CN110087666A - 用于治疗糖尿病、高血压和高胆固醇血症的组合物和方法 - Google Patents
用于治疗糖尿病、高血压和高胆固醇血症的组合物和方法 Download PDFInfo
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- CN110087666A CN110087666A CN201780069543.0A CN201780069543A CN110087666A CN 110087666 A CN110087666 A CN 110087666A CN 201780069543 A CN201780069543 A CN 201780069543A CN 110087666 A CN110087666 A CN 110087666A
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Abstract
本发明提供了一种组合物,其包含治疗有效量的对应于SEQ ID NO:1、2、3或4中的一种或多种的多肽、肽或类似物,和或多种药学上可接受的载体、药学上可接受的稀释剂、和/或药学上可接受的赋形剂。本发明的多肽治疗剂可以配制成作为口服制剂、肠胃外制剂、局部制剂、水性制剂、固体制剂、冻干制剂或透皮制剂施用给需要治疗的受试者。还公开了用于治疗受试者中的糖尿病、和/或高血糖症、和/或高胆固醇血症、和/或高血压、和/或代谢综合征中的至少一种的方法,其包括:向受试者施用本发明的多肽或本发明的制剂。
Description
背景技术
当不加控制时,糖尿病或单纯糖尿病会导致高血糖症,或高血糖。随着时间的推移,高血糖症会对身体的许多系统造成严重损害,尤其是神经和血管。有多种糖尿病变异型。在1型糖尿病中,胰腺产生很少或几乎不产生胰岛素。1型糖尿病的治疗需要胰岛素注射。在最常见类型的糖尿病,2型糖尿病中,胰腺无法产生足够量的胰岛素,或者由于细胞抗性产生的胰岛素效果较差,或二者兼而有之。世界卫生组织规定,2型代表全世界90%的糖尿病病例。治疗2型糖尿病包括健康饮食和身体活动,以及药物和胰岛素治疗。
糖尿病慢性高血糖症的并发症包括内皮损伤、增生性视网膜病、神经病变、肾病、高血压和缺血性心脏病。糖尿病是导致心脏病、中风、肾衰竭、失明和截肢的主要原因之一,因此它对所有工业国家的经济都是一种消耗。
通常在2型糖尿病的情况下,药物干预是治疗所必需的。对于2型糖尿病有许多类型的批准药物,诸如磺酰脲类、二肽基肽酶IV(DPP-IV)抑制剂、氯茴苯酸类、双胍类、噻唑烷二酮类和α-葡糖苷酶抑制剂。然而,这些药物会产生不良副作用,包括胃部不适、低血糖症、体重增加、肝脏问题、皮疹、头痛和呼吸道感染。此外,这些药物通常一起用作组合疗法以便更有效。然而,多种药物的使用增加了不希望的副作用的可能性。近50%的2型糖尿病患者最终需要施用胰岛素。
胰岛素施用仍然是1型糖尿病的唯一治疗选择。此外,胰岛素治疗I型糖尿病无法避免由于难以确定改变生理状况所需的确切胰岛素剂量所致的由高血糖和低血糖的每日循环引起的长期并发症。
高血压、高胆固醇和高血糖通常存在于患有两种类型糖尿病的个体中,尤其是2型糖尿病中。高血压、高胆固醇和糖尿病的组合会显著增加心脏病发作或中风的风险。目前,用于治疗这三种疾病(高血压、高胆固醇和糖尿病)的药物有着不同程度的副作用。因此,具有降低血糖也调节血压和胆固醇,而没有在目前可用的药物中看到的副作用的治疗组合物将是有用的。这种组合物可用于治疗高血压、胆固醇以及糖尿病。
发明内容
本发明涉及用于治疗临床疾病的新型药物组合物和方法,该临床疾病包括与高血压和升高的血糖水平(高血糖症)相关的那些疾病,诸如:糖尿病、中风、外周血管疾病、肺动脉高血压、代谢综合征、高胆固醇血症和动脉粥样硬化。
出乎意料的是,已经发现,相应与40s核糖体蛋白S2(“RPS2”)的活性区序列同源的多肽作为口服和静脉内给药的治疗剂是有益的,如其促进血糖水平降低、胰岛素抗性降低、肝葡萄糖生成降低、胰高血糖素水平降低、血压降低(收缩和舒张水平)以及血液胆固醇水平降低的能力所证明的。
本文提供了涉及包含RPS2多肽、RPS2肽类似物和/或其混合物的药物组合物的方法和组合物。在一个实施方式中,RPS2多肽包含SEQ ID NO:1中所示的氨基酸序列。在另一个实施方式中,RPS2多肽包含与SEQ ID NO:1中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。在另一个实施方式中,RPS2多肽与SEQ ID NO:1中所示的氨基酸序列具有至少50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。
在一个实施方式中,RPS2多肽包含SEQ ID NO:1中所示的氨基酸序列2。在另一个实施方式中,RPS2多肽包含与SEQ ID NO:2所示氨基酸序列具有至少50%序列一致性的氨基酸序列。在另一个实施方式中,RPS2多肽与SEQ ID NO:2中所示的氨基酸序列具有至少50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。
在一个实施方式中,RPS2多肽包含SEQ ID NO:1中所示的氨基酸序列3。在另一个实施方式中,RPS2多肽包含与SEQ ID NO:3所示氨基酸序列具有至少50%序列一致性的氨基酸序列。在另一个实施方式中,RPS2多肽与SEQ ID NO:3中所示的氨基酸序列具有至少50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。
在第一方面中,本发明提供了一种分离多肽,其包含40s核糖体蛋白S2(RPS2)或其片段或类似物,40s核糖体蛋白S2(RPS2)或其片段或类似物包含与SEQ ID NO:1、2、3或4中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。在一个实施方式中,本发明提供了一种分离多肽,其由40s核糖体蛋白S2(RPS2)或其片段组成,40s核糖体蛋白S2(RPS2)或其片段包含与SEQ ID NO:1、2、3或4中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。
