产品速递 | 双免疫联合抗血管靶向疗法，HLX53联合H药与汉贝泰一线治疗肝细胞...

2024年4月17日，复宏汉霖宣布，公司自主开发的创新型抗TIGIT Fc融合蛋白HLX53联合H药 汉斯状（斯鲁利单抗，HLX10）及汉贝泰（贝伐珠单抗，HLX04）的新药临床试验申请获得国家药品监督管理局（NMPA）批准，用于局部晚期或转移性肝细胞癌的一线治疗。公司计划启动一项探索该三药联合疗法的耐受性、安全性和有效性的II期临床试验。

肝癌是全球范围内常见的恶性肿瘤。据GLOBOCAN统计，2022年全球肝癌发病数和死亡数分别为87万及76万例^[1]。在中国，原发性肝癌是第四大最常见的癌症，以及第二大致死癌症。2022年中国新发肝癌病例约37万例，肝癌死亡病例32万例^[2]。其中，肝细胞癌是最常见的原发性肝癌类型，约占总病例数的85%-90%^[3]。因原发性肝癌起病隐匿，早期无症状或症状不明显，进展迅速，确诊时大多数患者已经达到局部晚期或发生远处转移，治疗困难，预后很差，五年生存率仅约18%^[4]。对晚期肝癌患者来说，目前一线治疗以靶向治疗和免疫治疗为主，免疫抑制剂及抗血管生成药物的联合治疗显示出显著的临床抗肿瘤活性和生存获益^[5]，但仍有较大比例的患者并不能从中获益，导致肿瘤复发或进展，尚存在迫切的临床需求以扩大免疫治疗的受益人群，并提高免疫治疗的疗效。

含免疫球蛋白和ITIM结构域的T细胞免疫受体（T cell immunoglobulin and ITIM domain, TIGIT）是近年来肿瘤免疫治疗中最有前景和潜力的靶点之一。TIGIT是一种抑制性受体，在淋巴细胞中表达，包括自然杀伤（NK）细胞、活化的CD8+ T和CD4+ T细胞以及Treg（调节性T细胞）等 ，其重要配体为主要表达于APC（抗原提呈细胞）或肿瘤细胞表面的CD155（脊髓灰质炎病毒受体，PVR）^[6-7]。作为免疫检查点蛋白，TIGIT可通过多种作用机制抑制固有和适应性免疫，在肿瘤免疫抑制中的“踩刹车”作用和PD-1/PD-L1类似^[8]。多项研究数据显示，TIGIT抑制剂有望治疗多种晚期癌症，包括肺癌、胃癌、黑色素瘤和多发性骨髓瘤等多种实体瘤和淋巴瘤^[9]。且已有临床前研究表明，TIGIT靶点可能与 PD-1 通路产生协同效应，同时阻断TIGIT和PD-1/PD-L1信号通路优于单独阻断任一通路，可增强抗肿瘤活性^[10]。

HLX53是复宏汉霖自主研发的创新型抗TIGIT的Fc融合蛋白，由重链抗体的可变区（VHH）和野生型 IgG1的Fc端组成。临床前研究结果表明，HLX53具有优异的肿瘤抑制效果^[11]且安全性良好。公司亦于2022年启动了一项I期临床研究，以评估HLX53在晚期或转移性、无标准疗法或标准治疗失败的实体瘤或淋巴瘤患者中的安全性、耐受性、药代动力学和初步疗效。鉴于抗PD-1/PD -L1单抗等免疫抑制剂及抗血管生成药物在晚期肝细胞癌患者中取得的良好疗效，及TIGIT与PD-1/PD-L1信号通路的协同效应，复宏汉霖拟进一步探索抗PD-1单抗与TIGIT抑制剂的双免疫治疗与抗血管靶向疗法的组合，以期为晚期肝细胞癌患者带来更高的临床获益。

未来，复宏汉霖还将推动更多创新产品的临床研究，积极开展联合治疗方案，持续突破现有疗法的瓶颈，期待早日为更多患者带来可负担的高品质生物药。

关于复宏汉霖

复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市5款产品，在国际上市2款产品，19项适应症获批，7个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，上海徐汇基地和松江基地（一）均已获得中国和欧盟GMP认证。

复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状的肿瘤免疫联合疗法。继国内首个生物类似药汉利康（利妥昔单抗）、中国首个自主研发的中欧双批单抗药物汉曲优（曲妥珠单抗，欧洲商品名：Zercepac）、汉达远（阿达木单抗）和汉贝泰（贝伐珠单抗）相继获批上市，创新产品汉斯状（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。

IND Application for the Clinical Trial of Novel Anti-TIGIT Fc Fusion Protein HLX53 in Combination with HANSIZHUANG Plus HANBEITAI for the First-Line Treatment of Locally Advanced or Metastatic Hepatocellular Carcinoma Patients Approved by NMPA

Shanghai, China, April, 17^th, 2024 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the investigational new drug application (IND) for the clinical trial of HLX53, an anti-TIGIT Fc fusion protein, in combination with HANSIZHUANG (serplulimab, HLX10) and HANBEITAI (bevacizumab, HLX04) for the first line treatment of locally advanced or metastatic hepatocellular carcinoma, has been approved by the National Medical Products Administration (NMPA). A phase 2 clinical trial will be initiated to evaluatethe safety, tolerance and efficacy of the multiple immunotherapy-based treatment combinations in patientswith advanced or metastatic hepatocellular carcinoma.

