CN113727996A - 重组蛋白用于治疗代谢疾病 - Google Patents
重组蛋白用于治疗代谢疾病 Download PDFInfo
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- CN113727996A CN113727996A CN202080017339.6A CN202080017339A CN113727996A CN 113727996 A CN113727996 A CN 113727996A CN 202080017339 A CN202080017339 A CN 202080017339A CN 113727996 A CN113727996 A CN 113727996A
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Abstract
本发明揭示用于预防或治疗代谢疾病的方法及组合物，其通过使用具有如SEQ ID NO:1所述的氨基酸序列的蛋白。
Description
背景技术
代谢疾病诸如第II型糖尿病(T2DM)及其他相关并发症为导致死亡的主因。这些疾病与营养摄取过量及缺乏锻炼的西方生活方式有关，且全世界正在增加中。T2DM(及胰岛素抗性病症)为慢性、进行性、不完全了解的代谢病症，其主要特征为高血糖症(hyperglycemia)(血液中葡萄糖浓度长期升高的状态)。胰岛素分泌受损、胰岛素的组织作用抗性，或二者兼而有之，被认为是导致T2DM病理生理学的最常见原因，T2DM最初为由胰岛素组织抗性所引起的一系列疾病，并逐渐发展成特征为胰脏β细胞完全失去分泌活性的状态。长时间的高血糖可导致血管及神经损伤。第II型糖尿病的发生率高且正在上升中，并成为全世界死亡率、发病率、及健康照护耗用的主因。
有多种治疗T2DM的药理学方法。口服抗糖尿病药物的主要类别包括双胍类(biguanides)、磺酰脲类(sulfonylureas)、苯丙胺酸衍生物(meglitinide)、噻唑烷二酮(thiazolidinedione；TZD)、二胜肽基胜肽酶4(dipeptidyl peptidase 4；DPP-4)抑制剂、钠葡萄糖共转运蛋白(SGLT2)抑制剂、及α-葡萄糖苷酶抑制剂。然而，上述方法具有一些副作用，如低血糖症(hypoglycemia)及体重增加。
因此，仍需要具有更少副作用的用于代谢疾病的改进疗法。
发明内容
本发明意外发现，具有如SEQ ID NO:1所述的氨基酸序列的重组蛋白(以下称作「ES135」)可有效治疗代谢疾病。举例而言，当以ES135投予患有代谢疾病，高血糖症，的个体时，明显降低血糖浓度。
因此，本发明的一方面涉及用于预防或治疗代谢疾病的组合物，其中组合物包含ES135。本文亦提供预防或治疗代谢疾病的方法，包含投予有效量的ES135。
应理解到，以上概述及以下详述仅为示例性及说明性，且不局限于本发明。
附图说明
图1显示不同剂量的ES135在C57BL/6与db/db小鼠中的降糖效果。
图2显示不同剂量的ES135在C57BL/6与ob/ob小鼠中的降糖效果。
具体实施方式
I.导论
本文提供用于预防或治疗代谢疾病的方法及组合物，其通过使用ES135。依据本文所述的糖尿病小鼠模型研究，发明人显示，相较于空白组，ES135可有效降低血糖浓度。
II.定义
本文使用下列缩写：
IM(i.m.)：肌肉注射
IV(i.v.)：静脉注射
IP(i.p.)：腹腔注射
SC(s.c.)：皮下注射
PO(p.o.)：口服投予
ICV(i.c.v.)：脑室注射
IT：鞘内注射
Bid：一天二次(每日两次)
除非另有定义，否则本文使用的技术性及科学性术语具有与本领域普通技术人员通常理解的相同意义。与本文所述的这些类似或等同的任何方法、装置、及材料皆可用于本发明的实践。提供以下定义，以促进对本文中经常使用的特定术语的理解，且不意味局限本发明的范畴。
本文中使用的冠词「一(a)」或「一者(an)」意指该冠词的语法对像的一或多者(即至少一者)，除非在该冠词的特定用途中仅以单数形式明确指出。
如本文所用，「ES135」一词意指含有SEQ ID NO:1的氨基酸序列的重组蛋白，其在美国专利号7,956,033中揭示，其内容在此全部并入本申请以作为参考资料。SEQ ID NO:1的氨基酸序列如下：Ala Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser Asn Gly GlyHis Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly Thr Arg Asp Arg Ser AspGln His Ile Gln Leu Gln Leu Ser Ala Glu Ser Val Gly Glu Val Tyr Ile Lys SerThr Glu Thr Gly Gln Tyr Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser GlnThr Pro Asn Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn ThrTyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys Asn GlySer Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala Ile Leu Phe Leu ProLeu Pro Val Ser Ser Asp。