预约演示

更新于：2025-05-07

BMP7

更新于：2025-05-07

基本信息

别名

BMP-7、BMP7、bone morphogenetic protein 7

+ [4]

简介

Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis (PubMed:31208997). Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2A (PubMed:12667445, PubMed:9748228). Once all three components are bound together in a complex at the cell surface, ACVR2A phosphorylates and activates ACVR1. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes (PubMed:12478285). For specific functions such as growth cone collapse in developing spinal neurons and chemotaxis of monocytes, uses also BMPR2 as type II receptor (PubMed:31208997). Can also signal through non-canonical pathways such as P38 MAP kinase signaling cascade that promotes brown adipocyte differentiation through activation of target genes, including members of the SOX family of transcription factors (PubMed:27923061). Promotes the expression of HAMP, this is repressed by its interaction with ERFE (PubMed:30097509).

关联

项与 BMP7 相关的药物

PG-005

靶点

BMP7

作用机制

BMP7刺激剂

在研机构

Peptigrowth, Inc.

原研机构

Peptigrowth, Inc.

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 BMP7 相关的临床结果

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100 项与 BMP7 相关的转化医学

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0 项与 BMP7 相关的专利（医药）

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3,415

项与 BMP7 相关的文献（医药）

2025-12-01·Molecular Biology Reports

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways

Article

作者: Afaloniati, Hara ; Markaki, Maria P ; Karagiannis, George S ; Argyris, Dimitrios G ; Poutahidis, Theofilos ; Angelopoulou, Katerina

BACKGROUNDLately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways.METHODS AND RESULTSTotal RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level.CONCLUSIONSThese findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

2025-06-01·Journal of Orthopaedics

Andrographolide suppresses fibrogenic phenotype of chondrocytes and ameliorates osteoarthritis by regulating miR-137/BMP7 axis

Article

作者: Sun, Fei ; Li, Yanlin ; Hu, Xidan ; Wang, Guoliang ; Xiang, Yaoyu ; Yang, Xianguang ; Song, En

BackgroundPathogenic degeneration of cartilage and the generation of fibrotic cartilage are crucial characteristics linked to the progression of osteoarthritis (OA). The current research aims to explore the potential function of the miR-137/BMP7 pathway in regulating the fibrogenic transition of chondrocytes associated with OA, as well as assess the therapeutic potential of andrographolide.MethodsSamples of cartilage from the knees of patients with OA and individuals without OA were gathered to investigate the expression patterns of miR-137, BMP7, and markers associated with fibrosis. A cell model using primary chondrocytes stimulated with interleukin (IL)-1β was developed to study the involvement of the miR-137/BMP7 axis during the fibrogenic transition of these cells. Additionally, we utilized an animal model of OA in order to assess the beneficial effects of the anti-inflammatory natural compound andrographolide on the fibrogenesis induced by OA in vivo.ResultsElevated levels of fibrogenic and inflammatory factors were linked to decreased miR-137 expression in OA samples. In IL-1β-treated chondrocytes, there was an upregulation of fibrogenic markers alongside a reduction in miR-137 levels. The overexpression of miR-137 inhibited fibrogenesis through the negative regulation of BMP7. Additionally, treatment with andrographolide was effective in attenuating the fibrogenic phenotype in chondrocytes and mitigating OA pathogenesis via modulating the miR-137/BMP7 pathway.ConclusionmiR-137 downregulation and BMP7 overexpression might contribute to the fibrogenic features in OA-related chondrocytes. Andrographolide attenuates fibrogenic phenotype in chondrocytes and alleviates the severity of OA by modulating the miR-137/BMP7 axis.

