CN115996740A - 用于治疗代谢综合征及与其相关疾病的新药物组合物 - Google Patents
用于治疗代谢综合征及与其相关疾病的新药物组合物 Download PDFInfo
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Abstract
本发明涉及一种用于治疗新的非酒精性脂肪肝或非酒精性脂肪性肝炎的药物组合物,且更具体地,涉及一种用于治疗代谢综合征及其相关疾病的药物组合物,其包含作为活性成分的双特异性融合蛋白,所述双特异性融合蛋白包含其中GLP‑1类似物连接至抗体Fc区的第一融合蛋白和其中GLP‑2类似物连接至抗体Fc区的第二融合蛋白,且通过所述第一和第二融合蛋白的二聚化产生。
Description
技术领域
本发明涉及一种新药物组合物,且更具体地,涉及一种用于治疗代谢综合征及与其相关疾病如非酒精性脂肪性肝炎(steatohepatitis)的药物组合物。
背景技术
代谢综合征是增加心脏病、卒中和2型糖尿病的风险的多种同时存在的物理现象的集合,包括升高的血压、高血糖、腰部体脂肪过多以及异常的血液胆固醇或甘油三酯浓度。代谢综合征可能具有威胁性,这是因为它不伴有明显的病征或症状。如果未被注意或任其恶化,则需要治疗或改善,这是因为它将最终发展为诸如动脉硬化和卒中的心血管疾病,或诸如2型糖尿病和非酒精性脂肪肝疾病的难治疾病。如果所述状况被忽视或恶化,其将最终发展为诸如动脉硬化和卒中的心血管疾病,或诸如2型糖尿病和非酒精性脂肪肝疾病的不能医治的疾病,因此有必要对这种状况进行治疗或改善。
非酒精性脂肪性肝炎(下文称为“NASH”)具有取决于进展阶段的特征性病因学。换言之,将逐渐牵涉到诸如胰岛素抵抗、葡萄糖/脂质调节异常、脂肪变性、炎症、纤维化和细胞死亡的病因学,从“非酒精性脂肪酸疾病(下文称为“NAFD”)”进展到NASH(分为F0、F1、F2、F3和F4期),且其进一步进展为肝纤维化(代偿的→失代偿的)。
非酒精性脂肪肝疾病是一种随着伴有肥胖症、糖尿病和高血压的代谢综合征快速增加的肝疾病,其可进展为肝硬变或肝癌,且许多NAS-H相关的肝相关治疗正在快速开发。
NASH具有取决于进展阶段的特征性病因学。换言之,将逐渐牵涉到诸如胰岛素抵抗、葡萄糖/脂质调节异常、脂肪变性、炎症、纤维化和细胞死亡的病因学,从“非酒精性脂肪酸疾病(下文称为“NAFD”)”进展到NASH(分为F0、F1、F2、F3和F4期),且其进一步进展为肝纤维化(代偿的→失代偿的)。
然而,不幸的是,迄今还没有药物被批准作为NASH的治疗,并且考虑到疾病负担,NASH的治疗是具有高度未满足的需要的药物,其不满足患者对治疗选择的需要。有助于NAFLD和NASH发生和进展的基本病理生理学机制非常复杂,且目前正在针对研究中的各种靶开发各种治疗剂中鉴定这些作用机制。在广泛的范围内,药物开发聚焦在影响代谢途径、炎症链反应和纤维化的作用机制的调节上。尽管正在鉴定NAFLD发展的许多作用机制,但由于临床试验设计的复杂性,在开发对于NAFLD的治疗中出现了许多困难。目前,进展到3期临床试验的候选物质提示了治疗的可能性,并且它们在减少脂肪肝、坏死性炎症和纤维化方面显示出良好的结果。如果通过各种群组研究确立长期安全性和功效,则将有助于降低潜在的发病率和死亡率。
另一方面,由于肠在解剖学和生理学上都与肝相连,并且对肝病理学具有各种影响,所以正确管理肠肝轴在预防酒精性和非酒精性脂肪性肝炎中的纤维化是有效的,这已被提议为减少肝硬变本身的基本治疗。已经提示,肠漏(leaky gut)可能是毒素、抗原或细菌在体内通过的前沿(cutting edge)并在进行性肝硬变中发挥致病作用,且正在多加注意肠道有益细菌如肠道微生物和直接饲喂微生物(益生菌和益生元等)在肝病领域中的作用。近来,肠道细菌菌群正在作为肠-肝轴的介质出现,且归因于过度高脂肪摄入的肠道屏障减弱产生了大量肠道微生物(微生物相关分子模式(MAMPs):如LPS、LTA等),且肠道细菌菌群本身可以扩散到肝,以促进诸如肝炎和肝纤维化的肝疾病。胆汁酸被主动吸收并进入结肠上皮,其是毒性的,从而导致DNA损伤,导致HSC(肝星状细胞)细胞中的衰老相关性分泌表型(SASP)分泌因子。肠道细菌菌群与胆碱代谢有关,且将胆碱转化为三甲胺(TMA),所述三甲胺(TMA)转移到肝并转化为三甲胺氧化物(TAMO),从而引起肝炎。肠道细菌菌群起到维持身体稳态的作用,且如果稳态受损,则从肠道细菌菌群提取的代谢物和组分移动到肝,从而引起肝中的病理作用,且代谢物甚至可能引起肝炎、纤维化和肝癌。为治疗NASH开发的基于分子的治疗使得可能理解NASH的进展机制,且提示肠-肝轴和肠道细菌菌群至少部分与FXR剂、ACC抑制剂和ASK-1抑制剂的作用机制有关。
此外,已经尝试使用GLP-1受体作为NAFLD或NASH的治疗靶。在这方面,WO2016043533A1公开了一种用于非酒精性脂肪肝疾病治疗的治疗剂,其包含泌酸调节肽衍生物,它是一种具有延长的半衰期的GLP-1/胰高血糖素受体双重激动剂,且US9938335也公开了胰高血糖素样肽,其是一种GLP-1/胰高血糖素,和一种使用它治疗NAFLD和NASH的方法。
尽管现有技术中描述的物质的一些作用已在动物模型中得到证实,但还没有最终通过临床试验的物质。
发明内容
发明目的
本发明是为了解决包括上述问题在内的各种问题,且本发明的目的是提供一种能够更有效地治疗包括NASH的各种代谢综合征的新药物组合物。然而,本发明的保护范围不限于上述目的。
技术方案
在本发明的一个方面,提供了一种用于治疗代谢综合征的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗肥胖症的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗2型糖尿病的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗肝纤维化的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有代谢综合征的主体中治疗代谢综合征的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有肥胖症的主体中治疗肥胖症的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有2型糖尿病的主体中治疗2型糖尿病的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有NAFLD或NASH的主体中治疗NAFLD或NASH的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有肝纤维化的主体中治疗肝纤维化的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
发明效果
根据本发明的实施方案的双特异性融合蛋白具有由于通过与小肠中的GLP-1和GLP-2受体结合增加绒毛长度和隐窝深度以及改善肠道细菌菌群而改善肠道环境的有利效果。此外,根据本发明实施方案的双特异性融合蛋白具有体重减轻以及胰岛素抵抗降低的效果。
附图说明
图1是显示根据本发明的实施方案的双特异性融合蛋白的大致结构的示意图。
图2是显示各种GLP-1和/或GLP-2类似物、GLP-1受体、GLP-2受体和其他胰高血糖素受体之间相互作用关系的示意图。
图3a是一系列凝胶图像,显示了在非还原(NR)条件和还原(R)条件中,根据本发明实施方案的各种双特异性融合蛋白在纯化后的SDS-PAGE分析结果。
M:大小标记;
1:MG12-1(5 μg);
2:MG12-2(5 μg);
3:MG12-3(5 μg);
4:MG12-4(5 μg);和
5:MG12-5(5 μg)。
图3b是一系列凝胶图像,显示了在非还原(NR)条件和还原(R)条件中,含有杵臼(Knobs-into-Holes)结构的GLP-2同二聚体(GLP-2-Fc同二聚体,左)和MG12-5(右)在纯化后的SDS-PAGE分析结果。
M:大小标记;
1和2:GLP-2-Fc同二聚体(homo)(10 µg);和
3和4:MG12-5(10 μg)。
图4a是显示根据本发明的实施方案的GLP-1-Fc同二聚体蛋白和GLP-1肽如通过萤光素酶报道基因测定所分析的生物活性的图。
图4b是显示如与GLP-1肽相比所测量的根据本发明的实施方案的MG12-1的生物活性的图。
图4c是显示如与GLP-1肽相比所测量的根据本发明的实施方案的MG12-3的生物活性的图。
图4d是显示如与GLP-1肽相比所测量的根据本发明的实施方案的MG12-4的生物活性的图。
图4e是显示如与GLP-1肽相比所测量的根据本发明的实施方案的MG12-5的生物活性的图。