在一些具体实施例中，ES135的序列至少70％、75％、80％、85％、90％、95％、98％、或100％等同于SEQ ID NO:1的氨基酸序列。在一些具体实施例中，SEQ ID NO:1的氨基酸序列具有一或多个修饰处。举例而言，SEQ ID NO:1的氨基酸序列具有N端磷酸葡糖酸化(phosphogluconoylation)或葡糖酸化(gluconoylation)，如美国专利号9,567,385的揭示，其内容在此全部并入本案以作为参考资料。
在本发明的一具体实施例中，ES135的氨基酸序列由SEQ ID NO:1的氨基酸序列组成。
如本文所用，「预防(prevent)」、「预防(preventing)」、或「预防(prevention)」等词意指排除、避免、消除、防止、阻碍、或阻止某事发生，特别是通过提前行动。
如本文所用，「治疗(treat)」、「治疗(treating)」、或「治疗(treatment)」等词意指治疗及预防性措施，其目的在于预防或减缓(减轻)不良的生理状况、病症、或疾病，或获得有益或所需的临床结果。针对本发明的目的，有益或所需的临床结果包括但不局限于，减轻症状；缩小病况、病症、或疾病的范围；稳定(即不恶化)病况、病症、或疾病的状态；推迟病况、病症、或疾病的发作或减慢其进展；改善病况、病症、或疾病状态；以及缓解(不论是部分或全部)，不论是可检测或不可检测，或病况、病症、或疾病的增进或改进。治疗包括引发临床上的显著反应，而无过多副作用。相较于未接受治疗的预定生存期，治疗亦包括延长生存期。
如本文所用，「治疗上有效量」或「有效量」等词意指本发明使用的ES135量，其预防、改善、或治疗本说明书中提及的疾病或病况所伴随的症状，或提供所需的治疗效果。ES135的治疗功效及毒性可通过细胞培养或实验动物的标准医药程序确定，如ED50(该剂量在50％群体中具有疗效)及LD50(该剂量使50％群体致死)。治疗指数为治疗作用与毒性作用之间的剂量比率，且其可以LD50/ED50比率表示。
如本文所用，「投予」一词在与治疗剂结合使用时，意指将治疗剂直接投予至标靶组织之内或其上，或投予病患治疗剂，从而治疗剂正向影响其靶向的组织。因此，如本文所用，术语「投予」一词，当与化合物、胜肽、或蛋白结合使用时，可包括但不局限于，将治疗剂提供在标靶组织之内或其上；利用诸如静脉注射，将治疗剂系统性提供至个体，从而治疗剂到达标靶组织。「投予」组合物可通过口服、注射、局部给药、或利用任一方法结合其他已知技术而达成。
本文中使用的「动物」、「个体」、或「病患」等词包括但不局限于，人类与非人类脊椎动物，如野生、餋养及农场动物，较佳为人类。
III.本发明的具体实施例
在一方面，本发明有关用于预防或治疗一个体的代谢疾病的医药组合物，其包含一具有如SEQ ID NO:1所述的氨基酸序列的蛋白。
在另一方面，本发明提供一具有如SEQ ID NO:1所述的氨基酸序列的蛋白，以用于预防或治疗一个体的代谢疾病。
在又另一方面，本发明提供一具有如SEQ ID NO:1所述的氨基酸序列的蛋白的用途，以制备一用于预防或治疗一个体的代谢疾病的药剂。
代谢疾病包括但不局限于，高血糖症、空腹血糖异常、葡萄糖耐性异常、胰岛素抗性、高胰岛素血症、第I型糖尿病、第II型糖尿病、难治性糖尿病、及其组合。在一些具体实施例中，代谢疾病为胰岛素抗性。较佳地，代谢疾病为第II型糖尿病。
高血糖症或高血糖可定义为空腹血糖浓度高于约7、约10、约15、或约20mmol/L。特定而言，高血糖症定义为个体的空腹血糖浓度高于正常范围，亦即大于110mg/dL(6.11mmol/L)。
空腹血糖异常(IFG)定义为个体的空腹血糖浓度或空腹血清葡萄糖浓度范围在100至125mg/dL(亦即5.6至6.9mmol/L)的情况，特别是大于110mg/dL及小于126mg/dL(7.00mmol/L)。「正常空腹血糖」个体的空腹血糖浓度小于100mg/dL，亦即小于5.6mmol/L。
葡萄糖耐性异常(IGT)为高血糖症的糖尿病前状态(pre-diabetic state)，其定义为在75克口服葡萄糖耐受性试验(依据WHO及ADA)中的二小时葡萄糖浓度(糖血症(glycemia))为约140至约199mg/dL(7.8至11.0mmol)。糖血症约200mg/dL或以上则视为糖尿病。
胰岛素抗性定义为正常量的胰岛素产生低于正常生物学反应的状态。胰岛素抗性可利用高胰岛素血糖常态箝制技术(hyperinsulinemic euglycemic clamp technique)、稳态模型评估(Homeostatic Model Assessment；HOMA)、或定量胰岛素敏感性检查指数(QUICKI)测定。
高胰岛素血症定义为具有胰岛素抗性的有或无血糖常态(euglycemia)的个体的空腹或餐后血清或血浆胰岛素浓度升至高于无胰岛素抗性且腰臀比<1.0(男性)或<0.8(女性)的正常精瘦个体的情况。空腹血清胰岛素浓度大于25mU/L或174pmol/L则视为高胰岛素血症。「血糖常态」一词定义为个体的空腹血糖浓度在正常范围内、大于70mg/dL(3.89mmol/L)、及小于110mg/dL(6.11mmol/L)的情况。
