CN112279920A - FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 - Google Patents
FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 Download PDFInfo
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Abstract
本发明第一方面提供了一种FGF21Fc融合蛋白。本发明第二方面提供了一种GLP‑1Fc融合蛋白。本发明第三方面涉及一种组合治疗剂,由包含FGF21Fc融合蛋白的第一药物组合物和包含GLP‑1Fc融合蛋白的第二药物组合物所组成。本发明的融合蛋白及其组合治疗剂在用于预防或治疗与心血管和/或代谢类疾病,在肥胖、糖尿病、高脂血症、非酒精性脂肪性肝病、动脉粥样硬化以及糖尿病性心肌病等疾病模型中,都表现出显著的协同效应。
Description
技术领域
本发明属于蛋白质和多肽技术领域,更具体地,涉及一种FGF21 Fc融合蛋白、一种GLP-1 Fc融合蛋白、和包含它们的组合治疗剂,用于预防或治疗心血管和/或代谢类疾病,包括但不局限于肥胖、高脂血症、动脉粥样硬化、非酒精性脂肪性肝病、糖尿病、糖尿病性心肌病、冠状动脉粥样硬化性心脏病及其它与胰岛素抵抗相关的疾病。
背景技术
成纤维细胞生长因子-21(fibroblast growth factor-21,FGF21)属于FGF家族,主要由肝脏合成,以内分泌形式进入循环,其C端与效应器官β-klotho跨膜蛋白结合后通过N端与FGFR1c特异性结合,形成稳定的FGF21/β-klotho/FGFR复合体,继而激活下游相关分子信号。大量基础研究表明,FGF21具有促进葡萄糖利用、增加胰岛素敏感性、促进脂肪酸分解、减少脂质新生、调节胆固醇平衡等多种生理学活性,显现出应用于心血管及代谢类疾病的巨大潜力。但天然FGF21易被肾小球过滤代谢且易受蛋白酶水解断裂,导致其体内半衰期短暂,严重制约其成药性。随着生物技术的深入发展,对天然FGF21进行结构修饰,延长其体内半衰期,提高生物利用度成为全球范围内各大制药企业研发的热点。目前已有多种长效FGF21蛋白进入临床研究阶段,大多采用聚乙二醇修饰、Fc蛋白融合或CovX-Body共价连接等方式来延长FGF21的半衰期。临床研究表明,长效FGF21蛋白对缓解非酒精性脂肪肝病患者肝脏脂肪变性、减重和调节血脂方面都表现出积极的治疗效果,但它对于糖尿病患者控制血糖作用与已上市的降糖类药物相比,却未表现出明显的药效学优势。
与哺乳动物GLP-1或Exendin-4相比,长效GLP-1受体激动剂是一类GLP-1或Exendin-4类似物经结构修饰获得的一类体内半衰期及生物利用度大幅度提高、注射频率降低的蛋白产品。目前已有如礼来公司的杜拉鲁肽以及诺和诺德公司的索马鲁肽等多种长效GLP-1受体激动剂处于上市销售阶段,在临床应用中与传统的口服降糖药、短效GLP-1受体激动剂或胰岛素制品相比在血糖控制或患者使用顺应性表现出显著的优越性。然而由于机理的局限性,长效GLP-1受体激动剂主要是在葡萄糖刺激下通过促进胰岛β细胞分泌和释放胰岛素发挥效应作用,其在糖代谢方面的生理学功能主要依赖于胰岛素活性,目前尚无明确的临床证据表明该类产品通过独立于减重之外的作用机制对糖尿病患者普遍并存的胰岛素抵抗、肥胖、非酒精性脂肪肝病或高脂血症等多种病症具有直接及明确的改善作用。该类产品可通过抑制患者摄食发挥一定的减重作用,但其作用多依赖于产品本身的胃肠道不良反应,尽管获得了部分积极的治疗结果,但治疗过程中患者的临床不适感增加。
临床上大部分心血管和代谢性疾病患者表现为高血脂、肥胖、高血糖、脂肪肝、动脉粥样硬化等多种疾病同时存在。如流行病学结果显示,2型糖尿病中肥胖患者约占60%,非酒精性肝病患者约占50%,超过70%的糖尿病患者伴有血脂水平异常;糖尿病患者患心血管疾病的危险性是非糖尿病患者的2-4倍,并且心血管事件已经成为糖尿病患者全因死亡的第一要素;心血管事件占非酒精性脂肪肝患者死亡原因的第二位。目前临床推荐多种药物组合疗法以期同时控制多种疾病的病程,但鉴于包括GLP-1 Fc融合蛋白在内的已获批上市药物治疗作用的局限性,目前尚未获得非常理想的单药或药物组合物治疗方案。因而,针对此类患者,临床上迫切需要提供一种更有效的、更全面的组合预防和治疗方案。我们创造性地设想,选择FGF21 Fc融合蛋白和GLP-1 Fc融合蛋白联合使用在心血管和代谢性疾病患者的综合管理治疗方面可以发挥巨大的治疗潜能并充分满足临床疗效需求。
发明内容