2025-06-01·Tissue and Cell

Modulation of HIF-1α and TNF-α in pre-osteoblasts treated with alcohol extract of propolis: Implications for cellular response and signaling pathways

Article

作者: Orsi, Ricardo de Oliveira ; de Almeida, Gerson Santos ; Zambuzzi, Willian Fernando ; de Camargo Andrade, Amanda Fantini ; Fernandes, Célio Jr Da Costa ; de Morais, Paula Bertin

Numerous studies have demonstrated the significant role of propolis in various biological processes, including inflammation and the repair of endothelial and bone tissues. The cascade of inflammation, proliferation, and tissue remodeling characterizes the injury site. Remarkable progress has been made in the field of alternative medicine with the utilization of propolis. In this study, we specifically investigated the effects of alcoholic extract of propolis on cell adhesion, survival, remodeling, and differentiation pathways in osteoblasts. Our findings revealed the activation of survival proteins such as AKT, ERK, and phosphorylated ERK during the adhesion phase, while interleukins, specifically IL-6 and TNF, exhibited increased expression during cell differentiation. Furthermore, treatment with propolis extract led to enhanced activity of metalloproteinases (MMP9 and MMP2) and HIF-1α, a crucial activator of angiogenesis and bone remodeling. It was observed that the alcoholic propolis extract stimulated cell proliferation, differentiation, and repair, with key molecules involved in these processes including pro-inflammatory factors IL-6 and TNFα, as well as HIF-1, MMP2, and BMP7 proteins. Collectively, these factors induced an initial state of proliferation followed by differentiation and repair. Therefore, the alcoholic extract of propolis holds promise as a potential therapeutic agent, particularly in cases involving tissue repair. Nevertheless, further comprehensive in vitro and in vivo studies targeting this area are necessary to advance our understanding.

项与 BMP7 相关的新闻（医药）

2025-04-09

·PRNewswire

Darnatein, an OSR Company, Broadens Intellectual Property Protection for Innovative Osteoarthritis Treatment Technology

SEOUL, South Korea, April 9, 2025 /PRNewswire/ -- Darnatein, a wholly-owned subsidiary of OSR Holdings, Inc. (NASDAQ: OSRH), today announces that it has successfully secured an additional international patent for its protein-based osteoarthritis treatment technology, marking a significant step in its expansion into the global market. Activin/BMP7 Chimera Protein Technology Registered in China Darnatein has officially registered a patent with the China National Intellectual Property Administration (CNIPA) for the core technology behind its break-through disease-modifying osteoarthritis drug (DMOAD) lead drug candidate, DRT-101. Following the national registration of the patent in South Korea in November last year, this marks the company's first successful international patent registration as part of its efforts to secure global intellectual property rights through the PCT (Patent Cooperation Treaty) route in key regions such as the EU, the United States, and China. The technology basis is an AI-enhanced innovative protein structure generator designed to provide therapeutics that overcome the current limitations of standard of care treatment in osteoarthritis—a condition for which only symptom management options currently exist. This technology represents a wholly new approach to protein design and is expected to address the underlying causes of disease. This treatment approach may significantly improve treatment