Hyponatremia is a common electrolyte imbalance which often results from hormonal disregulation. The study aims to investigate whether the apelin hormone, which plays a role in regulating salt and water balance in the body, can be used to treat hyponatremia.
The study will involve healthy volunteers who will be given a medication that causes their bodies to retain water, thus inducing a temporary hyponatremia state. The researchers will measure the volunteers' blood and urine electrolyte levels to see how these are influenced by apelin administration. As comparison, the same measurements will be done in volunteers dosed with placebo instead of apelin.
The researchers believe that apelin may be able to help to correct hyponatremia by increasing urine output. If the study focused in the healthy volunteers population is successful, the investigators will assess the effect of apelin administration in patients with chronic hyponatremia.
The study's hypothesis is that intravenous apelin will increase urinary excretion and sodium levels in healthy participants with artificially induced hyponatremia.

开始日期2024-03-01

申办/合作机构-

NCT03449251

/ Active, not recruiting临床2期IIT

A Series of Pilot Studies to Evaluate the Haemodynamic and Metabolic Effects of Apelin and Relaxin in Healthy Humans, Subjects With Increased Weight and Patients With Type 2 Diabetes Mellitus

Type two diabetes mellitus (T2DM) is a common, long term metabolic disorder characterised by hyperglycaemia (high blood glucose) resulting from insulin resistance and relative insulin insufficiency. The risk of developing insulin resistance and subsequently T2DM is increased by being overweight and also through a sedentary lifestyle. As the onset can be gradual, physiological damage may have occurred prior to diagnosis. Diabetes is associated with the development of microvascular complications (diabetic nephropathy, neuropathy, and retinopathy), and macrovascular complications (coronary artery disease, peripheral arterial disease, and stroke). While there are many treatments available for T2DM, these complications may still arise, leading to significant morbidity and mortality. There is therefore an urgent need to identify novel signalling pathways that may contribute to the development of diabetes related complications. The identification of these pathways may ultimately lead to the development of new therapies targeting better blood glucose control and preventing these subsequent complications.
Both animal and human studies have indicated that two endogenous peptides, apelin and relaxin both act as vasodilators in the human cardiovascular system and could also have beneficial action in T2DM. Therefore, we aim to carry out experimental medicine studies to test this hypothesis, and explore the signalling pathway in the human vascular system.

开始日期2018-03-28

申办/合作机构

Cambridge University Hospitals NHS Foundation Trust

[+3]

NCT02724566

/ Completed临床1期IIT

Influence of Apelin on Insulin Sensitivity in Type 2 Diabetic Volunteers

Preclinical studies have demonstrated in mouse models that (PYR1)-apelin-13 exerts a glucose-regulating action in vivo. The (PYR1)-apelin-13 effect on insulin sensitivity in healthy overweighed volunteers has been previously assessed in a phase I clinical trial (APELINS study; NCT02033473). The APELINS-2 clinical trial aims to expand the initial proof of concept to the population targeted by future innovative insulin-sensitizing therapies: patients living with type 2 diabetes.

开始日期2016-05-01

申办/合作机构

Société Francophone Du Diabete

100 项与爱帕琳肽相关的临床结果

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100 项与爱帕琳肽相关的转化医学

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100 项与爱帕琳肽相关的专利（医药）

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962

项与爱帕琳肽相关的文献（医药）

2025-12-31·RENAL FAILURE

Apelin-13 exerts protective effects against acute kidney injury by lysosomal function regulation

Article

作者: Pan, Hao ; Hu, Zhizhi ; Li, Shuangshuang ; Ning, Yong

BACKGROUND:

Recent studies suggest that the loss of lysosomal function is associated with acute kidney injury (AKI), potentially leading to impaired autophagy. Apelin has been known to regulate autophagy processes in cardiovascular and pulmonary diseases. We sought to explore its potential contribution in lysosomal function and autophagy modulation during AKI.

METHODS:

Apelin-13 (30 μg/kg) or a vehicle control was administered to mice intraperitoneally 24 h prior to and at 0 h, 24 h, and 48 h following renal ischemia-reperfusion (I/R) injury or a sham procedure. Kidney and serum samples were collected for analysis 24 or 72 h postoperatively.

RESULTS:

Our findings indicate that apelin-13 significantly mitigated renal damage and inhibited apoptosis post-AKI. Flow cytometry analysis revealed that apelin-13 treatment modulates the macrophages polarization within the kidney from M1 to M2 phenotype. Additionally, apelin-13 was found to reduce the expression of the (pro)renin receptor, restore lysosomal membrane permeability, augment lysosomal biogenesis, and enhance autophagic flux in the kidney following AKI.

CONCLUSIONS:

Our study elucidates novel mechanisms underlying the protective effects of apelin in AKI through modulating lysosomal function and autophagy.