在一个实施方式中,本发明提供了一种分离多肽,其包含40s核糖体蛋白S2(RPS2)或由40s核糖体蛋白S2(RPS2)组成,40s核糖体蛋白S2(RPS2)包含与SEQ ID NO:1中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。在一个实施方式中,本发明提供了一种分离多肽,其包含40s核糖体蛋白S2(RPS2)片段或由40s核糖体蛋白S2(RPS2)片段组成,40s核糖体蛋白S2(RPS2)片段包含与SEQ ID NO:2中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。在一个实施方式中,本发明提供了一种分离多肽,其包含40s核糖体蛋白S2(RPS2)片段或由40s核糖体蛋白S2(RPS2)片段组成,40s核糖体蛋白S2(RPS2)片段包含与SEQ ID NO:3中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。在一个实施方式中,本发明提供了一种分离多肽,其包含40s核糖体蛋白S2(RPS2)片段或由40s核糖体蛋白S2(RPS2)片段组成,40s核糖体蛋白S2(RPS2)片段包含与SEQ ID NO:4中所示的氨基酸序列具有至少50%序列一致性的氨基酸序列。
在一个实施方式中,RPS2或其片段与SEQ ID NO:1、2、3或4中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。在一个实施方式中,RPS2与SEQ ID NO:1中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。在一个实施方式中,RPS2片段与SEQ ID NO:2中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。在一个实施方式中,RPS2片段与SEQ ID NO:3中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。在一个实施方式中,RPS2片段与SEQ ID NO:4中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。
在一个实施方式中,RPS2或其片段包含SEQ ID NO:1、2、3或4中所示的氨基酸序列。在一个实施方式中,RPS2包含SEQ ID NO:1中所示的氨基酸序列。在一个实施方式中,RPS2片段包含SEQ ID NO:2中所示的氨基酸序列。在一个实施方式中,RPS2片段包含SEQ IDNO:3中所示的氨基酸序列。在一个实施方式中,RPS2片段包含SEQ ID NO:4中所示的氨基酸序列。
在一个实施方式中,RPS2或其片段由SEQ ID NO:1、2、3或4中所示的氨基酸序列组成。在一个实施方式中,RPS2由SEQ ID NO:1中所示的氨基酸序列组成。在一个实施方式中,RPS2片段由SEQ ID NO:2中所示的氨基酸序列组成。在一个实施方式中,RPS2片段由SEQ IDNO:3中所示的氨基酸序列组成。在一个实施方式中,RPS2片段由SEQ ID NO:4中所示的氨基酸序列组成。
在第二方面中,本发明提供了一种包含至少一种根据本发明的多肽的制剂。根据本发明的至少一种多肽可以是至少一种根据第一方面的多肽。
在一个实施方式中,制剂是口服药物制剂。在一个实施方式中,制剂是药物肠胃外制剂。在一个实施方式中,制剂是药物局部制剂。
在一个实施方式中,制剂包含一种或多种药学上可接受的载体和/或一种或多种药学上可接受的稀释剂和/或一种或多种药学上可接受的赋形剂。制剂可包含一种或多种药学上可接受的载体。制剂可包含一种或多种药学上可接受的稀释剂。制剂可包含一种或多种药学上可接受的赋形剂。
在一个实施方式中,制剂是水性药物制剂。在水性药物制剂中,肽可以以0.05至5μg/L的浓度存在。例如,肽可以以0.08至3μg/L的浓度或可以以0.1至1μg/L的浓度存在。肽可以以至少0.05μg/L的浓度,例如至少0.7、0.1或0.15μg/L的浓度存在。肽可以以不大于5μg/L,例如不大于4、3或2μg/L(例如,不大于1μg/L)的浓度存在。水性药物制剂可包含缓冲剂。缓冲液可具有约7至约8的pH,例如缓冲液可具有约7.2至约7.6的pH,例如缓冲液可具有生理pH(约7.4的pH,例如pH为从7.3至7.5)。缓冲液可以是磷酸盐缓冲盐水(磷酸盐缓冲液,phosphate buffered saline)。
在第三方面中,本发明提供了包含本发明的多肽或本发明的制剂的药物。本发明的多肽可以是第一方面的至少一种多肽。本发明的制剂可以是第二方面的制剂。
在第四方面中,本发明提供了一种用于治疗疾病的方法的本发明的多肽或本发明的制剂。本发明的多肽可以是第一方面的至少一种多肽。本发明的制剂可以是第二方面的制剂。该疾病可以是1型和/或2型糖尿病、高血糖症、高胆固醇血症、高血压和代谢综合征中的至少一种。该疾病可以是1型和/或2型糖尿病。这种疾病可以是高血糖症。这种病可以是高胆固醇血症。这种疾病可以是高血压。这种疾病可以是代谢综合征。
在第五方面中,本发明提供了一种本发明的多肽或本发明的制剂,用于在治疗1型和/或2型糖尿病的方法中的用途。本发明的多肽可以是至少一种第一方面的多肽。本发明的制剂可以是第二方面的制剂。该用途可以提供肝葡萄糖生成降低、和/或胆固醇水平降低、和/或胰高血糖素水平降低、和/或血压降低。该用途可以提供肝葡萄糖生成降低。该用途可以提供胆固醇水平降低。该用途可以提供胰高血糖素水平降低。该用途可以提供血压降低。
在第六方面中,本发明提供了至少一种根据本发明的多肽用于制备用于治疗1型和/或2型糖尿病的药物中的用途。根据本发明的多肽可以是至少一种第一方面的多肽。
在第七方面中,本发明提供了至少一种根据本发明的多肽用于制备用于治疗高血糖症、和/或高胆固醇血症、和/或高血压和/或代谢综合征中的至少一种的药物中的用途。根据本发明的多肽可以是至少一种第一方面的多肽。该药物可以治疗高血糖症。该药物可治疗高胆固醇血症。该药物可治疗高血压。该药物可治疗代谢综合征。
