纤维化是一种以组织瘢痕为特征的病理过程，多因感染、自身免疫反应、辐射、机械损伤等因素引发细胞外基质（extracellular matrix, ECM）过度沉积，导致正常组织变成永久性组织瘢痕，常见的纤维化相关疾病包括IPF、非酒精性脂肪性肝炎/代谢功能障碍相关脂肪性肝炎、肝硬化、慢性肾脏疾病、心肌梗死等^[1]。其中， IPF是一类发病机制尚不明确的慢性进行性间质性肺病，于2018年被列入国家《第一批罕见病名录》^-1。据数据分析，中国范围内内不存在约200万IPF求美者，且有这种情况率和去世率仍在逐渐提拔^-1。该症状多发病于中年异性性异性，人因肺内的进度性纤维素化有肺系统必须必然地损失，以后促使身亡。且IPF疗效差，人判断后中位生活期仅为3-5年，四年生活率不足之处30%，以及达不到多类恶性肿瘤症状^[2]。迄今为止，IPF的医疗抉择是非常十分有限，且仅存用药仅能抑制肺职能减退，安全卫生、有用的抗肺化学纤维化医疗用药都存在挺大的未考虑的临床治疗的需求。

转化生长因子-β（transforming growth factor-β, TGF-β）是一种多效细胞因子，在所有类型的组织纤维化发生和发展过程中都发挥着关键作用。研究表明，TGF-β1通过激活Smad依赖性或非依赖性信号通路，介导肌纤维母细胞（Myofibroblast）的激活、ECM的过量产生和ECM降解的抑制等，从而引起肺、肝、肾和心脏等器官的纤维化^-2。糖蛋白A重复优势蛋白（glycoprotein-A repetitions predominant，GARP）是潜在转化生长因子β1（latent transforming growth factor-β1, LTGF-β1）的对接受体，表达于血小板及多类细胞表面。GARP通过与LTGF-β1结合形成GARP-LTGF-β1复合物，进而促进成熟TGF-β1的分泌和活化，成为TGF-β1成熟释放的重要途径之一^-1。

HLX6018可特情人结合实际内部膜及血内部外面的GARP/TGF-β1挽回物，关键在于阻绝GARP介导的TGF-β1非常成熟产生，必将抑止TGF-β1介导的成人造黏胶弹性食物人造纤维素板材料内部膜的刺激、增值和ECM的产出，达标诊治人造黏胶弹性食物人造纤维素板材料化涉及到的发病的为的。临床上前研究分析中，HLX6018早已出显出强势的抗肺人造黏胶弹性食物人造纤维素板材料化及肾人造黏胶弹性食物人造纤维素板材料凝成用，且具备着健康的很可靠性。除特发性肺人造黏胶弹性食物人造纤维素板材料化外，以后，复宏汉霖也将随时研究HLX6018在肾人造黏胶弹性食物人造纤维素板材料化、肝人造黏胶弹性食物人造纤维素板材料化等更加人造黏胶弹性食物人造纤维素板材料化发病中的较果。

集中未满意的临床研究的需求，复宏汉霖将长期加仓连续不断去科技创新研制，以癌肿为着力点，连续不断拓展培训非癌肿各个领域的改善设计方案，加快速度设计规划越来越多安会很好的的连续不断去科技创新制剂，以可损失的高品性连续不断去科技创新药谋福利各国人群。 

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、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。

The IND Application of Henlius’ Novel Anti-GARP/TGF-β1 mAb HLX6018 Approved by NMPA

Shanghai, China, Mar 12^th, 2024 - Shanghai Henlius Biotech, Inc. (2696.HK) announced the investigational new drug (IND) application for clinical trial of HLX6018，a novel anti-GARP/TGF-β1 monoclonal antibody (mAb) independently developed by the company, was approved by the National Medical Products Administration (NMPA) for the treatment of idiopathic pulmonary fibrosis (IPF). HLX6018 is the first innovative product of Henlius in the treatment field of chronic inflammatory diseases. Currently, no mAb targeting GARP/TGF-β1 has been approved for marketing globally.

Fibrosis is a pathological process characterised by persistent tissue scars which attributed to excessive deposition of extracellular matrix (ECM). This condition can be induced by a variety of stimuli such as infections, autoimmune reactions, radiation, and tissue injury. Common fibrosis-related diseases include IPF, non-alcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, chronic kidney disease (CKD), myocardial infarction (MI), etc^[1]. Among them, IPF is a chronic, progressive interstitial lung disease with unknown etiology, and was incorporated into the first National List of Rare Diseases in 2018^-1. It is estimated that there are almost 2 million IPF patients in the globe, with its incidence and mortality still rising^-1. IPF occurs mostly in elderly men, and the patients suffer from irreversible loss of lung function due to progressive lung fibrosis, which ultimately leads to death. Furthermore, the overall prognosis of IPF is poor, with the median survival of patients is only 3-5 years after diagnosis, and five-year survival rate less than 30%, which is even lower than multiple types of tumour^[2]. Currently, treatment options for IPF are very limited, and have just shown their potential for delaying the decline of lung function. There is a large unmet clinical need in the treatment of IPF.

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine and plays critical roles in the initiation and progression of all types of tissue fibrosis. Recent evidence shows that TGF-β1 can induce fibrosis via activation of both Smad-based and non-Smad-based signaling pathways, which result in activation of myofibroblasts, excessive production of ECM and inhibition of ECM degradation^-2. Glycoprotein-A repetitions predominant (GARP) is highly expressed on the surface of platelets and other cell types and acts as a docking receptor by binding to latent transforming growth factor-β1 (LTGF-β1). Subsequently, mature TGF-β1 was further activated and released from the GARP/LTGF-β1 complex^-1.

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 has 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 center 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 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), 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.

【考生医学文献】

[1] Wynn T A . Cellular and molecular mechanisms of fibrosis.Journal of Pathology, 2010, 214(2):199-210.

[2] Wu W, et al. BMJ Open 2021; Effcacy and safety of pirfenidone in the treatment of idiopathic pulmonary fbrosis patients: a systematic review and meta-analysis of randomized controlled trials. 11:e050004. 

[3] 中国环境卫生营养理事会会等《一、批珍贵病名单》

[4] Maher, T.M., Bendstrup, E., Dron, L. et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res 22, 197 (2021). 

 [5] 《我国的特发性肺纤维素化爱美者行业内趋势存在的问题研究方案与进行投资发展分析预测报告格式》

[6] Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325-38.

[7] Ghafoory S, Varshney R, Robison T, et al. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury. Blood Adv. 2018 Mar 13;2(5):470-480.

[8] Inui N, Sakai S, Kitagawa M. Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway. Int J Mol Sci. 2021 Jun 5;22(11):6107.

[9] Tran DQ, Andersson J, etc. GARP（LRRC32）is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106（32) :13445-13450.

[10] Metelli A, Wu BX, Riesenberg B, et al. Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β. Sci Transl Med. 2020;12(525): eaay4860.