2025-05-06·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy

Article

作者: Xiong, Yixiao ; Zhu, Jiayi ; Shao, Zhenhua ; Sun, Qiu ; Li, Tao ; Tian, Xiaowen ; Wang, Yujia ; Tan, Lun ; Liu, Sicen ; Feng, Yuying ; Xiao, Huan ; Yan, Wei ; Zhang, Lele ; Deng, Yan ; Ouyang, Liang ; Guo, Yingqiang

Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as the apelin receptor (APLNR), is a promising target for treating HFpEF due to its role in modulating cardiovascular function. Despite the cardioprotective effects of endogenous ligand, apelin, achieving G-protein-biased agonism for therapeutic benefit poses a significant challenge. In this study, we unravel the biased signal transduction pathway mediated by a reported partial G i -protein-biased APLNR agonist CMF-019 and developed a biased chemical space remodeling approach to identify exclusive G-protein-biased agonists targeting APLNR. These agonists exhibited enhanced Gi-protein-biased function and protective effects in both in vitro and in vivo. Our findings not only enhance comprehension of APLNR-biased agonism but also establish drug design strategies for modifying and reshaping biased chemical landscapes in other G-protein-coupled receptors (GPCRs).

2025-05-01·CANADIAN JOURNAL OF CARDIOLOGY

The Metabolically Resistant Apelin-17 Analogue LIT01-196 Reduces Cardiac Dysfunction and Remodelling in Heart Failure After Myocardial Infarction

Article

作者: Girault-Sotias, Pierre-Emmanuel ; Berdeaux, Alain ; Riché, Stephanie ; Llorens-Cortes, Catherine ; Iturrioz, Xavier ; Boitard, Solène Emmanuelle ; Parlakian, Ara ; Agbulut, Onnik ; Daubeuf, François ; Bonnet, Dominique ; Deloux, Robin ; De Mota, Nadia

BACKGROUND:

To protect patients after myocardial infarction (MI) and preserve cardiac function, the development of new therapeutics remains an important issue. Apelin, a neuro-vasoactive peptide, increases aqueous diuresis and cardiac contractility while reducing vascular resistance. However, its in vivo half-life is very short. We therefore developed a metabolically resistant apelin-17 analogue, LIT01-196 and investigated its effects on cardiac function and remodelling in a murine MI model.

METHODS:

The selectivity of LIT01-196 toward the apelin receptor was checked in vitro. Its in vivo half-life was assessed in male Swiss mice using radioimmunoassay. After permanent coronary artery ligation to induce MI, mice received subcutaneous administration of LIT01-196 (MI + LIT01-196, 9 mg/kg/d) or saline (MI + vehicle) for 4 weeks. Left ventricular (LV) function was assessed using echocardiography and Millar (Houston, TX) catheter, vascular density using immunofluorescence, and cardiac fibrosis using Sirius red staining. Real-time quantitative PCR was used to measure mRNA expression of heart failure (HF) fibrosis biomarkers and sarco/endoplasmic reticulum Ca²⁺-ATPase-2.

RESULTS:

The in vivo half-life of LIT01-196, a specific and selective apelin receptor agonist, was 2.5 hours. MI + LIT01-196 showed significantly improved LV function, reduced HF biomarkers, and enhanced cardiac contractility and sarco/endoplasmic reticulum Ca²⁺-ATPase-2 expression compared with MI + vehicle. LIT01-196 treatment almost doubled cardiac vascular density and maintained LV wall thickness post MI. It also significantly reduced cardiac fibrosis and fibrosis biomarkers, without decreasing arterial blood pressure.

CONCLUSIONS:

Chronic LIT01-196 treatment post MI improves LV function without decreasing blood pressure, increases cardiac vascular density, and reduces cardiac remodelling. This suggests that apelin receptor activation by LIT01-196 might constitute an original pharmacological approach for HF treatment after MI.