图5a是显示如与GLP-2肽相比通过荧光光谱学所分析的根据本发明的实施方案的GLP-2-Fc同二聚体蛋白的GLP-2活性的图。
图5b是显示如与GLP-2肽相比通过荧光光谱学所分析的根据本发明的实施方案的MG12-1蛋白的GLP-2活性的图。
图5c是显示如与GLP-2肽相比通过荧光光谱学所分析的根据本发明的实施方案的MG12-3蛋白的GLP-2活性的图。
图5d是显示如与GLP-2肽相比通过荧光光谱学所分析的根据本发明的实施方案的MG12-4蛋白的GLP-2活性的图。
图5e是显示如与GLP-2肽相比通过荧光光谱学所分析的根据本发明的实施方案的MG12-5蛋白的GLP-2活性的图。
图6a是显示如使用GLP-1-Fc通过ELISA所分析的在施用于动物(大鼠)时根据本发明的实施方案的各种双特异性融合蛋白的药物代谢动力学(PK)概况的图。
图6b是显示如使用GLP-2-Fc通过ELISA所分析的在施用于动物(大鼠)时根据本发明的实施方案的各种双特异性融合蛋白的药物代谢动力学(PK)概况的图。
图7a至7m表示测量具有延长的半衰期的根据本发明实施方案的双特异性蛋白(GLP1/2-Fc)在实验动物中的各种生理效果的结果。图7a是表示在每周两次皮下施用包括根据本发明的实施方案的融合蛋白的各种药物达4周后随着时间的过去测量体重的结果的图;图7b是表示在每周两次皮下施用包括根据本发明的实施方案的融合蛋白的各种药物达4周后随着时间的过去测量体重变化程度的结果的图;图7C是表示各实验组中的动物实验结束后测量附睾脂肪量的结果的图;图7d是表示各实验组中的动物实验结束后测量血液中总胆固醇水平的结果的图;图7e是表示各实验组中的实验结束后测量血液中HDL水平的结果的图;图7f是表示各实验组中的动物实验结束后测量血液甘油三酯水平的结果的图;图7g是表示各实验组中进行3周的IPITT的结果的图;图7h是表示各实验组中进行4周的IPGTT的结果的图;图7i是表示各实验组中处理肽后监控血糖水平达0-4周的结果的图;图7j是表示各实验组中测量胰岛素水平达4周的结果的图;且图7k是表示各实验组中计算HOMO-IR的结果的图。数据是平均值 ± SEM(n = 6-12/组),通过单因素或双因素ANOVA继之以Turkey或Dunnett氏检验进行分析。对每组中施用之前和之后血糖水平的变化进行配对斯氏t-检验。与阴性对照比较*
p < 0.05,**
p < 0.01,***
p < 0.001,****
p < 0.0001。IPITT:腹膜内胰岛素耐量试验,IPGTT:腹膜内葡萄糖耐量试验,HOMO-IR:胰岛素抵抗的稳态模型评价。
图8a至8l显示了根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)以剂量依赖性方式对重量和葡萄糖稳态的影响。图8a是表示每周两次皮下施用本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)达4周的实验动物每周测量体重的结果的图;图8b是表示4周后监控实验动物体重变化的结果的图,图8C是表示实验动物4周后测量附睾脂肪的结果的图;图8d是举例说明各实验组开始药物施用后4周测量血液甘油三酯水平的结果的图;图8e是表示各实验组测量血液中总胆固醇水平的结果的图;图8f是举例说明实验动物中测量血液HDL水平的结果的图;图8g是表示施用包括根据本发明的实施方案的双特异性融合蛋白的各种药物后4周测量各实验组中的总胆红素水平的结果的图;图8h是显示以各种浓度施用根据本发明实施方案的双特异性融合蛋白(GLP-1/2-Fc)后4周测量血液中总胆红素浓度的结果的图;图8i是显示以各种浓度施用根据本发明实施方案的双特异性融合蛋白后最多到三周进行的IPITT的结果的图;图8j是显示以各种浓度施用根据本发明实施方案的双特异性融合蛋白后最多到4周进行的IPGTT的结果的图;图8k是显示各实验组中药物施用前测量基础血糖水平的结果的图;且图8l是显示各实验组中动物实验结束后测量基础血糖水平的结果的图。数据以平均值 ± SEM (n=6-12/组)通过单因素或双因素ANOV检验继之以Turkey或Dunnett氏检验进行分析。与阴性对照比较*
p < 0.05,**
p < 0.01,***
p <0.001,****
p < 0.0001。
图9a至9g显示了具有改善的半衰期的根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)减少肝中脂质累积和炎症的效果。图9a是动物实验结束后从各实验组切除的肝的一系列照片;图9b是来自各实验组的肝组织冷冻切片的H&E染色结果;图9c是显示实验结束后测量从各实验组切除的肝重量的结果的图;图9d是显示实验结束后测量各实验组中的肝体重比的结果的图;图9e是显示实验结束后测量各实验组中肝组织中甘油三酯(TG)水平的结果的图;图9f是显示实验结束后测量各实验组中肝损伤的指示物血清ALT水平的结果的图;图9g是显示实验结束后测量各实验组中肝损伤的另一个指示物血清AST水平的结果的图。数据是平均值 ± SEM(n = 6-12只动物/组),且通过单因素ANOVA分析继之以Dunnett氏检验进行分析。与阴性对照比较*
p <0.05,**
p <0.01,***
p <0.001,****
p<0.0001。H&E:苏木精和伊红;TG:甘油三酯;ATL:丙氨酸转氨酶;AST:天冬氨酸转氨酶。
图10a至10f显示GLP1/2-Fc以剂量依赖性方式对肝脂质累积的影响。图10a是显示在结束动物实验后从各实验动物切除的整个肝的一系列照片;图10b是表示从各实验动物切除的肝的冷冻切片的H&E染色以分析各实验组中的脂质沉积的结果的一系列照片;图10c是表示动物实验结束后从各实验动物切除的肝的重量的图;图10d是动物实验结束后各实验组中的肝TG水平的图;图10e是表示各实验组中的肝损伤的指示物血清ALT水平的图;且图10f是表示各实验组中的肝损伤的另一个指示物血清AST水平的图。数据通过单因素ANOVA检验继之以Dunnett氏检验进行分析。与阴性对照比较*
p < 0.05,**
p < 0.01,***
p < 0.001,****
p < 0.0001。H&E:苏木精和伊红,TG:甘油三酯,ATL:丙氨酸转氨酶,AST:天冬氨酸转氨酶。
图11a至11e表示分析根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)是否可以改善肝纤维化的结果。图11a是显示进行Cyrus红(Cyrus red)染色用于评价各实验组的肝纤维化的结果的照片;图11b是显示使用 Image J 软件对图11a中拍摄的图像进行定量的结果的图(数据通过单因素ANOV检验继之以Dunnett氏检验进行分析,并显示为平均值± SEM。与阴性对照比较*** p < 0.001);图11c是显示通过Pearson相关分析在个体基础上评价肝TG与天狼猩红(Sirius red)染色的区域的相关性的结果的图;图11d是显示通过Pearson相关分析评价各实验组的肝TG与天狼猩红染色的区域的相关性的结果的图;且图11e是各实验组的代表性照片,其是显示通过免疫组织化学分析对肝中3型胶原沉积程度进行分析的结果的一系列显微镜照片。比例尺:200 µm。
图12a和12b显示了检查根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对肝纤维化的浓度依赖性作用的结果。图12a是显示分别施用阴性对照和各种浓度的GLP1/2-Fc的动物肝组织上的天狼猩红染色结果的一系列照片;且图12b是使用Image J软件定量图12a的图像的图。数据通过单因素ANOVA检验继之以Dunnett氏检验进行分析,并表示为平均值 ± SEM(n = 7-9/组)。与阴性对照比较****
p < 0.0001,比例尺:200 μm。
图13a至13m举例说明了检查根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对肠的作用的结果。图13a是从各实验组切除的肠的一系列照片;图12b是表示各实验组中整个肠的重量的图;图12c是表示各实验组中整个肠的长度的图;图12d是表示测量各实验组中小肠长度的结果的图;图12e是表示测量各实验组中结肠长度的结果的图;图12f是通过各实验组中肠的横断面的H&E染色获得的一系列照片;图12g是显示各实验组中Ki-67蛋白(绿色)的免疫荧光染色结果的照片,且通过DAPI染色显示细胞核;图12h是表示测量各实验组中十二指肠隐窝深度的结果的图;图12i是显示测量各实验组中空肠隐窝深度的结果的图;图12j是显示测量各实验组中回肠隐窝深度的结果的图;图12k是显示测量各实验组中十二指肠绒毛高度的结果的图;图12l是显示测量各实验组中空肠绒毛高度的结果的图;且图12m是显示测量各实验组中回肠绒毛高度的结果的图。数据为平均值 ± SEM,并通过单因素ANOVA检验继之以Dunnett氏检验进行分析。与阴性对照比较*