outcomes not only for osteoarthritis but also for a wide range of other musculoskeletal disorders. In particular, the DRT-101 chimeric protein, which recombines the natural BMP7 and Activin proteins into a wholly novel structure, has already been shown to enhance both therapeutic efficacy and safety in vivo, in studies conducted between 2020 and 2024 at the University of California, San Diego, School of Medicine. Senyon Choe, Darnatein Chief Executive Officer, stated, "The protein design technology now also patented in China has been developed over years from a core platform strategy to the current technology with the potential to revolutionize the global OA treatment market. Securing intellectual property rights in China, one of the largest markets in the world, is a crucial stepping-stone for our global expansion." Constance Höfer, Chief Scientific Officer of OSR Holdings, stated, "Darnatein's groundbreaking technology represents a wholly new, AI-enhanced approach to therapeutic protein design. The successful patent registration in China underscores the novelty and relevance of this technology to the development of better treatment options for OA patients worldwide." Global Technological Competitiveness and Licensing Potential The osteoarthritis treatment market continues to grow, due to globally aging populations. In 2023, the market size reached approximately USD 8.9 billion and is projected to grow at an average annual rate of about 7%, reaching approximately USD 16.1 billion by 2032. China is experiencing rapid population aging and a surge in osteoarthritis cases, making it a highly promising market. Industry experts have remarked, "Darnatein's Activin/BMP7 chimera technology offers a superior profile to be developed into a potential DMOAD, or disease-modifying OA drug, compared to existing standard of care for osteoarthritis treatments," adding, "Big Pharma is looking for novel treatments that can slow, stop, or even reverse the cartilage degeneration and joint damage that occurs with OA. On this backdrop, Darnatein's chimeric protein approach represents a paradigm shift away from only symptom relief (e.g. painkillers and anti-inflammatories) to treatment options targeting the underlying pathobiology of OA" Darnatein is currently completing preclinical studies with DRT-101, its degenerative OA treatment candidate, with the goal to initiate Phase 1 clinical trials later this year. About Darnatein Founded in 2012, Darnatein is a biotherapeutics company based in South Korea developing a pipeline of innovative treatments for osteoarthritis and bone fusion, including DRT-101 as a ground breaking disease-modifying OA drug (DMOAD) candidate. Darnatein was established by Dr. Senyon Choe, one of the co-founders of the structural protein laboratory of the prestigious Salk Institute for Biological Studies in La Jolla, CA, and a faculty member of UC San Diego since 1993. Darnatein operates as a wholly owned subsidiary of OSR Holdings, Inc. following its acquisition in 2023. About OSR Holdings, Inc. OSR Holdings, Inc. is a global healthcare company dedicated to advancing biomedical innovation. Through its subsidiaries, OSR is engaged in oncology immunotherapies, degenerative disease biologics, and medical device distribution. OSR's vision is to acquire and operate a portfolio of innovative healthcare companies, improving patient care through cutting-edge research and development. For more information, visit . Contact [email protected] SOURCE OSR Holdings Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

