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复宏汉霖创新型抗PD-L1/TIGIT双抗获批在澳大利亚开展临床试验

复星医药 • 1 周前 • 10 次点击  

2021年11月24日,复宏汉霖(2696.HK)宣布,公司自主开发的重组人源抗PD-L1与抗TIGIT双特异性抗体注射液HLX301已通过澳大利亚药品管理局(Therapeutic Goods Administration,TGA)的临床试验备案,被批准于澳大利亚开展1期临床研究,拟用于局部晚期或转移性实体瘤的治疗。目前,全球范围内尚无同类靶向PD-1/L1和TIGIT的双特异性抗体获批上市。


近年来,免疫检查点疗法为肿瘤治疗提供了新的途径。目前研究和应用最广泛的免疫检查点抑制剂包括CTLA-4(细胞毒性T淋巴细胞相关抗原-4)、PD-1(程序性细胞死亡蛋白1)及其配体PD-L1(程序性细胞死亡配体1)的抑制剂等。PD-1/PD-L1信号通路在肿瘤免疫中具有重要作用,PD-1和PD-L1抑制剂治疗癌症的疗效显著,目前已被批准用于黑色素瘤、非小细胞肺癌、肝细胞癌、经典霍奇金淋巴瘤等。T细胞免疫球蛋白和ITIM结构域(T cell immunoglobulin and ITIM domain,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)1-2。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,有望用于多种晚期肿瘤的治疗,包括非小细胞肺癌、胃癌、黑色素瘤、多发性骨髓瘤等。



HLX301为复宏汉霖自主开发的创新型抗PD-L1与抗TIGIT双特异性抗体,其TIGIT结合域来源于公司人源化羊驼重链可变区单域抗体(VHH)噬菌体展示库筛选的对TIGIT具有高亲和力、高特异性的VHH,通过重组技术与抗PD-L1单抗组合。临床前研究结果表明,对比抗PD-L1单抗、抗TIGIT单抗以及两种单抗的联合疗法,HLX301可与人PD-L1和TIGIT特异性结合并同时阻断PD-1/PD-L1和TIGIT/PVR负向信号通路,抑制肿瘤细胞的生长,且耐受性、安全性良好,充分体现双抗疗法的协同增强效应,为后续临床研究的开展提供了科学基础。同时,对比抗PD-L1单抗、抗TIGIT单抗以及两种单抗的联合疗法,HLX301可更有效恢复T细胞受体下游信号,提高抗肿瘤活性,充分体现双抗疗法的协同增强效应。


复宏汉霖从临床需求出发,目前已打造出多元化的创新产品管线,在PD-1/L1、CTLA-4、LAG-3等免疫检查点全面布局,为免疫联合治疗的探索创造更多可能。公司持续丰富创新靶点布局,产品覆盖c-MET、TROP2和BRAF等新兴靶点,并积极开展双特异性抗体、抗体偶联药物(ADC)等产品的开发,同时公司将持续加码创新,加强优质创新资产的引进和合作,“内外兼修”,为全球患者带去高质量、可负担的创新治疗方案。

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3款产品,在欧盟上市1款产品,3款产品获得中国上市注册申请受理。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研发中心,按照国际GMP标准进行生产和质量管控,位于上海徐汇的生产基地已获得中国和欧盟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20多种创新单克隆抗体,并全面推进基于自有抗PD-1单抗斯鲁利单抗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,欧盟商品名:Zercepac®)、公司首个自身免疫疾病治疗产品汉达远®(阿达木单抗)相继获批上市,创新产品斯鲁利单抗MSI-H实体瘤的上市注册申请已纳入优先审评审批程序,HLX04贝伐珠单抗、斯鲁利单抗鳞状非小细胞肺癌适应症、HLX01利妥昔单抗类风湿关节炎新适应症的上市注册申请也正在审评中。公司亦同步就11个产品、8个免疫联合治疗方案在全球范围内开展20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。

Henlius Novel Anti PD-L1/TIGIT Bispecific Antibody Received Clinical Trial Approval in Australia


Shanghai, China, Nov, 24th, 2021 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the filing of a clinical trial for HLX301, a Recombinant Humanized Anti-PDL1 and Anti-TIGIT Bispecific Antibody, in Patients with locally advanced or metastatic solid tumours has been approved by the Bellberry Human Research Ethics Committee (“HREC”), and Clinical Trial Notification (“CTN”) has been acknowledged by the Therapeutic Goods Administration (“TGA”), Australia. The Phase 1 clinical study of the project in Australia is intended to be initiated in the near future. At present, no bispecific antibody targeting PD-1/PD-L1 and TIGIT has been approved for marketing globally.


