Translational advancement of HCB101, a third-generation SIRPα–Fc ligand trap targeting the CD47-SIRPα axis: Integrated phase 1 monotherapy and phase 1b/2a combination development.

TPS89 Background: The CD47–SIRPα axis functions as a central innate immune checkpoint that suppresses macrophage-mediated phagocytosis and enables tumor immune evasion. Clinical development of CD47-targeted agents has been constrained by on-target hematologic toxicity and a limited therapeutic window. HCB101 is a rationally engineered SIRPα–IgG4 Fc fusion protein incorporating AI-guided structural optimization designed to reduce red blood cell binding while preserving macrophage activation and Fc effector function. Published preclinical studies demonstrated high-affinity CD47 engagement, enhanced phagocytosis, macrophage repolarization within the tumor microenvironment, and broad antitumor activity across xenograft models without hematologic toxicity in nonhuman primates, supporting advancement into clinical evaluation and rational combination development. HCB101 has been granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of gastric cancer. Methods: HCB101-101 (NCT05892718) is an open-label, first-in-human Phase 1 BOIN-guided dose-escalation study evaluating weekly intravenous HCB101 monotherapy (0.08 to 36 mg/kg) in patients with advanced solid tumors or lymphomas. Primary objectives are safety, tolerability, and determination of the recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics, receptor occupancy, and antitumor activity. HCB101-201 (NCT06771622) is a multicenter Phase 1b/2a multicohort study evaluating HCB101 as an innate immune checkpoint backbone in combination with tumor-specific standard-of-care regimens across nine advanced solid tumor types, including gastric cancer, triple-negative breast cancer, colorectal cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, ovarian cancer, and small cell lung cancer. The Phase 1b portion employs BOIN-guided dose escalation to establish the combination RP2D, followed by tumor-specific expansion cohorts. Primary endpoints include safety and RP2D determination. Secondary endpoints include pharmacokinetics, pharmacodynamics, and antitumor activity per RECIST v1.1. Enrollment in both studies is ongoing. Clinical trial information: NCT05892718 .