并购

2024-12-13

·拜尔迪生物

近岸 | 类器官培养关键细胞因子—FGF-4

关于FGF-4 成纤维细胞生长因子（Fibroblast Growth Factors，FGFs）是一类普遍存在于哺乳动物体内的促细胞分裂肝素结合蛋白，其与受体FGFR均在种间高度保守。FGFs可诱导调节细胞增殖分化、胚胎发育、血管再生、损伤修复、肿瘤发生等多个生理进程[1]。近岸类器官课堂：类器官培养关键细胞因子之FGF家族 FGF-4隶属FGF旁分泌亚家族，最初从人胃肿瘤中分离，正常情况下在成人体内少量表达于十二指肠、回肠和结肠中以维持肠干细胞稳态[2]。FGF-4通过硫酸乙酰肝素依赖性路径传递信号，可激活配体FGFR（与FGFR4结合特异性最强）启动损伤修复、器官再生和代谢调控[3]。在人胚胎发育过程中，FGF-4助力干细胞的自我更新与胚胎磨牙芽的发育。 FGF-4与类器官培养 1 肠道类器官 2014年，研究人员使用iPSC来源的类器官首度在体外构建了3D人体肠道组织模型。实验发现，生长因子FGF-4和WNT-3a可促进CDX2+后肠内胚层特异性模式化，并产生三维球状体[4]。2015年的一篇论文则提出，FGF-4在肠道类器官培养中的主要作用可能是抑制hPSC向肝谱系的分化[5]。在2017年和2018年相继发表的两项研究指出，类器官在短期暴露于FGF-4和CHIR 99021（一种Wnt/β-catenin信号通路激活剂）的培养条件下，更倾向于形成十二指肠类器官；而长期暴露则引导其向回肠组织的基因表达模式发展。值得注意的是，当完全缺乏CHIR 99021和FGF-4的添加时，体外实验中未能观察到后肠球状体的形成[6,7]。图1 从iPSC体外分化肠道类器官的示意图[4] 2 胃类器官 2021年发表于Nature Protocol的文章介绍了使用hPSC产生功能性胃细胞的方法。该实验方法使用Activin A将hPSC分化成定形内胚层（DE），然后添加FGF 4与CHIR 99021产生自由漂浮的3D前肠后部球状体，并最终形成胃窦和胃底类器官[7]。图2 hPSC诱导产生胃窦和胃底类器官的路径[7] 3 肺类器官为了应对SARS-CoV-2等呼吸道疾病，体外肺部3D模型一直是研究的重点。来自美国密歇根大学医学院的研究团队通过添加Noggin、SB、FGF-4、CHIR99021，从hPSC开发出人肺类器官（HLO）[8]。该研究得到的HLO由肺的上皮和间充质隔室组成，具有上气道样上皮以及被平滑肌和肌成纤维细胞包围的基底细胞。与此同时，HLO还拥有未成熟纤毛细胞和肺泡样结构域。 2021年，发表于Nature的一篇文章使用FGF-4+CHIR 99021从hPSC获得肺类器官，并检测到类器官中肺泡II型细胞标志物的表达[9]。使用SARS-CoV-2感染肺类器官，观测到趋化因子被高度诱导，与COVID-19患者感染症状类似。基于肺类器官模型，研究者对FDA批准的药物进行了高通量筛选，发现SARS-CoV-2感染抑制剂伊马替尼、麦考酚酸（MPA）和盐酸奎纳克林（QNHC）等，为COVID-19治疗提供了新思路。图3 肺类器官不同培养阶段的代表性图像[10] 4 肝脏类器官脂肪型肝炎由多种因素导致，其中非酒精性脂肪肝（NAFLD）以及非酒精性脂肪性肝炎（NASH）的全球患病率及病死率非常高。为了深入探究脂肪性肝炎基因型-表型关联及其与糖类代谢之间的联系，2022年，发表于Cell上的一篇研究通过添加FGF-4和CHIR 99021，构建了单纯性脂肪变性和脂肪性肝炎的类器官模型[11]。实验发现葡萄糖激酶调节蛋白（GCKR）-rs1260326-T等位基因仅在同时患有糖尿病的前提下加重NASH，为糖尿病-NAFLD/NASH的治疗奠定了分子基础。 5 心脏类器官 FGF及其受体FGR1在心脏发育中发挥至关重要的作用，如FGF-4-FGFR1通路调节心肌细胞与其他细胞之间的增殖平衡以确保心室结构正确。为了探究心脏发育机制，2020年的一篇研究探索了体外心脏类器官模型建立的路径[12]。向来自小鼠胚胎干细胞的胚状体添加外源FGF-4后，成功诱导初始心肌细胞的增殖和第八天心室的形成。与家族内的其他因子比较，FGF-4的诱导效率最高（两次实验中，FGF-4为88%和78%，FGF10为42%和25%）。最终成功获得具有心肌细胞超微结构特性的心脏类器官，并表达相关转录因子与结构基因，为体外心脏药物筛选、诊疗等提供了新的平台。图5 心脏类器官不同培养阶段的代表性图像[12] 近岸蛋白提供高活性，高批间一致性的重组FGF-4蛋白，并经过类器官培养验证，让您的类器官培养更可控！产品数据高活性 Measured in a cell proliferation assay using MCF7 Human breast cancer cells.The ED50 for this effect is 2-20 ng/ml. 高批间一致性 Three independent lots were tested for activity and plotted on the same graph to show lot-to-lot consistency of FGF-4(Cat#CR08). 类器官培养验证 Human intestinal organoids (ipsc source) were cultured with Activin A(Cat#C687) , BMP-4(Cat#CR93) , EGF (Cat#C029) , Wnt3a (Cat#C22R), Noggin (Cat#C028), R-spondin 1 (Cat#CX83) and FGF-4 (Cat#CR08) . The organoids showed good morphology. 