第I型糖尿病因人体无法产生胰岛素所引发，亦称作「胰岛素依赖型糖尿病」(IDDM)或「幼年糖尿病(juvenile diabetes)」。第II型糖尿病由胰岛素抗性所引起，为细胞无法正确使用胰岛素，有时还伴有绝对的胰岛素缺乏。其亦称作「非胰岛素依赖型糖尿病」(NIDDM)或「成年糖尿病」。人体组织对胰岛素的不良反应据信与胰岛素受体有关。糖尿病的特征在于反复发作或持续存在的高血糖症，在一些实例中，通过表现出以下任何一特征而诊断：a.空腹血清葡萄糖浓度≧7.0mmol/L(126mg/dL)；b.如同葡萄糖耐受性测试，在口服75克葡萄糖负荷量后二小时，血浆葡萄糖≧11.1mmol/L(200mg/dL)；c.高血糖症的症状，且随机血浆葡萄糖≧11.1mmol/L(200mg/dL)；d.糖化血红素(Hb A1C)≧6.5％。
难治性糖尿病的特征在于，尽管有适当的治疗，但血糖控制差。在此情况下，即使是专门针对快速症状缓解及达到血糖目标的最佳治疗方案亦可能不起作用。许多的假设，诸如寻求健康照护的行为不佳与部分病患缺乏依从性、临床惯性、及部分医生对治疗方案的选择不当，以及家庭成员或糖尿病照护提供者的社会心理支持不足，都是此状态的建议因子。如文献(J Diabetes.2016Jan；8(1):76-85)中所述，发病年龄早、糖尿病持续时间长、治疗复杂性与治疗次数增加、胰岛素的使用、及微血管并发症的存在，皆为难治性糖尿病的预测因子。
在另一方面，本发明有关一用于预防或治疗一个体的代谢疾病的方法，包含投予该个体一治疗上有效量的具有如SEQ ID NO:1所述的氨基酸序列的蛋白。如本文所述，该蛋白的治疗效果已在糖尿病动物模型中证实。
在一些具体实施例中，将ES135投予db/db与ob/ob糖尿病动物模型，以评估其降糖效果。较佳地，ES135以皮下注射(s.c.)投予。在一些具体实施例中，ES135每天投予一次、二次、三次、或更少次，如每隔一天、每隔两天、每周、每隔一周、或更少。如本发明所证实，ES135以皮下注射投予一次。详细研究程序如以下实施例所示。
在一些具体实施例中，投予ES135可使个体血糖浓度正常化。在db/db小鼠中，当相较于空白组，在治疗后第6与第30小时，0.5mg/kg SC的ES135明显降低血糖浓度(p<0.05)。在治疗后第6、第18、第30、及第42小时，1mg/kg SC的ES135亦显示统计学上可明显降低血糖浓度。然而，在研究期间的db/db小鼠中，0.2mg/kg ES135与500U/kg肝素的组合治疗组显示适度的降糖效果(图1)。
相较于空白组，在ob/ob小鼠中，皮下注射投予0.5mg/kg ES135一次，在治疗后第6小时明显降低血糖浓度(p<0.05)。相较于空白组，在治疗后第6、第18、及第30小时，1mg/kgSC的ES135亦显示统计学上可明显降低血糖浓度。然而，在研究期间的ob/ob小鼠中，0.2mg/kg ES135与500U/kg肝素的组合治疗组显示适度的降糖效果(图2)。
在C57BL/6小鼠的研究期间，以皮下注射投予一次ES135(1mg/kg)不影响血糖浓度(图1与2)。
在一些具体实施例中，ES135的投予剂量相当于个体每公斤体重0.001-1mg ES135(亦即0.001-1mg/kg)，例如相当于每公斤体重0.001-0.01、0.01-0.05、0.05-0.1、0.1-0.2、0.1-0.4、0.05、0.1、0.2、0.3、0.4、0.5、或更高的ES135毫克数。如图1与2所示，ES135在糖尿病动物模型中的降糖效果具有剂量依赖性。在db/db与ob/ob动物模型中，观察到剂量依赖性降糖效果。
总括来说，ES135的治疗使血糖评估浓度显著降低。
依据本发明，ES135可构成适合所选投予方式的任何形式。较佳地，ES135可以皮下、局部、神经内、静脉内、肌肉内、脑室内、或鞘内方式投予。更佳地，ES135以皮下方式投予。
实施例
本发明以下列实施例更具体说明。然而，应注意的是，本发明不以任何方式局限这些实施例。
db/db与ob/ob小鼠在投予ES135后的降糖效果
每组8只正常C57BL/6小鼠及非胰岛素依赖型糖尿病(NIDDM)雄性小鼠(ob/ob，B6.Cg-Lep<ob>/J，及db/db，C57BLKS/J Iar-+Leprdb/+Leprdb)以皮下注射方式投予ES135(0.2、0.5、及1mg/kg)一次。容许所有动物自由取用正常实验室食物及饮水。除了正常C57BL/6小鼠以外，在投予之前，所使用的ob/ob与db/db小鼠的平均血糖浓度为≥300mg/dL并维持3-5天。
在0小时(投予前)及ES135处理后6小时、18小时、30小时、42小时、54小时及66小时，以血糖仪(OptiumTM XceedTM Diabetes Monitoring System，Abbott)自非禁食动物的尾血流测定血糖值。计算血清葡萄糖及治疗后相对于治疗前组别数值的百分比，且随后应用双因子ANOVA及后续的庞费洛尼检定(Bonferroni test)，以比较治疗组与空白组。*P<0.05、**P<0.01、及***P<0.001视为与空白对照组的显著差异。