p < 0.05,**
p <0.01,***
p < 0.001,****
p < 0.0001。
图14a至14e显示了根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对胃肠道的浓度依赖性作用。图14a是举例说明在施用了各种剂量的GLP1/2-Fc的小鼠中测量肠总重量的结果的图;图14b是举例说明测量肠的总长度的结果的图;图14c是举例说明测量小肠长度的结果的图;图14d是举例说明测量结肠长度的结果的图;且图14e是显示测量各实验组中结肠中的隐窝深度的结果的图。数据用单因素ANOV检验继之以Dunnett氏检验进行分析。与阴性比较**
p < 0.01,****
p < 0.0001。
图15a至15g表示检查根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对肠透性和血清中内毒素水平的作用的结果。图15a是显示口服施用FITC-葡聚糖后通过测量血清荧光强度测量肠透性的结果的图(n=3-4/组);图15b是显示测量血清中内毒素水平的结果的图;图15c是通过检测回肠中的zo-i蛋白(绿色)和细胞核(蓝色)获得的选自各实验组的一系列代表性免疫荧光显微镜照片;图15d是显示对各实验组中肠横断面进行PAS染色的结果的一系列照片;图15e是显示测量各实验组中黏蛋白层厚度的结果的图;图15f是显示测量各实验组中回肠中的每个绒毛的杯形细胞数目的结果的图;且图15g是显示测量各实验组中杯形细胞的丰度的结果的图(n=6-10/组)。数据通过单因素ANOVA检验继之以Dunnett氏检验进行分析。与阴性对照比较*
p < 0.05,**
p < 0.01,***
p < 0.001,****p < 0.0001。比例尺:200 μm。
图16a至16l是检查根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对肠道细菌菌群的影响的结果。图16a是显示通过PCoA(加权unifrac)分析的β多样性的图;图16b是分析的肠道细菌菌群的UPGMA系统发育树的比较图;图16c是显示在门水平测量的各实验组中鉴定的肠道细菌菌群的相对系统发育丰度的条线图;图16d是显示在属水平测量的在门水平测量的各实验组中鉴定的肠道细菌菌群的相对系统发育丰度的条线图;图16e是显示阴性对照组和GLP1/2-Fc施用组中微生物物种的18个操作分类单位(OTUs)的热图(heatmap)。各组中具有至少0.1%相对丰度的OUT用于进行统计学分析,颜色键(color keys)表示对数比例的相对丰度,且X轴上的字母表示各组中的个体;且图16f至16l是显示嗜黏蛋白阿克曼菌(
Akkermansia muciniphila)(16f)、
Mailhella massiliensis(16g)、
Alistips
segalensis(16h)、肠乳杆菌(
Lactobacillus intestinalis)(16i)、
Prevotellamassilia
timonensis(16j)、
Faecalibaculum rodentium(16K)和
Acetatifactor muris(16l)的相对比例的图。数据表示为平均值±SEM。数据通过单因素ANOV继之以Dunnett氏检验进行分析。与阴性对照比较*
p < 0.05,**
p < 0.01,***
p < 0.001,****
p < 0.0001,PCoA:主坐标分析,UPGMA:非加权平均耦合法(nonweighted mean coupling method)。
具体实施方式
术语的定义:
如本文所用的,术语“GLP-1”是“胰高血糖素样肽-1”的缩写并且是通过胰高血糖素原肽的组织特异性翻译后加工衍生的由30或31个氨基酸组成的肽激素。GLP-1由肠的肠内分泌L-细胞和脑干孤束核内的某些神经元在食物摄入时产生和分泌。初始产物GLP-1(1-37)容易被酰胺化并通过切割转化为两种等效的生物活性形式(GLP-1(7-36)酰胺和GLP-1(7-37))。活性GLP-1在氨基酸位置 13-20 和 24-35 处含有两个α螺旋区和一个连接两个α螺旋区的接头区。GLP-1由于其以葡萄糖依赖性方式降低血糖水平的功能,已被开发并用作2型糖尿病的治疗药物。然而,GLP-1在体内被二肽基肽酶-4(DPP-4)快速降解,且因此具有仅为2分钟的体内半衰期,并因此作为天然肽具有极其有限的作用。
如本文所用的,术语“GLP-2”是通过胰高血糖素原的翻译后切割与GLP-1一同产生的33个氨基酸长的肽,并且由肠内分泌L细胞和中枢神经系统中的各种神经元产生。在食物摄入时,肠GLP-2与GLP-1一同共分泌。当施用时,已知GLP-2增强肠生长和肠功能,减少骨分解并提供神经保护,且目前已开发为用于诸如短肠综合征、克罗恩病和骨质疏松症的疾病的治疗药物。
如本文所用的,术语“GLP-1类似物”指发挥GLP-1的生物学功能并可以通过与GLP-1/毒蜥外泌肽-4受体结合介导下游信号传导的蛋白,且也称为“GLP-1受体激动剂”。
如本文所用的,术语“GLP-2类似物”指发挥GLP-2的生物学功能并可以通过与GLP-2受体结合介导下游信号传导的蛋白。
如本文所用的,术语“融合蛋白”指重组蛋白,其中两种或更多种负责蛋白中特定功能的蛋白或结构域连接,从而使得每种蛋白或结构域负责其固有功能,且也称为“GLP-2受体激动剂”。
如本文所用的,术语“半衰期延长部分”指与重组蛋白连接以提高所述重组蛋白的体内半衰期的官能团。对于这种“半衰期延长部分”,可以使用抗体Fc区(Capon等人,
Nature 337: 525-531, 1989)、PEG(Caliceti和Veronese,
Adv. Drug Delivery Rev.55: 1261-1277, 2003)、XTEN(Schellenberger等人,
Nat. Biotechnol. 27: 1186-1190,2009)、PAS(Pro-Ala-Ser,Schlapschy等人,
Protein Eng. Des. Sel. 26: 489-501,2013)、ELP(弹性蛋白样肽,Floss等人,
Trends Biotechnol. 28: 37-45, 2010)、富甘氨酸HAP(同型氨基酸聚合物,Schlapschy等人,
Protein Eng. Des. Sel. 20: 273-284,2007)、GLK(明胶样蛋白,Huang等人,
Eur. J. Pharm. Biopharm. 74(3): 435-441,2010) 和血清清蛋白 (Sheffield等人,
Cell Physiol. Biochem., 45(2): 772-782,2018)等。此外,这种添加到蛋白中的“半衰期延长部分”贯穿综述刊物等是众所周知的(Strohl, W. R.,
BioDrugs, 29(4): 215-239, 2015)。因此,现有技术文献和各个因素的综述论文都引入本文作为参考。
如本文所用的,术语“抗体Fc区”指当抗体用木瓜蛋白酶切割时产生的片段中的结晶片段并与称为Fc受体的细胞表面受体和补体系统的少数蛋白相互作用。Fc区代表同二聚体结构,其中含有重链的第二和第三恒定区(CH2和CH3)的片段通过铰链区的分子间二硫键连接。IgG的Fc区具有许多N-糖基化位点,其已知在Fc受体介导的作用中起重要作用。
如本文所用的,术语“杂种Fc区”指由免疫球蛋白(Igs)的各种亚型的Fc区的部分的组合产生的Fc区肽,例如,IgA、IgE、IgD、IgD和IgM等,并且通过Fc区的这些部分的组合,可以就与Fc受体和补体的结合亲和力而论区别于野生型Fc区。
如本文所用的,术语“毒蜥外泌肽”是从蜥蜴吉拉毒蜥(Heloderma suspectum)的毒液分离的由39个氨基酸组成的肽。毒蜥外泌肽4在氨基酸序列中与GLP-1具有50%的同一性,是胰高血糖素肽家族的成员,并且已知作为GLP-1受体的激动剂执行与GLP-1相同的作用。毒蜥外泌肽-4也称为“extenatide”。 毒蜥外泌肽3是一种变体,其中毒蜥外泌肽4中的第二个和第三个氨基酸分别被丝氨酸和天冬氨酸取代。
如本文所用的,术语“利西拉来(Lixisenatide)”是GLP-1受体激动剂之一,由Sanofi制造并在欧洲在商品名Lyxumia下和在美国在商品名Adlyxin下作为用于治疗2型糖尿病的每日一次的注射液销售。
本文所用的术语“阿必鲁肽(Albiglutide)”是GLP-1受体激动剂之一,其由GSK在欧洲在Eperzan的商品名下和在美国在Tanzeum的商品名下作为2型糖尿病的治疗药物销售。
