Tri-specific immune checkpoint engineering: Clinical translation of HCB301 targeting SIRPα, PD-L1, and TGF.

Abstract

TPS90 Background: Tumor immune escape arises from coordinated suppression across innate, adaptive, and stromal compartments, including PD-1/PD-L1-mediated T-cell inhibition, CD47-SIRPα-mediated suppression of macrophage phagocytosis, and TGF-β-driven immune exclusion within the tumor microenvironment. Therapeutic strategies targeting single or dual pathways may incompletely address this layered resistance architecture. HCB301 was developed following clinical translation of SIRPα-based macrophage checkpoint targeting to extend modulation across multiple nonredundant resistance mechanisms within a single biologic molecule. HCB301 is a first-in-class tri-specific IgG4 Fc fusion protein integrating an anti-PD-L12 domain, an engineered high-affinity SIRPα variant to disrupt CD47 signaling, and a mutant TGF-β receptor II ligand trap designed to sequester active TGF-β isoforms. Preclinical evaluation demonstrated simultaneous engagement of all three targets, restoration of PD-1/PD-L1 T-cell signaling, enhancement of macrophage-mediated phagocytosis without erythrocyte engulfment, and selective inhibition of TGF-β-induced Smad2 phosphorylation, and coordinated immune activation in humanized xenograft and transgenic tumor models. These findings support tri-axis immune checkpoint modulation as a strategy to remodel the tumor microenvironment. Methods: HCB301-101 (NCT06487624) is an open-label, multicenter Phase 1 dose-escalation study enrolling patients with advanced solid tumors or relapsed/refractory classical Hodgkin lymphoma. The study employs a Bayesian Optimal Interval (BOIN) design to evaluate escalating intravenous dose levels. Primary objectives are safety, tolerability, and determination of the maximum tolerated dose and/or the recommended Phase 2 dose. Secondary objectives include pharmacokinetics, pharmacodynamic assessment of pathway modulation, and antitumor activity. Exploratory analyses include immune profiling to characterize coordinated modulation of macrophage, T-cell, and stromal compartments. Enrollment is ongoing. Clinical trial information: NCT06487624 .