潜在First-in-class创新抗GARP单抗联合H药双单抗联合疗法，I期临
2022年12月14日，复宏汉霖（2696.HK）宣布，公司自主开发的HLX60（创新型抗GARP单抗）联合公司自主开发的PD-1抑制剂H药 汉斯状 （斯鲁利单抗）的I期临床研究（NCT05483530）已于澳大利亚完成在晚期或转移性实体瘤患者中的首例受试者给药。HLX60是中国首个获批临床的靶向GARP的单抗产品，近期亦于中国完成I期研究首例受试者给药。
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。尽管如此，研究发现只有30-40%的患者可从免疫检查点疗法治疗中受益，且仍将面临肿瘤复发或进展的可能，此外，一些特定癌种亦对免疫检查点疗法缺少响应[1-2]。基于未满足的巨大临床需求，更多新的疗法亟需被开发。
转化生长因子-β（TGF-β）是一种多效细胞因子，在多种组织中均有表达，有TGF-β1、TGF-β2、TGF-β3三个主要亚型，其中TGF-β1在细胞增殖、发育、凋亡、纤维化、血管生成、伤口愈合、癌症免疫等生物学过程的许多方面都发挥着重要作用[3-5]。糖蛋白 A 重复优势蛋白（glycoprotein-A repetitions predominant，GARP）是潜伏转化生长因子β1（LTGF-β1）的对接受体，其主要在活化的调节性T细胞（Tregs）和血小板上表达[6]，在肿瘤微环境（TME）中富集并激活TGF-β1，从而抑制抗肿瘤免疫应答，促进肿瘤细胞生长、增殖和侵袭[7-8]。
HLX60为复宏汉霖自主研发的靶向GARP的创新型单抗，其可通过特异性结合GARP，阻断GARP介导的TGF-β1的释放，逆转TME中的免疫抑制效应，提高抗肿瘤免疫应答。此外，HLX60可以通过抗体依赖细胞介导的细胞毒作用（ADCC）清除GARP阳性肿瘤细胞和Tregs等免疫抑制性细胞，从而增强抗肿瘤作用。临床前研究结果显示，HLX60与汉斯状 联用的抗肿瘤效果明显优于汉斯状 或HLX60单药治疗效果，具有良好的耐受性和安全性，充分体现出双免疫疗法的协同抗肿瘤效应。
复宏汉霖从临床需求出发，目前在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。同时，公司充分运用自有管线覆盖肿瘤特异性靶点、抗血管生成靶点和肿瘤免疫靶点等多个类别的特点，助力H药与自有单抗产品、化疗等治疗手段开展联合治疗，已广泛覆盖肺癌、食管癌、头颈鳞癌和胃癌等适应症，有助于充分挖掘免疫疗法的治疗潜力，为全球患者带去高品质、可负担的创新治疗方案。
关于NCT05483530
本研究为一项评估HLX60联合斯鲁利单抗在晚期或转移性实体瘤患者中的安全性、耐受性及初步疗效的I期临床研究。研究将采用加速滴定设计（ATD）联合“3+3”设计。合格的受试者将在第一周期接受静脉输注不同剂量HLX60单药（每三周一次：0.5、2、5、15和25 mg/kg）的治疗，并从第二周期开始联合斯鲁利单抗（每三周一次：300 mg）。本研究的主要终点为HLX60首次给药后3周内的剂量限制毒性（DLT）、其最大耐受剂量（MTD）及HLX60联合斯鲁利单抗的II期推荐剂量（RP2D）。次要终点包含安全性、药代动力学参数、药效学特征、免疫原性及疗效。
H药 汉斯状 为重组人源化抗PD-1单抗注射液（通用名：斯鲁利单抗注射液），是复宏汉霖首个自主研发的创新型单抗，目前2项适应症获批上市，2项适应症上市申请获受理，10余项临床试验同步在全球开展。
2022年3月，H药正式获批上市，目前可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（sqNSCLC)。围绕H药，复宏汉霖积极推进其与公司其他产品的协同以及与创新疗法的联合，相继获得中国、美国、欧盟等国家及地区的临床试验许可，在全球同步开展12项肿瘤免疫联合疗法临床试验，广泛覆盖肺癌、食管癌、头颈鳞癌和胃癌等适应症，全面覆盖肺癌一线治疗。截至目前，H药已于中国、土耳其、波兰、格鲁吉亚等国家和地区累计入组超3100人，其中2项国际多中心临床试验入组白人的比例超过30%，是拥有国际临床数据较多的抗PD-1单抗之一。H药联合化疗一线治疗广泛期小细胞肺癌（ES-SCLC）和食管鳞状细胞癌（ESCC）的NDA已获得NMPA受理，H药有望成为全球首个一线治疗小细胞肺癌（SCLC）的抗PD-1单抗。此外，该药入选《2022 CSCO小细胞肺癌诊疗指南》作为ES-SCLC治疗推荐，针对ES-SCLC的国际多中心临床研究ASTRUM-005成为全球首个登上JAMA的小细胞肺癌免疫治疗临床研究。H药治疗SCLC也已获得美国FDA孤儿药资格认定，并在美国启动了一项H药对比一线标准治疗阿替利珠单抗的头对头桥接试验。
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，在欧洲上市1款产品，15项适应症获批，4个上市注册申请获得中国药监局受理。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，上海徐汇基地已获得中国和欧盟药品GMP认证，松江基地（一）也已获得中国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 ，澳大利亚商品名：Tuzucip 和Trastucip ）、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，其广泛期小细胞肺癌和食管鳞状细胞癌2项适应症的上市注册申请也正在审评中。公司亦同步就15个产品、12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。