本发明目的是提供一种FGF21 Fc融合蛋白、一种GLP-1 Fc融合蛋白、和以它们作为FGF21R/GLP-1R双重长效激动剂的组合治疗剂,用于预防和治疗心血管和/或代谢类疾病,尤其是针对并发多种心血管或代谢类疾病的患者提供了一种综合管理和防治手段。本发明还提供的FGF21 Fc融合蛋白与GLP-1 Fc融合蛋白联合施用,在肥胖、糖尿病、高脂血症、非酒精性脂肪性肝病、动脉粥样硬化以及糖尿病性心肌病等疾病动物模型中,都出人意料地表现出显著的协同效应。
一方面,本发明提供了一种FGF21 Fc融合蛋白,其氨基酸序列:
(1)如SEQ ID NO:4所述;或
(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
另一方面,本发明提供了一种GLP-1 Fc融合蛋白,其氨基酸序列:
(1)如SEQ ID NO:5、SEQ ID NO:6或SEQ ID NO:7所示;或
(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
又一方面,本发明提供一种组合治疗剂,所述组合治疗剂由包含长效FGF21 Fc融合蛋白的第一药物组合物和包含长效GLP-1 Fc融合蛋白的第二药物组合物组成;且其中长效FGF21 Fc融合蛋白的氨基酸序列选自SEQ ID NO:4或与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代))、缺失和/或添加的序列;和所述长效GLP-1 Fc融合蛋白的氨基酸序列选自SEQ ID NO:5、SEQ ID NO:6或SEQ ID NO:7或与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代))、缺失和/或添加的序列。
进一步地,所述第一药物组合物和第二药物组合物还包含药学上可接受的载体、和/或赋形剂和/或稳定剂。
进一步地,所述FGF21 Fc融合蛋白和GLP-1 Fc融合蛋白可以预防有效量或治疗有效量包含于所述药物组合物中;其中,所述预防或治疗有效量根据治疗目的或预防目的而定,例如需要治疗的患者的状况、所需的给药途径等。
进一步地,所述第一药物组合物和第二药物组合物被配制成适于经口服或注射给药的剂型。
进一步地,所述第一药物组合物和第二药物组合物被分别配制成适于经口服或注射给药的剂型。
再一方面,本发明还提供所述组合治疗剂在用于制备预防或治疗心血管和/或代谢类疾病药物中的用途。
进一步地,所述心血管和/或代谢类疾病包含但不限于肥胖、高脂血症、动脉粥样硬化、非酒精性脂肪性肝病、糖尿病、糖尿病性心肌病、冠状动脉粥样硬化性心脏病以及其它与胰岛素抵抗相关的疾病。
又一方面,本发明提供了所述组合治疗剂用于预防和治疗上述疾病的方法。
进一步地,所述方法包括向受试者或患者联合施用预防或治疗有效量的第一药物组合物和第二药物组合物;其中,所述预防或治疗有效量根据治疗目的或预防目的而定,例如需要治疗的患者的状况、所需的给药途径等。
进一步地,当第一药物组合物和第二药物组合物联合施用时,二者同时一起给予、同时但分别给予或者不同时给予;所述不同时给予为先后连续给予或者先后间隔一段时间给予。
进一步地,所述第一药物组合物和第二药物组合物可以本领域已知的任何方式给予,例如注射,例如静脉(i.v.)或皮下(s.c)注射。
本发明优点在于一方面从临床实际治疗效果和药物的作用机制出发,应用FGF21R/GLP-1R双重激动剂组合应对疾病发生机制的复杂性,满足治疗需求的多样性,并通过科学的实验研究充分阐明长效FGF21 Fc融合蛋白与长效GLP-1 Fc融合蛋白联合使用的优越性及可行性。本发明提供的治疗方法优化了目前心血管及代谢类疾病的临床治疗手段;尤其为并发多种心血管或代谢类疾病患者提供了更有效、更全面的组合治疗方案;另一方面本发明选择的组合治疗剂的活性成份均为长效性蛋白药物,临床上均可实现1周1次的给药频率,其病患接受度远高于其他胰岛素或GLP-1类似物产品。
发明详述
术语“FGF21”是指天然的人FGF21以及保持FGF21活性的其类似物及衍生物。
天然的人FGF21蛋白的序列可获自UNIPROT数据库,登录号为Q9NSA1。前体蛋白由209个氨基酸组成,包括信号肽(氨基酸1-28)和成熟蛋白(氨基酸29-209)。
尤其从US2001012628A1可得知在成熟蛋白中具有Pro替代Leu(在本发明SEQ IDNO:1的第174位)的天然人FGF21同等型(isoform)或等位形式(allelicform)。另一种天然人FGF21同等型的Gly被Ser取代(在本发明SEQ ID NO:1的第141位)。
从WO2003/011213可得知具有较短信号肽(本发明中SEQ ID NO:1第23位Leu丢失)的另一种同等型(参见WO2003/011213公布中的SEQ ID NO:2,具有27个氨基酸残基的信号肽)。
