhibited a manageable safety profile and on-target pharmacodynamic activity, with limited antitumor activity as a single agent. Further evaluation in disease-focused cohorts and rational combination regimens is warranted, including in ES-SCLC. Clinical Trial number registration NCT05028556