The differentiated SIRPα–IgG4 Fc fusion protein HCB101 in monotherapy and combination therapy.

2655 Background: The CD47–SIRPα axis is a central innate immune checkpoint that enables tumor immune evasion. No prior CD47-directed program has demonstrated meaningful monotherapy activity, limited by on-target hematologic toxicity, constraining development. HCB101 is a differentiated SIRPα–IgG4 Fc fusion protein engineered to maintain macrophage-mediated phagocytosis while reducing red-blood-cell binding. This study assesses whether HCB101 can overcome historical class limitations by achieving a wide therapeutic safety margin and durable monotherapy antitumor activity, while also serving as a backbone for combination immunotherapy efficacy across standard-of-care (SOC) regimens. Methods: HCB101-101 (NCT05892718) is a first-in-human Phase 1 monotherapy dose-escalation study evaluating weekly IV dosing from 0.08 to 36 mg/kg. HCB101-201 (NCT06771622) is a Phase 1b/2a multi-cohort trial assessing HCB101 combined with SOC agents across 9 solid tumor types, including gastric cancer (GC), triple-negative breast cancer (TNBC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma, ovarian cancer, and small cell lung cancer. Primary endpoints are safety, tolerability, and determination of the recommended Phase 2 dose; secondary and exploratory endpoints include pharmacokinetics (PK), pharmacodynamics, efficacy, and biomarkers. Results: In HCB101-101, 36 mg/kg has been reached. To 09JAN2026, 2 confirmed partial responses (HNSCC: –42% at 5.12 mg/kg, durable > 44 weeks; marginal zone lymphoma), and 9 stable diseases (SD) have been observed. PK was dose-proportional (T 1/2 ~2.9 days) with receptor occupancy plateauing at > 99% by ≥8 mg/kg. In HCB101-201, 2L-GC treated with HCB101 plus ramucirumab and paclitaxel demonstrated 8 PRs and 5 SDs, with two additional patients at 12 mg/kg pending first assessment. In mid-dose cohorts (5.12–8 mg/kg), 8 of 10 subjects achieved PRs and 100% achieved disease control, with regressions up to –78.2%. In 1L HER2+ GC, 4 subjects showed 3 PR (up to –57.6%) and 1 SDs. In 1L-TNBC, 6 of 6 subjects achieved disease control, including 3 PRs. Across cohorts, HCB101 demonstrated manageable safety with reversible cytopenias and no unexpected immune-mediated toxicities. Conclusions: HCB101 demonstrates a class-distinguishing profile for a macrophage checkpoint inhibitor, with durable monotherapy antitumor activity and a wide therapeutic window up to 36 mg/kg, addressing long-standing limitations of CD47-directed therapies. The early and reproducible combination activity across multiple solid tumors, including GC, HER2+ GC, and TNBC, has supported rapid cohort expansion. These data position HCB101 as a next-generation innate immune checkpoint backbone with broad clinical applicability and a clear rationale for future combination-based registrational development. Clinical trial information: NCT05892718 .