本发明中,天然人FGF21包含SEQ ID NO:1及L174P或G141S取代同等型去除前导肽后所示成熟蛋白部分序列(氨基酸29-209);另外,还包括这些序列之前添加了上述27或28个氨基酸信号肽的前体蛋白全长序列。
术语“GLP-1”是指人GLP-1(7-37)(SEQ ID NO:2的第1-31个氨基酸)、毒蜥外泌肽-4(7-45)(SEQ ID NO:3的第1-39个氨基酸)以及保持GLP-1活性的其类拟物及衍生物。
术语“FGF21类似物”和“GLP-1类似物”是指以下多肽,其通过修饰其氨基酸序列或可通过修饰其氨基酸序列分别推导或衍生自SEQ ID NOs:1、2和3的各自的FGF21、GLP-1和毒蜥外泌肽-4(Exendin-4)序列。这样的修饰可包括一个或多个氨基酸的取代、缺失和/或添加。例如,氨基酸可在氨基酸序列的C端、N端或内部添加和/或缺失。优选氨基酸在C端和/或N端,更优选在N端添加和/或缺失。带有C端或N端缺失的氨基酸的氨基酸序列也可称为截短序列,如本领域所已知。
包含本发明的FGF21 Fc融合蛋白和GLP-1融合蛋白的药物组合物可进一步包含药学上可接受的载体。对于注射,所述载体例如可以是水或生理盐水。还可使用其它药学上可接受的物质,例如稀释剂和适当的缓冲液。若需要的话,还可使用其它药学上可接受的物质,例如乳化剂、助悬剂、溶剂、填充剂、膨胀剂、佐剂、防腐剂、抗氧化剂、着色剂和/或调味剂。所述FGF21 Fc融合蛋白和GLP-1 Fc融合蛋白可以纯化的多肽的形式使用,或者利用合适的药学上可接受的赋形剂配制,如本领域所已知。所述药物组合物可以本领域已知的任何方式给予,例如注射,例如静脉(i.v.)或皮下(s.c)注射。
所述FGF21 Fc融合蛋白和GLP-1 Fc融合蛋白可以治疗有效量或预防有效量包含于药物组合物中。所述有效量根据治疗目的或预防目的而定,例如需要治疗的患者的状况、所需的给药途径等。
术语“胰岛素抵抗”是指正常剂量的胰岛素产生低于正常生物学效应的一种状态,使得脂肪和骨骼肌对葡萄糖的摄取速度减慢,但增加了肝脏的葡萄糖释放和脂肪组织的游离脂肪酸释放。胰岛素抵抗的第一反应是胰岛素的代偿性产生和分泌,以弥补机体降低的敏感性,导致高胰岛素血症。这样,高胰岛素水平和组织从血流中清除葡萄糖的反应性降低成为胰岛素抵抗的特征。胰岛素抵抗是导致一系列代谢变化的主要事件,包括代偿性高胰岛素血症、血脂异常、胰腺β细胞代偿机能减退以及高血糖症。
与胰岛素抵抗相关的疾病具体选自胰岛素抵抗综合征(IRS)、2型糖尿病、糖耐受受损、代谢综合症、高血糖症、高胰岛素血症、动脉硬化、高胆固醇血症、高甘油三酯血症、高脂血症、血脂异常、肥胖、中心性肥胖、多囊卵巢综合征、凝血过快、高血压、微蛋白尿。
术语“糖尿病”是由于胰岛素分泌绝对或相对不足引起的内分泌代谢疾病。2型糖尿病的发病机制包括肝脏和外周组织中胰岛素抵抗的逐步发展,伴随胰腺β细胞的胰岛素分泌缺陷,导致明显的高血糖症(血液中葡萄糖含量异常高)。
术语“糖尿病并发症”是由慢性高血糖引起的身体其它部位的功能障碍如糖尿病肾病、糖尿病神经病变、糖尿病足(足部溃疡和循环低下)和眼部病变(视网膜病)。糖尿病还增加心脏病以及骨和关节病症风险。糖尿病的其它长期并发症包括皮肤问题、消化问题、性功能障碍和牙齿与牙龈问题。
术语“糖尿病性心肌病”是指发生于糖尿病患者,不能用高血压性心脏病、冠状动脉粥样硬化性心脏病及其他心脏病变来解释的心肌疾病。该病在代谢紊乱及微血管病变的基础上引发心肌广泛灶性坏死,出现亚临床的心功能异常,最终进展为心力衰竭、心律失常及心源性休克重症患者甚至猝死。
术语“冠状动脉粥样硬化性心脏病”是冠状动脉血管发生动脉粥样硬化病变而引起血管腔狭窄或阻塞,造成心肌缺血、缺氧或坏死而导致的心脏病。
术语“血脂异常”是脂蛋白代谢病症,包括脂蛋白过度生产或缺陷。血脂异常可以表现为血液中总胆固醇、低密度脂蛋白(LDL)胆固醇和甘油三酯浓度升高,和高密度脂蛋白(HDL)胆固醇浓度减少。
术语“非酒精性脂肪肝疾病”或“NAFLD”是指由脂肪变性引起的而不是由过量饮酒引起的肝脏的所有疾病。NAFLDs包括但不限于单纯的非酒精性脂肪肝(“NAFL”)、非酒精性脂肪肝炎(“NASH”)、伴有肝纤维化的NAFL、伴有肝硬化的NAFL、伴有肝纤维化的NASH、伴有肝硬化的NASH以及由肝炎、肥胖、糖尿病、胰岛素抵抗、高甘油三酯血症、脂蛋白血症、糖原贮积疾病、韦伯-克里斯钦疾病、沃尔曼病、怀孕或脂肪营养不良引起的脂肪肝疾病。
术语“非醇型脂肪性肝炎(NASH)”是与醇消耗无关的肝病,其特征是肝细胞脂肪变性,伴随小叶内炎症和纤维化。