在第八方面中,本发明提供了一种用于治疗受试者中的糖尿病,和/或高血糖症,和/或高胆固醇血症,和/或高血压中的至少一种的方法,包括:向受试者施用本发明的多肽或本发明的制剂。本发明的多肽可以是至少一种第一方面的多肽。本发明的制剂可以是第二方面的制剂。该方法可包括施用有效量的所述多肽或所述制剂。该方法可以治疗糖尿病(例如,1型和/或2型糖尿病)。该方法可以治疗高血糖症。该方法可以治疗高胆固醇血症。该方法可以治疗高血压。
本发明提供了一种药物组合物,其包含治疗有效量的RPS2多肽或肽类似物,RPS2多肽或肽类似物对应于SEQ ID NO:1、2、3或4中的一种或多种,和/或多种药学上可接受的载体、和/或一种或多种药学上可接受的稀释剂、和/或一种或多种药学上可接受的赋形剂。本发明的多肽治疗剂可以配制成作为口服制剂、肠胃外制剂、局部制剂、水性制剂、固体制剂、冻干制剂或透皮制剂施用给需要治疗的受试者。
附图说明
图1是示出了用静脉内(10μg)和口服(200μg)施用的二甲双胍和/或IMG-1治疗的糖尿病动物(Zucker糖尿病大鼠动物模型)的体重之间的关系的图,示出了动物中的体重增加是一致的。
图2是示出了与对照和二甲双胍相比,用IMG-1制剂(口服和IV)治疗糖尿病动物导致正常血糖水平的图。
图3是示出了与对照和二甲双胍相比,用IMG-1制剂(口服和IV)治疗糖尿病动物导致正常血压(收缩和舒张)水平的图。
图4是示出了与对照和二甲双胍相比,用IMG-1制剂(口服和IV)治疗糖尿病动物导致HbA1c水平降低的柱状图。
图5是示出了用IMG-1制剂(口服和IV)治疗糖尿病动物不影响胰岛素水平(mcU/mL)的柱状图。
图6是示出了与对照和二甲双胍相比,用IMG-1制剂(口服和IV)治疗糖尿病动物导致胰高血糖素水平降低的柱状图。
图7是示出了与未处理对照相比,从施用IMG-1(口服和静脉内)的糖尿病动物测量的平均胆固醇水平(mg/dL)较低的柱状图。处理的动物平均<170mg/dL,而对照测量为224mg/dL。
图8是示出了IMG-1制剂在降低1型糖尿病动物模型中的血糖水平方面有效的柱状图,与对照(未治疗的)糖尿病诱导的动物相比降低是显著的。
图9是示出了在斯普拉格-道利动物模型中24小时内从血清中清除IMG-1(以pg/mL测量的)的图。示出了的结果标记为BES17-02-1,2,2(表示三只动物)。
图10是示出了用IMG-1制剂处理的斯普拉格-道利动物中的血糖水平的图。
图11是示出了以1.0μg至1000.0μg的剂量施用的IMG-1制剂不影响斯普拉格-道利大鼠中的肌酸酐水平的图。
图12是示出了以1.0μg至1000.0μg的剂量施用的IMG-1制剂不影响斯普拉格-道利大鼠中的转氨酶水平的图。
图13是示出了基于葡萄糖输注速率(mg/kg/m),与对照相比,以2μg剂量(静脉内)施用的IMG-1制剂降低糖尿病诱导的肥胖(DIO)小鼠中的胰岛素抗性的柱状图。
图14是示出了与对照相比,以2μg剂量(静脉内)施用的IMG-1制剂抑制DIO小鼠中的肝葡萄糖生成(HGP)柱状图。
图15是示出了以2μg剂量(静脉内)的IMG-1制剂不影响DIO小鼠的全身葡萄糖周转、糖酵解或糖原合成的柱状图,并且基本上等同于对照。
图16是示出了以2μg剂量(静脉内)的IMG-1制剂不影响骨骼肌或白色脂肪葡萄糖摄取的柱状图。
图17是示出了与全长RPS2(IMG-1)相比和与未处理的相比,截短的RPS2肽的活性的柱状图,命名为(IMG-1L和IMG-1S)。与IMG-1(全长)相比,IMG-1L的制剂(其对应于全长蛋白质的C末端的片段)在体外表现出相似的活性;然而,IMG-1S的制剂(对应于全长蛋白质的N-末端片段)似乎没有表现出活性,如通过使用内皮细胞的MTT测定的光密度测量的。
具体实施方式
提供以下详细描述是为了帮助本领域技术人员实施本发明,但不应解释为限制本发明,因为在不脱离了本发明的范围和精神的情况下,本领域普通技术人员可以做出对本文公开的实施方式的修改和变化。本申请中引用的所有出版物和其他参考文献都通过引用其全部内容并入本文。
定义
在本公开中使用以下术语来描述本发明的不同方面。这些术语仅用于说明目的,并不意图限制本发明任何方面的范围。
如本文所用,“活性成分(active ingredient)”、“活性化合物(activecompound)”、“活性组分(active component)”和/或“活性剂(active agent)”可互换使用,并且是指具有包含SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或其组合的氨基酸序列的氨基酸序列的多肽、肽片段或其类似物。包含活性成分/化合物的本发明的制剂统称为“IMG-1”制剂,不暗示任何特定剂量或浓度的活性化合物。
如本文所用,“有效量”是指活性成分/化合物的量,当施用给受试者时,其有效地将血糖水平降低至小于200mg/dl,将胆固醇降低至小于200mg/dl,和/或将血压降低至小于140/90mmHg。
如本文所用,“药物制剂”、“药物组合物”、“制剂”或“组合物”是指(可互换地)液体(水性、凝胶或软膏),或含有一定量活性化合物的固体形式,其被制备使得其适于直接或在重构后施用给哺乳动物如人或其他动物。如果需要,制剂可含有药学上可接受的载体和/或添加剂。例如,洗涤剂/表面活性剂(例如,PEG、吐温(20、80等)、普朗尼克)、赋形剂、抗氧化剂(例如,抗坏血酸、蛋氨酸)、着色剂、调味剂、防腐剂、稳定剂、缓冲剂、螯合剂(例如,EDTA)、悬浮剂、等渗剂、粘合剂、崩解剂、润滑剂、流动性促进剂和矫味药。本发明的药物组合物可以含有在本文中所述的RPS2多肽和/或多肽类似物组合的其他活性成分。