First Patient Dosed in a Phase 1 Clinical Study of Henlius Novel Anti-GARP and Anti-PD-1 Dual mAb Therapy in Australia Shanghai, China, Dec 14th, 2022 - Shanghai Henlius Biotech, Inc. (2696.HK) announced the first subject was dosed in Australia in a phase 1 clinical trial (HLX60HLX10-FIH101) of its independently developed HLX60 (recombinant anti-GARP humanised monoclonal antibody injection) in combination with HANSIZHUANG, an innovative anti-PD-1 mAb independently developed by the company for the treatment of advanced or metastatic solid tumours. HLX60 is the first anti-GARP monoclonal antibody (mAb) that has been approved to conduct clinical studies in China. Recently, the first subject has been dosed for phase 1 clinical trial of HLX60 in China.
Immune checkpoint inhibitor (ICI) therapies have offered a novel way to attack tumour cells in recent years. Current research on immune checkpoint inhibitors is mainly focused on anti-CTLA-4 (cytotoxic T lymphocyte associated antigen-4) antibody, anti-PD-1 (programmed cell death protein 1) antibody, and anti-PD-L1 (programmed cell death-ligand 1) antibody. PD-1/PD-L1 plays a vital role in immune suppression and have been approved for treating several indications including melanoma, non-small cell lung cancer, hepatocellular carcinoma, and classical Hodgkin lymphoma. However, only 30-40% of patients benefit from the treatment of immune checkpoint inhibitors and their tumours still recur or progress. Some cancer species still lack response to ICIs [1-2]. Therefore, there is an urgent need to develop new therapies to meet the huge medical needs.
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine expressed by the majority of cells and found in many tissues. There are three TGF-β receptor ligands: TGF-β1, TGF-β2, and TGF-β3, with TGF-β1 playing critical roles in a variety of biological processes including cell proliferation, development, apoptosis, fibrosis, angiogenesis, wound healing, cancer, and many others [3–5]. The glycoprotein-A repetitions predominant (GARP) is highly expressed on the surface of activated Tregs and platelets and acts as a docking receptor by binding to latent transforming growth factor-β1 (LTGF-β1) [6]. It concentrates LTGF-β1 on the cell surface and releases active TGF-β1 in the tumour microenvironment (TME), thus inhibiting anti-tumour immune response and inducing tumour cell growth, proliferation and invasion [7-8].