项与爱帕琳肽相关的新闻（医药）

2025-03-11

·peplib.cn

靶蛋白非肿瘤特异性因素对靶向药疗效的影响

细胞膜作为细胞与外界环境交流的重要通道，其上的膜蛋白在细胞的生理功能中发挥着至关重要的作用。正常细胞和肿瘤细胞的细胞膜蛋白存在显著差异。肿瘤细胞为实现不受控制的生长、侵袭和转移，会在其表面表达一些特殊的膜蛋白。这些蛋白有的参与细胞生长信号的传递，比如表皮生长因子受体（Epidermal growth factor receptor， EGFR）；有的帮助肿瘤细胞逃避免疫系统的监视，像程序性死亡配体 - 1（Programmed cell death ligand 1，PD-L1）；还有的在肿瘤血管生成过程中起关键作用，例如血管内皮生长因子受体（Vascular endothelial growth factor，VEGFR）。这些独特的细胞膜蛋白，成为了抗肿瘤药物精准打击的理想靶点。细胞膜的脂质双层结构如同一个天然屏障，分隔了细胞外和细胞内的物质，使其无法自由交换和直接沟通。因此，环境中的分子或细胞内分子不得不遵循细胞固有法则，借助特异受体、离子通道、转运体、黏附蛋白等完成各自的功能。与传统的细胞毒性化疗不同，靶向细胞表面蛋白的疗法提供了一种提高癌细胞特异性，同时最大限度地减少毒性的策略。许多治疗性靶向药物（如抗癌药）的主要治病机制是通过特异性高表达的靶抗原或膜上受体将非靶向药物递送到肿瘤细胞内，从而达到特异性肿瘤杀伤的效果。目前，已经开发了多种类型的细胞表面蛋白靶向疗法，具有不同的作用机制。科研人员已对75 种候选的细胞表面蛋白进行了深入研究，但在美国或欧盟，仅有25个治疗相关的细胞表面蛋白被批准用于癌症疗法[1]。尽管抗体-药物偶联物（Antibody-drug conjugate，ADC）和放射性药物疗法（Radiopharmaceutical therapy，RPT）等几类细胞表面靶向疗法已经获得了美国食品药品监督管理局（FDA）的批准，得以应用于临床实践，但不得不承认的是，这些疗法的许多疗效机制至今尚未完全明晰，仍存在着诸多待解之谜。临床抗肿瘤疗效的评估是一个复杂的系统工程，靶点蛋白的肿瘤特异性毋庸置疑是公认的重要指标，但并非唯一的决定因素，还需要考虑其他多种因素，如表达水平（临床常用免疫组织化学（Immunohistochemistry，IHC）和荧光原位杂交（Fluorescence in situ hybridization，FISH）的阳性分数以及生物学特征的丰度）、靶点蛋白的分布特性和肿瘤组织中靶点异质性等。这些因素同样对疗效、毒性以及成药性起着决定性作用。本文将围绕以上几点，对这些因素与靶向药的临床疗效关系逐一进行阐述。膜蛋白表达水平通常采用临床常用的IHC和FISH的阳性分数，以及生物学特征的丰度这两种方法进行研究。1）靶点高表达：是指在细胞或组织中，某个特定的靶点（如基因、蛋白质等）的表达水平呈现显著高于正常状态的现象，这可能是由于基因突变、染色体异常、转录调控机制的改变或其他因素所导致。值得注意的是，过表达是一个相对的概念，通过与正常生理状态下的表达情况进行对比后得出，强调的是表达水平的异常增高，这一现象往往与疾病的发生、发展密切相关，例如在许多肿瘤细胞中，某些癌基因会出现过表达，进而促进肿瘤的生长和增殖。2）表达丰度：是指在特定细胞、组织或生物样本中，某种基因或蛋白质的实际含量或数量。它是一个更侧重于量化的概念，主要用来描述靶点在样本中的具体表达量，并不涉及与正常状态的比较，仅仅单纯地反映该靶点在某个环境中的丰富程度。表达丰度可以借助多种技术手段进行测量。在基因层面，可采用PCR、RNA 测序实时定量；在蛋白质层面，可运用蛋白质免疫印迹法（Western blot）、酶联免疫吸附测定（Enzyme-linked immunosorbent assay，ELISA）等方法，得到具体的拷贝数、浓度、相对含量等数值。这二者的区别在于：高表达反映肿瘤组织中阳性细胞的占比情况，属于相对参数，多用于临床研究中的病人筛选。而表达量体现单个细胞内的蛋白个数，如HER-2受体最高表达量可达106，当小于103则被认为是低表达，这是一个定量参数，多用于药物机制研究。在临床实践中，医生通常会通过 IHC 和 FISH 等方法来检测肿瘤细胞的 HER-2 阳性水平，以指导治疗方案的选择并预测患者的预后。一般而言， IHC 检测为 3 + 或 FISH 检测显示基因扩增的患者，被认为是 HER-2 高表达，这类患者更有可能从 HER-2 靶向治疗中获益[2]（如下表）。 Orforglipron‌（LY3502970）是由礼来开发的口服GLP-1受体激动剂，一日一次。该小分子能够刺激GLP-1R诱导的cAMP积累，未检测到GLP-1R介导的β-arrestin蛋白的募集‌作用。II期临床试验结果显示[3]，在第26周时，Orforglipron剂量组（12, 24, 36,或45 mg）的体重与基线相比的平均变化范围为-8.6%至-12.6%，安慰剂组为-2.0%。在第36周，Orforglipron的平均变化范围为-9.4%至-14.7%，显示显著的减重效果。目前Orforglipron已经进入III期临床试验阶段，预计2026年上市。该药的上市将冲击注射型司马格鲁肽及替尔泊肽的市场份额。 CT-388原由Carmot Therapeutics公司开发，属于GLP-1/GIP受体双重调节剂，可以一周一次注射给药。2023年12月罗氏收购Carmot Therapeutics公司，继续进行开发。I期临床试验显示，健康肥胖成人每周皮下注射一次CT-388，24周后，平均体重可减少18.8%。该肽对β-arrestin的作用弱，可减少药物对心肌方面的副作用，目前正处于II期临床试验阶段（Roche官网）。