Collagen x Enzymes

OTC2024类器官前沿应用与3D细胞培养论坛圆满落幕，点击图片可查看会后报告，咨询OTC2025类器官论坛请联系：王晨 180 1628 8769 引言：要说起这几年来自免领域，什么适应症的交易最火，那非IBD（炎症性肠病）莫属！ 针对IBD，我们之前的文章中写过TNF-α、JAK、TL1A等靶点（感兴趣的朋友可点相关蓝字观看）！ 今天这篇我们要写一个自免领域一个非常牛掰的靶点：α4β7！ 它的牛掰之处在于，横跨自免和抗感染两大领域！绝对有爆款潜质！ 针对此靶点开发的维多珠单抗已经成为IBD领域的一颗明珠，同时近几年也有公司另辟蹊径，针对此靶点开发了治疗HIV的产品，且已进入临床二期，不过最重要的事情先说在前面：这个靶点目前还不卷！ 图注：现有自免靶点、靶向药物和作用机制(MOA)。 01 α4β7 靶点介绍 整合素α4β7是一种异二聚体的I型跨膜糖蛋白，由α4和β7亚基组成，也是由这两个亚基而得名。 α4β7作为在淋巴细胞表面表达的归巢受体，在T细胞、B细胞、NK细胞及其他免疫细胞上表达。通过与粘膜地址蛋白细胞粘附分子-1（MAdCAM-1） 的相互作用，介导淋巴细胞运输到肠道相关淋巴组织（GALT）。 MAdCAM-1作为α4β7的主要天然配体，表达在肠粘膜高内皮小静脉（HEV）的管腔表面。 除MAdCAM-1外，动物细胞中大多数细胞外基质蛋白（包括胶原蛋白、纤连蛋白和层粘连蛋白）的主要受体也是整合素。整合素以较低的亲和力和他们结合，除发挥粘附作用外，也具有将细胞外信号向细胞内传递的作用。 02 α4β7在IBD和HIV发病中的病理作用 淋巴细胞归巢是指在正常生理条件下，淋巴细胞选择性地迁移到某些淋巴器官。这种迁移由粘附分子（包括整合素α4β7、整合素LFA-1和L-选择素）之间的级联相互作用介导。 在病理条件下，淋巴细胞不受控地迁移到炎症部位，产生自身免疫疾病等病症。在这种情况下，淋巴细胞首先附着在内皮细胞上，然后沿着内皮细胞滚动。最终，粘附稳定下来，并实现向HEV的迁移。这种病理过程主要由整合素α4β7和MAdCAM-1的相互作用介导。 2.1 IBD  慢性炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是由自身免疫反应引起的肠道疾病。 克罗恩病主要累及回肠和结肠, 且整个小肠和大肠的任意位置都有可能发生病变，患者的典型症状是肛周病变、瘘管和组织学肉芽肿。 溃疡性结肠炎则主要累及直肠和部分结肠。此外, 溃疡性结 肠炎患者的典型特征为血性腹泻, 并伴随着腹痛、体重减轻、 呕吐等症状。 IBD的免疫学病理特征是肠系膜血管中淋巴细胞粘附和迁移受阻，导致淋巴细胞不受控制地聚集在肠道。 如上文所述，α4β7与高内皮小静脉（HEV）的AdCAM-1间的相互作用在此过程中起着关键作用。因此，靶向α4β7和MAdCAM-1成为了开发IBD药物的策略之一。 2.2 HIV  肠道相关淋巴组织(GALT)是HIV-1复制的主要部位。在感染的急性期，GALT 中的CD4+ T细胞是HIV-1的主要靶标。 高表达α4β7的CD4+ T细胞更容易受到HIV-1的生产性感染。HIV-1包膜蛋白gp120可与α4β7结合，导致CD4+T细胞LFA-1快速激活，从而促进HIV-1的高效细胞间传播。 艾伯维开发的ABBV-382可以通过干扰α4β7与其配体MAdCAM-1和gp120之间的相互作用来阻断CD4+ T细胞刺激和HIV-1感染。另外，ABBV-382还可以与HIV-1 形成免疫复合物，增强抗原的免疫原性，从而潜在地诱导HIV-1特异性免疫反应。目前，ABBV-382与抗PD-1单抗Budigalimab联合使用，正在进行一项二期研究（NCT06032546）。 03 已上市的大单品——维多珠单抗 维多珠单抗是武田开发的，靶向α4β7的，异二聚体单抗药物。2014年5月20日被FDA批准上市，随后在全球不同领域获得批准，获批的适应症为中度至重度活动性溃疡性结肠炎和活动性克罗恩病。 作为肠道选择性的α4β7整合素拮抗剂，维多珠单抗通过选择性阻断α4β7整合素与其天然配体 MAdCAM-1间的相互作用，抑制T淋巴细胞进入肠道固有层和肠道相关淋巴组织（GALT），减轻肠道炎症，而不损害全身免疫反应。 维多珠单抗是武田的主要资产之一，为公司的整体收入带来了巨大的利润。2022年，Entyvio（商品名）的总销售额为$5364M，2018年-2022年的五年销售情况见下图。 04 有哪些玩家？ 因为这个靶点的“通吃”特点，其前景那是非常无法估量的，虽然目前只有一个药物获批，但胖猫认为，将来这个靶点肯定能在药物江湖中掀起“腥风血雨”！ 除武田外，其实布局该靶点的管线并不多。这样一个已经被验证有效性且横跨两个大的治疗领域的靶点，为啥就没有人卷呢？值得立项的团队深思！ 目前处于后期的管线如下表所示： 除此外，我们还人肉整理了自免适应症领域的上市药物，请大家自行参考。其中，标黄的一栏为维多珠单抗。 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 OTC2024类器官前沿应用与3D细胞培养论坛圆满落幕，点击图片可查看会后报告，咨询OTC2025类器官论坛请联系：王晨 180 1628 8769

引言 减数分裂是有性生殖生物用于产生配子的一种特殊的细胞分裂。在减数分裂过程中，同源染色体配对并通过同源重组进行染色体的相互交换，这对同源染色体在第一次减数分裂过程中的准确分离至关重要【1】。减数分裂重组因此也是遗传多样性和有性生殖生物适应性演化的原动力之一。减数分裂重组是由Spo11核心复合物制造的DNA双链断裂（DSB）所启动的，由此后续的DSB修复则可以产生染色体交叉结构，进而保证染色体的稳定配对和互换【2】。尽管Spo11是由古细菌拓扑异构酶VI（Topo VI）的切割亚基Top6A演化而来，并且几乎所有的生殖生物都利用Spo11来产生减数分裂DSB，然而Spo11核心复合物的组成成分，与Topo VI的对应关系，及其与DNA底物的结合和切割DNA双链的分子机制等目前仍不清楚【3】。 近日，由来自ZJE（浙江大学爱丁堡大学联合学院）的于游研究员为第一作者，山东大学高等医学研究院王军成研究员，MSKCC（纪念斯隆凯特琳癌症中心）博士后刘凯先和博士生郑植为共同第一作者，在Nature Structural & Molecular Biology上发表题为Cryo-EM structures of the Spo11 core complex bound to DNA的研究论文。该论文首次报道了分辨率为3.7Å/3.3 Å 的DNA（hairpin DNA/gapped DNA）结合的Spo11核心复合物（Spo11-Rec102-Rec104-Ski8）的冷冻电镜结构。这些结构展示了Spo11核心复合物中各亚基间的相互作用细节，以及Spo11核心复合物与DNA骨架，3'-OH凹槽和5'悬垂核苷酸的广泛相互作用。 