Liver cancer is one of the most prevalent malignancy in the world. According to GLOBALCAN 2022, there are about 870,000 new cases diagnosed and 760,000 deaths for the tumour in the globe^[1]. Meanwhile, primary liver cancer (PLC) is the fourth most common cause and the second mortality cancer in China, with about 370,000 new cases and 320,000 deaths in 2022^[2]. From which, hepatocellular carcinoma (HCC) is the predominant pathological type of PLC, which accounts for between 85% and 90% of liver cancer cases^[3]. Due to its insidious onset, lack of symptom in its early stage, and quick progression, PLC usually has been in its locally advanced stage or develops distant metastasis when it is diagnosed. As a result, the management becomes extremely difficult and the prognosis usually is poor. The 5-year survival rate of PLC is only about 18%^[4]. For patients with advanced liver cancer, the first-line treatment is based on targeted therapy and immunotherapy. And the standard therapy (combination therapies of immune inhibitor plus anti-angiogenic treatment) have shown significant clinical anti-tumour efficacy and survival benefit^[5]. However, some patients failed to benefit from the standard therapy and suffered from recurrence or progression of the disease. Thers is still an urgent clinical need to further expand the benefit population with advanced liver cancer and improve the efficacy of immunotherapy.

T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as popular inhibitory checkpoint receptor, which is mainly expressed on natural killer (NK) cells, activated CD8+ T and CD4+ T cells, and T regulatory cells. TIGIT binds to the ligand CD155 (poliovirus receptor, PVR)^[6-7], mainly expressed on antigen-presenting cells (APC) or the surface of tumour cells, to down-regulate T cell and NK cell functions1-2. As an immune checkpoint protein, TIGIT can inhibit innate and adaptive responses in various mechanisms of action and act as “brakes” like PD-1/PD-L1 does to stop T cells from attacking  tumours^[8]. Studies have shown that TIGIT inhibitor are effective against lung cancer, gastric cancer, melanoma, multiple myeloma, etc^[9]. Moreover, TIGIT has shown a synergistic effect with the PD-1 pathway in preclinical studies, indicating that simultaneous blocking of TIGIT and PD-1/PD-L1 signaling pathways is superior to blocking either pathway alone, which can enhance anti-tumour activity^[10].

HLX53 is an anti-TIGIT Fc fusion protein independently developed by Henlius, consisting of variable domain of heavy chain of heavy-chain antibody (VHH) and wildtype IgG1 Fc. Pre-clinical studies have demonstrated that HLX53 exhibits excellent tumour inhibition^[11] with good safety. In addition, Henlius has initiated a phase 1 study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of HLX53 in patients with advanced or metastatic solid tumours or lymphomas who have no standard therapy or failed the standard therapy. Considering the good efficacy of immune checkpoint inhibitor such as anti-PD-1/PD-L1antibody plus anti-angiogenic drug in the first-line treatment ofpatients with advanced HCC, as well as the synergistic effect of TIGIT andPD-1/PD-L1 signaling pathway, Henlius intends to further combine TIGIT inhibitor based on the standard therapy in order to bring greater clinical benefits to patients with advanced HCC.

Looking forward, Henlius will further accelerate the clinical research of diversified novel portfolio, proactively exploring immuno-oncology combination therapy to provide more effective treatment options to fulfill the unmet clinical needs.

About Henlius

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, 2 have been approved for marketing in overseas markets, 19 indications are approved worldwide, and 7 marketing applications have been accepted for review in China, the U.S., and the EU, respectively. 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 Facility and Songjiang First Plant, both certificated by China and the EU GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules 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), 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), and esophageal squamous cell carcinoma (ESCC), making it the world's first anti-PD-1 mAb for the first-line treatment of SCLC. What's more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

【参考文献】

[1] Bray F et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4.

[2] Han B，Zheng R，Zeng H，et al. Cancer incidence and mortality in China，2022[J].Journal of the National Cancer Center, 2024.

[3] 《CSCO原发性肝癌诊疗指南(2022版)》

[4] Asafo-Agyei KO, Samant H. Hepatocellular Carcinoma. 2023 Jun 12. In: StatPearls [Internet].Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32644603.

[5] Cheng, Ann-Lii et al. “Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma.” Journal of hepatology vol. 76,4 (2022): 862-873.

[6] Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8(2).

[7] Sanchez-Correa B, Valhondo I, Hassouneh F, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy. Cancers (Basel). 2019;11(6):877.

[8] Yue C, Gao S, Li S, et al. (2022) TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front. Immunol. 13:911919.

[9] Zhang, Peng et al. “Targeting TIGIT for cancer immunotherapy: recent advances and future directions.” Biomarker research vol. 12,1 7. 16 Jan. 2024.

[10] Chu, Xianjing et al. “Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials.” Molecular cancer vol. 22,1 93. 8 Jun. 2023

[11] Hua, B. et al. A novel single domain antibody targeting TIGIT for cancer use in combination therapies. Cancer Research 81, 2451-2451 (2021).

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