如在本文中所用的,术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”和本文所用的其他语法等同物包括减轻、减少或改善疾病或病症症状,预防另外症状,改善或预防症状的潜在代谢原因,抑制疾病或病症,例如,阻止疾病或病症的发展,缓解疾病或病症,引起疾病或病症的消退,缓解由疾病或病症引起的病症,或者阻止疾病或病症的症状和预防。该术语还包括实现治疗益处和/或预防益处。治疗益处是指根除或改善所治疗的潜在病症。此外,通过根除或改善与潜在病症相关的一种或多种生理症状来实现治疗益处,从而在患者中观察到改善。尽管患者可能仍然患有潜在疾病。为了预防益处,可将组合物施用给有发展特定疾病风险的患者,或施用给报告一种或多种疾病的生理症状的患者,即使可能没有做过这种疾病的诊断。
如在本文中所用的,治疗诸如糖尿病或高血压的病症的“治疗有效量”是能够在患者或患者群体中实现临床相关终点的活性化合物的量,例如糖尿病的降低的血糖水平或高血压的血压降低或高甘油三酯血症或高胆固醇血症的胆固醇降低。作为非限制性实例,在动物研究中已示出了施用有效量的IMG-1组合物以将血糖降低至小于200mg/dL(在糖尿病动物模型中);降低血压至小于140/90mmHg;和将总胆固醇降至小于200mg/dL。
本发明提供了一种用于治疗受试者中的一种或多种疾病的药物组合物,该疾病包括糖尿病(I型和/或2型)、高血压、高胆固醇血症、血管疾病或代谢综合征中的一种或多种。药物组合物包含对应于SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4中的一种或多种的纯化的或合成的RPS2多肽或肽类似物,或其活性区域,结合一种或多种药学上可接受的载体、稀释剂或赋形剂。可以将药物组合物配制成用于口服、肠胃外或皮肤/局部施用给需要治疗的受试者。
在另一个实施方式中,本发明提供了一种水性药物制剂,其包含纯化的或合成的RPS2肽、其类似物或活性区域、缓冲液,诸如磷酸盐缓冲盐水(PBS),其中该制剂具有在正常生理范围内的pH(约7.4)并且其中RPS2多肽或肽类似物包含SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、或SEQ ID NO:4中的一个或多个所示的氨基酸序列。
还提供了一种预防、延迟一种或多种病症的发作或减轻其严重性的方法,该病症包括高血糖症、高血压和/或高胆固醇血症。本发明还提供了用于改善细胞培养物(特别是酵母、细菌和哺乳动物细胞培养物,包括用于生长蛋白质表达细胞的培养基和针对蛋白质表达优化的细胞培养物生产培养基)中的蛋白质表达的方法和组合物。
还通过实施例和实验结果描述了本发明,这些实施例和实验结果旨在说明而非穷举,并且应理解为不限于此。
40s RPS2肽和氨基酸序列
令人惊讶的是,已发现包括截短的片段的纯化的分离的40s核糖体蛋白S2(RPS2)在施用给受试者时表现出治疗益处,包括:降低血糖水平;使血糖水平正常化;降低血胆固醇水平;降低和正常化血压水平;降低血红蛋白A1c水平;降低胰高血糖素水平;和降低胰岛素抗性的能力。作为参考,40s RPS2是属于核糖体蛋白的S5P家族的蛋白质。对于人类,RPS2基因编码核糖体蛋白,其是40S亚基的组分并位于细胞质中。
RPS2氨基酸序列不含典型的核定位信号。使用缺失突变体分析和rpS2-半乳糖苷酶嵌合蛋白,确定RPS2中核靶向结构域的推定鉴定。包含72-75个氨基酸的中心结构域是必需的并且足以将嵌合β-半乳糖苷酶靶向细胞核。核靶向结构域与核糖体蛋白或其他核蛋白中的已经表征的核定位信号没有显著的相似性。
全长RPS2氨基酸序列是293个氨基酸序列,命名为SEQ ID NO:1;SEQ ID NO:1的截短的C末端片段是159个氨基酸片段,并且命名为SEQ ID NO:2;非常规核定位信号是位于SEQ ID NO:1的氨基酸161-235之间的75个氨基酸片段,并命名为SEQ ID NO:3;位于SEQ IDNO:1的氨基酸135-221之间的87个氨基酸片段,命名为SEQ ID NO:4;SEQ ID NO:1的截短的N-末端片段是134个氨基酸片段,并且命名为SEQ ID NO:5。
当通过利用BLAST数据库(https://blast.ncbi.nlm.nih.gov)进行的序列分析进行比较时,SEQ ID NO:1的RPS2多肽在所有动物中是94%-100%同源的。由SEQ ID NO:2的159个氨基酸组成的C末端区域对于动物门而言是99-100%同源的。对应于SEQ ID NO:3的75个氨基酸的核定位序列在所有动物和细菌之间有99-100%的同源性。尽管动物/细菌蛋白质序列平均具有98-100%的同源性,但与植物的同源性可低至77%同源性。
本发明的RPS2氨基酸序列(293个氨基酸)如下所示,并命名为SEQ ID NO:1:
MADDAGAAGGPGGPGGPGMGNRGGFRGGFGSGIRGRGRGRGRGRGRGRGARGGKAEDKEWMPVTKLGRLVKDMKIKSLEEIYLFSLPIKESEIIDFFLGASLKDEVLKIMPVQKQTRAGQRTRFKAFVAIGDYNGHVGLGVKCSKEVATAIRGAIILAKLSIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGNFAKATFDAISKTYSYLTPDLWKETVFTKSPYQEFTDHLVKTHTRVSVQRTQAPAVATT
本发明的RPS2C-末端片段是≈18kDa的159个氨基酸片段。C-末端片段如下所示,并命名为SEQ ID NO:2:
GHVGLGVKCSKEVATAIRGAIILAKLIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGNFAKATFDAISKTYSYLTPDLWKETVFTKSPYQEFTDHLVKTHTRVSVQRTQAPAVATT
本发明的75个氨基酸核定位信号(对应于SEQ ID NO:1的氨基酸161-235之间的序列)如下所示并命名为SEQ ID NO:3:
SIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGN
对应于SEQ ID NO:1的氨基酸135-221之间的N-末端附近的核定位信号的一部分的87个氨基酸序列如下所示,并命名为SEQ ID NO:4
GHVGLGVKCSKEVATAIRGAIILAKLSIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDD
本发明的RPS2N-末端片段是≈13kDa的片段并且命名为SEQ ID NO:5:
MADDAGAAGGPGGPGGPGMGNRGGFRGGFGSGIRGRGRGRGRGRGRGRGARGGKAEDKEWMPVTKLGRLVKDMKIKSLEEIYLFSLPIKESEIIDFFLGASLKDEVLKIMPVQK QTRAGQRTRFKAFVAIGDYN
可以根据本领域已知的方法对本发明的氨基酸序列中含有的氨基酸进行转译后修饰。例如,通过焦谷氨酰化将N-末端谷氨酰胺(Gln)残基修饰成焦谷氨酸(pGlu)残基是本领域技术人员公知的。当然,这种转译后修饰的氨基酸包括在氨基酸序列中并且在本发明的范围内。
体外纯化RPS2和RPS2的表达
将编码人40S核糖体蛋白S2的RPS2基因和各种肽部分亚克隆到pMAL-5载体(NewEngland Biolabs)中。使用正向引物(序列:atggcggatgacgccggtgc)和反向引物(序列:ctatgttgtagccacagctgg)扩增RPS2基因,并将得到的PCR片段磷酸化并从低熔点琼脂糖中纯化。将得到的序列连接到pMAL-5载体中,并在连接和孵化后,在含有100μg/ml氨苄青霉素的LB平板上涂布,并在37℃下孵化过夜以产生用于体内蛋白质产生的转化体。
体内生成RPS2蛋白质
将RPS2转化体接种到5ml的液体培养基中并生长至2×108个细胞/ml。该培养物用于接种200mL LB amp 0.2%葡萄糖至约0.5的A600。然后,通过加入ITPG(异丙基硫代-β-半乳糖苷)至终浓度为0.3mM以诱导培养物,并在30℃下生长另外4小时。然后,将细胞离心并重悬于25ml柱缓冲液/升培养物中。通过冻融裂解细胞,然后通过20号针头进行传代。将裂解的细胞离心,并通过每25ml粗提取物加入125ml的冷CB稀释上清液。将稀释的粗提取物加入到15ml直链淀粉柱中,并用12柱体积的CB洗涤。用CB和麦芽糖(10mM)洗脱蛋白质。在室温下将得到的洗脱液与稀释至200μg/ml的1μl因子Xa一起孵化4小时。将融合蛋白裂解混合物在pH 8.0下透析,并用缓冲液洗涤淀粉酶柱,并将融合蛋白裂解混合物上样到柱上。收集溢流物并通过二喹啉甲酸测定法(BSA)测定分离的蛋白质的量,并通过ELISA评估蛋白质的量。
对于体内动物研究,在柱纯化后的溶液中对应于SEQ ID NO:1的纯化的RPS2蛋白质用PBS稀释至期望浓度(取决于口服或静脉内施用)。然后如实施例中所述,将后续溶液通过0.22μm过滤器过滤以对制剂过滤灭菌,以施用给动物受试者。
用与人RPS2相比在体内产生类似结果的细菌RPS2的基因进行类似研究。进行各种研究以测试分离的RPS2多肽和肽片段作为治疗剂的安全性和功效,包括在糖尿病动物模型中测试IMG-1制剂,以及在对照动物模型中的毒理学研究。进行的研究和获得的结果在本文中作为实施例和附图一起呈现。
实施例1:2型糖尿病动物模型
大鼠的Zucker糖尿病脂肪(ZDF)菌株是众所周知的并且通常用于研究与肥胖相关的2型糖尿病,以及高血压和高胆固醇。ZDF菌株是早发性糖尿病的近交大鼠模型,其中所有的fa/fa雄性大鼠在喂食Purina 5008(Charles River Laboratories International,Inc.,Wilmington,MA,USA)的特殊饮食时在10至12周龄时患上糖尿病。表型是同质的,主要是由于该菌株是遗传近交的并且提供特殊的饮食的事实。
给Zucker糖尿病脂肪(ZDF)大鼠喂食Purina 5008(Charles River LaboratoriesInternational,Inc.)的特殊饮食以增加它们的体重。在研究之前,评估动物的血糖水平;只有血糖水平大于200mg/dl的大鼠才被用于该研究。将动物随机分为4组,未治疗(n=7),每日一次二甲双胍(200mg/kg,n=7),静脉内每日一次10μg IMG-1(IV,n=8)和每日一次口服施用200μg IMG-1(PO,n=9)。将动物维持该饮食35天,它们的体重每周测量两次。35天后,处死动物。图1示出了在30天时间内测量的每组体重(克)的分布。
使用Accutrend Plus系统在整个实验中在ZDF中评估空腹血糖(FBG)水平。最早在治疗后3天,用IMG-1治疗的ZDF大鼠示出了血糖水平显著降低,无论给予何种模式,(IV施用IMG-1的平均FBG水平为179mg/dl且PO施用IMG-1为135mg/dl,相比于在未治疗组和二甲双胍治疗组中,FBG水平分别为281mg/dl和258mg/dl),在第7天,所有IMG-1治疗的动物具有正常的FBG水平(水平低于200mg/dl)。未治疗的对照和二甲双胍治疗的动物在整个研究中具有显著升高的FBG水平,在研究结束时平均水平超过400mg/dl(分别为481mg/dl和468mg/dl)。图2示出了IMG-1使糖尿病动物模型中的血糖水平正常化;用IMG-1治疗的动物与对照和二甲双胍相比,血糖水平降低。
使用尾袖血压监测仪(CODA,来自Kent Scientific的监测仪)每周两次监测ZDF大鼠的血压。治疗3天内接受IMG-1治疗的大鼠开始出现血压降低,且口服接受IMG-1的ZDF大鼠在第7天具有正常血压,而接受静脉内IMG-1的那些大鼠在第10天具有正常血压(对于IV和PO施用的IMG-1分别为120/82mmHg和115/80mmHg)。而未治疗和二甲双胍治疗的ZDF大鼠有高血压(未经治疗的>140/90mmHg,141/95mmHg,且二甲双胍治疗的为142/99mmHg)。图3示出了用IMG-1治疗的动物与对照和二甲双胍治疗的动物相比的收缩压和舒张压水平;IMG-1治疗使糖尿病动物模型中的血压正常化。
为了评估HbA1c水平,在第0天、第15天和在第35天处死时对所有动物进行抽血。对收获的血液和血清进行生物测定。在所有三个时间点测量所有动物的血红蛋白A1c(HbA1c)水平。如图4所示,平均Hb1Ac水平在第0天没有显著差异(在9.7和10.8之间);在第15天,与未治疗组和二甲双胍组相比,IMG-1治疗组的HblAc水平显著降低(10.2IV和9.5PO vs 12.1未治疗和11.0二甲双胍),并且到第35天IMG-1治疗的动物比未治疗和二甲双胍治疗的动物(12.3未治疗和11.8二甲双胍)以及它们自己的初始起始水平(10.4IV和10.5PO)具有显著降低的水平(7.4IV和7.5PO)。