目前发现激活素受体ACVR、肌肉生长抑素MSTN、Apelin受体APJ、‌甲状腺激素受体β(THR-β)、选择性雄性激素受体（SARM）调节剂、瘦素leptin、黑色素受体MC4R、GDF-15、Gherin受体等具有发展减肥增肌或减肥不减肌药潜力，一些重要的单靶药物或与GLP-1激动剂多靶点药物或联合用药已进入I-III期临床试验（表1）。下面对几个重要的靶点及药物研发进展进行简要介绍。激活素受体ActR2包括激活素受体ACVR2A及ACVR2B，是转化生长因子β（TGF-β）受体超家族中的两个重要成员，其在细胞生长、分化和组织修复等多种生理过程中发挥关键作用[4]。肌肉生长和发育是一个复杂的过程，受到多种因素的调控，其中ACVR2A和ACVR2B作为关键受体，扮演着重要角色。研究表明，抑制这两种受体可以促进肌肉生长并防止肌肉萎缩，这种双重作用使其成为治疗肥胖和相关代谢疾病有吸引力的靶点。目前，ACVR2A及ACVR2B融合蛋白用于治疗肺动脉高压、地中海贫血、骨髓增生异常综合征抑郁症等，如默沙东Sotatercept、BMS的Luspatercept已上市，一些也进入临床II-III期[5]。近期发现，靶向该受体的抗体药物具有显著的减重增肌活性。靶向ActR2A/B单抗Bimagrumab（礼来研发）的II期试验(NCT03005288)结果显示，75名体重指数介于28和40之间的2型糖尿病患者在48周内接受了bimagrumab治疗后，脂肪减少超过20.5%，而安慰剂组体重仅减少0.5%。除促进脂肪减少外，受试者瘦体重增加了3.6%，而安慰剂组瘦体重降低了0.8%[6]。此外，Alnylam、Arrowhead Pharmaceuticals等开展了Activin E、ActRIc(ALK7)的siRNA单药及与GLP-1联合用药用于减肥增肌的临床前研究（数据来源于公司网站），具有减肥不减肌活性。国内来凯医药的对ActRIIA的单克隆抗体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6月，LAE102已开始临床I期试验。该公司的LAE-103（靶标ACVR2B）、LAE-123（靶标ACVR2AxACVR2B）也正在积极推进中。此外，宜明昂科的IMC-003（靶标ACVR2A）及一个双靶抗体（IMC-004）也在研发中。肌肉生长抑制素（MSTN）(也称生长分化因子8（GDF8）)也属TGF-β家族成员，在骨骼肌中广泛表达，基因突变或敲除MSTN会导致肌肉质量显著增加。该靶点在肌肉萎缩症和肌肉衰减综合征等疾病治疗中具有显著疗效[7]。Trevogrumab是再生元开发的一款MSTN单抗，目前正在联合garetosmab（抗激活素A单抗）针对肥胖适应症开展临床Ⅱ期研究。2024年11月，再生元披露了Trevogrumab联合garetosmab的Ⅰ期临床结果。在单剂量研究中，设置了Trevogrumab （6 mg/kg, N=6）、garetosmab (10 mg/kg，N=6），Trevogrumab （6mg/kg）联合garetosmab（1 mg/kg、3 mg/kg、10 mg/kg）或安慰剂（N=12）组。结果显示，Trevogrumab（6 mg/kg）联合garetosmab（10 mg/kg）给药8周后，女性大腿肌肉体积较基线增加7.7%，而总脂肪量和腹部脂肪量较基线出现下降（-4.6%和-6.7%），显示联用疗法具有显著的减脂增肌效果。 Apitegromab 由Scholar Rock研发，其选择性地靶向MSLN的前体或非活性形式，阻断其在肌肉中的激活，主要适应症为脊髓性肌萎缩症。Apitegromab 的III期临床研究达到了主要终点，显著改善了患者的运动功能[8]。今年1月Scholar Rock已向美国FDA提交了Apitegromab上市申请。2024年5月，Apitegromab与GLP-1R药物（semaglutide或tirzepatide）联合使用治疗肥胖症的II期临床试验申请也获得FDA批准（来自Scholar Rock公司网站）。甲状腺激素受体β（THR-β）通过甲状腺激素的多种代谢作用对肝脏稳态起着至关重要的作用，其激动剂可以改善脂质代谢。针对该靶点的ASC47（歌礼制药）已在澳大利亚完成Ib临床试验。结果显示，ASC47在LDL-C偏高的健康受试者(10毫克、30毫克、90毫克)和肥胖症患者(90 毫克)中单次皮下注射后，经安慰剂校准的LDL-C降幅为22%，总胆固醇(TC)降幅为16%。在与司美格鲁肽治疗的DIO小鼠比较试验中，低剂量ASC47联合司美格鲁肽显示显著减重增肌效果（表2），单剂量ASC47(9 mg/kg)的减重幅度不大（1.55%），但低剂量ASC47（3 mg/kg或9 mg/kg）联合司美格鲁肽（30 nmol/kg，皮下注射，每日一次）用药使体重下降36%，显著高于司美格鲁肽单药疗法（体重下降23%），且肌肉总量/总体重显著提高。 Apelin受体（APJ）属于孤儿G蛋白偶联受体，Apelin及其受体在多种器官和组织中表达，包括中枢神经系统、心脏、肺、脂肪组织和胃肠道等[9]。APJ的内源性配体包括Apelin和Elabela两类多肽。Apelin对APJ受体的激活触发细胞内G蛋白依赖性信号传导途径，增加心肌收缩性和血管舒张，而机械拉伸激活APJ介导的β-arrestin信号传导，导致心脏肥大。因此，G蛋白偏向的APJ激动剂可以用于心力衰竭的治疗。此外，APJ介导的β-arrestin信号传导的丧失可以缓解饮食诱导的代谢功能障碍等。 BioAge（AMG占股）开发的Azelaprag(AMG986)激动剂，可预防肌肉萎缩。