尽管本发明的前述书面说明使得本领域技术人员能制造及使用目前视为其最佳模式的工具，但本领域技术人员将理解并体会本文特定具体实施例、方法、及实例的变形、组合、及等同物的存在。因此，本发明不应局限于上述的具体实施例、方法、及实例，而应受限于本发明范畴及精神之内的所有具体实施例及方法。
序列表
<110> 雅祥生技医药股份有限公司
黄金鼎
张婉雅
叶哲铭
<120> 重组蛋白用于治疗代谢疾病
<130> EUS0006WO
<150> US 62/811,616
<151> 2019-02-28
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 135
<212> PRT
<213> 人工序列
<220>
<223> 修饰自智人酸性成纤维细胞生长因子的胜肽
<400> 1
Ala Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser Asn Gly Gly His
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Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly Thr Arg Asp Arg
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Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu Ser Val Gly Glu
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Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu Ala Met Asp Thr
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Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu Glu Cys Leu Phe
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Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr Ile Ser Lys Lys
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His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys Asn Gly Ser Cys
100 105 110
Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala Ile Leu Phe Leu
115 120 125
Pro Leu Pro Val Ser Ser Asp
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Claims (9)
1.一种具有如SEQ ID NO:1所述的氨基酸序列的蛋白用于制备预防或治疗一个体的代谢疾病的药剂的用途。
2.根据权利要求1所述的用途，其中该代谢疾病选自于由高血糖症、空腹血糖异常、葡萄糖耐性异常、胰岛素抗性、高胰岛素血症、第I型糖尿病、第II型糖尿病、难治性糖尿病、及其组合所组成的群组。
3.根据权利要求1所述的用途，其中该药剂配制成用于皮下、局部、神经内、腹腔内、静脉内、肌肉内、脑室内、或鞘内投予。
4.一种用于预防或治疗代谢疾病的方法，包含投予一有需求的个体一治疗上有效量的具有SEQ ID NO:1的氨基酸序列的蛋白。
5.根据权利要求4所述的方法，其中该蛋白以皮下、局部、神经内、腹腔内、静脉内、肌肉内、脑室内、或鞘内等方式投予。
6.根据权利要求5所述的方法，其中该蛋白以皮下方式投予。
7.根据权利要求4所述的方法，其中该代谢疾病选自于由高血糖症、空腹血糖异常、葡萄糖耐性异常、胰岛素抗性、高胰岛素血症、第I型糖尿病、第II型糖尿病、难治性糖尿病、及其组合所组成的群组。
8.根据权利要求4所述的方法，其中该蛋白以每天一或二次的0.01至1mg/kg的剂量投予。
9.一种具有如SEQ ID NO:1所述的氨基酸序列的蛋白，用于预防或治疗一个体的代谢疾病。
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201006845A (en) * | 2008-06-10 | 2010-02-16 | Eu Sol Biotech Co Ltd | Modified peptide of human acidic fibroblast growth factor |
| CN102086227A (zh) * | 2009-12-04 | 2011-06-08 | 雅祥生技医药股份有限公司 | 人类酸性纤维母细胞生长因子的修饰肽 |
| US20130116171A1 (en) * | 2010-04-16 | 2013-05-09 | Salk Institute For Biological Studies | Methods for treating metabolic disorders using fgf |