相关产品：类器官培养类型相关因子胃类器官 Activin A、BMP-4、EGF、FGF-4、FGF-10、Noggin、R-spondin 1、Wnt3a 肠类器官 Activin A、BMP-4、EGF、FGF-4、Noggin、R-spondin 1、Wnt3a 肝类器官 Activin A、BMP-4、BMP-7、FGF-7、FGF-10、FGF-19、HGF、OSM、R-Spondin 1 肺类器官 Activin A、FGF-4、FGF-7、FGF-10、Noggin、SHH、Wnt3a 前列腺类器官 EGF、FGF-10、Noggin、R-spondin 1、Wnt-3a 脑类器官 BDNF、EGF、FGF basic、GDNF、NT-3 内耳类器官 BMP-4、FGF basic 视网膜类器官 SHH、Wnt-3a 乳腺类器官 EGF、FGF basic、FGF-7、FGF-10、Heregulinβ-1、Noggin、R-Spondin 1、R-Spondin 3、Wnt-3a 肾脏类器官 BMP-2、BMP-4、BMP-7、FGF basic、FGF-9、Activin A、FGF-7、GDNF、R-Spondin 1 心脏类器官 Activin A、BMP-4、FGF basic、TGF-beta 1、Transferrin 血管类器官 BMP-4、FGF basic、VEGF 参考文献 [1]Xie, Yangli et al. “FGF/FGFR signaling in health and disease.” Signal transduction and targeted therapy vol. 5,1 181. 2 Sep. 2020, doi:10.1038/s41392-020-00222-7 [2]Tian, Haoyu et al. “Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges.” International journal of molecular sciences vol. 24,5 4583. 26 Feb. 2023, doi:10.3390/ijms24054583 [3]Morita, Hideaki, and Masaaki Hoshiga. “Fibroblast Growth Factors in Cardiovascular Disease.” Journal of atherosclerosis and thrombosis vol. 31,11 (2024): 1496-1511. doi:10.5551/jat.RV22025 [4]McCracken, Kyle W et al. “Generating human intestinal tissue from pluripotent stem cells in vitro.”Nature protocolsvol. 6,12 1920-8. 10 Nov. 2011, doi:10.1038/nprot.2011.410 [5]Tamminen, Kaisa et al. “Intestinal Commitment and Maturation of Human Pluripotent Stem Cells Is Independent of Exogenous FGF-4 and R-spondin1.”PloS onevol. 10,7 e0134551. 31 Jul. 2015, doi:10.1371/journal.pone.0134551 [6]Tsai, Yu-Hwai et al. “In vitropatterning of pluripotent stem cell-derived intestine recapitulatesin vivohuman development.”Development (Cambridge, England)vol. 144,6 (2017): 1045-1055. doi:10.1242/dev.13845 [7]Zhang, Ran-Ran et al. “Human iPSC-Derived Posterior Gut Progenitors Are Expandable and Capable of Forming Gut and Liver Organoids.” Stem cell reports vol. 10,3 (2018): 780-793. doi:10.1016/j.stemcr.2018.01.006 [8]Dye, Briana R et al. “In vitro generation of human pluripotent stem cell derived lung organoids.” eLife vol. 4 e05098. 24 Mar. 2015, doi:10.7554/eLife.05098 [9]Han, Yuling et al. “Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.”Naturevol. 589,7841 (2021): 270-275. doi:10.1038/s41586-020-2901-9 [10]Pei, Rongjuan et al. “Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection.”Protein & cellvol. 12,9 (2021): 717-733. doi:10.1007/s13238-020-00811-w [11]Kimura, Masaki et al. “En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.”Cellvol. 185,22 (2022): 4216-4232.e16. doi:10.1016/j.cell.2022.09.031 [12]Lee, Jiyoung et al. “In vitro generation of functional murine heart organoids via FGF-4 and extracellular matrix.” Nature communications vol. 11,1 4283. 3 Sep. 2020, doi:10.1038/s41467-020-18031-5 上下滑动查看更多北京拜尔迪是近岸蛋白的授权代理商，更多产品，敬请咨询！