如本文所用的,术语“利拉鲁肽(Liraglutide)”是由Novo Nordisk在商品名“Victoza”下作为用于2型糖尿病和肥胖症的治疗药物销售的皮下注射型GLP-1受体激动剂。
本文所用的术语“他司鲁泰(Taspoglutide)”是由Ipsen和Roche共同开发的GLP-1受体激动剂,其是一种用于2型糖尿病的治疗药物,并且是GLP-1衍生物,其中GLP-1(7-36)肽中的第8个和第35个氨基酸被甲基化并且末端氨基酸被酰胺化。然而,当以与其他肽的融合蛋白的形式制备时,C-末端可以是没有酰胺化的正常羧基。
如本文所用的,术语“XTEN”是由Amunix开发的具有低免疫原性的非结构化(unstructured)肽,含有添加的6个氨基酸以改善蛋白药物的体内半衰期,并且一般以144个氨基酸为单位并且由多个单位的其氨基酸组成(US20100239554A1)。
如本文所用的术语“替度鲁肽(Teduglutide)”是一种突变体,其中GLP-2中的第2个氨基酸丙氨酸(A)被甘氨酸(G)取代,并且是在美国在商品名Gattex下和在欧洲在商品名Revestive下作为短肠综合征的治疗药物销售的GLP-2类似物。
如本文所用的术语“Glepaglutide”是一种具有延长的半衰期的GLP-2类似物,被开发为短肠综合征的治疗药物,且目前正在进行用于短肠综合征的3期临床试验。
如本文所用的,术语“GLP-2类似物10”是GLP-2中的第11个和第18个氨基酸被半胱氨酸取代的GLP-2类似物之一,并且通过利用两个取代的半胱氨酸的硫醇基之间的脂化(lapidated)交联剂的分子内交联而具有稳定的结构,并且其特征还在于毒蜥外泌肽4的C-末端的9个氨基酸(Yang等人,
J. Med. Chem. 61: 3218-3223, 2018)在C-末端添加。
如本文所用的,术语“接头肽”指用于通过连接两种或更多种具有不同生物活性的蛋白或肽来制备融合蛋白的非结构化肽。
发明详述:
在本发明的一个方面,提供了一种用于治疗代谢综合征的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗肥胖症的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗2型糖尿病的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种用于治疗肝纤维化的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在药物组合物中,双特异性融合蛋白可以不是其中在体内天然表达的GLP-1和GLP-2通过插入肽(intervention peptide)或其类似物连接的胰高血糖素原,而是可以是其中GLP-1类似物和GLP-2类似物直接连接或两个肽通过除插入肽之外的另一种形式的接头肽连接的融合蛋白。
在药物组合物中,GLP-1类似物可以是GLP-1、毒蜥外泌肽3、毒蜥外泌肽4、GLP-1/毒蜥外泌肽4杂种肽、GLP-1-XTEN、毒蜥外泌肽4-XTEN、利西拉来、阿必鲁肽、利拉鲁肽或他司鲁泰。任选地,GLP-1类似物可以是具有通过接头肽连接的两个GLP-1的GLP-1串联重复。
在药物组合物中,双特异性融合蛋白可以进一步包含半衰期延长部分,且半衰期延长部分可以插入GLP-1类似物和GLP-2类似物之间或添加到总融合蛋白的N-末端或C-末端,且优选地,可以是抗体Fc区、PEG、XTEN、PAS(Pro-Ala-Ser)、ELP(弹性蛋白样肽)、富甘氨酸HAP(同型氨基酸聚合物)、GLP(明胶样蛋白)或血清清蛋白。
在药物组合物中,GLP-1可以包含由SEQ ID NO: 1或2表示的氨基酸序列。
在药物组合物中,毒蜥外泌肽3可以包含由SEQ ID NO: 3表示的氨基酸序列。
在药物组合物中,毒蜥外泌肽4可以包含由SEQ ID NO: 4表示的氨基酸序列。
在药物组合物中,GLP-1/毒蜥外泌肽4杂合体可以包含由SEQ ID NO: 5表示的氨基酸序列。
在药物组合物中,利西拉来可以包含由SEQ ID NO: 6表示的氨基酸序列。
在药物组合物中,毒蜥外泌肽4-XTEN可以包含由SEQ ID NO: 7表示的氨基酸序列。
在药物组合物中,阿必鲁肽可以包含由SEQ ID NO: 8表示的氨基酸序列。
在药物组合物中,利拉鲁肽可以包含由SEQ ID NO: 9表示的氨基酸序列。
在药物组合物中,他司鲁泰可以包含由SEQ ID NO: 10表示的氨基酸序列。
在药物组合物中,GLP-1串联重复可以包含由SEQ ID NO: 11表示的氨基酸序列。
在药物组合物中,抗体Fc区可以是杂种抗体Fc区,且杂种抗体Fc区可以由选自SEQID NO:12至16的氨基酸序列组成。此外,杂种抗体Fc区可以是进一步修饰的,以便在体内施用时不引起不利的副作用,例如ADCC(抗体依赖性细胞毒作用)和CDC(依赖补体的细胞毒性)。这种杂种抗体Fc区可以是韩国专利No. 897938中公开的一种,或者可以是由SEQ IDNO: 14表示的氨基酸序列组成的杂种Fc区变体,其中在由SEQ ID NO: 13表示的氨基酸序列组成的杂种Fc区中第18个氨基酸苏氨酸(T)被谷氨酰胺(Q)取代且第196个氨基酸甲硫氨酸(M)被亮氨酸(L)取代,或者可以是由SEQ ID NO: 15表示的氨基酸序列组成的杂种Fc区变体,其中在由SEQ ID NO: 12表示的氨基酸序列组成的杂种Fc区中第18个氨基酸苏氨酸(T)被谷氨酰胺(Q)取代并且第196个氨基酸甲硫氨酸(M)被亮氨酸(L)取代。
在双特异性融合蛋白中,GLP-2类似物可以是GLP-2、替度鲁肽、Glepaglutide或GLP-2类似物10。
在药物组合物中,GLP-2可以包括SEQ ID NO:17至20中任一项的氨基酸序列。由SEQ ID NO: 18表示的氨基酸序列组成的肽是野生型人GLP-2肽,并且由SEQ ID NO: 17表示的氨基酸序列组成的人GLP-2变体,其中第2个氨基酸丙氨酸被甘氨酸取代,且也称为替度鲁肽。同时,由SEQ ID NO:19表示的氨基酸序列组成的GLP-2变体包括GLP-2变体(GLP-2A2G、N16G、L17Q),其中第2个氨基酸丙氨酸(A)被甘氨酸(G)取代,且第16个氨基酸天冬酰胺(N)也被甘氨酸(G)取代,以及第17个氨基酸亮氨酸(L)被谷氨酰胺(Q)取代。已知这种GLP-2变体在重组生产过程中抑制GLP-2的二聚化或后来的聚集体形成,同时完整地保持GLP-2的功能。任选地,其中野生型GLP-2肽中的第2个氨基酸丙氨酸被甘氨酸取代并且第17个氨基酸亮氨酸被谷氨酰胺取代的GLP-2变体(A2G,L17Q,SEQ ID NO:20)具有与由上述由序列号19表示的氨基酸序列组成的肽组成的GLP-2类似物类似的功能,且因此可以用作本发明中的GLP-2类似物。
在药物组合物中,替度鲁肽可以包含由SEQ ID NO: 17表示的氨基酸序列。
在药物组合物中,Glepaglutide可以包含由SEQ ID NO: 21表示的氨基酸序列。
在药物组合物中,GLP-2类似物10可以包含由SEQ ID NO: 22表示的氨基酸序列。
在药物组合物中,第一融合蛋白可以包含选自SEQ ID NOs:23至30的氨基酸序列。
在药物组合物中,第二融合蛋白包含选自SEQ ID NOs:31至36的氨基酸序列。
此外,在本发明的药物组合物中使用的双特异性融合蛋白中,GLP-1类似物和GLP-2类似物中的至少一个可以是串联重复,并且GLP-1类似物和GLP-2类似物可以具有不同数目的重复。这种结构是为了双特异性融合蛋白的不对称性而引入的,且后来构成异二聚体的单位融合蛋白大小的变化使得容易监控同二聚体形成的程度,且因此与作为传统的半衰期延长技术是众所周知的聚乙二醇化(PEGylation)相比使得能够进行质量控制,且简化了生产过程,且因此提供了降低生产成本的优点。GLP-1类似物和GLP-2类似物的重复单位的数目可以根据所需的与GLP-1R和GLP-2R的结合亲和力进行调整。
在药物组合物中,第一融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域(杵(Knob)结构)中第10个氨基酸丝氨酸(S)被半胱氨酸(C)取代;且第22个氨基酸苏氨酸(T)被色氨酸(W)取代,且第二融合蛋白包含修饰的杂种Fc区,其中在CH3结构域(臼(Hole)结构)中第5个氨基酸酪氨酸(Y)被半胱氨酸(C)取代;第22个氨基酸苏氨酸(T)被丝氨酸(S)取代;第24个氨基酸亮氨酸(L)被丙氨酸(A)取代;且第63个氨基酸酪氨酸(Y)被缬氨酸(V)取代,或者第一融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域(臼结构)中第5个氨基酸酪氨酸(Y)被半胱氨酸(C)取代;第22个氨基酸苏氨酸(T)被丝氨酸(S)取代;第24个氨基酸亮氨酸(L)被丙氨酸(A)取代;且第63个氨基酸酪氨酸(Y)被缬氨酸(V)取代,且第二融合蛋白包含修饰的杂种Fc区,其中在CH3结构域(杵结构)中第10个氨基酸丝氨酸(S)被半胱氨酸(C)取代;且第22个氨基酸苏氨酸(T)被色氨酸(W)取代。
