First-in-human phase 1 evaluation of the world’s first tri-specific SIRPα–PD-1–TGF-β Fc fusion protein HCB301 in advanced solid tumors.

e14570 Background: Tumor immune resistance arises from coordinated suppression of innate immunity, adaptive T-cell activity, and stromal immune exclusion. HCB301 is a world-first tri-specific Fc fusion protein rationally engineered to simultaneously block macrophage inhibition (SIRPα), relieve T-cell exhaustion (PD-1/PD-L1), and neutralize TGFβ–mediated immune exclusion through a mutant TGFβRII-based TGFβ trap. Preclinical studies confirmed concurrent activation across all three pathways, including innate and adaptive immune responses, while preserving hematologic safety. This first-in-human study evaluates the safety, tolerability, pharmacokinetics, and preliminary biological and antitumor activity of HCB301. Methods: HCB301-101 (NCT06487624) is an ongoing, open-label, multicenter, Phase 1 dose-escalation study using an adaptive BOIN-guided design to evaluate 7 predefined weekly HCB301 dose levels in patients with advanced solid tumors or relapsed/refractory classical Hodgkin lymphoma. Primary endpoints include safety, dose-limiting toxicities, and determination of maximum tolerated dose. Secondary endpoints include pharmacokinetics and immunogenicity. Exploratory endpoints include cytokine profiling, peripheral immune-cell phenotyping, circulating tumor DNA, and preliminary antitumor activity assessed by RECIST v1.1. Safety is assessed per CTCAE v5.0. Results: Across the initial dose levels evaluated, HCB301 demonstrated linear pharmacokinetics and a half-life of ~2.5 days. Treatment-related adverse events were consistent with immune activation and included transient hypoxemia, hypertension, and cytokine-associated symptoms, predominantly Grade 1–2 and manageable with protocol-specified monitoring. No unexpected immune-mediated, hematologic, or TGF-β–related toxicities were observed. Early pharmacodynamic analyses showed modulation of immune-associated biomarkers consistent with multi-specific target engagement across innate, adaptive, and stromal immune pathways. Preliminary signals of antitumor activity were observed in heavily pretreated patients. Conclusions: These first-in-human data establish the clinical feasibility of tri-specific Fc fusion immunotherapy, validating simultaneous targeting of innate, adaptive, and stromal immune resistance mechanisms within a single molecule. The favorable early safety profile, predictable pharmacokinetics, and initial biological and antitumor signals support continued dose escalation and cohort expansion of HCB301. Clinical trial information: NCT06487624 .