临床研究临床结果

2024-10-24

·CPHI制药在线

靶点 | ActRⅡ：减脂、增肌潜力看好，礼来、阿斯利康重仓

关注并星标CPHI制药在线 ActRⅡ存在于脂肪和肌肉细胞中。在脂肪细胞中，激活素通过ActRⅡ进行脂质存储，阻断该信号通路可促进脂肪代谢。在肌肉细胞中，ActRⅡ受体传导的信号通路能够抑制肌肉生长并导致其萎缩，阻断骨骼肌中的激活素信号可以抑制这种萎缩，并可以促进肌肉质量的增加，帮助肥胖患者在减肥的同时改善身体成分和代谢。因此，ActRⅡ认为是下一代热门减肥药物的开发靶点。关于ActRⅡ ActRII，即激活素Ⅱ型受体，是转化生长因子β（TGF-β）受体家族的成员，包括活化素A和活化素B，以及BMP7、BMP9、BMP10、GDF1、GDF8（Myostatin）、 GDF11和Nodal在内的其他TGF-β家族成员的II型受体。 ActRII有ACVR2A（又称为ActRIIA）和ACVR2B（又称为ActRIIB）两种，其多个配体被证明是骨骼肌质量负调控因子，如Activin和GDF11，其中ActRIIB最初被确定为GDF8的主要受体。 ActRII的生物学功能与激活素I型受体（ActRI）密不可分。激活素、GDF8和GDF11通过ActRII和ActRI触发信号传导。ActRII是主要的配体结合受体，与ActRII结合后，配体和ActRII与ActRI形成复合物，刺激细胞质中Smad2和Smad3转录因子的磷酸化。磷酸化的Smad2/3随后转运至细胞核，调节包括MyoD在内的靶基因的转录。其中GDF8/ActRII通路被确定为调节骨骼肌大小的关键。激活素与ActRII结合后触发的信号是机体胚胎发育、器官形成、激素合成、细胞分化、免疫调节等重要生理活动的执行者，其异常与多种疾病高度相关，包括代谢性和免疫性等多种疾病类型，如骨骼肌肉萎缩、肥胖、贫血、肺纤维化。 ActRII靶点进展目前全球监管机构已批准两款ActRII药物，即BMS的ActRIIB-Fc融合蛋白药物Luspatercept和默沙东/Acceleron的ActRIIA-Fc融合蛋白药物Sotatercept。 Luspatercept是一种可溶性融合蛋白,由人免疫球蛋白G1（IgG1）的Fc结构域与ActRIIB的细胞外结构域融合而成。Luspatercept能够作为TGF-β的配体陷阱，防止TGF-β激活Smad2/3信号通路，进而促进晚期红细胞的分化和成熟，提高血红蛋白水平。目前，Luspatercept已在美国获批三项适应症：需要定期输注红细胞（RBC）的成人β-地中海贫血；骨髓增生异常综合征（MDS）伴环形铁粒幼细胞或骨髓增生异常/骨髓增殖性肿瘤伴环形铁粒幼细胞和血小板增多相关贫血；未经红细胞生成刺激剂（ESA）治疗、需要定期接受红细胞输注（RBC）的中低危MDS成人患者的贫血。该药最初由BMS旗下的新基研发，新基在与BMS整合前，曾与 Acceleron联合开发 Luspatercept。 Sotatercept是一款ActRIIA融合蛋白，其将ActRIIA经过改造的细胞外域与抗体的Fc端融合在一起，可以阻断激活素与细胞膜上的受体结合，从而降低激活素介导的信号传导。2024年3月，该药被FDA批准用于治疗成人肺动脉高压（PAH），以提高运动能力，改善WHO功能分级，并降低临床事件恶化风险。值得一提的是，Sotatercept最初由Acceleron 研发，2021年10月默沙东斥资115亿美元收购Acceleron，将Sotatercept纳入囊中。据Evaluate预测，Sotatercept 2028年销售额有望达到26亿美元，产品的净现值达116亿美元。此外，据公开资料全球还有多款在研ActRII药物，详见下表。