与Hb1Ac水平一起,在三个时间点测量所有动物的胰岛素水平。如图5所示,但与图4中所示的HblAc水平不同,在三个时间点中的任何一个时间点,未治疗组和IMG-1治疗组之间的胰岛素水平没有显著差异。此外,在对照中看到的结果与文献一致。
尽管IMG-1、二甲双胍和对照动物的胰岛素水平没有变化,但在第15天,IV和POIMG-1治疗的动物的胰高血糖素水平显著降低(分别从115pg/ml和119pg/ml到90pg/ml和92pg/ml)和35(89pg/ml和92pg/ml);在整个研究中,对照和二甲双胍治疗的动物在胰高血糖素水平上没有显著差异。图6示出了IMG-1降低糖尿病动物模型中的胰高血糖素水平;与对照相比,胰高血糖素水平的降低在口服和IV施用IMG-1之间是一致的。
在连续接触饮用水中的IMG-1或未治疗(n=4)后,在单次剂量注射20μg的IMG-1后48小时评估ZDF大鼠的胆固醇水平。与未治疗的组群相比,IMG-1治疗的动物具有显著降低的胆固醇水平。图7示出了IMG-1减少
糖尿病动物模型中的胆固醇;未治疗的动物的胆固醇水平为224mg/dL,而IMG-1治疗的动物的胆固醇水平分别为171mg/dL(IV)和156mg/dL(口服)。
实施例2:I型糖尿病动物模型
由于IMG-1示出了使血糖水平正常化并且在2型糖尿病动物模型中降低HA1C,因此确定IMG-1是否可以影响1型糖尿病动物模型中的血糖水平。通过使用链脲佐菌素(STZ)可以在小鼠中诱导糖尿病,该链脲佐菌素是对胰腺β细胞具有优先毒性的化合物,并且是用于在啮齿动物中诱导实验性糖尿病的广泛使用的化学品。STZ是由细菌链霉菌achromogens产生的抗生素,并含有葡萄糖分子(呈脱氧形式),其与高反应性甲基亚硝基脲部分连接,其对胰腺β细胞发挥细胞毒性作用。
为了研究IMG-1在STZ诱导的糖尿病模型中的功效,在3-4个月时,通过IP注射对20雄性C57BL/6J小鼠施用STZ5天,以促进高血糖症的发展。STZ注射后,在禁食4小时后测量预治疗(基线)血糖水平,并用于选择小鼠进入2个研究组:对照组(安慰剂,n=7)和IMG-1组(n=8/组)。将动物治疗3周,每天一次口服强饲对照或33μg IMG-1PO。在治疗阶段期间,以2-3天的间隔测量空腹血糖水平,并且还测量胰岛素和胰高血糖素水平。在STZ治疗后18天,示出了对照组动物的空腹血糖水平从216mg/dl升高至319mg/dl,并且对照组动物之一(约14%)由于发育停滞必须被安乐死。然而,IMG-1组的血糖水平仅示出了葡萄糖水平略微增加,从209mg/dl至237mg/dl,并且到第18天示出了IMG-1组具有比对照动物显著更低的血糖水平,如图8所示。
实施例3:毒理学和PK研究
使用斯普拉格-杜勒模型来获得IMG-1制剂的清除率和毒理学。用20μg活性化合物(对应于SEQ ID NO:1)通过静脉内施用治疗三只雄性斯普拉格-杜勒大鼠,然后每隔一段时间抽血,具体为:施用IMG-1后0、5分钟(min)、15分钟、30分钟、60分钟、90分钟、2小时(h)、4小时、6小时、24小时和48小时。在施用后直至2小时在所有三只动物的血液中检测到活性化合物,第三只动物在治疗后直至4小时示出了可检测水平,如图9中在6小时的时间段内测量的IMG-1活性化合物的血清水平(pg/mL)所示。与活性化合物水平一起,在斯普拉格-杜勒模型中评估血糖水平。虽然IMG-1施用显著降低了ZDF大鼠的血糖水平,但施用于斯普拉格-杜勒大鼠的单剂量IMG-1制剂(20μg)在48小时内没有促进低血糖症(如图9所示),如斯普拉格-杜勒动物在48小时时间内的血糖水平所示。
为了评估IMG-1制剂的毒性,用斯普拉格-杜勒大鼠进行中试剂量-发现毒性测定。测试由5组组成,其中每组3只雌性动物和3只雄性动物。治疗组给予单剂量的以下IMG-1浓度之一:1.0ug、10ug、100ug或1000μg。对照组未接受任何治疗。在施用后4小时每1小时进行临床观察,并且对于所有5组每天进行总共14天的临床观察。对于5组(治疗组和未治疗组)中的每一组,在施用后7和14天抽血。在任何动物中均未观察到不良临床观察结果。测量肌酸酐水平以评估肾功能并测量丙氨酸转氨酶水平以评估5组中每一组的肝功能。在肌酸酐和丙氨酸转氨酶水平中观察到用IMG-1制剂治疗的动物和未治疗的动物之间没有可辨别的差异,分别如图10和图11所示。
实施例4:胰岛素钳夹研究
用于量化胰岛素分泌和抗性的最广泛接受的研究方法是血糖正常性胰岛素钳夹技术方法,其测量动物代谢葡萄糖的程度或动物对胰岛素的敏感程度。利用该程序,输注外源胰岛素,以便在禁食时保持恒定的血浆胰岛素水平,而通过以不同的速率输注葡萄糖将葡萄糖固定在基础水平(在100-150mg/dl之间)。
为了评估IMG-1治疗的动物(n=8)与对照(n=8)中的胰岛素作用和葡萄糖代谢,饮食诱导的肥胖(DIO)C57BL/6J小鼠经历2小时的高胰岛素血症-正常血糖钳夹程序。在钳夹之前,与PBS治疗的动物相比,在钳夹试验前48小时和24小时通过尾静脉静脉内施用2μgIMG-1制剂(每只动物)。IMG-1治疗的动物在钳夹期间具有比PBS治疗的动物(30mg/kg/mL)显著更高的稳态葡萄糖输注速率(38.8mg/kg/mL)。如图12所示,用IMG-1治疗降低了DIO小鼠的胰岛素抗性。在用IMG-1治疗的所有动物中,肝葡萄糖生成(HGP)也被显著抑制,如图13所示。此外,在高胰岛素血症-正常血糖钳夹期间,在所有IMG-1治疗的动物中肝胰岛素作用(HGP的抑制百分比)增加。然而,IMG-1不影响任何治疗动物的全身葡萄糖周转、糖酵解或糖原合成,如图14所示,示出了对照动物和治疗动物之间的葡萄糖周转、糖酵解和糖原合成水平几乎相等。钳夹程序的结果还表明,在钳夹测定期间,IMG-1或PBS治疗的动物中骨骼肌和脂肪组织中的葡萄糖代谢没有显著差异,如图15所示,其示出了未治疗和治疗的动物之间的骨骼肌葡萄糖摄取和白色脂肪组织葡萄糖摄取几乎相同。