术语“动脉粥样硬化(atherosclerosis,AS)”是一种与脂质代谢障碍有关的全身性疾病,其病变特点是血液中的脂质进入动脉管壁并沉积于内膜形成粥样斑块,导致动脉增厚、变硬。AS主要累及大中动脉、基本病变是动脉内膜的脂质沉积,内膜灶状纤维化,粥样斑块形成,致管壁变硬、官腔狭窄,并引发一系列继发性疾病,特别是发生在心、脑、肾等器官,引起缺血性改变。
术语“药学上可接受的载体和/或赋形剂和/或稳定剂”,是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂/或稳定剂,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂,稀释剂,维持渗透压的试剂,延迟吸收的试剂,防腐剂。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元醇(如甘油)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性,包括但不限于谷氨酸钠,明胶,SPGA,糖类(如山梨醇,甘露醇,淀粉,蔗糖,乳糖,葡聚糖,或葡萄糖),氨基酸(如谷氨酸,甘氨酸),蛋白质(如干燥乳清,白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。
术语“患者”、“受试者”、“个体”和“对象”是指接受预防性或治疗性治疗的任何人类或非人类动物,尤其是人。例如,本文所述的组合治疗剂和方法可用于治疗患有糖尿病、NASA、NAFLD或动脉粥样硬化疾病的受试者。术语“非人动物”包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物,绵羊,狗,牛,鸡,两栖动物,爬行动物等。
术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如,肿瘤或感染)有效量是指,当单独使用或与另一种或多种治疗剂组合使用时,足以预防,阻止,或延迟疾病(例如,肿瘤或感染)的发生的量;治疗疾病有效量是指,当单独使用或与另一种或多种治疗剂组合使用时,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。术语关于治疗的“有效”和“有效性”包括药理学有效性和生理学安全性二者。药理学有效性是指药物促进患者病症或症状消退的能力。生理学安全性是指由于药物施用导致的细胞、器官和/或生物体水平上的毒性或者其它不良生理效果(不良作用)的水平。
对受试者的“治疗”或“疗法”是指以逆转、减轻、改善、抑制、减缓或防止与疾病有关的症状、并发症、病症或生化指标的出现、进展、发展、严重程度或复发为目的对受试者进行任何类型的干预或处理,或者向其施用本发明所述组合治疗剂。
附图说明
图1、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对肥胖小鼠体重的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,**P<0.01;与FP4I单用组相比,△△P<0.01。
图2、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对肥胖小鼠血清肝功能的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,**P<0.01;与FP4I单用组相比,△△P<0.01。
图3、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A联合使用对肥胖小鼠肝脏甘油三酯含量的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,**P<0.01;与FP4I单用组相比,△△P<0.01。
图4、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B或FP-A分别联合使用后肥胖小鼠肝脏组织病理学图片。
图5、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对肥胖小鼠血清胰岛素含量的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,**P<0.01;与FP4I单用组相比,△△P<0.01。
图6、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对非酒精性脂肪肝炎小鼠血清肝功能的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,**P<0.01;与FP4I单用组相比,△△P<0.01。
