• First patient dosed with HLX3901, marking clinical validation of Henlius’ proprietary multi-specific TCE platform

• DLL3×CD3×CD28 synergistic mechanism designed to overcome immunotherapy resistance in hard-to-treat tumors such as SCLC

• Innovation-driven pipelines continue to advance, with multiple next-generation assets entering clinical stages

Shanghai, China – April 30, 2026 – Shanghai Henlius Biotech, Inc. (2696.HK) today announced that the first patient has been dosed in a phase 1 clinical study (HLX3901-FIH101) of HLX3901, a next-generation tetra-specific antibody (DLL3×DLL3×CD3×CD28) developed based on the company’s proprietary T-cell engager (TCE) platform, in patients with advanced small cell lung cancer (SCLC) or neuroendocrine carcinoma. This milestone marks the initial clinical validation of Henlius’ multi-specific TCE platform.

Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand^1-2 highly expressed in approximately 80% of SCLC and various neuroendocrine carcinomas,^3-5 while showing minimal expression in normal tissues,^6-7 making it an ideal therapeutic target. To date, bispecific TCEs targeting DLL3 and CD3 have been approved⁸ and demonstrated promising clinical activity.⁹ However, insufficient T-cell infiltration and the immunosuppressive state within the tumor microenvironment (TME) remain critical bottlenecks limiting the efficacy of TCEs.^10-11

Importantly, in the absence of co-stimulatory signaling (signal 2), CD3-mediated activation alone (signal 1) may lead to T-cell anergy,¹² thereby restricting the durability of anti-tumor responses. CD28, a critical co-stimulatory receptor expressed on T cells, provides the essential second signal for full T-cell activation through interaction with its ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APCs) .^13-14

HLX3901 is designed to address these challenges through a tetra-specific architecture targeting dual epitopes of DLL3, CD3, and CD28, enabling a “dual-signal” mechanism that integrates T-cell activation (signal 1) with co-stimulation (signal 2). By simultaneously engaging CD3 and CD28 on the T-cell surface, HLX3901 enhances T-cell activation, proliferation, and survival, thereby strengthening targeted cytotoxicity against DLL3-positive tumor cells. This synergistic activation is expected to improve the therapeutic window and sustain anti-tumor immune responses, even in tumors with low T-cell infiltration.

Preclinical studies indicate that HLX3901 exhibits enhanced cytotoxic effects at low effector-to-target ratios. In human pan-T cell reconstitution models, HLX3901 demonstrated stronger and more durable anti-tumor activity compared to reference molecules such as tarlatamab. Furthermore, preliminary toxicity studies in cynomolgus monkeys showed that HLX3901 was well-tolerated with a broad therapeutic window, supporting its further clinical development.

Developed through the synergistic integration of AI‑driven molecular design and the company’s TCE platform, HLX3901 exemplifies a next‑generation TCE engineered to overcome key limitations of earlier constructs in solid tumors—achieving sustained and specific T‑cell activation, improved efficacy in the tumor microenvironment (TME) with low TIL density, and a reduced risk of cytokine release syndrome (CRS). The rapid advancement of HLX3901 highlights Henlius’ systematic R&D capabilities in multi-specific antibody engineering.

Building on these capabilities, Henlius has established a diversified innovation platform ecosystem, including PD(L)1-based immune checkpoint inhibitor platform, immune cell engager platforms (such as multi-specific TCEs), the proprietary Hanjugator™ ADC platform, and the AI-powered, all-in-one early-stage R&D platform HAI Club. Together, these platforms support the continuous generation and efficient advancement of a globally competitive innovation pipeline.

Focusing on areas of high unmet medical need, Henlius continues to expand its early-stage pipeline with high-potential assets. Several programs have recently achieved key milestones. Among them, HLX701 (a novel SIRPα-Fc fusion protein) has initiated a phase 2 clinical trial in China, leveraging its potentially improved safety profile. HLX37 (an innovative anti-PD-L1/VEGF bispecific antibody) has received IND approval for advanced/metastatic solid tumors and finished dosing its first patient. HLX97 (a novel oral small molecule KAT6A/B inhibitor) has recently received IND approval from the CDE. Additional next-generation candidates, including HLX3902 (STEAP1×CD3×CD28 tri-specific antibody TCE), HLX49 (HER2 dual-epitope ADC), HLX48 (cMET × EGFR bispecific antibody ADC), and HLX105 (a fusion protein), are expected to rapidly advance into clinical development.

Looking ahead, Henlius will continue to adhere to its "patient-centric" R&D philosophy. Leveraging its integrated, platform‑based innovation engine, the company is committed to accelerating the development of a differentiated, globally competitive innovative pipeline, striving to provide more accessible and effective treatment options for patients worldwide.

About HLX3901-FIH101

This is an open-label, first-in-human phase 1 clinical study to evaluate the safety, tolerability, pharmacokinetic profiles, and preliminary efficacy of HLX3901 in patients with advanced small cell lung cancer or neuroendocrine carcinoma. The study consists of two stages: phase 1a dose-escalation and backfill stage and phase 1b dose-expansion stage. Phase 1a includes seven dose levels ranging from 0.1 mg to 30 mg, with a 4‑week treatment cycle. The 0.1 mg dose level employs an accelerated titration design, while the remaining six dose levels use a standard “3+3” dose-escalation design; During dose escalation, backfilling of subjects into certain dose cohorts is permitted once safety has been verified. Phase 1b is planned to include three dose-expansion cohorts at 10 mg, 20 mg, and 30 mg, with dosing strategies consistent with those used in the corresponding phase 1a dose levels. The primary objectives of this study are to evaluate the safety and tolerability of HLX3901 in patients with advanced small cell lung cancer or neuroendocrine carcinoma, to determine its maximum tolerated dose (“MTD”) and recommended phase 2 dose (“RP2D”), and to preliminarily evaluate its antitumor efficacy. The primary endpoints include the incidence of dose-limiting toxicities (DLTs), the MTD and RP2D of HLX3901, and the investigator-assessed objective response rate (ORR).

References

1. Kim JW, et al. DLL3 regulates Notch signaling in small cell lung cancer. iScience. 2022;25(12):105603.

2. Ladi E, et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol. 2005;170(6):983-992.

3. Owen DH, et al. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019;12(1):61.

4. Tanaka K, et al. Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer. Lung Cancer. 2018;115:116–120.

5. Yao J, et al. DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. Oncologist. 2022 Nov 3;27(11):940-951.

6. Rudin CM, et al. Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. J Hematol Oncol. 2023;16(1):66.

7. Lobenhofer E, et al. P1.12-18 Nonclinical Safety Assessment of AMG 757, a DLL3 Bispecific T Cell Engager, in the Cynomolgus Monkey. Journal of Thoracic Oncology. 2019;14(10):S541.

8. Dhillon S. Tarlatamab: First Approval. Drugs. 2024;84(8):995-1003.

9. Ahn MJ, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075.

10. Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity.2020;52(1):17-35.

11. Belmontes B, et al. Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors. Sci Transl Med. 2021;13(608): eabd1524.

12. Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305-334.

13. Esensten JH, et al. CD28 Costimulation: From Mechanism to Therapy. Immunity. 2016;44(5):973-988.

14. Bhatia S, et al. Different cell surface oligomeric states of B7-1 and B7-2: implications for signaling. Proc Natl Acad Sci U S A. 2005;102(43):15569-15574.