任选地,第一融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域中第22个氨基酸苏氨酸(T)被酪氨酸(Y)取代,并且第二融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域中第63个氨基酸酪氨酸(Y)被苏氨酸(T)取代,或者第二融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域中第63个氨基酸酪氨酸(Y)被苏氨酸(T)取代,并且第一融合蛋白可以包含修饰的杂种Fc区,其中在CH3结构域中第63个氨基酸酪氨酸(Y)被苏氨酸(T)取代。然而,如果遵循IMGT(international ImMunoGeneTics information system)编号规则(Lefranc等人,
Dev. Comp. Immunol., 27: 55-77, 2003),而不是基于具有由 SEQ IDNO: 69 表示的氨基酸序列的人IgG1的CH3结构域的氨基酸序列的编号,则第63个氨基酸的变异可能表示为Y86T等。
在药物组合物中,可以在融合蛋白的融合配偶体之间,即肽或结构域之间插入一个或多个接头肽。也就是说,在具有相互融合的GLP-1类似物和GLP-2类似物的双特异性融合蛋白的情况中(i),可以在GLP-1类似物和GLP-2类似物之间插入接头肽。在通过第一融合蛋白和第二融合蛋白的二聚化产生的双特异性融合蛋白的情况中(ii),可以在第一融合蛋白中的抗体Fc区和GLP-1类似物之间插入接头肽,且同样地,可以在第二融合蛋白中的抗体Fc区和GLP-2类似物之间插入接头肽。在这里,接头肽可以包括或可以不包括N-糖基化位点,且更优选地,第一融合蛋白可以不包括接头肽中的N-糖基化位点,且第二融合蛋白可以包括接头肽中的N-糖基化位点。任选地,第一融合蛋白和第二融合蛋白两者都可以不包括N-糖基化位点,或者第一融合蛋白可以不包括接头肽中的N-糖基化位点并且第二融合蛋白可以包括接头肽中的N-糖基化位点。
接头肽是EPKSSDKTHTCPPCP(SEQ ID NO: 37)、 EPKSCDKTHTCPPCP(SEQ ID NO:38)、GGGGSGGGGSGGGGSEPKSSDKTHTCPPCP(SEQ ID NO: 39)、GGGGSGGGGSGGGGSEPKSCDKTHTCPPCP(SEQ ID NO: 40)、AKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECP(SEQ ID NO: 41)、GGGGSGGGGSGGGGSEKEKEEQEERTHTCPPCP(SEQ ID NO: 42)、GGGGSGGGGSGGGGSAKNTTAPATTRNTTRGGEEKKKEKEKEEQEERTHTCPPCP(SEQ ID NO: 43)、AAGSGGGGGSGGGGSGGGGS(SEQ ID NO: 44)、GGGGSGGGGSGGGGS(SEQ ID NO: 45)、GGSGG(SEQID NO: 46)、GGSGGSGGS(SEQ ID NO: 47)、GGGSGG(SEQ ID NO: 48)、SEQ ID NO:(G4S)n(亚单位:SEQ ID NO: 49,n是1-10的整数)、(GGS)n(n是1-10的整数)、(GS)n(n是1-10的整数)、(GSSGGS)n(亚单位:SEQ ID NO: 50,n是1-10的整数)、KESGSVSSEQLAQFRSLD(SEQ ID NO:51)、EGKSSGSGSESKST(SEQ ID NO: 52)、GSAGSAAGSGEF(SEQ ID NO: 53)、(EAAAK)n(亚单位:SEQ ID NO: 54,n是1-10的整数)、CRRRRRREAEAC(SEQ ID NO: 55)、A(EAAAK)4ALEA(EAAAK)4A(SEQ ID NO: 56)、GGGGGGGG(SEQ ID NO: 57)、GGGGGG(SEQ ID NO: 58)、AEAAAKEAAAAKA(SEQ ID NO: 59)、PAPAP(SEQ ID NO: 60)、(Ala-Pro)n(n是1-10的整数)、VSQTSKLTRAETVFPDV(SEQ ID NO: 61、PLGLWA(SEQ ID NO: 62)、TRHRQPRGWE(SEQ ID NO:63)、AGNRVRRSVG(SEQ ID NO: 64)、RRRRRRRR(SEQ ID NO: 65)、GFLG(SEQ ID NO: 66)、GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE(SEQ ID NO: 67)或GSTSGSGKPGSGEGS(SEQ ID NO:68)。
组合物可以包含药学上可接受的载体,并且除了载体之外可以进一步包含药学上可接受的佐剂、赋形剂或稀释剂。
术语“药学上可接受的”指生理上可接受并且当施用于人时正常不引起胃肠病症、变态反应如头昏或类似反应的组合物。载体、赋形剂或稀释剂的实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。此外,组合物可以进一步包含填充物、抗聚集剂(antiaggregant)、润滑剂、润湿剂、调味剂(flavor)、乳化剂、防腐剂等。
另外,根据本发明的实施方案的药物组合物可以使用本领域已知的方法以剂型形成,其使得当施用于哺乳动物时能够使活性成分快速释放或持续或延迟释放。剂型可包括粉末、颗粒、片剂、乳剂、糖浆、气溶胶、软或硬明胶胶囊、无菌注射溶液和无菌包装粉末。
根据本发明实施方案的组合物可以通过各种途径施用,例如口服,肠胃外,例如可以施用栓剂、经皮、静脉内、腹膜内、肌内、病灶内(intralesional)、鼻、鞘内施用,且也可以使用用于持续释放或连续或重复释放的可植入设备施用。给药频率在所期望的范围内可以是一天一次或多次,且给药的持续时间也没有特别限制。
根据本发明实施方案的组合物可以与常用的药学上可接受的载体一起制成合适的剂型。药学上可接受的载体的实例包括用于肠胃外施用的载体,例如水、合适的油、盐水、含水葡萄糖和乙二醇,并且可以进一步包括稳定剂和防腐剂。合适的稳定剂的实例包括抗氧化剂,例如亚硫酸氢钠、亚硫酸钠或抗坏血酸。合适的防腐剂的例子包括苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和氯代丁醇。另外,根据本发明的组合物如根据施用方法或其剂型所必需的可以适当地包含混悬液、加溶剂、稳定剂、等渗剂、防腐剂、吸附抑制剂、表面活性剂、稀释剂、赋形剂、pH调节剂、安抚剂、缓冲剂、抗氧化剂等。适合于本发明的药学上可接受的载体和试剂,包括上述那些,在文献[Remington's PharmaceuticalSciences,最新版]中有详细描述。
组合物对患者的剂量取决于许多因素,包括患者的身高、体表面积、年龄、所施用的化合物、性别、施用时间和途径、一般健康状况以及同时施用的其他药物。可以以100 ng/体重(kg)至10 mg/体重(kg),更优选1至500 μg/kg(体重),且最优选5至50 μg/kg(体重)的量施用药物活性蛋白,且药物活性蛋白的剂量可考虑到上述因素进行调整。
在本发明的另一个方面,提供了一种在患有代谢综合征的主体中治疗代谢综合征的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有肥胖症的主体中治疗肥胖症的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有2型糖尿病的主体中治疗2型糖尿病的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有NAFLD或NASH的主体中治疗NAFLD或NASH的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
在本发明的另一个方面,提供了一种在患有肝纤维化的主体中治疗肝纤维化的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