图7、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对非酒精性脂肪肝炎小鼠肝脏甘油三酯含量的影响(means±SEM);统计学差异标记注释:与溶媒对照组相比,##P<0.01;与对应的GLP-1 Fc融合蛋白单用组相比,*P<0.05;与FP4I单用组相比,△P<0.05。
图8、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用后非酒精性脂肪肝炎小鼠肝脏组织病理学图片。
图9、FP4I与GLP-1 Fc融合蛋白杜拉鲁肽、FP-B和FP-A分别联合使用对db/db小鼠全心质量的影响(means±SEM);统计学差异标记注释:与正常对照组相比,##P<0.01;与溶媒对照组相比,**P<0.01。
具体实施方式
本发明选择一种长效FGF21-Fc融合蛋白(命名为FP4I,参见中国专利CN107995914A)分别与长效GLP-1 Fc融合蛋白杜拉鲁肽(商品名:Trulicity)或Ex(1-39)-L3-CTP1-vFcγ2-3(命名为FP-A,参见中国专利CN106117370B),或Ex-(1-45)-L-vFc(命名为FP-B,参见中国专利CN106279430B)组合使用,以肥胖、高脂血症、非酒精性脂肪肝病或糖尿病动物模型为研究对象,充分阐明两类产品联用的治疗优势并为心血管和代谢疾病的综合管理和防治提供一种更有效、更全面的解决方案。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1、组合使用对高脂肪饲料诱导的小鼠肥胖,脂代谢紊乱及脂肪肝治疗的作用
1.1药品来源
长效FGF21-Fc融合蛋白(命名为FP4I),制备方法参见CN107995914A,本发明中其氨基酸序列如SEQ ID NO:4所示)、杜拉鲁肽(美国Lily公司,本发明中其氨基酸序列如SEQID NO:5所示)、Ex(1-39)-L3-CTP1-vFcγ2-3(命名为FP-A,制备方法参见中国专利CN106117370B,本发明中其氨基酸序列如SEQ ID NO:6所示)、Ex-(1-45)-L-vFc(命名为FP-B,制备方法参见中国专利CN106279430B,本发明中其氨基酸序列如SEQ ID NO:7所示)。
1.1分组给药及样本收集
8周龄雄性C57BL/6J小鼠,购自于上海斯莱克实验动物有限责任公司。饲养环境22~24℃,相对湿度45~65%,照明时间12h/天。以D12492饲料(脂肪热量60%,美国ResearchDiets公司产品)喂养20周后,根据体质量将小鼠随机分为溶媒对照组、FP4I-5mg/kg组(简称FP4I组)、杜拉鲁肽-1.5mg/kg组(简称杜拉鲁肽组)、FP-B-1.5mg/kg组(简称FP-B组)、FP-A-1.5mg/kg组(简称FP-A组)、FP4I-5mg+杜拉鲁肽-1.5mg/kg组(简称FP4I+杜拉鲁肽组)、FP4I-5mg/kg+FP-B-1.5mg/kg组(简称FP4I+FP-B组)和FP4I-5mg+FP-A-1.5mg/kg组(简称FP4I+FP-A组),每组8只小鼠。溶媒对照组和单药治疗组颈背部皮下注射给予相应蛋白溶液或缓冲液;组合用药组颈背部皮下注射给予FP4I,腹部皮下分别注射给予杜拉鲁肽、FP-A或FP-B。每6天给药1次,共计给药4次。末次给药周期后,各组小鼠禁食16h,眼眶取全血,2000g离心15分钟,分离得血清样本。分离肝脏组织,称重,肝左外叶液氮急冻后转移至-80℃冰箱保存,肝右叶保存于10%福尔马林溶液中。
1.2实验方法
全自动生化分析仪(欧霸XL-200全自动生化分析仪,德国欧霸公司产品)及其配套试剂盒(宁波美康生物科技有限公司产品)检测小鼠血清ALT、AST、TG、TC、LDL-c、HDL-c含量。ELISA法(小鼠超敏胰岛素ELISA检测试剂盒,美国ALPCO公司产品)检测小鼠空腹血清中胰岛素含量。取小鼠肝左外叶组织约55mg,Floch法检测单位肝质量中甘油三酯含量。取小鼠肝右叶,HE染色,并开展组织病理学检查。
数据以均数±标准误(means±SEM)形式表示,采用SPSS18.0统计软件分析数据。正态分布,多组间均数差异采用单因素方差分析,方差齐性采用LSD检验,方差不齐采用Dunnet T3检验;非正态性分布采用非参数检验,P<0.05表示具有显著性统计学差异。
1.3实验结果
结果如图1所示,与溶媒对照组相比,杜拉鲁肽组、FP-A组、FP-B组和FP4I组小鼠体质量显著降低。相比于单独给予FGF21 Fc融合蛋白或GLP-1 Fc融合蛋白,联合用药组小鼠体质量进一步显著降低。结果如图2和图3所示,联合用药组小鼠肝功能改善程度显著优于单用组,而肝脏甘油三酯含量显著低于单用组。