在研ActRII药物适应症多样，涉及骨髓增生异常综合征、肥胖、肺动脉高压等。ActRII药物的药物类型也比较多元化，涉及抗体类融合蛋白、单特异性抗体和双特异性抗体。研发进度上，在研ActRII药物大多处于临床前阶段。Elritercept和Bimagrumab进展较快，已进入临床III期阶段。其中Elritercept（KER-050）是一种工程化配体陷阱，由ActRIIA的修饰配体结合域与人类抗体Fc结构域部分融合组成。 2021年12月，翰森制药与Keros Therapeutics达成合作协议，获得KER-050的大中华区权益，翰森制药将支付2000万美元预付款以及1.705亿美元里程碑金额，外加两位数比例的销售分成。 2024 EHA上公布的Elritercept在较低风险MDS患者中开展的临床II期试验数据显示：55.6%的患者在治疗的前24周内达到了血液学改善红系反应（HI-E）和/或输血独立，包括50.0%的高输血负担患者。基线促红细胞生成素（EPO）<500U/L的患者与总体患者相比总缓解率（ORR）更高（60.6% vs 55.6%），且非环状铁粒细胞（RS） MDS患者中的8周以上输血独立率显著较高（40% vs 22.2%），特别是在高输血负担患者中（50% vs 23.1%）。同时，基线EPO<500U/L的患者中有26例（32%）维持了≥24周的输血独立性。数据截止时，输血独立的中位时间仍未达到，维持了≥24周的输血独立性患者中仍有16例患者持续保持输血独立性，11例（11/16）输血独立时间超过52周，其中6例在基线时具有高输血负担。对于输血独立患者，FACIT-疲劳评分的平均改善在24周内超过了临床意义阈值，特别是对于那些输血独立超过24周的患者，研究观察到了血红蛋白和血小板上升。安全性方面，97.7%的患者经历了治疗期间不良事件（TEAE），大多数为轻度至中度。最常见的TEAE为腹泻（27.6%）、疲劳（25.3%）、呼吸困难（20.7%）、头晕（19.5%）、COVID-19（18.4%）、恶心（18.4%）和贫血（17.2%）。 Bimagrumab是一种靶向ActRII的人单克隆抗体，礼来通过斥资19亿美元收购Versanis将其纳入囊中。Bimagrumab在肥胖或超重2型糖尿病患者中开展的临床II期试验的第48周数据显示：与安慰剂相比，Bimagrumab 组受试者总体脂肪减少（-20.5% vs-0.5%）,去脂体重增加（+3.6%vs-0.8%），腰围减少（-9cm vs +0.5cm），体重减少（-6.5% vs-0.8%）。安全性方面，Bimagrumab组最常报告的不良事件是轻度腹泻(41% vs 11%)和肌肉痉挛(41% vs 3%)，其中首次给药后腹泻频率最高，此后逐渐减少。2024年10月，Bimagrumab联合替尔泊肽增肌减脂的临床II期临床启动。 Cibotercept（KER-012）处于临床II期阶段。该药是Keros Therapeutics开发的一款蛋白质治疗候选产品，由与人类抗体Fc结构域部分融合的ActRIIB的修饰配体结合结构域组成，其被设计用于结合并抑制包括激活素A和激活素B在内的TGF-β配体的信号转导，从而潜在地增加骨骼质量。同时，KER-012介导的对激活素A和激活素B的抑制也具有增加BMP信号通路的潜力。目前，Keros正在针对KER-012开展一项探讨KER-012联合背景疗法治疗成人肺动脉高压(PAH)的安全性和有效性的研究（NCT05975905）。已公布的KER-012在健康绝经后妇女中开展的临床I期试验数据显示：与安慰剂相比，单次给予KER-012后，受试者中与炎症和结构重塑通路相关的血清蛋白发生了改变，例如纤维化标志物MMP-7和MMP-10减少、促炎细胞因子IL-6和IL-11减少、抗炎细胞因子IL-4和IL-35增加，以及巨噬细胞极化标志物MARCO和sCD163增加。