2024年6月启动了与替尔泊肽联用治疗肥胖的临床II期试验，最近的结果显示患者出现转氨酶升高副作用，而单独的替尔泊肽无类似副作用，目前已终止临床试验。类似的激动剂还有BMS公司的BMS-986224[10]。总的来说，目前的APJ激动剂偏向性不高。最近APJ激动剂与APJ受体复合物结构被解析[10]，发现了完全偏向的激动剂，但活性仅为100 nM [11]。瘦素单药减重效果不显著，但与pramlintide的联合使用后，可使超重者的体重减轻更多。再生元的瘦素单抗激动剂REGN4461，在全身性脂肪营养不良的小鼠模型中，REGN4461缓解了高食欲、高血糖、胰岛素抵抗、血脂异常和肝脂肪变性。I期临床结果显示，用REGN4461治疗超重或肥胖的人，在循环瘦素浓度低（<8 ng/ml）的人中，体重在12周内有所下降，但对基线瘦素水平较高的人的体重没有影响[12]。最近诺和诺德公司开展了GLP-1R/LepR双重激动剂研发，该多肽在leptin缺乏的肥胖小鼠模型中表现出显著的减少进食量和降低体重的效果（图3）[13]。 MC4R是公认的治疗肥胖的靶点，但目前还缺乏高选择性和安全的MC4R激动剂[14，15]。Palatin Technologies公司将上市的MC4R bremelanotide与替尔泊肽联合使用，小鼠试验显示，MC4R激动剂可增强GLP-1激动剂利拉鲁肽的药效[16], 2024年已开展II期临床试验。笔者认为一些潜在的新靶点，如受体蛋白酪氨酸激酶Mer (MERTK)、GPR75、Irisin、Dysferlin、ANGPTL8、脂肪酸受体4（Ffar4）以及一些新发现多肽、蛋白质还未找到确切受体的靶点（表3）可能在减肥增肌中发挥作用[17-26]。BRP是最近发现的一种全新、非胰岛素促分泌素类的抗肥胖多肽，在小鼠和小型猪模型中，BRP单次给药即可显著降低食物摄入量，效果持续数小时。此外，BRP不会引起低血糖或恶心等GLP-1药物常见的不良反应，且减脂不减肌（图4）。其作用机制与GLP-1等不同，主要通过激活大脑下丘脑区域特定神经元中的cAMP-PKA-CREB-FOS信号通路来抑制食欲[18]。目前已发现的减肥增肌靶点不少，但单独用药减肥效果不及GLP-1R激动剂及其多靶药激动剂，联合用药后的效果高于GLP-1R激动剂或具有显著的减肥增肌效果。一些原来只用于肿瘤患者恶质病的肌肉增强剂，与GLP-1R激动剂联合用药后，获得减肥增肌效果。从进展来看，一些改进型的GLP-1R单靶点及多靶点激动剂将率先获得批准，如GLP-1/葡萄糖依赖性促胰岛素多肽和胰高血糖素受体激动剂（Retatrutide）、口服的GLP-1R小分子体激动剂（Orforglipron）等。新的GLP-1迭代产品预期在减少副作用、减少停药后体重反弹、使用方便方面发挥作用。在减肥增肌方面，激活素受体ACVRII、肌肉生长抑素MSTN抗体类拮抗剂可能跟进获批，靶向Apelin受体APJ、选甲状腺激素受体β、瘦素leptin、黑色素受体MC4R分子还需更多的临床试验，验证其减肥增肌或不减肌效果。近期出现的新靶点可能在减肥增肌中发挥作用，显示诱人的发展潜力，但需进一步的动物实验及临床研究证实其效果。 1.Dolgin E. Dozens of new obesity drugs are coming: these are the ones to watch. Nature. 2025 Feb;638(8050):308-310. doi: 10.1038/d41586-025-00404-9. 2.Kokkorakis M, Chakhtoura M, Rhayem C, et al. Emerging pharmacotherapies for obesity: A systematic review. Pharmacol Rev. 2025, 77(1):100002. 3.Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023, 389(10):877-888. 4.Morvan F, Rondeau JM, Zou C, et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci U S A. 2017, 114(47):12448-12453. 5.Nunn E, Jaiswal N, Gavin M, et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024, 101880. 6.Heymsfield SB, Coleman LA, Miller R, et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021, 4(1):e2033457. 7.Stefanakis K, Kokkorakis M, Mantzoros CS. The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation. Metabolism. 2024, 161:156057. 8.Crawford TO, Darras BT, Day JW, et al. Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study. Neurology. 2024, 102(5):e209151. 9.Hu G, Wang Z, Zhang R, et al. The Role of Apelin/Apelin Receptor in Energy Metabolism and Water Homeostasis: A Comprehensive Narrative Review. Front Physiol. 