组织病理学结果显示,溶媒对照组小鼠肝脏变现为大泡和小泡混合型脂肪变性,且脂肪融合成片状。单独给予杜拉鲁肽、FP-B、FP-A或FP4I具有改善小鼠肝脏脂肪变性的作用。相比于单独给予FGF21融合蛋白或GLP-1 Fc融合蛋白,组合用药组小鼠肝脏脂肪病变程度得到更大程度上的缓解,结果见图4。
结果如表1和表2所示,联合给予FGF21融合蛋白和GLP-1 Fc融合蛋白,其对于肥胖小鼠高脂血症的治疗作用优于单独给药组。
表1.FGF21 Fc融合蛋白与长效GLP-1 Fc融合蛋白联合使用对肥胖小鼠血清TG和TC含量的影响
备注:与溶媒对照组相比,#P<0.05,##P<0.01;与对应GLP-1 Fc融合蛋白单用组相比,*P<0.05,**P<0.01;与FP4I单用组相比,△P<0.05,△△P<0.01;其余表格统计学标注注释同表1所述。
表2.FP4I与GLP-1 Fc融合蛋白联合使用对肥胖小鼠血清HDL-c和LDL-c含量的影响
如图5结果所示,FP4I、杜拉鲁肽、FP-B和FP-A单独使用均可有效改善肥胖小鼠高胰岛素血症症状。FP4I与上述GLP-1 Fc融合蛋白组合使用后,其改善胰岛素抵抗的作用显著性增强。
本实施例研究内容表明,以具有典型的代谢综合征特点的肥胖小鼠为研究对象,长效FGF21融合蛋白与长效GLP-1 Fc融合蛋白组合使用相对于单独用药,其在减重、逆转脂肪肝及其诱发的肝损伤、缓解和治疗血脂紊乱、胰岛素抵抗及低密度脂蛋白升高所诱发的血管病变性疾病方面表现出更为优异的治疗作用。
实施例2、组合使用对高果糖高脂肪高胆固醇饲料诱导的非酒精性脂肪肝炎小鼠的治疗作用
2.1分组给药及样本收集
8周龄雄性C57BL/6J小鼠,购买于北京华阜康生物科技股份有限公司。饲养环境22~24℃,相对湿度45~65%,照明时间12h/天。D09100301饲料(脂肪热量40%,果糖热量40%,胆固醇质量2%,美国Research Diets公司产品)喂养30周后,禁食12h,眼内眦静脉丛取全血约120μl,分离血清检测ALT水平。根据体质量和血清ALT水平将小鼠随机分为溶媒对照组、FP4I-5mg/kg组(简称FP4I组)、杜拉鲁肽-1.5mg/kg组(简称杜拉鲁肽组)、FP-B-1.5mg/kg组(简称FP-B组)、FP-A-1.5mg/kg组(简称FP-A组)、FP4I-5mg+杜拉鲁肽-1.5mg/kg组(简称FP4I+杜拉鲁肽组)、FP4I-5mg/kg+FP-B-1.5mg/kg(简称FP4I+FP-B组)和FP4I-5mg+FP-A-1.5mg/kg组(简称FP4I+FP-A组),每组8只小鼠。溶媒对照组和单药治疗组颈背部皮下注射给予相应蛋白溶液或缓冲液;组合用药组颈背部皮下注射给予FP4I,腹部皮下分别注射给予杜拉鲁肽、FP-A或FP-B。每6天给药1次,共计给药8次。末次给药周期后,各组小鼠禁食16h,眼内眦静脉丛取全血,2000g离心15分钟,分离得血清样本。分离肝脏组织,称重,肝左外叶液氮急冻后转移至-80℃冰箱保存,肝右叶保存于10%福尔马林溶液中。
2.2实验方法
非酒精性脂肪肝炎评分体系(NAS积分)评估治疗效果,标准参照美国国立卫生研究院病理工作组指南,具体如下:肝细胞脂肪变性0分(<5%)、1分(5%~33%)、2分(34%~66%)、3分(>66%);20倍镜下小叶内炎症:0分(无)、1分(<2个)、2分(2~4个)、3分(<4个);肝细胞气球样变:0分(无)、1分(少见)、2分(多见)。血清生化检测、肝脏甘油三酯含量检测、组织病理学检查、统计学分析方法同实施例1中相应部分。
2.3实验结果
如图6和图7所示,在单独用药的治疗基础上,组合用药组能进一步改善非酒精性脂肪肝炎小鼠肝功能,减低肝脏甘油三酯含量。
组织病理学结果表明溶媒对照组小鼠肝脏表现为严重的脂肪变性、炎性细胞浸润并偶见肝细胞气球样变。在本实施例设计的给药剂量及给药周期条件下,单独给予FGF21Fc融合蛋白FP4I或GLP-1 Fc融合蛋白杜拉鲁肽、FP-A或FP-B可在一定程度上缓解非酒精性脂肪肝炎小鼠肝脏病变。相比于单独治疗组,组合用药组小鼠肝脏病理组织形态改善明显,NAS积分显著降低。结果见图8和表3。
本实施例研究内容表明,FGF21 Fc融合蛋白与GLP-1 Fc融合蛋白组合使用对非酒精性脂肪肝炎表现出更为积极的治疗作用,其效果明显优于单独治疗组。
表3.NAS积分结果
实施例3、组合使用对db/db小鼠降血糖及心脏保护作用的实验研究
3.1分组给药及样本收集