该研究确定了Spo11核心复合物特异性结合DNA末端的分子机制，并揭示了Spo11核心复合物在体内偏好性切割DNA的分子机制。同时，酵母功能实验也验证了Spo11核心复合物中亚基之间及蛋白-核酸之间的相互作用，并揭示了与古细菌Top6BL同源的Rec102亚基结构的特异性（图1）。最后，该研究提供了对Spo11核心复合物二聚化及二价金属离子在催化DNA双链断裂的酶切反应中的作用的深入理解。 图1. Gapped DNA结合Spo11核心复合物的冷冻电镜结构及蛋白-核酸相互作用（Credit: Nature Structural & Molecular Biology） 参考文献 1. Keeney, S., Lange, J., and Mohibullah, N. (2014). Self-Organization of Meiotic Recombination Initiation: General Principles and Molecular Pathways. Annual Review of Genetics. 10.1146/annurev-genet-120213-092304. 2. Lukaszewicz, A., Lange, J., Keeney, S., and Jasin, M. (2018). Control of meiotic double-strand-break formation by ATM: local and global views. Cell Cycle. 10.1101/236984. 3 Claeys Bouuaert, C., Tischfield, S.E., Pu, S., Mimitou, E.P., Arias-Palomo, E., Berger, J.M., and Keeney, S. (2021). Structural and functional characterization of the Spo11 core complex. Nature Structural & Molecular Biology. 10.1038/s41594-020-00534-w. 4. Yu, Y.*, Li, S.*, Ser, Z.*, Sanyal, T.*, Choi, K., Wan, B., Kuang, H., Sali, A., Kentsis, A., Patel, D.J., et al. (2021). Integrative analysis reveals unique structural and functional features of the Smc5/6 complex. Proceedings of the National Academy of Sciences. 10.1073/pnas.2026844118. 5. Yu, Y.*, Li, S.*, Ser, Z., Kuang, H., Than, T., Guan, D., Zhao, X., and Patel, D.J. (2022). Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes. Proceedings of the National Academy of Sciences. 10.1073/pnas.2202799119. 6. Li, S.*, Yu, Y.*, Zheng, J., Browne, V.M., Zheng, S., Kuang, H., Patel, D.J. and Zhao, X., (2023). Molecular basis for Nse5-6 mediated regulation of Smc5/6 functions. Proceedings of the National Academy of Sciences. 10.1073/pnas.2310924120. 7. Baca, C.*, Yu, Y.*, Rostøl, J.*, Majumder, P., Patel, D., and Marraffini, L. The CRISPR effector Cam1 mediates membrane depolarization for phage defence. Nature. 10.1038/s41586-023-06902-y. https://www.nature.com/articles/s41594-024-01382-8 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

An Insilico Medicine drug candidate spawned by the company’s artificial intelligence technology now has clinical data showing breathing improvement in patients who have a debilitating lung disorder. While these preliminary results are encouraging for the company and for an AI drug discovery field that has weathered setbacks, there’s little detail to evaluate the Insilico drug on its own merits, let alone see how it matches up to competitors that includes one molecule some industry observers view as potentially best in class. The disease is idiopathic pulmonary fibrosis (IPF), a chronic disorder that causes scarring in the lungs and an irreversible decline in the organ’s function. IPF is a prevalent disease, affecting an estimated 5 million people worldwide, mainly older adults. Once diagnosed, patients survive a median of three to four years. The cause of IPF is unknown; standard therapies are older drugs that