2021, 12:632886. 10.Gargalovic P, Wong P, Onorato J, et al. In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure. Circ Heart Fail. 2021, 14(3):e007351. 11.Wang WW, Ji SY, Zhang W, et al. Structure-based design of non-hypertrophic apelin receptor modulator. Cell. 2024, 187(6):1460-1475.e20. 12.Altarejos JY, Pangilinan J, Podgrabinska S,et al. Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. Sci Transl Med. 2023, 15(723):eadd4897. 13. Polex-Wolf J, Deibler K, Hogendorf WFJ, et al. Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist. Sci Transl Med. 2024, 16(776):eadk4908. 14.Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022, 21(3):201-223.] 15.Liu Z, Hruby VJ. MC4R biased signalling and the conformational basis of biological function selections. J Cell Mol Med. 2022, 26(15):4125-4136. 16.Dahir NS, Gui Y, Wu Y, et al. Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice. J Clin Invest. 2024, 134(14):e178250. 17.Deaton AM, Dubey A, Ward LD, et al. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022, 13(1):4319. 18.Coassolo L, B Danneskiold-Samsøe N, et al. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide. Nature. 2025 Mar 5. doi: 10.1038/s41586-025-08683-y. 19.Shi X, Hu X, Fang X, et al. A feeding-induced myokine modulates glucose homeostasis. Nat Metab. 2025 Jan;7(1):68-83. doi: 10.1038/s42255-024-01175-9. Epub 2025 Jan 2. Erratum in: Nat Metab. 2025 Feb 11. doi: 10.1038/s42255-025-01231-y. 20.Akbari P, Gilani A, Sosina O, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021, 373(6550): eabf8683. 21.Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab. 2021, 320(4):E680-E690. 22.Wang YT, Zheng SY, Jiang SD, et al. Irisin in degenerative musculoskeletal diseases: Functions in system and potential in therapy. Pharmacol Res. 2024, 210:107480. 23.Cho H, Lai CC, Bonnavion R, et al. Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes. Science. 2025, 387(6734):674-682. 24.Paulke NJ, Fleischhacker C, Wegener JB, et al. Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy. Circ Res. 2024, 135(5):554-574. 25.Hu L, Wei J, Zhang Y, et al. ANGPTL8 is a negative regulator in pathological cardiac hypertrophy. Cell Death Dis. 2022, 13(7):621. 26.Kiepura A, Stachyra K, Wiśniewska A, et al. The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE-Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype. Int J Mol Sci. 2021, 22(18):9772.

