Abstract B076: Phase 1 Monotherapy and Combination Data for HCB101, a Novel SIRPα–Fc Innate Checkpoint Fusion Protein

Abstract Background HCB101 is a rationally engineered 3.5th-generation SIRPα–Fc fusion protein via the FBDBTM platform to overcome the safety and efficacy limitations of first- and second-generation CD47 inhibitors. Affinity- and Fc-based modifications minimize red blood cell binding, reduce cytopenias, and enhance macrophage-mediated tumor clearance. Preclinical studies demonstrated potent CD47-SIRPα blockade, strong macrophage activation, and broad combinability with chemotherapy, PD-1 inhibitors, and anti-angiogenic agents. We report new clinical and translational findings from the ongoing HCB101-101 monotherapy trial and the HCB101-201 combination study. Methods HCB101-101 (NCT05892718) is a Phase 1, open-label, BOIN-guided dose-escalation study evaluating weekly IV HCB101 in subjects with advanced solid tumors and lymphoma. Endpoints include safety, pharmacokinetic (PK), receptor occupancy (RO), immune biomarkers, and preliminary antitumor activity. HCB101-201 (NCT06771622) is a Phase 1b/2a study evaluating HCB101 in combination with standard-of-care backbones across multiple tumor types, including chemo-, VEGF-, HER2-, PD-1-, and EGFR-directed regimens such as ramucirumab + paclitaxel in gastric cancer. Endpoints include safety, RP2D determination, PK/PD, efficacy, and translational biomarkers. Results As of the data cutoff, 61 subjects received HCB101 monotherapy across dose levels up to 30 mg/kg QW. One DLT (Grade 3 thrombocytopenia at 2.56 mg/kg) occurred, and the MTD was not reached. HCB101 showed a distinct cytopenia-sparing profile, with infrequent Grade ≥3 cytopenias and manageable, low-grade infusion reactions. Evidence of antitumor activity was observed in tumor types historically unresponsive to prior CD47 agents, including confirmed partial responses (PRs) in head and neck cancer (durable ≥42 weeks) and marginal zone lymphoma, as well as durable stable disease in ovarian cancer (>40 weeks). PK was approximately dose-proportional (T1/2 ∼2.98 days), receptor occupancy exceeded 99% at ≥8 mg/kg, confirming biologically active exposures. In HCB101-201, early combination cohorts showed no unexpected overlapping toxicities with chemotherapy, PD-1 inhibitors, or anti-VEGF regimens, allowing full-dose administration of combination partners. Exploratory pharmacodynamic analyses demonstrated enhanced macrophage activation, favorable cytokine modulation, and early reductions in ctDNA in selected subjects. Preliminary tumor shrinkage was observed across gastric cancer, triple-negative breast cancer, and head and neck cancer cohorts, supporting biological synergy with standard-of-care backbones. Conclusions HCB101 demonstrates clean, cytopenia-sparing innate checkpoint inhibition, robust target engagement, and broad innate immune activation across monotherapy and combination settings. Early combination results show favorable tolerability and biologic synergy with chemotherapy and anti-angiogenic agents. Dose escalation to 36 mg/kg and Phase 2 expansion cohorts in gastric, colorectal, and head and neck cancers are ongoing. Citation Format: Fangling Ning, Nicholas O. Iannotti, Wei-Hong Cheng, Chia-Chi Lin, Ji Ma, Peter Mu-Hsin. Chang, Ying Wang, William Jeffery. Edenfield, Wenyu Li, Tian Zhang, Jian Zhang, Guohua Chen, Fei Mo, Langtian Abigail. Yu, Alvin Luk. Phase 1 Monotherapy and Combination Data for HCB101, a Novel SIRPα–Fc Innate Checkpoint Fusion Protein [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B076.