| CN105793281A (zh) * | 2013-10-07 | 2016-07-20 | 雅祥生技医药股份有限公司 | 经修饰的人类酸性纤维母细胞生长因子及其组合物 |
| US20160206695A1 (en) * | 2013-10-21 | 2016-07-21 | Salk Institute For Biological Studies | Chimeric fibroblast growth factor (fgf) 2/fgf1 peptides and methods of use |
| CN106397607A (zh) * | 2016-09-13 | 2017-02-15 | 河南师范大学 | 重组人成纤维细胞生长因子21融合蛋白及其在制备治疗代谢疾病药物中的应用 |
| CN106432509A (zh) * | 2016-09-13 | 2017-02-22 | 河南师范大学 | 一种治疗代谢疾病的重组人成纤维细胞生长因子21融合蛋白及其制备方法和应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI434698B (zh) * | 2009-08-14 | 2014-04-21 | Eu Sol Biotech Co Ltd | 人類酸性纖維母細胞生長因子之醫藥用途 |
| JP2011121882A (ja) * | 2009-12-09 | 2011-06-23 | Eu Sol Biotech Co Ltd | ヒト酸性繊維芽細胞増殖因子の改変ペプチド |
| MX2016005101A (es) * | 2013-10-21 | 2017-01-09 | Salk Inst For Biological Studi | Factor de crecimiento de fibroblastos (fgf) 1 mutado y procedimientos de uso. |
| EP3491011A1 (en) * | 2016-08-01 | 2019-06-05 | Salk Institute for Biological Studies | Fibroblast growth factor (fgf) 1 proteins with glucose lowering ability and reduced mitogenicity |
-
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201006845A (en) * | 2008-06-10 | 2010-02-16 | Eu Sol Biotech Co Ltd | Modified peptide of human acidic fibroblast growth factor |
| CN102086227A (zh) * | 2009-12-04 | 2011-06-08 | 雅祥生技医药股份有限公司 | 人类酸性纤维母细胞生长因子的修饰肽 |
| US20130116171A1 (en) * | 2010-04-16 | 2013-05-09 | Salk Institute For Biological Studies | Methods for treating metabolic disorders using fgf |
| CN105793281A (zh) * | 2013-10-07 | 2016-07-20 | 雅祥生技医药股份有限公司 | 经修饰的人类酸性纤维母细胞生长因子及其组合物 |
| US20160206695A1 (en) * | 2013-10-21 | 2016-07-21 | Salk Institute For Biological Studies | Chimeric fibroblast growth factor (fgf) 2/fgf1 peptides and methods of use |
| CN106397607A (zh) * | 2016-09-13 | 2017-02-15 | 河南师范大学 | 重组人成纤维细胞生长因子21融合蛋白及其在制备治疗代谢疾病药物中的应用 |
| CN106432509A (zh) * | 2016-09-13 | 2017-02-22 | 河南师范大学 | 一种治疗代谢疾病的重组人成纤维细胞生长因子21融合蛋白及其制备方法和应用 |
Non-Patent Citations (1)
| Title |
|---|
| JAE MYOUNG SUH: "Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer", 《NATURE》, vol. 513, pages 436 - 439, XP055335222, DOI: 10.1038/nature13540 * |
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| CN113727996B (zh) | 2024-09-13 |
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