抗体药物偶联物放射疗法

2025-01-28

·FierceBiotech

BioAge axes obesity asset over liver toxicity, pivots to preclinical prospects

BioAge Labs has picked brain-penetrant molecule BGE-102 as its development candidate. \n BioAge Labs has given up on its lead obesity candidate. Weeks after stopping a trial in response to phase 2 data, the biotech has jettisoned the molecule and shifted its focus to a preclinical neuroinflammation prospect.California-based BioAge raised around $200 million in an IPO in September and swiftly reminded public investors that biotechs are risky bets. Two months after going public, BioAge stopped a phase 2 trial of its oral apelin receptor agonist azelaprag. Investors fled, but the biotech left the door open, noting that it remained encouraged by preclinical and early-phase data and vowing to share updated plans in 2025.BioAge closed the door on azelaprag Tuesday, explaining that the elevated liver enzymes seen in some patients without clear dose dependence had persuaded it to call time on the program. The biotech has structurally distinct molecules in its pipeline and aims to pick a follow-up candidate this year.With the apelin program bouncing back to preclinical, BioAge’s NLRP3 inhibitor has become the biotech’s most advanced prospect. Management has picked brain-penetrant molecule BGE-102 as its development candidate and is running studies to support a filing to test the asset in humans. BioAge expects to post phase 1 single-ascending dose data on the candidate this year. NLRP3 was a hot target as the 2010s drew to a close, when Bristol Myers Squibb, Novartis and Roche—both through its mothership and Genentech subsidiary—all acquired assets. None of the deals has led to an approved NLRP3 inhibitor.BioAge is initially focused on molecules that are active in the central nervous system. NodThera, Ventyx Biosciences, Roche and Ventus Therapeutics have all worked on similar molecules, but BioAge is bullish, with CEO Kristen Fortney, Ph.D., using a Citi event last month to claim the candidates are “an order of magnitude more potent than the competition.”The biotech’s focus on the neuroinflammatory uses of NLRP3 inhibition is built on longevity data linking the protein to accelerated cognitive aging and shorter life spans. BioAge also has evidence that inhibiting the protein could suppress appetite, suggesting there is scope to expand into obesity.Investors appeared to have priced in the pivot away from azelaprag, with the stock opening flat Tuesday. BioAge’s stock has fallen more than 75% since last year’s IPO, but the biotech has the money to write a second act—the company\'s cash runway extends beyond 2029. BioAge disclosed a collaboration with Lilly ExploR&D to discover two antibodies against metabolic aging targets identified by the biotech.

