Nicotinamide riboside/Pterostilbene

近日，复宏汉霖针对创新型抗PD-1单抗H药（汉斯状®，斯鲁利单抗）作用机制的研究结果在抗体领域权威期刊mAbs成功发表。研究结果揭示了斯鲁利单抗发挥优异疗效的差异化分子机制。同时，研究发现，相较斯鲁利单抗单药治疗，斯鲁利单抗与复宏汉霖自研抗TIGIT Fc融合蛋白HLX53及抗LAG-3单抗HLX26等免疫检查点抑制剂的双免疫疗法可进一步提高抗肿瘤疗效，有望为肿瘤患者带来更高效的临床治疗选择。 近年来，免疫检查点抑制剂的开发促进了肿瘤免疫治疗的快速发展。免疫检查点是维持免疫应答、保护正常组织的关键蛋白分子，但也会被肿瘤细胞利用，逃避免疫系统的监测和攻击[1-3]。其中，以抗PD-1/L1抗体为代表的免疫检查点抑制剂，可通过阻断PD-1/L1信号通路，恢复免疫系统对肿瘤细胞的杀伤能力，已广泛应用于多类恶性肿瘤的临床治疗[4]。H药 汉斯状®为复宏汉霖自主研发的重组人源化抗PD-1单抗注射液，目前已被批准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）、广泛期小细胞肺癌（ES-SCLC）和食管鳞状细胞癌（ESCC）4项适应症，惠及逾80,000患者。 基于斯鲁利单抗在小细胞肺癌的治疗中展现出优异疗效，H药成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。相关研究结果显示，H药斯鲁利单抗具有与Pembrolizumab相近的结合表位，但其在重链和轻链的空间利用方式上较为独特，或将促成了斯鲁利单抗与PD-1受体间差异化的相互作用。此外，鉴于独特的识别模式，斯鲁利单抗相对同类PD-1抑制剂而言展现出较高的人PD-1亲和力水平（KD=2.42 nM)，且拥有较强的PD-1内吞活性，减少T细胞表面留存的PD-1受体数目[5]。为进一步探索斯鲁利单抗的分子作用机制，本研究分析了PD-1/L1信号通路上关键蛋白的表达水平。研究结果显示，斯鲁利单抗能够减少PD-1对免疫共刺激分子CD28的募集，从而减少磷酸化酶SHP2对CD28的去磷酸化作用，更大程度保留CD28传递的信号[6-8]，因此，斯鲁利单抗进一步提高了信号通路下游AKT蛋白的活性[9]，促进T细胞的持续、稳健活化。  与此同时，研究者进一步探索了斯鲁利单抗、Pembrolizumab等抗PD-1单抗协同其他免疫检查点抑制剂的双免疫联合疗法的抗肿瘤疗效。研究结果显示，斯鲁利单抗联合 HLX53（抗TIGIT Fc融合蛋白）能够双重阻断 PD-1/TIGIT信号传导，在抗肿瘤活性（TGI/生存率）上优于PD-1抑制剂单药疗法，且斯鲁利单抗/HLX53联合治疗组较Pembrolizumab/HLX53潜在抗肿瘤活性更高。与Pembrolizumab 和Tiragolumab（抗TIGIT抗体） 的联合疗法相比，斯鲁利单抗联合HLX53能够显著增强效应CD4+T细胞、CD8+T细胞等免疫细胞在肿瘤内的浸润。此外，一系列研究数据表明，与Pembrolizumab/HLX53或Pembrolizumab/Tiragolumab联合疗法相比，斯鲁利单抗/HLX53的联合疗法对肿瘤微环境的诱导作用更强，有利于调动免疫细胞将 “冷 ”肿瘤变为 “热 ”肿瘤（SCLC通常被认为是一种免疫冷肿瘤），从而提高肿瘤免疫疗法的疗效。除TIGIT抑制剂外，斯鲁利单抗联合 HLX26（抗LAG-3单抗）也呈现出较单药治疗更强的抗肿瘤活性，有望进一步放大斯鲁利单抗作为免疫基石药物的治疗优势。 未来，复宏汉霖将继续以临床需求为导向，进一步拓展H药差异化、多维度的临床布局；同时，基于丰富的自研管线，积极探索H药与自有单抗产品、化疗等治疗手段开展联合治疗，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mAbs mAbs 为多学科开放获取期刊，专攻抗体工艺技术的研究与开发。该杂志聚焦科学和医学领域，读者群体广泛，包括：科学家、临床研究人员和医生，以及技术转让、法规、投资、疗法规划规范等方面的专家。 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，已有6款产品在中国获批上市，3款产品在国际获批上市，24项适应症获批，4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，公司商业化生产基地已相继获得中国、欧盟和美国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。截至目前，公司已获批上市产品包括国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）、汉贝泰®（贝伐珠单抗）以及汉奈佳®（奈拉替尼），此外，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。 Latest Research into the Differentiated Mechanisms of Action of Serplulimab Published in mAbs Journal Recently, the preclinical study results of serplulimab, Henlius’ innovative anti-PD-1 monoclonal antibody (mAb) were published in antibody R&D focus journal mAbs. The study revealed insights into the possible mechanisms underlying the excellent efficacy of serplulimab. Furthermore, the study found that the combined treatment with serplulimab and another immune checkpoint inhibitor, such as Henlius’ innovative anti-TIGIT Fc fusion protein HLX53 and anti-LAG-3 mAb HLX26, enhanced anti-tumour activity compared with serplulimab alone, which shows promise of more efficient clinical treatment options for cancer patients. In recent years, the research into immune checkpoint inhibitors has facilitated the rapid development of tumour immunotherapy. Immune checkpoints are crucial proteins in maintaining the immune response and protecting normal tissues. Nevertheless, these molecules may also be exploited by tumour cells to evade immune surveillance[1-3]. Immune checkpoint inhibitors represented by anti-PD-1/L1 antibodies can restore the immune system's anti-tumour activity by blocking the binding of immune checkpoints to their ligands, and have been widely used for the treatment of various types of malignant tumuors[4]. Serplulimab (HANSIZHUANG) is a recombinant humanised anti-PD-1 mAb injection independently developed by Henlius, and the world's first anti-PD-1 mAb approved for the first-line treatment of small cell lung cancer (SCLC). Up to date, HANSIZHUANG has been approved by China’s National Medical Products Administration for the treatment of microsatellite instability-high (MSI-H) solid tumours, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), benefiting approximately 80,000 patients. Based on its outstanding therapeutic efficacy in the treatment of small cell lung cancer (SCLC), serplulimab has became the world's first anti-PD-1 mAb approved for the treatment of SCLC. According to related research results, serplulimab targeted against a similar binding epitope compared with that targeted by pembrolizumab, while the spatial organisation of the heavy and light chains of serplulimab is unique, which may contribute to the different spatial interaction between serplulimab and PD-1 