如本文所用的,术语“治疗有效量”意指足以以适用于医学治疗的合理利益/风险比治疗疾病的量,且有效剂量水平取决于包括主体的类型和严重程度、年龄、性别、药物活性、对药物的敏感性、施用时间、施用途径和排泄率、治疗持续时间、伴随使用的药物以及医学领域众所周知的其他因素的因素。本发明的组合物的治疗有效量可以为0.1 mg/kg-1 g/kg,更优选1 mg/kg-500 mg/kg,且有效剂量可以取决于患者的年龄、性别和状况进行调整。
在两个或更多个蛋白或结构域之间,可以插入通常具有柔性结构的接头肽。接头肽是EPKSSDKTHTCPPCP(SEQ ID NO: 37)、 EPKSCDKTHTCPPCP(SEQ ID NO: 38)、GGGGSGGGGSGGGGSEPKSSDKTHTCPPCP(SEQ ID NO: 39)、GGGGSGGGGSGGGGSEPKSCDKTHTCPPCP(SEQ ID NO: 40)、AKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECP(SEQ ID NO: 41)、GGGGSGGGGSGGGGSEKEKEEQEERTHTCPPCP(SEQ ID NO: 42)、GGGGSGGGGSGGGGSAKNTTAPATTRNTTRGGEEKKKEKEKEEQEERTHTCPPCP(SEQ ID NO: 43)、AAGSGGGGGSGGGGSGGGGS(SEQ ID NO: 44)、GGGGSGGGGSGGGGS(SEQ ID NO: 45)、GGSGG(SEQ ID NO: 46)、GGSGGSGGS(SEQ ID NO: 47)、GGGSGG(SEQ ID NO: 48)、SEQ ID NO:(G4S)n(亚单位:SEQ ID NO: 49,n是1-10的整数)、(GGS)n(n是1-10的整数)、(GS)n(n是1-10的整数)、(GSSGGS)n(亚单位:SEQ ID NO: 50,n是1-10的整数)、KESGSVSSEQLAQFRSLD(SEQ ID NO: 51)、EGKSSGSGSESKST(SEQ ID NO: 52)、GSAGSAAGSGEF(SEQ ID NO: 53)、(EAAAK)n(亚单位:SEQ ID NO: 54,n是1-10的整数)、CRRRRRREAEAC(SEQ ID NO: 55)、A(EAAAK)4ALEA(EAAAK)4A(SEQ ID NO: 56)、GGGGGGGG(SEQID NO: 57)、GGGGGG(SEQ ID NO: 58)、AEAAAKEAAAAKA(SEQ ID NO: 59)、PAPAP(SEQ IDNO: 60)、(Ala-Pro)n(n是1-10的整数)、VSQTSKLTRAETVFPDV(SEQ ID NO: 61、PLGLWA(SEQID NO: 62)、TRHRQPRGWE(SEQ ID NO: 63)、AGNRVRRSVG(SEQ ID NO: 64)、RRRRRRRR(SEQID NO: 65)、GFLG(SEQ ID NO: 66)、GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE(SEQ ID NO: 67)或GSTSGSGKPGSGEGS(SEQ ID NO: 68)。
根据本发明的另一个方面,所述双特异性融合蛋白可以通过在宿主细胞中转导重组表达载体后的重组表达产生,所述重组表达载体包含第一基因构建体和第二基因构建体,所述第一基因构建体包含编码所述第一融合蛋白的多核苷酸,所述第二基因构建体包含编码第二融合蛋白的多核苷酸。
在这种情况下,第一基因构建体和第二基因构建体可以插入单个表达载体中并表达,或者可以插入两个单独的表达载体中并表达。对于前一种情况,可以设计载体从而使得每个基因构建体可操作地连接到两个不同的调节序列,或使得两个基因构建体可操作地连接到单个调节序列并且两个基因构建体通过内部核糖体进入位点(IRES)连接。
如本文所用的短语“可操作地连接到”指感兴趣的核酸序列(例如,在体外转录/翻译系统中或在宿主细胞中)以这样的方式连接到调节序列以致于可以实现其表达的缔合。
如本文所用的术语“调节序列”包括启动子、增强子和其他调节元件(例如,多腺苷酸化信号)。调节序列包括指导靶核酸在多种宿主细胞中一致表达的序列、指导靶核酸仅在特定组织细胞中表达的序列(例如,组织特异性调节序列)和指导表达由特定信号诱导的序列(例如,诱导型调节序列)。本领域技术人员可以理解,表达载体的设计可以取决于诸如要转化的宿主细胞的选择、所期望的蛋白表达水平等的因素而不同。可以将本发明的表达载体引入宿主细胞并表达融合蛋白。使得能够在原核细胞和真核细胞中表达的调节序列是本领域普通技术人员众所周知的。如下文所述的,这种调节序列包括负责转录起始的调节序列和任选地负责转录终止和转录物稳定的聚腺苷酸(poly-A)信号。除了转录调节因子之外,额外的调节序列可以包括翻译增强子和/或天然组合的或异源的启动子区域。例如,使得能够在哺乳动物宿主细胞中表达的可用调节序列包括CMV-HSV胸苷激酶启动子、SV40、RSV启动子(劳斯肉瘤病毒)、人肾元件1α-启动子、糖皮质激素诱导型MMTV-启动子(莫洛尼小鼠肿瘤病毒) 、金属硫蛋白诱导型或四环素诱导型启动子或诸如CMV增强剂(amplifier)或SV40-增强剂的增强剂。对于在神经细胞中的表达,考虑神经丝启动子、PGDF-启动子、NSE-启动子、PrP-启动子或thy-1-启动子的可能使用。这些启动子在本领域中是已知的并且在文件(Charron,
J. Biol. Chem. 270: 25739-25745, 1995)中公开。对于在原核细胞中的表达,公开了多种启动子,包括lac-启动子、tac-启动子或trp启动子。除了能够起始转录的因子之外,上述调节序列根据本发明的实施方案还可以在多核苷酸的下游包括转录终止信号,例如SV40-聚腺苷酸位点或TK-聚腺苷酸位点。在所述文件中,合适的表达载体在相关领域是已知的,且其例子包括Okayama-Berg cDNA表达载体、pcDV1(Parmacia)、pRc/CMV、pcDNA1、pcDNA3(Invitrogene)、pSPORT1(GIBCO BRL)、pGX-27 (专利No. 1442254)、pX(Pagano等人,
Science 255: 1144-1147, 1992)、酵母2-杂交载体例如pEG202和dpJG4-5(Gyuris等人,
Cell 75: 791-803, 1995) 或原核表达载体例如λgt11或pGEX (AmershamPharmacia)。除了本发明的核酸分子,载体可以进一步包含编码分泌信号的多核苷酸。分泌信号为本领域普通技术人员众所周知。此外,取决于所使用的表达系统,将能够将融合蛋白引入细胞区室的前导序列与根据本发明实施方案的多核苷酸的编码序列组合,且优选地,前导序列能够将解码的蛋白或其蛋白直接分泌入细胞质或细胞质基质的周围环境。
此外,本发明的载体可以通过例如标准重组DNA技术来制备,且标准重组DNA技术的例子包括平端和黏端连接、限制酶处理以提供正确的末端、通过碱性磷酸酶处理的去磷酸化以防止不正确的键合以及通过T4 DNA连接酶的酶促连接等。通过将编码通过化学合成或遗传重组技术获得的信号肽的DNA和编码本发明的双特异性融合蛋白的DNA与包含适当调节序列的载体重组,可以制备本发明的载体。含有上述调节序列的载体可以商购或制备,且在本发明的一个实施例中,使用pBispecific主链载体(Genexine, Inc.,韩国)或pAD15载体作为主链载体。
表达载体可以进一步包含编码分泌信号序列的多核苷酸,且所述分泌信号序列诱导细胞外蛋白分泌,且可以是tPA(组织纤溶酶原激活物)信号序列、HSV gDs(单纯疱疹病毒糖蛋白Ds)信号序列或生长激素信号序列。
根据本发明实施方案的表达载体可以是能够在宿主细胞中表达蛋白的表达载体,且所述表达载体可以采用任何形式,如质粒载体、病毒载体、黏粒载体、噬菌粒载体、人工人染色体等。
实施本发明的方式
下面,将通过实施例和实验例更详细地描述本发明。然而,本发明不限于以下公开的实施例和实验例,而是可以以各种不同的形式实施。提供以下实施例和实验例是为了使本发明的公开内容完整,并向本发明所属技术领域的本领域普通技术人员提供对本发明的范围的充分的理解。
实施例:双特异性融合蛋白的设计
本发明人设计了各种双特异性融合蛋白,包括GLP-1类似物和GLP-2类似物两者,如图1和表1中所示的。