IPO临床2期临床1期

2025-01-21

·学术经纬

助力肥胖、衰老疾病药物研发！上科大团队破解关键受体调控机制

▎药明康德内容团队编辑（来源：上海科技大学）近日，上海科技大学iHuman研究所徐菲课题组与华中科技大学刘剑峰团队合作，在《自然·通讯》（Nature Communications）上发表了题为“Structural insights into the regulation of monomeric and dimeric apelin receptor”的研究论文，系统解析了爱帕琳肽受体（apelin receptor, APJR）在单体与二聚体状态下的配体结合和信号调控机制，揭示了G蛋白偶联受体（G protein-coupled receptor, GPCR）二聚化对配体识别及信号调控的重要影响。这一发现不仅深化了对GPCR信号转导机制的理解，也为肥胖、心血管疾病以及衰老相关的疾病新药研发提供了重要的理论支撑。徐菲课题组长期致力于Apelin受体研究，继2017年率先在国际上发表首个APJR晶体结构，以及2022年首次揭示APJR的单体/二聚体与下游Gi蛋白复合物结构后，此次利用单颗粒冷冻电镜技术进一步解析了APJR在结合内源性多肽配体apelin-13时, 以单体和二聚体状态与Gi蛋白结合的复合物结构（APJR: Gi蛋白分别为1:1和2:1）(图1)。此外，团队还解析了无配体状态下（apo）的APJR二聚体结构，并利用先前研究报道的功能性纳米抗体（激动剂JN241-9与拮抗剂JN241），系统考察了配体结合对APJR结构及二聚体动态变化的影响，揭示了在受体激活过程中，二聚体中两个单体之间可能存在负向变构调控的特征。 ▲图1：APJR二聚体-Gi和APJR单体-Gi复合物结合apelin-13的冷冻电镜结构。（a）两种内源性多肽配体对APJR产生的药理学效应模型。（b）Apelin13-APJR二聚体-Gi复合物和Apelin13-APJR单体-Gi复合物的冷冻电镜密度图及三维结构模型。（图片来源：原始论文[1]）研究发现，APJR二聚体在结合不同配体（如Apelin和ELA两种内源性多肽）时展现出显著的差异化结合模式：Apelin主要作用于与Gi蛋白结合的APJR单体（图1），而ELA则同时作用于两个APJR单体。同时，拮抗剂抗体JN241以及无配体状态下（apo）的APJR二聚体结构更为紧凑，而结合apelin-13以及G蛋白之后，二聚体内部之间的距离变大（图2）。值得关注的是，研究还解析了分别在有无G蛋白结合情况下的激动剂抗体JN241-9与APJR的复合物结构（图2）：在G蛋白不存在的情况下，结合激动剂抗体JN241-9的APJR主要以二聚体形式存在；而当G蛋白存在并结合时，结合激动剂抗体JN241-9的APJR主要处于单体形式（图2）。该研究首次揭示了G蛋白偶联可能在APJR激活过程中起到促进二聚体解离的作用。在此基础上，研究团队通过分子动力学模拟、突变与功能验证，并结合已解析的多个APJR不同功能状态下的单体和二聚体结构，全面揭示了APJR从非活性到活性状态的动态调控机制。这一系统性研究为理解APJR的信号传导及调控提供了全新视角。 ▲图2：不同状态下APJR二聚体与单体的构象转化。（a）JN241-APJR与apo-APJR结构的叠合。（b）JN241-9-APJR二聚体复合物的三维结构模型，APJR基本处于二聚体状态。（c）JN241-9-APJR–Gi复合物的三维结构模型，APJR基本处于单体状态。（d）APJR二聚体由抑制状态（JN241结合的对称二聚体）转变为激活状态（apelin-13结合的非对称二聚体）。叠加基于ProtB，并用红色箭头标注ProtA从抑制到激活状态的运动。（图片来源：原始论文[1]） Apelin受体因其在肥胖、心血管疾病、肌肉再生及衰老过程中的关键作用，被认为是颇具潜力的药物靶点，特别是与目前广泛开发的GLP-1R靶点联合作用，显示了卓越的减肥增肌疗效，具有广阔的药物研发前景。相较于多肽和小分子药物，抗体等大分子药物在慢性代谢类疾病治疗中具有更优越的长效性和安全性。本研究首次揭示了两个功能性纳米抗体结合APJR的分子机制，提供了抗体与靶点相互作用的清晰图谱，为抗体药物设计和优化提供了精准模板。徐菲课题组针对Apelin受体的长期系统性研究以及对一系列复合物结构的深入解析为GPCR信号转导和药理学领域提供了新思路，也为开发针对心力衰竭、肥胖及衰老相关疾病的创新药物奠定了坚实基础。上海科技大学iHuman研究所高级工程师岳洋、iHuman研究所副研究员武丽杰、生命科学与技术学院2024届博士研究生刘立尔以及华中科技大学副研究员许婵娟为该论文共同第一作者；华中科技大学刘剑峰教授和上海科技大学iHuman研究所、生命学院常任正教授徐菲为共同通讯作者。上海科技大学为第一完成单位。原始论文： [1]Yue, Y., Liu, L., Wu, L. et al. Structural insights into the regulation of monomeric and dimeric apelin receptor. Nat Commun 16, 310 (2025). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-024-55555-6 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

临床结果临床研究

100 项与爱帕琳肽相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	爱帕琳肽	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
心血管疾病	临床2期	英国	AstraZeneca PLC	2018-03-28
2型糖尿病	临床2期	英国	AstraZeneca PLC	2018-03-28

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


EASD2015	N/A	-	-	Apelin	鬱獵顧夢襯繭襯獵顧廠(鹽醖淵製齋廠夢廠鏇網) = Average frequency of NO hypothalamic release is significantly reduced following infusion of low-doses of apelin in the digestive tract (0,11 ± 0,003 Hz vs 0,12 ± 0,002 for control; P<0.001) 網鏇簾廠繭簾繭齋網蓋 (襯簾鹹積淵構襯鏇淵簾 ) 更多	-	2015-09-16
				apelin (Control (Krebs-Ringer))
ERS2015	N/A	apelin	11	Pyr1apelin-13	構鬱觸繭衊醖餘膚觸鹽(築鬱艱鏇衊鹽憲鹽憲憲) = 選窪淵壓鑰構窪鬱廠憲廠構蓋願艱窪網鑰遞鹽 (餘齋鹽鹹糧餘醖觸醖淵 ) 更多	不佳	2015-09-01
				Placebo	構鬱觸繭衊醖餘膚觸鹽(築鬱艱鏇衊鹽憲鹽憲憲) = 膚醖選艱壓壓範衊築構廠構蓋願艱窪網鑰遞鹽 (餘齋鹽鹹糧餘醖觸醖淵 ) 更多
Pubmed \| J Mol Cell Cardiol	N/A	-	-	Apelin-13	餘構觸鹹簾構齋衊鬱製(淵鬱範廠積願衊襯醖築) = Apelin also increased I(Na) "window" current by up to 600% 衊醖醖夢選廠鬱積艱醖 (衊窪構構蓋積窪鏇膚鬱 )	-	2010-04-01
				Apelin-17