实施例5:RPS2活性区域的鉴定
用羟胺(NH2OH)消化全长纯化的RPS2蛋白,其在两个位置切割RPS2:P1位的Asn处的氨基酸134和P1'处的Gly,产生两个亚基,命名为大约13kDa的RPS2-短(IMG-1s),和大约18kDa的RPS2长(IMG-1L)。将得到的片段在非变性聚丙烯酰胺凝胶上分离,观察,然后从凝胶中电洗脱。将片段用于制备用于在细胞培养基中测试的制剂。
人真皮微血管内皮细胞(CADMEC/HMVEC)提供了一个很好的模型系统来研究内皮功能和疾病的许多方面,特别是与微脉管系统有关的那些。MTT测定法是用于评估细胞代谢活性的比色测定法。在限定条件下,NAD(P)H-依赖性细胞氧化还原酶可反映存在的活细胞数。这些酶能够将四唑鎓染料MTT 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物还原成其不溶的甲瓒,其具有紫色。为了评估IMG制剂对细胞活性的影响,用各种制剂之一处理CADMEC培养物,例如可从Cell Applications,Inc.获得的培养物:0.5μg/mL全长蛋白质(称为IMG-1)、0.5μg/mL C末端片段(称为IMG-1L)、或0.5μg/mL N末端片段(称为IMG-1s)。使处理过的培养物生长72小时。细胞生长72小时后,用10μL的12mM的MTT处理100μL的细胞培养物,并在37℃下孵化4小时。在用MTT孵化4小时后,将100μL的SDS-HCl溶液加入到MTT处理的细胞培养物中,以使晶体溶解,并进一步孵化另外4小时。然后使用微孔板吸收分光光度计(类似于BioRad的xMarkTM)在570nm处读取吸光度。如图17所示,在72小时,用IMG-1和IMG-1L制剂治疗的细胞中的相对光学OD显著增加(分别为164%和157%),而IMG-1S没有出现影响细胞生长,且未处理的水平符合IMG-1S制剂。IMG-1L对应于全长蛋白质的C末端的片段;而IMG-1S的制剂对应于全长蛋白质的N-末端片段。因此,RPS2的C-末端及其片段和/或类似物与全长RPS2蛋白一起具有治疗价值。
示例性的IMG-1制剂
本发明提供了一种药物组合物,其包含一种或多种对应于SEQ ID NO:1、SEQ IDNO:2、SEQ ID NO:3、和/或SEQ ID NO:4中的一种或多种的多肽、肽和/或类似物。
包含对应于SEQ ID:1、SEQ ID NO:2、SEQ ID NO:3、和/或SEQ ID NO:4的纯化或合成肽或肽类似物的本发明制剂可以根据本领域普通技术人员可获得的方法配制。在一个实施方式中,药物制剂包含RPS2多肽或类似物,或其活性肽区,对应于SEQ ID No:1-4之一,在小于20μg和多达150μg的范围内,如固体剂型或溶液。在一个实施方式中,制剂包含以0.05至5μg/L的浓度存在的肽;在另一个实施方式中,制剂包含以0.1至1μg/L的浓度存在的肽;在另一个实施方式中,制剂包含对口服制剂以50-150μg/kg的浓度存在的肽和对于静脉内制剂以5-15μg/kg的浓度存在的肽。活性成分的浓度和相应的剂量将部分取决于受试者的体重、施用途径、待治疗的症状/病症和症状的严重程度。
在一个实施方式中,本发明的药物制剂还包含一种或多种吸收促进剂,其包括洗涤剂、表面活性剂、胆汁盐、Ca2+螯合剂、脂肪酸、中链甘油酯、酰基肉碱、烷酰基胆碱、N-乙酰化α-氨基酸、N-乙酰化非α-氨基酸、壳聚糖、粘膜粘附聚合物和磷脂中的一种或多种。
在一个实施方式中,可用于本发明的示例性赋形剂包括:缓冲剂、盐、表面活性剂、多元醇/二糖/多糖、氨基酸和抗氧化剂。保持pH水平在4.7至7.4的示例性的缓冲液包括:乙酸盐、柠檬酸盐、组氨酸、琥珀酸盐、磷酸盐和羟甲基氨基甲烷(Tris)。示例性的表面活性剂包括:聚山梨醇酯80(吐温80)、聚山梨醇酯20(吐温20)和泊洛沙姆188。冻干(冷冻干燥)制剂可以使用多元醇/二糖/多糖(例如甘露醇、山梨糖醇、蔗糖、海藻糖和葡聚糖40)中的一种或其混合物。糖为冻干制剂提供了容量,并且已知其用作治疗性蛋白质的稳定剂。氯化钠(NaCl)通常与蛋白质制剂一起使用。示例性的抗氧化剂包括:抗坏血酸、蛋氨酸和乙二胺四乙酸(EDTA)。
在另一个实施方式中,本发明的药物制剂还包含通过一种或多种亲脂部分的表面修饰。在另一个实施方式中,药物制剂包含任选与一种或多种载体分子的浓溶液共同施用的活性剂。
在另一个实施方式中,药物制剂还包含一种或多种包含聚丙烯酸或纤维素衍生物的合成生物粘附聚合物。基于聚丙烯酸的聚合物的实例包括但不限于卡波姆、聚卡波非、聚丙烯酸(PAAc)、聚丙烯酸酯、聚(甲基乙烯基醚-共-甲基丙烯酸)、聚(2-羟乙基甲基丙烯酸酯)、聚(甲基丙烯酸酯)、聚(氰基丙烯酸烷基酯)、聚(氰基丙烯酸异己酯)和聚(氰基丙烯酸异丁酯)。纤维素衍生物包括但不限于羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素钠、甲基纤维素和甲基羟乙基纤维素。此外,半天然生物粘附聚合物包括壳聚糖和各种树胶如瓜尔胶、黄原胶、聚(乙烯基吡咯烷酮)和聚(乙烯醇)。
在另一个实施方式中,本发明的药物制剂还包含胃肠粘膜粘附贴剂系统(GI-MAPS),其包含具有包含在肠溶胶囊中的分层膜的活性剂,其中背衬层包含水不溶性聚合物、乙基纤维素(EC);表面层,其包含肠溶性pH敏感性聚合物,诸如羟丙基甲基纤维素邻苯二甲酸酯,Eudragit L100或S100;包含粘合剂层的涂层;和中间层、含肽层、由附着在背衬层上的纤维素膜制成。口服施用后,表层在靶向的肠道部位溶解并粘附在小肠壁上,通过粘附在粘膜上,在胃肠粘膜的靶部位上形成封闭空间。结果,活性剂和吸收增强剂共同存在于封闭空间中,并且在系统内部和肠细胞之间形成高浓度梯度,这有助于增强肽的吸收。
对于本领域技术人员来说显而易见的是,关于上述任何实施方式描述的特征可以在不同实施方式之间互换地应用。上述实施方式是说明本发明的各种特征的实例。