HLX60 is a self-developed novel anti-GARP mAb that binds to GARP and specifically blocks the release of GARP mediated TGF-β1, thus relieving the immunosuppression caused by TGF-β1, reversing the immunosuppressive TME, and improving anti-tumour immune response. Furthermore, by inducing antibody dependent cell-mediated cytotoxicity (ADCC) effect, HLX60 can deplete GARP positive tumour cells as well as immunosuppressive cells such as Tregs. Several pre-clinical studies have shown that combining HLX60 and HANSIZHUANG has a synergistic effect in inhibiting tumour growth and has good tolerance and safety. These findings suggested that the combination therapy of HLX60 and HANSIZHUANG is superior to either HANSIZHUANG or HLX60 monotherapy.
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. Meanwhile, Henlius actively promotes HANSIZHUANG in conjunction with in-house products of the company such as tumour-specific target, angiogenesis target, immunotherapeutic target, etc. and chemotherapy drugs to conduct immune combination therapies in a wide variety of indications, such as lung cancer, esophageal carcinoma, head and neck squamous cell carcinoma and gastric cancer, etc., committing to bringing affordable and high-quality innovative biologics to patients around the world.
About NCT05483530
This phase 1 study aims to evaluate the safety, tolerability, and preliminary efficacy of HLX60 plus serplulimab in patients with advanced or metastatic solid tumours. The study will follow an accelerated titration design (ATD) in combination with “3+3” design. Eligible subjects will be given different doses of HLX60 as monotherapy (Q3W: 0.5, 2, 5, 15, and 25 mg/kg) intravenously in cycle 1, and then combined with serplulimab (Q3W: 300 mg) starting from cycle 2. The primary endpoints of this study are the dose-limiting toxicities (DLT) assessed within 3 weeks after the first dose of HLX60, as well as the maximum tolerated dose (MTD) of HLX60 and recommended phase 2 dose (RP2D) of HLX60 plus serplulimab. Secondary endpoints include safety, pharmacokinetic parameters, pharmacodynamic characteristics, immunogenicity, and efficacy.
HANSIZHUANG (recombinant humanised anti-PD-1 monoclonal antibody injection, generic name: serplulimab injection) is the first innovative monoclonal antibody developed by Henlius. Up to date, 2 indications are approved for marketing in China, 2 NDAs have been accepted by the NMPA, and more than 10 clinical trials are ongoing across the world.
HANSIZHUANG was launched in March 2022 and has been approved by the NMPA for the treatment of MSI-H solid tumours and squamous non-small cell lung cancer (sqNSCLC). Its synergy with in-house products of the company and innovative therapies are being actively promoted. It has successively obtained clinical trial licenses in China, the United States, the European Union and other countries and regions to initiate 12 clinical trials on immuno-oncology combination therapies in a wide variety of indications, such as lung cancer, esophageal carcinoma, head and neck squamous cell carcinoma and gastric cancer, etc., and covering the full range of first-line treatments of lung cancers. As of now, the company has enrolled more than 3,100 subjects in China, Turkey, Poland, Georgia and other countries and regions, and the proportion of White is over 30% in two MRCTs, making HANSIZHUANG an anti-PD-1 mAb with one of the largest global clinical data pools. The NDAs of the first-line treatment for squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC) have been accepted by the NMPA, which makes HANSIZHUANG potentially the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. Furthermore, HANSIZHUANG was recommended for the treatment of ES-SCLC in the 2022 CSCO Guidelines for Diagnosis and Treatment of Small Cell Lung Cancer (SCLC), and the associated clinical trial became the first study published in JAMA on SCLC immunotherapy. Serplulimab was also granted orphan drug designation by the FDA for the treatment of SCLC, and the first patient has been dosed in a bridging head-to-head trial in the United States to comparing HANSIZHUANG to standard of care Atezolizumab (anti-PD-L1 mAb) for the first-line treatment of ES-SCLC.
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, 15 indications approved worldwide, and 4 New Drug Applications (NDAs) 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 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, 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 and squamous non-small cell lung cancer (sqNSCLC). Its NDAs for the treatment of extensive-stage small cell lung cancer (ES-SCLC) and esophageal squamous cell carcinoma (ESCC) are under review. What's more, Henlius has conducted over 20 clinical studies for 15 products and 12 immuno-oncology combination therapies, expanding its presence in major markets as well as emerging markets.
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