Shanghai Henlius Biotech has registered a first-in-human Phase I clinical trial evaluating pipeline candidate HLX3901 in adults with advanced small cell lung cancer (SCLC) or neuroendocrine carcinoma (NEC) who have progressed on prior platinum-based therapy. The open-label study, posted to ClinicalTrials.gov under identifier NCT07416695, plans to enroll up to 138 patients at Shanghai Chest Hospital. HLX3901 is a proprietary DLL3 × DLL3 × CD3 × CD28 tetra-specific antibody — designed to deliver two mechanistically distinct T-cell activation signals while anchoring to two separate epitopes on the same tumor-associated antigen. No other molecule with this four-specificity architecture has entered human testing for SCLC or NEC.
HLX3901’s tetraspecific design rationale
HLX3901 is an intravenously administered multispecific antibody engineered by Shanghai Henlius to bind four targets simultaneously: two distinct epitopes on DLL3 (delta-like ligand 3), plus CD3 on the T-cell receptor complex and the co-stimulatory receptor CD28. The biparatopic DLL3 engagement is intended to increase binding avidity to tumor cells, while the simultaneous ligation of CD3 and CD28 provides both the primary activation signal and the co-stimulatory signal needed for full T-cell effector function — a pairing often described in immunology as “signal 1 plus signal 2.”
DLL3 is a Notch pathway ligand expressed on the surface of the majority of SCLC tumors and a substantial fraction of extrapulmonary neuroendocrine carcinomas, with minimal expression on normal adult tissues. That expression pattern has made it a focus of drug development across multiple modalities, including bispecific antibodies, antibody-drug conjugates, and CAR-T cells. Preclinical data from independent groups have shown that DLL3-targeted bispecific antibodies can redirect T cells to kill SCLC cells, and that combining DLL3 bispecifics with PD-1 blockade enhances anti-tumor activity in mouse models.
The addition of CD28 co-stimulation is the design element that most clearly distinguishes HLX3901 from existing DLL3-directed T-cell engagers. First-generation CD3-only bispecifics can induce T-cell exhaustion over repeated stimulation cycles because they lack the co-stimulatory input that physiological T-cell activation requires. Whether incorporating CD28 into a multispecific format resolves this limitation in patients without introducing disproportionate cytokine release or other immune toxicities is the central question that this Phase I trial is designed to address.
Trial specifics
The study is structured in two parts. Phase Ia uses an accelerated titration design transitioning to a conventional 3+3 dose-escalation scheme across seven prespecified dose levels, with a 28-day dose-limiting toxicity (DLT) observation window after first administration. A backfill cohort of two to three dose groups will collect additional safety and pharmacokinetic data. Phase Ib is a dose-expansion study at the recommended Phase II dose (RP2D) identified during escalation, intended to generate preliminary efficacy and confirmatory safety data in both SCLC and NEC.