slow its progression but do not alter the course of the disease. Insilico’s drug, ISM001-055, targets and inhibits Traf2- and Nck-interacting kinase (TNIK), an enzyme that plays a role in signaling pathways associated with disease. While TNIK inhibition has been studied as a way to treat cancer, Insilico’s technology identified this target as a promising one for fibrosis, the formation of scar tissue characteristic of IPF. The company then used generative AI to design the small molecule that is now its IPF drug candidate. Details about this development process were published in March in Nature Biotechnology. Included in the paper were preclinical data and results from Phase 0 (small doses of drug tested in low numbers of people) and Phase 1 studies. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health The results announced last week are from a placebo-controlled Phase 2a study that enrolled 71 IPF patients in China. Patients were randomly assigned to receive a 30 mg dose of the drug once daily, a 30 mg dose twice daily, a 60 mg dose once daily, or a placebo. The main goal of the 12-week study is assessing the ISM001-055’s safety and tolerability across all dose levels. Measuring improvement in forced vital capacity (FVC), which is how much air a person can exhale, is a secondary endpoint. Without disclosing any figures, Insilico said ISM001-055 met the primary endpoint of safety and posted positive results on the secondary efficacy endpoint. The company added that these results show a dose-dependent improvement in FVC, with the largest improvement observed in the cohort that received the 60 mg dose once daily. Insilico said more details about the preliminary data will be released at an upcoming medical conference and the trial results will be submitted for publication in a peer-reviewed journal. A parallel Phase 2 study in the U.S. is actively enrolling patients. Following the positive results from this mid-stage study, Insilico said it will discuss with regulatory authorities the design of a Phase 2b study that will explore extended treatment durations and larger groups of patients. Meanwhile, the clinical trial results so far keep Insilico in the mix of drug developers pursuing IPF, though it still trails those rivals. On Sept. 16, Boehringer Ingelheim announced its IPF drug candidate hit the main goal of its pivotal studies, paving the way for regulatory submissions to the FDA and other health authorities around the world. The Boehringer drug, nerandomilast, is a small molecule designed to inhibit phosphodiesterase 4B (PDE4B), an enzyme whose roles include regulating inflammation. Sponsored Post Get Ready for HLTH 2024: A Preview Guide HLTH 2024, scheduled for October 20-23 at the Venetian Expo Center in Las Vegas, will highlight new programming, a physicians roundtable, generative AI, the shifting landscapes of telemedicine, retail health, women's health, and lots more. By Stephanie