在设计双特异性融合蛋白时,主要考虑的因素是,如图2中所示的,毒蜥外泌肽4(Ex4)、泌酸调节肽(OXM)和GLP-2以及GLP-1都与GLP-1受体GLP-1R结合,而只有GLP-2与GLP-2R结合。因此,为了调节GLP-1类似物对GLP-1R的结合亲和力,本发明人使用了包含聚糖结合结构域的GLP-1类似物,从而使得聚糖可以附着到GLP-1类似物的接头区域。同样,设计了双特异性融合蛋白(MG12-6),从而使得包含GLP-2的第二融合蛋白包含聚糖接头,而包含GLP-1类似物的第一融合蛋白包含不含有聚糖结合位点的未修饰的接头。进一步地,本发明人使用GLP-2中第17个氨基酸丙氨酸被谷氨酰胺取代的GLP-2类似物,设计了双特异性融合蛋白MG12-7和MG12-8。在这种情况下,MG12-7和MG12-8之间的区别在于MG12-7使用SEQID NO: 1的A2G变体作为GLP-1类似物,而MG12-8使用由两个通过(G4S)6接头连接的A2G变体组成的A2G变体的串联重复。
表1
同样,对于上述双特异性融合蛋白,应用了杵臼(KiH)技术以允许优先形成异二聚体。特别地,第一融合蛋白可以是具有杂种Fc区的融合蛋白(杵),其中CH3结构域中的第10个氨基酸丝氨酸(S)被半胱氨酸(C)取代;且第22个氨基酸苏氨酸(T)被色氨酸(W)取代。第二融合蛋白可以是具有Fc区的融合蛋白(臼),其中CH3结构域中的第5个氨基酸酪氨酸(Y)被半胱氨酸(C)取代;第22个氨基酸苏氨酸(T)被丝氨酸(S)取代;第24个氨基酸亮氨酸(L)被丙氨酸(A)取代;并且第63个氨基酸酪氨酸(Y)被缬氨酸(V)取代。在这里,发生这种变化的氨基酸位置是根据参考序列(SEQ ID NO:69的人IgG1 CH3结构域的氨基酸序列)的。即使在与CH3结构域上的杵臼结构无关的位点发生额外的变异例如氨基酸的添加、缺失或取代,也可以使用具有与基于参考序列的位置相对应的氨基酸变异的那种。任选地,可以通过本领域已知的其他氨基酸改变来引入杵臼结构。这种变异在现有技术文件中详细描述(Wei等人,
Oncotarget 2017, 8(31): 51037-51049;Ridgway等人,
Protein Eng. 1996, 9(7):617-621;Carter, P.,
J. Immunol. Methods 2001, 48(1-2): 7-15;Merchant等人,
Nat. Biotechnol. 1998, 16(7): 677-681)。这种选择性变异包括,例如,其中第一融合蛋白的CH3结构域的第22个氨基酸苏氨酸被酪氨酸取代的杵结构,和其中第二融合蛋白的CH3结构域的第63个氨基酸酪氨酸被苏氨酸取代的臼结构,且通过这些结构的组合,可以产生双特异性二聚体融合蛋白。另一方面,可以通过将臼结构引入第一融合蛋白并将杵结构引入第二融合蛋白来形成杵臼结构。在通过使用PCR和位点定向诱变引物扩增合成编码实施例1至8的双特异性融合蛋白的第一融合蛋白和第二融合蛋白的基因构建体之后,然后将基因构建体插pAD15载体(Genexine, Inc.,韩国)中以制备表达载体。
如上所述制备的载体构建体的瞬时表达使用Thermo Fisher的ExpiCHO试剂盒进行。具体而言,在ExpiCHO-S细胞中,将如上所述制备的载体构建体与试剂盒中包括的ExpiFectamine试剂混合后,将所得混合物于37℃在具有8%CO2的培养箱中温育1天,且在降低温度至32℃后,温育直到第7天为止。
将具有通过A蛋白柱和二级柱纯化的实施例1至5的融合蛋白(分别为'MG12-1'、'MG12-2'、'MG12-3'、'MG12-4'和'MG12-5')的从温育获得的上清液用4X LDS样品缓冲液和注射用水适当地稀释至3-10 μg/20 μL的终体积。对于还原条件样品,将每种待分析物质、4X LDS样品缓冲液、10X还原剂和注射用水适当稀释至3-10 μg/20 μL的终体积,并在70℃加热块上加热 10 分钟。将20 μL制备的样品加样到固定在预先安装的电泳设备上的每个凝胶孔中。大小标记以3-5 μL/孔加样。在将电源设置为120 V和90分钟后,进行电泳。在电泳结束后,分离凝胶,并使用染色液和脱色液进行染色,且分析其结果。
作为分析的结果,如图3a中所示的,在非还原条件下50至75 kDa和还原条件下37kDa的位点观察到所有双特异性融合蛋白。在异二聚体形式的本发明的双特异性融合蛋白中,在一个铰链处含有糖链的实施例1至4的融合蛋白的情况下,在还原条件下观察到具有两种不同大小的单体,并且在在铰链处不含糖链的实施例5的融合蛋白(MG12-5)的情况下,观察到具有一种大小的单体。
另外,本发明人对与不含杵臼(KiH)结构的Fc融合的GLP-2同二聚体(GLP-2-Fc同二聚体,SEQ ID NO:25)和含有杵臼结构的MG12-5分别在与上述相同的还原/非还原条件下进行了SDS-PAGE分析。
结果,如图3b中所示的,发现在具有KiH结构的MG12-5的情况下,与不含这种结构的GLP-2-Fc同二聚体相比,在非还原条件下单体杂质的形成被显著抑制。
总之,通过SDS-PAGE证实根据本发明的所有双特异性融合蛋白都可以正常生产和纯化,且特别地。如通过MG12-5和GLP-2-Fc同二聚体的比较所证明的,在向其应用了KiH结构的双特异性二聚体蛋白的情况下,与不应用这种结构时相比,单体形式的杂质的形成显著减少。
实验例1:GLP-1体外活性的确认
本发明人通过cAMP分析研究了在上述实施例中制备的双特异性融合蛋白的GLP-1的体外活性。具体而言,为了评价通过GLP-1特异性反应的cAMP诱导的程度,制备转化的细胞系(GLP1R_cAMP/luc)以便在cAMP-特异性萤光素表达细胞系中共表达GLP-1受体。将细胞解冻并正确维持后,通过添加0.05% TE(胰蛋白酶EDTA)将细胞从瓶中脱离并计数活细胞数目。收集活性评价所需的细胞数目并洗涤,用0.5% FBS、DMEM/高葡萄糖培养基稀释,并以2x104个细胞/80 μL/孔接种。在37℃、5%CO2培养箱中培养细胞约16小时后,用20 μL/孔的待评价的各种浓度的测试溶液处理细胞,并使其在37℃、5% CO2培养箱中反应5小时。在反应结束后,用Bright-Glo™测定试剂以100 μL/孔处理平板,且然后使其于室温反应2分钟。在反应结束后,将平板插入发光计并测量生物发光程度。
作为分析的结果,如表2和图4a至4e中所示的,与天然GLP-1肽相比,GLP-1-Fc同二聚体表现出约72%的活性,且根据本发明实施例1、3、4和5的双特异性融合蛋白(分别为MG12-1、3、4和5)分别显示9%、118%、39%和35%的相对活性。引入N-末端突变以防止被DPP-4酶切割,且发现包含与GLP-1缀合的铰链中的糖链的MG12-1由于糖基化而表现出降低到约1/11的活性,且在MG12-1中,引入了毒蜥外泌肽4而不是GLP-1的MG12-3与MG12-1相比显示了增加到约13倍的活性。在 MG12-1中,与存在铰链的糖基化无关,在其中引入了GLP-1/毒蜥外泌肽4杂合体而不是GLP-1的MG12-4和MG12-5显示出约35-39%的相似的相对活性。
表2
根据本发明实施例的双特异性融合蛋白的体外GLP-1活性
实验例2:GLP-2体外活性的确认
本发明人通过cAMP分析研究了在上述实施例中制备的双特异性融合蛋白的GLP-2的体外活性。
具体而言,为了评价通过GLP-2特异性反应的cAMP诱导的程度,获得了具有在表达以cAMP-特异性方式打开的CNG通道的细胞系中表达的GLP-2受体的转化的细胞系 (HumanGLP2R ACTOne™)。将细胞解冻并正确维持后,在与GLP-1体外活性测定相同的条件下将细胞从瓶分离,并收集活性评价所需的细胞数目且洗涤。洗涤的细胞用细胞培养基(DMEM/高葡萄糖培养基,补加了10% FBS、5% G418、0.01%嘌呤霉素)稀释,且以3~5x104个细胞/100 μL/孔接种,并于37℃、5% CO2在培养箱中温育约20小时。从CO2培养箱中取出平板后,在显微镜下观察细胞,且当细胞汇合达到80%或更高时,以100 μL/孔添加1X染料加样的溶液(EliteTM荧光膜电位染料试剂盒,eEnzyme)。在于室温下遮光的同时,进行反应达2-2.5小时,且在添加测试溶液前,使用ELISA测量荧光基线(F0)。此后,以50 μL/孔处理待评价的各种浓度的测试溶液,反应0.5小时,且然后使用ELISA测量荧光值(Ft)。使用Ft /F0比率评价每种测试溶液的反应性。
结果,如图5a至5e中所示的,与天然GLP-2肽相比,GLP-2-Fc同二聚体表现出约132%的活性,且根据本发明实施例1、3、4和5的双特异性融合蛋白(分别为MG12-1、3、4和5)分别显示43%、54%、48%和59%的相对活性。因为所有MG12变体都引入N-末端突变以防止被DPP-4酶切割,且与GLP-1不同,因为与GLP-2缀合的铰链不含糖链,所以所有变体都显示出相似的GLP-2活性。
表3
根据本发明实施例的双特异性融合蛋白的体外GLP-2活性
实验例3:体内药物代谢动力学概况分析
通过比较上面制备的根据实施例1和3至5的双特异性融合蛋白(MG12-1、3、4和5)的半衰期、曲线下面积(AUC)、最高血液浓度(Cmax)等,确认了药物代谢动力学(PK)概况。