6周龄雄性db/db小鼠,购买于江苏集萃药康生物科技有限公司。饲养环境22~24℃,相对湿度45~65%,照明时间12h/天。D12450B饲料喂养至14周龄后,眼内眦静脉丛取约全血20μl,检测糖化血红蛋白含量。根据体质量和糖化血红蛋白水平将db/db小鼠随机分为溶媒对照组、FP4I-5mg/kg组(简称FP4I组)、杜拉鲁肽-1.5mg/kg组(简称杜拉鲁肽组)、FP-B-1.5mg/kg组(简称FP-B组)、FP-A-1.5mg/kg组(简称FP-A组)、FP4I-5mg+杜拉鲁肽-1.5mg/kg组(简称FP4I+杜拉鲁肽组)、FP4I-5mg/kg+FP-B-1.5mg/kg(简称FP4I+FP-B组)和FP4I-5mg+FP-A-1.5mg/kg组(简称FP4I+FP-A组),同周龄的db/m小鼠作为正常对照组,每组8只小鼠。对照组和单药治疗组颈背部皮下注射给予相应蛋白溶液或缓冲液;组合用药组颈背部皮下注射给予FP4I,腹部皮下分别注射给予杜拉鲁肽、FP-A或FP-B。每3天给药1次,共计给药12次。末次给药周期后,各组小鼠禁食过夜,眼内眦静脉丛取全血用于检测糖化血红蛋白含量,取血后脱颈椎处死小鼠,分离小鼠心脏组织,称全心质量。
3.2实验方法
使用NycoCard Reader II特种蛋白金标检测仪(挪威Alere Technologies AS公司产品),微粒色谱法检测小鼠糖化血红蛋白含量。统计学分析方法同实施例1相应部分。
3.3实验结果
结果如表4所示,单独给予FGF21 Fc融合蛋白或GLP-1 Fc融合蛋白对于db/db小鼠表现出良好的控制血糖作用,但仍高于正常血糖小鼠的水平。组合用药后的db/db小鼠糖化血红蛋白含量显著低于单独治疗组,其水平基本恢复至正常小鼠的血糖水平。
db/db是自发型糖尿病小鼠,其特征与临床病症相似度高,故其能较精确反应降血糖药物的治疗效果。本实施例研究表明,组合用药可使db/db小鼠血糖恢复正常,优于单独治疗组。
糖尿病心肌病是糖尿病主要并发症之一,主要病理特征表现为心脏肥大。结果如图9所示,20周龄的db/db小鼠全心质量显著高于正常对照小鼠,表现出糖尿病心肌病特征。单独给予FGF21 Fc融合蛋白或GLP-1 Fc融合蛋白对db/db小鼠全心质量无明显影响。组合用药后,db/db小鼠全心质量显著降低。本实施例研究表明,组合用药可预防和治疗糖尿病心肌病的发生发展。
表4.糖化血红蛋白含量
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 安源医药科技(上海)有限公司
<120> FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途
<130> 20190717
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Claims (10)
1.FGF21Fc融合蛋白,其氨基酸序列:
(1)如SEQ ID NO:4所述;或
(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
2.GLP-1Fc融合蛋白,其氨基酸序列:
(1)如SEQ ID NO:5、SEQ ID NO:6或SEQ ID NO:7所示;或
(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
3.组合治疗剂,其特征在于,所述组合治疗剂由包含权利要求1所述的FGF21Fc融合蛋白的第一药物组合物和包含权利要求2所述的GLP-1Fc融合蛋白的第二药物组合物组成。
4.如权利要求3所述的组合治疗剂,其特征在于,所述FGF21Fc融合蛋白和GLP-1Fc融合蛋白可以预防有效量或治疗有效量包含于所述第一和第二药物组合物中。
5.如权利要求3所述的组合治疗剂,其特征在于,所述第一药物组合物还包含药学上可接受的载体、和/或赋形剂、和/或稳定剂。
6.如权利要求3所述的组合治疗剂,其特征在于,所述第二药物组合物还包含药学上可接受的载体、和/或赋形剂、和/或稳定剂。
7.如权利要求3-6任一项所述的组合治疗剂,其中,所述第一和第二药物组合物被配制成适于经口服或注射给药的剂型。
8.如权利要求3-6任一项所述的组合治疗剂,其中,所述第一和第二药物组合物被分别配制成适于经口服或注射给药的剂型。
9.权利要求1所述的FGF21Fc融合蛋白和/或权利要求2所述的GLP-1Fc融合蛋白在制备用于预防或治疗心血管和/或代谢类疾病的药剂(优选是权利要求3-8任一项所述的组合治疗剂)中的用途。
10.如权利要求9所述的用途,其特征在于,所述心血管和/或代谢类疾病包含但不限于肥胖、高脂血症、动脉粥样硬化、非酒精性脂肪性肝病、糖尿病、糖尿病性心肌病、冠状动脉粥样硬化性心脏病以及其它与胰岛素抵抗相关的疾病。
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CN201910675288.5A CN112279920B (zh) | 2019-07-25 | 2019-07-25 | FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 |