Baum Boehringer studied its twice-daily pill in two placebo-controlled Phase 3 studies, one in IPF and the other in progressive pulmonary fibrosis (PPF), a progressive and fibrotic disease that shares characteristics with IPF. The main goal of both studies was to show the absolute change in FVC measured at 52 weeks. Without releasing details, Boehringer said preliminary results show nerandomilast met this goal. The company added that full efficacy and safety data will be presented in the first half of next year. The company did not specify a timeline for the expected regulatory submissions for the drug. Pliant Therapeutics’ contender is bexotegrast, a small molecule inhibitor of TGF-beta. This signaling protein contributes to IPF by sparking high levels of collagen, which in turn leads to a progressive loss of elasticity and function in the lungs. During the recent European Respiratory Society (ERS) meeting, Pliant presented Phase 2 results showing its drug led to a reduction in collagen after 12 weeks of treatment. Study participants who received a placebo experienced an increase in collagen. The reduction in treated patients correlates with improvement in lung function, specifically FVC and cough severity, Pliant said. In a note sent to investors this after the ERS meeting, Leerink Partners analyst Faisal Khurshid said bexotegrast’s collagen data provide “compelling proof of disease modification.” He added that the safety analyses continue to suggest the Pliant drug has a clean profile. Khurshid said bexotegrast has potential to become a best-in-class treatment option in IPF and the collagen data give incremental confidence ahead of Phase 2b data expected in mid-2026. PureTech Health’s approach to IPF is to improve on pirfenidone, brand name Esbriet, an old IPF drug whose gastrointestinal and skin side effects lead many patients to stop taking the medication. Despite those limitations, Leerink Partners’ Khurshid noted in a research note that branded Esbriet generated $1.3 billion in peak sales before going generic. PureTech’s IPF drug, LYT-100, is pirfenidone with chemical modifications to improve its tolerability. “We have a favorable view on LYT-100 as it improves on a known anti-fibrotic drug in a manner that should diminish well-recognized safety liabilities,” Khurshid said. “While this is an improvement on an existing molecule, we see it as a real opportunity in an area of high unmet need.” A Phase 2b test of LYT-100 is currently evaluating two doses of the drug compared to pirfenidone and a placebo. With the lower dose, the study aims to show whether the PureTech drug improves on the safety profile of pirfenidone. Evaluating the higher dose is meant to assess whether higher exposure of the drug offers even better efficacy while still retaining acceptable safety. Khurshid said there is less evidence to support the latter hypothesis, but Leerink sees it as an intriguing upside opportunity.