Immunotherapies targeting immune checkpoint protein interactions between ligands and receptors have offered a novel way to attack tumour cells in recent years. Current research on immune checkpoint inhibitors is focused on CTLA-4 (cytotoxic T lymphocyte associated antigen-4) antibody, PD-1 (programmed cell death protein 1) antibody, and PD-L1 (programmed cell death-ligand 1) antibody. PD-1/PD-L1 plays a vital role in immune suppression; PD-1 and PD-L1 inhibitors show significant effectiveness in cancer treatment and have been approved for treating melanoma, non-small cell lung cancer, hepatocellular carcinoma, classical Hodgkin lymphoma, etc. TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domains) is an inhibitory receptor, mainly expressed on natural killer (NK) cells and activated CD8+ T cells, CD4+ T cells, and T regulatory cells. TIGIT binds to the major ligand CD155 (poliovirus receptor, PVR), mainly expressed on antigen-presenting cells (APC) or tumour cells, to down-regulate T cell and NK cell functions. As an inhibitory receptor, TIGIT can inhibit innate and adaptive responses in various mechanisms of action and act as a “brake” like PD-1/PD-L1 does to stop T cells from attacking tumours. Several pre-clinical studies have indicated that TIGIT blockade may be effective against multiple advanced cancers, including non–small-cell lung cancer, gastric cancer, melanoma, and multiple myeloma.


Independently developed by Henlius, HLX301 is an innovative anti-PD-L1 and anti-TIGIT bispecific antibody, composed of an anti-PD-L1 IgG1 subtype monoclonal antibody coupled with an anti-TIGIT variable domain of heavy-chain antibody. Its TIGIT binding domain is derived from VHH fragments with high affinity and high specificity to TIGIT, selected from the company’s synthetic humanized llama VHH library. Pre-clinical studies reported that HLX301 can simultaneously block both PD-1/PDL1 and TIGIT/PVR pathways, restore TCR signaling, inhibit tumour growth, and has good tolerance and safety. These results suggested that HLX301 is superior to blocking either pathway alone or anti-PD-L1 + anti-TIGIT combinational therapy, thus paving the way for further clinical development.


Underpinned by the patient-centric strategy, Henlius has achieved an overall layout of the immune checkpoint products of PD-1/L1, CTLA-4, LAG-3, etc., proactively exploring immuno-oncology combination therapy. The company has also built an innovative product pipeline with many emerging targets, including c-MET, TROP2, BRAF, etc. and has been developing a forward-looking presence in bispecific antibodies and the antibody-drug conjugates (ADC). Looking forward, Henlius will continue its momentum for innovation, further strengthening the in-licensing and collaboration on external innovative assets, and bringing more high-quality and affordable therapies to patients worldwide.

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, 3 products have been launched in China, 1 in the European Union (EU), the New Drug Applications (NDAs) of 3 products accepted for review in China. 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 commercialisation. It has established global R&D centres and a Shanghai-based manufacturing facility certificated by China and the EU Good Manufacturing Practice (GMP).


Henlius has proactively 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 serplulimab (anti-PD-1 mAb) as backbone. Apart from the launched products 汉利康® (rituximab), the first China-developed biosimilar, 汉曲优® (trastuzumab, Zercepac® in the EU), the first China-developed mAb biosimilar approved both in China and in the EU and 汉达远® (adalimumab), the Company's first product indicated for autoimmune diseases, the NDA of innovative product serplulimab indicated for MSI-H solid tumors has been granted priority review, and the NDAs of HLX04 (bevacizumab), HLX01 (rituximab) for the treatment of rheumatoid arthritis and serplulimab for the treatment of squamous non-small cell lung cancer are also under review. What's more, Henlius has conducted over 20 clinical studies for 11 products and 8 combination therapies worldwide, expanding its presence in major market as well as emerging market.

【参考文献】

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

[2] 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.


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