Phase 1 trial of HCB101, a novel Fc-based anti-SIRPα-CD47 fusion protein, in subjects with advanced cancers.

2584 Background: CD47-targeting agents face challenges, including “on-target, off-tumor” toxicities affecting red blood cells, limited efficacy, and manufacturing complexities. Clinical holds and discontinued trials highlight these difficulties. These issues have constrained their therapeutic potential and broadened the need for better solutions. HCB101 is an engineered human SIRPα fused to human IgG4 crystallizable fragment (Fc) protein developed using the proprietary FBDB platform, blocks the signal of the SIRPα-CD47 pathway, enhancing macrophage-mediated phagocytosis. Preclinical studies show HCB101’s potent antitumor activity across solid tumors and hematological malignancies. HCB101’s safety profile in repeat-dose cynomolgus monkey toxicity studies revealed acceptable red blood cell or platelet abnormalities, supporting its potential as a best-of-the-kind SIRPα-CD47 directed immunotherapy. Methods: This Phase 1, open-label, dose-escalation trial evaluates HCB101’s safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in advanced solid tumors or non-Hodgkin lymphoma (NHL) in the US, Taiwan, and mainland China. Eligible adults have treatment-refractory cancers, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. The 3+3 dose-escalation Bayesian Optimal Interval (BOIN) design assesses dose-limiting toxicities (DLTs) in the first 28-day cycle. Secondary endpoints include objective response rate (ORR), duration of response, and progression-free survival. Exploratory endpoints include CD47 receptor occupancy (RO), correlating response, and immune cell infiltration (NCT05892718). Results: 32 participants (median age 61 years; 74% male) enrolled across 7 escalating cohorts (0.08-5.12 mg/kg, QW). Patients had a median of 4 prior regimens. 68% had solid tumors, and 32% had NHLs. HCB101 was well tolerated, only 1 DLT reported at 2.56 mg/kg dose level (G3 platelet decrease). The most common treatment related AEs were anemia (17%), all grade 1or 2, that did not require blood transfusion or other treatments. HCB101 systemic exposure increased in a dose-dependent manner. Preliminary efficacy showed 29% stable disease (6 patients) in 21 evaluable patients, with 2 patients have SD > 16 wks, and 1 patient has SD > 23 wks. Doses ≥1.28 mg/kg achieved ≥90% CD47 RO in peripheral T cells. Conclusions: HCB101 demonstrated an acceptable safety profile and preliminary antitumor activity in heavily pretreated advanced cancer patients. These findings support its further clinical development, including expansion cohorts to evaluate efficacy in specific tumor types or in combination with other agents. Clinical trial information: NCT05892718 .