receptor. Moreover, due to its unique mode of recognition, serplulimab exhibits higher affinity (KD=2.42 nM) than other PD-1 inhibitors and robustly induces PD-1 receptor endocytosis, resulting in reduction of PD-1 receptors retained on the surface of T cells[5]. To further investigate the molecular mechanism of serplulimab, researchers analysed the expression level of key modulators on PD-1/L1 signalling pathway. The results showed that, serplulimab reduced the recruitment of immune co-stimulatory receptor CD28 by PD-1, thereby decreasing the dephosphorylation of CD28 mediated by phosphatase SHP2 and retaining the signal transmitted by CD28[6-8]. Further downstream the signalling pathway, the activity of protein kinase AKT was enhanced[9], thereby promoting sustained activation of T cells. Moreover, the researchers examined the anti-tumour activity of a PD-1 inhibitor, such as serplulimab or pembrolizumab, in combination with another immune checkpoint inhibitor. The results suggest that compared with serplulimab alone, combined treatment with serplulimab/HLX53 (anti-TIGIT Fc protein) resulted in dual PD-1/L1-TIGIT blockade and greater tumour growth inhibition(TGI) and survival rate reduction. Also, the serplulimab/HLX53 combination demonstrated higher potential as an immunotherapy compared with pembrolizumab/HLX53. Specifically, serplulimab/HLX53 significantly promoted the infiltration of effector CD4+ T cells and effector CD8+ T cells within tumours versus pembrolizumab/tiragolumab (an anti-TIGIT mAb). In addition, a series of analysis and data suggest that serplulimab/HLX53 induced strong modulation on the tumour microenvironment, mobilising immune cells to turn “cold” tumours into “hot” ones to improve the efficacy of anti-tumour immunotherapy (SCLC is often considered an immune-cold tumour). In addition, the serplulimab/HLX26 combination also enhanced anti-tumour activity compared with their respective monotherapies, which may further amplify the therapeutic advantages of serplulimab as an immune cornerstone product. Looking forward, Henlius will further expand HANSIZHUANG’s differentiated and multi-dimensional layout underpinned by the patient-centric strategy. Meanwhile, the company will actively promote HANSIZHUANG in combination with in-house products of Henlius and chemotherapy drugs to conduct immune combination therapies in a wide variety of indications, committing to bringing affordable and high-quality innovative treatments to patients around the world. About mAbs mAbs is a multidisciplinary, open access journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus but serves a broad readership, including specialists in technology transfer, legal issues, investment, planning and the regulation of therapeutics. 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, 6 products have been launched in China, 3 have been approved for marketing in overseas markets, 24 indications are approved worldwide, and 4 marketing applications have been accepted for review in China,the US 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 centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. 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, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab), HANBEITAI (bevacizumab) and HANNAIJIA (neratinib), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, 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. Ai L, et al. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020; 1248:33-59.  2. Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268.  3. Dong H, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion [published correction appears in Nat Med 2002 Sep;8(9):1039]. Nat Med. 2002;8(8):793-800. 4. Curran MA. Preclinical Data Supporting Antitumor Activity of PD-1 Blockade. Cancer J. 2018;24(1):2-6.  5. Issafras H, et al. Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy. PLoS One. 2021;16(12):e0257972.  6. Hui E, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355(6332):1428-1433.  7. Patsoukis N, et al. Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. 2020;3(1):128.  8. Fenwick C, et al. Tumor suppression of novel anti-PD-1 antibodies mediated through CD28 costimulatory pathway. J Exp Med. 2019;216(7):1525-1541.  9. Primavera E, et al. Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein. Pharmaceuticals (Basel). 2023;16(7):993.  联系方式 媒体：PR@Henlius.com 投资者：IR@Henlius.com 喜欢本文内容 点击下方按钮·分享 ·收藏 ·点赞 ·在看