此外，接受KER-012的受试者的心脏功能障碍生物标志物血清N末端脑钠肽前体（NT-proBNP）也持续减少。 LAE102、STM 434处于临床I期，其中LAE102是来凯医药自主研发的一款针对ActRIIA的选择性单克隆抗体，相较Bimagrumab有望提升安全性，公司计划将其开发用于治疗肥胖和代谢疾病、肺动脉高压等。在临床前研究中，LAE102已显示出增加肌肉并减少脂肪的效果。而且，LAE102与GLP-1受体激动剂联用，可进一步减少脂肪，并显著降低GLP-1受体激动剂导致的肌肉流失。2024年上半年，LAE102先后在美国和中国获批临床，针对肥胖。2024年6月，该药在国内针对超重/肥胖的临床I期试验完成首例患者给药。此外，来凯医药围绕ActRII受体还自主开发两款候选药物，即ActRIIB选择性抗体LAE103和ActRIIA/IIB双靶点抑制剂LAE123，拟用于肌肉再生及与之相关的适应症。 ActRII药物减重增肌潜力看好，引发多起合作整体来看，ActRII靶点并未取得巨大成功，但已引起多家药企重视，并引发多起交易。 2023年7月，礼来斥资19.25亿美元收购Versanis Bio。Versanis Bio旨在开发一种治疗代谢性疾病和肥胖症的first-in-class疗法，其核心产品Bimagrumab是一种结合激活素II型A和B受体以阻断激活素和肌肉抑制素信号传导的单克隆抗体，目前正在BELIEVE IIb期研究中单独进行评估，并与Semaglutide（司美格鲁肽）联合治疗成人超重或肥胖。 2024年5月，阿斯利康与SixPeaks达成了一项战略合作。据合作协议，阿斯利康参与A轮融资，并承诺提供包括预付款和短期付款在内的最高8000万美元资金。作为交换，阿斯利康获得在公司为其主导抗体提交IND申请时以预定价格收购SixPeaks的选择权。 SixPeaks致力于开发潜在“first-in-class“和“best-in-class”健康减肥疗法，其研发管线中包含一款旨在保存人体骨骼肌质量，靶向激活素（activin）受体IIA/B的抗体。在小鼠模型中进行的临床前研究表明，SixPeaks的主打在研疗法无论是单独使用，还是与GLP-1受体激动剂联用，在保存肌肉质量方面可能具有“best-in-class”的潜力。而且，SixPeaks还开发出一种与GLP-1肽偶联的抗激活素受体IIA/B抗体，这可能成为一种潜在“first-in-class”疗法，在最大限度发挥GLP-1受体激动剂介导减重效果的同时保存肌肉质量。 2024年6月，Supercede Therapeutics与复旦大学和华东师范大学达成一项全球权益合作。据协议，Supercede Therapeutics将获得复旦大学和华东师范大学共同研发的处于临床前的小分子抗肿瘤恶病质肌萎缩、肌少症和增肌创新药物全球开发和商业化权益。据悉，该药物是一种新型口服小分子ActRII抑制剂，用于治疗肥胖症。纵观这三项交易，企业都非常看中ActRII靶点在减重领域的潜力。与目前大火的GLP-1类减重疗法相比，ActRII抑制剂在减少脂肪的同时，还可增加身体的肌肉组成，被认为是下一代减肥药物的“种子选手”。总结相较大火的GLP-1靶点，ActRII在减重领域还有很长的路要走。目前，ActRII领域的竞争并不算激烈，在研药物也不多，其中Bimagrumab、LAE102在减重领域进展相对较快。期待ActRII药物早日获得重大突破，破解目前减肥药会使肌肉流失的困局。 END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~