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。据估计显示，欧洲位置内就有约200万IPF病号，且患病率和死率仍在不断的不断提升^-1。该消化道病单发于中老人雄性，爱美者因肺上的重大突破性合成纤维化引发肺能力切不可可逆转地影响，终极影响意外死亡。且IPF生活工作游戏下载率差，爱美者初步判断后中位生活工作游戏下载期仅为3-5年，六年生活工作游戏下载率缺陷30%，以至于不超过多类癌肿消化道病^[2]。现今，IPF的开展选定非常的非常有限，且存世性治疗药物仅能廷缓肺作用急剧下降，健康、很好的的抗肺钎维化开展性治疗药物长期存在过大的未满意的临床试验供需。

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就能非特异朋友搭配神经癌细胞及血癌细胞漆层的GARP/TGF-β1分手后复合物，而传导GARP介导的TGF-β1心智成熟释放出来，因而遏制TGF-β1介导的成玻纤神经癌细胞的重置、繁殖和ECM的产生，达标开展玻纤化各种相关病的依据。临床上前科研中，HLX6018都已经 展显出出强势的抗肺玻纤化及肾玻纤凝成用，且兼具良好的的可靠性。除特发性肺玻纤化外，险遭，复宏汉霖也将立刻探秘HLX6018在肾玻纤化、肝玻纤化等更加多玻纤化病中的治疗效果。

焦点未无法的临床检验的需求，复宏汉霖将一直推升什么是全新生产研发，以恶性肉瘤为支柱，一直开拓非恶性肉瘤前沿技术的进行治疗计划书，加快开发设计更多的安全性高能够的什么是全新口服药物，以可损失的高品味什么是全新药受益全球性病号。

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.

【基准专著】

[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] 国家地区卫生监督绿色常务政法委员会等《一、批令人震惊病明录》

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

[5] 《国特发性肺仟维化求美者餐饮行业发展趋势行业现状实验与投资费用发展趋势預測意见书》

[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.