2023年3月15日，复宏汉霖（2696.HK）宣布，公司自主开发的创新型抗OX40四价激动型人源化单克隆抗体HLX51获国家药品监督管理局（NMPA）批准在中国开展1期临床研究，拟用于晚期/转移性实体瘤和淋巴瘤的治疗。目前，全球范围内尚无靶向OX40的产品获批上市。

近年来，免疫疗法为肿瘤治疗提供了新的途径，具有独特的优势和巨大的潜力，而肿瘤免疫检查点是免疫治疗中的重要组成部分[1]。免疫检查点主要分为两大类，一类是以PD-1/PD-L1、CTLA-4为代表的免疫抑制型检查点，另一类是以OX40（肿瘤坏死因子受体超家族成员4）为代表的免疫激动型检查点[2]。OX40又称CD134、TNFRSF4，是肿瘤坏死因子受体（TNFR）超家族成员，主要表达于活化的T细胞表面。OX40与其配体OX40L结合可释放共刺激信号，抑制活化诱导的细胞死亡（activation induced cell death，AICD），并促进抗原特异性记忆T细胞的存活[3-4]。与免疫检查点抑制剂通过解除T细胞活化的抑制性信号，为肿瘤免疫反应“松刹车”的作用不同，靶向免疫激动型检查点的免疫检查点激动剂可通过“踩油门”增强T细胞的活化，目前已成为下一代免疫治疗热门靶点[5]。

HLX51是复宏汉霖自主研发的抗OX40激动型人源化单克隆抗体。HLX51通过与OX40L 竞争性结合OX40，可代替OX40L刺激OX40，而不会降低OX40刺激信号，从而刺激T 细胞增殖/活化，进而诱导或增强T细胞的杀伤能力；此外，还可以抑制调节性T细胞（Treg）细胞增殖及激活，解除Treg 细胞介导的免疫抑制功能，改善肿瘤微环境中的免疫抑制作用，进一步促进T 细胞释放细胞因子，从而发挥更强的抗肿瘤作用。临床前研究结果显示，HLX51可显著抑制肿瘤生长，具有良好的耐受性和安全性。

(资料图)

复宏汉霖从临床需求出发，目前已全面布局PD-1/PD-L1、CTLA-4、LAG-3、TIGIT等免疫检查点，为免疫联合治疗的探索创造更多可能。未来，HLX51也有望与复宏汉霖多个类型抗肿瘤药物开展联合用药的探索。公司也将推动更多创新产品的临床研究，以抗体技术为核心，积极开展联合治疗方案、创新靶点双特异性抗体以及抗体偶联药物（ADC）等产品的布局，期待早日为更多患者带来可负担的高品质生物药。

Henlius Novel anti-OX40 HLX51 Received Clinical Trial Approval in China Shanghai, China, Mar 15th, 2023 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the phase 1 clinical trial for the company’s self-developed HLX51, a novel humanized agonistic anti-OX40 monoclonal antibody (mAb) for the treatment of patients with advanced/metastatic solid tumours and lymphomas has been approved by the National Medical Products Administration (NMPA). At present, there is no anti-OX40 mAb has been approved for marketing globally.

Immune checkpoints are playing a crucial part in immunotherapy, which has emerged in recent years as a novel approach to combating tumour cells with distinct advantages and enormous promise [1]. In general, immune checkpoints fall into two categories: immunosuppressive checkpoints such as PD-11/PD-L1 and CTLA-4, and stimulatory immune checkpoints such as OX40 (Tumour necrosis factor receptor superfamily member 4) [2]. OX40, also known as CD134 and TNFRSF4, is mainly expressed on activated T cells. When OX40 is combined with its ligand OX40L, it induces co-stimulatory signals, which prevent activation induced cell death and consequently promote the survival of effector T cells, resulting in the generation of memory T cells [3-4]. Unlike immune checkpoint inhibitors, which "removes the brakes" on the tumour immune response by releasing inhibitory signals that activate T cells, immune checkpoint agonists that target stimulatory immune checkpoints can enhance T cells by "stepping on the gas pedal", becoming a popular target for next-generation immunotherapy [5].

HLX51 is an agonistic anti-OX40 humanized mAb independently developed by Henlius. By competitively binding OX40 with OX40L, HLX51 can replace OX40L to activate OX40 without reducing the downstream signal of OX40, thereby promoting the proliferation of immune cells, and promoting the killing ability of T cells. it can also inhibit the differentiation and activity of regulatory T cells (Treg), relieve the immunosuppression mediated by Treg and in the tumour microenvironment and further enhance the function of effector T cells. Preclinical studies have shown that HLX51 can inhibit tumour growth and has good tolerance and safety.

Underpinned by the patient-centric strategy, Henlius has achieved an overall layout of the immune checkpoints of PD-1/L1, CTLA-4, LAG-3, TIGIT, etc., proactively exploring immuno-oncology combination therapy. Future exploration of HLX51 is also anticipated to involve combinations with various in-house antitumor medicines. Looking forward, Henlius will continue conducting clinical studies for more innovative products in bispecific antibodies and the antibody-drug conjugates (ADC) and exploring combination therapies with enhanced efficacy to provide patients with quality and affordable biologics.

Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 5 products have been launched in China, 1 approved for marketing in overseas markets, 18 indications approved worldwide, 1 New Drug Application (NDA) accepted for review in China, and 1 Biologics License Application (BLA) accepted for review in the U.S. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab for injection, trade name in Europe: Zercepac ; trade names in Australia: Tuzucip and Trastucip , the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. Its NDA for the treatment of esophageal squamous cell carcinoma (ESCC) is under review. What"s more, Henlius has conducted over 20 clinical studies for 16 products and 12 immuno-oncology combination therapies, expanding its presence in major markets as well as emerging markets.

[1]. Robert, C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 11, 3801 (2020). https://doi.org/10.1038/s41467-020-17670-y

[2]. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol. 2018;8:86. Published 2018 Mar 28. doi:10.3389/fonc.2018.00086

[3]. Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229(1):173-191. doi:10.1111/j.1600-065X.2009.00766.x

[4]. Watts TH, DeBenedette MA. T cell co-stimulatory molecules other than CD28. Curr Opin Immunol. 1999;11(3):286-293. doi:10.1016/s0952-7915(99)80046-6

[5]. Sugamura, K., Ishii, N. & Weinberg, A. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 4, 420–431 (2004). https://doi.org/10.1038/nri1371