CA3145475A CA3145475A1 (en) | 2019-07-25 | 2020-07-08 | Fgf21 fc fusion protein, glp-1 fc fusion protein, and combination therapeutic agent comprising same and use thereof |
EP20844267.3A EP4006058A4 (en) | 2019-07-25 | 2020-07-08 | FC FUSION PROTEIN FGF21, FC FUSION PROTEIN GLP-1, COMBINATION THERAPEUTIC AGENT COMPRISING THE SAME AND USE THEREOF |
JP2022505283A JP7360751B2 (ja) | 2019-07-25 | 2020-07-08 | FGF21 Fc融合タンパク質、GLP-1 Fc融合タンパク質、それらの併用治療剤および使用 |
MX2022000984A MX2022000984A (es) | 2019-07-25 | 2020-07-08 | Proteina de fusion fgf21 fc, proteina de fusion glp-1 fc, y agente terapeutico de combinacion que comprende el mismo y su uso. |
PCT/CN2020/100774 WO2021012947A1 (zh) | 2019-07-25 | 2020-07-08 | FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 |
AU2020317780A AU2020317780A1 (en) | 2019-07-25 | 2020-07-08 | FGF21 Fc fusion protein, GLP-1 Fc fusion protein, and combination therapeutic agent comprising same and use thereof |
KR1020227006670A KR20220039790A (ko) | 2019-07-25 | 2020-07-08 | FGF21 Fc 융합 단백질, GLP-1 Fc 융합 단백질 및 이들의 조합 치료제와 용도 |
BR112022001295A BR112022001295A2 (pt) | 2019-07-25 | 2020-07-08 | Proteína de fusão fgf21 fc, proteína de fusão glp-1 fc e agente terapêutico de combinação compreendendo as mesmas e uso dos mesmos |
US17/629,277 US20220242926A1 (en) | 2019-07-25 | 2020-07-08 | Fgf21 fc fusion protein, glp-1 fc fusion protein, and combination therapeutic agent comprising same and use thereof |
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CN113735960A (zh) * | 2021-03-12 | 2021-12-03 | 江南大学 | 一种fgf重组蛋白治疗nash的应用 |
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EP4006058A4 (en) | 2023-11-01 |
JP7360751B2 (ja) | 2023-10-13 |
US20220242926A1 (en) | 2022-08-04 |
MX2022000984A (es) | 2022-03-02 |
JP2022542151A (ja) | 2022-09-29 |
KR20220039790A (ko) | 2022-03-29 |
CA3145475A1 (en) | 2021-01-28 |
CN112279920B (zh) | 2024-01-16 |
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