在本说明书的整个说明书和权利要求书中,词语“包括(comprise)”和“包含(contain)”及其变体意味着“包括但不限于”,并且它们不旨在(并且不)排除其他部分、添加剂、组分或步骤。在本说明书的整个说明书和权利要求书中,除非上下文另有要求,否则单数形式包含复数形式。特别地,在使用不定冠词的情况下,除非上下文另有要求,否则说明书应被理解为考虑复数以及奇点。
结合本发明的特定方面、实施方式或实施例描述的特征、特性、化合物、化学部分或基团应理解为适用于本文描述的任何其他方面、实施方式或实施例,除非与其不相容。本说明书中公开的所有特征(包括任何所附权利要求、摘要和附图)和/或如此公开的任何方法或过程的所有步骤可以任何组合进行组合,除了至少一些这样的特征和/或步骤是互斥的的组合。本发明不限于任何前述实施方式的细节。本发明扩展到本说明书中公开的特征(包括任何所附权利要求、摘要和附图)中的任何新颖的或任何新颖组合,或如此公开的任何方法或过程的步骤的任何新颖的或任何新颖的组合。
读者的注意力针对与关于本申请的本说明书同时或在其之前提交的并且与本说明书一起公开供公众查阅的所有论文和文件,并且所有这些论文和文件的内容通过引证结合于此。
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<120> 用于治疗糖尿病、高血压和高胆固醇血症的组合物和方法
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Claims (21)
1.一种分离的多肽,其包含40s核糖体蛋白S2(RPS2)或其片段或由40s核糖体蛋白S2(RPS2)或其片段组成,所述40s核糖体蛋白S2(RPS2)或其片段包含与SEQ ID NO:1、2、3或4中所示的氨基酸序列具有至少50%的序列一致性的氨基酸序列。
2.如权利要求1所述的多肽,其中所述RPS2或其片段与SEQ ID NO:1、2、3或4中所示的氨基酸序列具有至少55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的序列一致性。
3.如权利要求1或权利要求2所述的多肽,其中所述RPS2或其片段包含SEQ ID NO:1、2、3或4中所示的氨基酸序列。
4.如前述权利要求中任一项所述的多肽,其中所述RPS2或其片段由SEQ ID NO:1、2、3或4中所示的氨基酸序列组成。
5.一种制剂,其包含至少一种根据前述权利要求中任一项所述的多肽。
6.如权利要求5所述的制剂,其中所述制剂是口服药物制剂。
7.如权利要求5所述的制剂,其中所述制剂是药物肠胃外制剂。
8.如权利要求5至7中任一项所述的制剂,其中所述制剂包含一种或多种药学上可接受的载体和/或一种或多种药学上可接受的稀释剂和/或一种或多种药学上可接受的赋形剂。
9.如权利要求5至8中任一项所述的制剂,其中所述制剂是水性药物制剂。
10.如权利要求9所述的制剂,其中所述肽以0.05至5μg/L的浓度存在。
11.如权利要求9所述的制剂,其中所述肽以0.1至1μg/L的浓度存在。
12.如权利要求9-11中任一项所述的制剂,其中所述水性药物制剂包含缓冲液,任选地具有生理pH的缓冲液。
13.如权利要求12所述的制剂,其中所述缓冲剂是磷酸盐缓冲液。
14.一种药物,其包含权利要求1至4中任一项所述的多肽或权利要求5至13中任一项所述的制剂。
15.如权利要求1至4中任一项所述的多肽或如权利要求5至13中任一项所述的制剂,用于在治疗疾病的方法中的用途。
16.如权利要求1至4中任一项所述的多肽或如权利要求5至13中任一项所述的制剂,用于在治疗1型和/或2型糖尿病的方法中的用途。
17.如权利要求16所述的多肽或制剂,其中所述用途提供肝葡萄糖生成降低、和/或胆固醇水平降低、和/或胰高血糖素水平降低、和/或胰岛素抗性降低、和/或血压降低。
18.如权利要求1至4中任一项所述的多肽或如权利要求5至13中任一项所述的制剂,用于在治疗高血糖症、和/或高胆固醇血症、和/或高血压、和/或代谢综合征中的至少一种的用途。
19.至少一种根据权利要求1至4中任一项所述的多肽用于制备用于治疗1型和/或2型糖尿病的药物的用途。
20.至少一种根据权利要求1至4中任一项所述的多肽用于制备用于治疗高血糖症、和/或高胆固醇血症、和/或高血压、和/或代谢综合征中的至少一种的药物的用途。
21.一种用于治疗受试者中的糖尿病、和/或高血糖症、和/或高胆固醇血症、和/或高血压中的至少一种的方法,其包括:向所述受试者施用如权利要求5至13中任一项所述的制剂。
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CN110087666B (zh) | 2024-04-30 |
KR20190084070A (ko) | 2019-07-15 |
AU2017357052B2 (en) | 2022-03-24 |
WO2018089909A1 (en) | 2018-05-17 |
EP3538124A4 (en) | 2020-07-22 |
US20180133280A1 (en) | 2018-05-17 |
JP2023071670A (ja) | 2023-05-23 |
JP2020502056A (ja) | 2020-01-23 |
AU2017357052A1 (en) | 2019-05-02 |
AU2022203741B2 (en) | 2024-02-15 |
BR112019009511A2 (pt) | 2019-07-30 |
AU2022203741A1 (en) | 2022-06-23 |
MX2019005466A (es) | 2019-10-02 |
KR102497242B1 (ko) | 2023-02-09 |
EP3538124A1 (en) | 2019-09-18 |
CA3041362A1 (en) | 2018-05-17 |
US20200222499A1 (en) | 2020-07-16 |
US10548941B2 (en) | 2020-02-04 |
US10751384B2 (en) | 2020-08-25 |
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