首先,通过皮下(SC)途径以1 mg/kg的剂量将每种蛋白施用于每组3只雄性SD(Sprague Dawley)大鼠。注射前和注射后0.5、1、5、10、24、48、72、120和168小时后,收集血液并于室温贮藏30分钟以聚集。将聚集的血液以3,000 rpm离心10分钟后,收集每个样品的血清并贮藏在低温冷冻机中。通过设计用于特异性检测施用的蛋白中的GLP-1位点和Fc的测定(GLP-1-Fc ELISA)和设计用于特异性检测施用的蛋白中的GLP-2位点和Fc的测定(GLP- 2-Fc ELISA)进行分析。具体而言,使用将生物样品加样到用与小鼠衍生的人免疫球蛋白G4(IgG4)结合的抗体包被的平板上以使用生物素化抗-GLP-1抗体检测靶蛋白的方法(GLP-1-Fc ELISA),以及将生物样品加样到用与GLP-2特异性反应的单克隆抗体包被的平板上以使用具有与小鼠衍生的人免疫球蛋白G4(IgG4)缀合的HRP的第二抗体检测靶蛋白的方法(GLP-2-Fc ELISA)。将所获得和制备的血清样品以适当的稀度加样以在标准曲线的直线上的位置进行分析。
结果,如表4和5以及图6a和6b中所示的,MG12-1、3、4和5在通过GLP-1-Fc ELISA和GLP-2-Fc ELISA分析的结果中显示彼此大致相似的PK概况。就Cmax而论,在这两种方法中,MG12-5显示最高的值,而MG12-3显示最低的值。在AUC最后中也类似地观察到了这种趋势。就终末半衰期而论,在两种方法中MG12-3都显示最长的半衰期,而在GLP-1-Fc ELISA方法中MG12-4显示最短的半衰期,且在GLP-2-Fc ELISA中MG12-5显示最短的半衰期。
表4
实施例 | <![CDATA[C<sub>max </sub>(ng/mL)]]> | <![CDATA[T<sub>max </sub>(h)]]> | <![CDATA[AUC<sub>最后</sub>(ng*h/mL)]]> | 半衰期(h) |
1 | 442.2±20.8 | 10 | 13919.8±824.9 | 16.5±6.3 |
3 | 301.0±57.4 | 10 | 9257.4±1543.3 | 29.5±2.7 |
4 | 328.7±34.5 | 10 | 7679.8±1228.9 | 9.0±0.3 |
5 | 1036.2±59.5 | 10 | 26059.6±3028.5 | 18.4±6.2 |
表5
实施例 | <![CDATA[C<sub>max </sub>(ng/mL)]]> | <![CDATA[T<sub>max </sub>(h)]]> | <![CDATA[AUC<sub>最后</sub>(ng*h/mL)]]> | 半衰期(h) |
1 | 1136.7±261.0 | 24.0±0.0 | 78639.0±11205.3 | 43.7±1.8 |
3 | 697.4±148.0 | 24.0±8.1 | 63977.3±10131.5 | 56.2±7.1 |
4 | 1052.5±112.8 | 24.0±0.0 | 78983.2±6542.8 | 49.0±2.1 |
5 | 3201.3±95.6 | 24.0±0.0 | 188741.6±7870.5 | 30.6±2.1 |
总之,发现MG12-1、3、4和5在皮下施用于正常模型大鼠时充分暴露,且MG12-5显示最高的C max和AUC最后。
实验例4:当施用双特异性融合蛋白时NASH模型动物中的生理学变化
为了研究根据本发明实施方案的双特异性融合蛋白(下文缩写为'GLP1/2-Fc')对能量代谢的影响,本发明人施用载体(PBS)、GLP1-Fc同二聚体、GLP2-Fc同二聚体或 GLP1/2-Fc达4周以作为诱导NASH达16周的小鼠的模型。然后,测量实验动物中的重量、脂肪累积、血清胆固醇浓度、血清高密度脂蛋白(HDL)浓度、血清甘油三酯(TG)浓度、血糖水平和胰岛素水平。结果,如图7中所示的,与阴性对照组相比,GLP1/2-Fc施用组2周后减少重量,而4周后重量显著下降(图7a)。与阴性对照组相比,2周后GLP2-Fc和GLP1/2-Fc两者中的体重减轻均显著(图7b)。此外,GLP1/2-Fc对重量的影响以剂量依赖性方式得到确认(图8a和8b)。与重量变化一致,GLP1/2-Fc比以高剂量(20 nmol/kg)施用时更有效地显著减少脂肪累积(图8c)。通过GLP1-Fc和GLP1/2-Fc(10 和 20 nmol/kg)处理,总血清胆固醇和高密度脂蛋白(HDL)水平统计学显著地降低(图7d、7e、8e和8f)。除了高剂量(20 nmol/kg)的GLP1/2-Fc之外,血清甘油三酯(TG)水平没有差异(图7f和图8d)。由于GLP-2与胆囊再装载(recharging)有关,所以外源性GLP-2的递送可能加速胆囊的异常扩张。因此,本发明人分析了胆囊大小(数据中未显示)和总血清胆红素水平。结果,在实验组之间没有差异,且确认了即使当施用高剂量的GLP1/2-Fc时也相同(图8g和8h)。如所预期的那样,与阴性对照相比,GLP2-Fc在重量(图7a和7b)、附睾脂肪量(图7c)、总胆固醇水平(图7d)、HDL水平(图7e)、TG水平(图7f)和总胆红素水平(图8g)中没有显示出显著差异。
因此,本发明人进行了胰岛素耐量试验(ITT)和葡萄糖耐量试验(GTT)以评价根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对葡萄糖稳态的作用。结果,GLP1/2-Fc和GLP1-Fc两者均显著改善了胰岛素敏感性(图7g和7h)。然而,在ITT和GTT两者中以高剂量施用GLP1/2-Fc均未显示出任何加性效应(图8i和8j)。监控血糖水平随着药物施用的变化证实了GLP1/2-Fc和GLP1-Fc施用组中血糖水平的显著下降,但GLP2-Fc施用组中血糖水平下降程度不显著(图7k)。GLP1/2-Fc在高剂量(20 nmol/kg)以及甚至在低剂量(5 nmol/kg)时都改善了血糖水平(图8k和8l)。更有趣的是,与阴性对照组相比,仅在GLP1/2-Fc施用组中发现低胰岛素水平。根据测量的血糖和胰岛素水平得出胰岛素抵抗的稳态模型评价(HOMA-IR)。结果,确认了GLP1/2-Fc施用组中的最低指标降低(图7k)。合起来看,上述结果提示GLP1/2-Fc对重量和血糖控制具有潜在的治疗作用。
实验例5:双特异性融合蛋白对NASH模型动物中肝TG累积和炎症的影响
本发明人研究了肝组织的脂肪含量以评价根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)对肝中脂质累积的影响。在融合蛋白处理过程中,肝呈深红色,大小比阴性对照组中观察到的小(图9a和10a),从而表明肝中的脂肪沉积较少。与上述结果一致,H&E染色揭示在GLP1/2-Fc施用组和GLP1-Fc施用组中脂肪滴减少(图9b和10b),以及在融合蛋白施用组中进一步降低的肝重量(图9c和10c)。然而,仅在GLP1/2-Fc施用组中,肝与体重的比率显著降低(图9d)。实际肝TG水平与H&E染色结果相似(图9e和图10d)。重要的是,与阴性对照组相比,GLP2-Fc施用组没有变化,但与GLP1-Fc施用组相比,GLP1/2-Fc施用组具有显著更低的肝TG和血清ALT水平(图9f和9e),但AST水平的变化不显著(图9g和10f)。这提示GLP1/2-Fc与单一部分(GLP1-Fc和GLP2-Fc)相比对肝炎症和脂肪累积具有协同作用。
实验例6:NASH模型动物中双特异性融合蛋白对肝纤维化和肝细胞细胞死亡的抑
制
为了研究根据本发明实施方案的双特异性融合蛋白(GLP1/2-Fc)是否改善肝纤维化,进行了针对胶原的天狼猩红染色和免疫染色。结果,只有GLP1/2-Fc显著减少了胶原沉积(图11a和11b、12a和12b)。此外,结果显示与肝中的TG水平的正相关(图11c)。在天狼猩红染色强度与TG水平的相关性分析中,GLP1/2-Fc施用组中TG的肝沉积和纤维化的发展程度最低(图11d)。与这些结果一致,在胶原III染色期间,在GLP1/2-Fc-施用组中证实了胶原沉积的明显减少(图11e)。这些结果提示,与单一部分(GLP1-Fc或GLP2-Fc)不同,GLP1/2-Fc可能在减轻肝纤维化中发挥新的作用。
实验例7:NASH模型动物中双特异性融合蛋白对肠体积和肠环境的影响
本发明人首先研究了肠的总形状,以评价GLP1/2-Fc是否可以影响肠。结果,如图13a中所示的,在GLP1/2-Fc施用组中,与阴性对照组相比,肠更粗且肠长度也增加(图13a)。此外,所有三组中肠的重量均显著增加(图13b至13d)。特别地,小肠的长度显示出强的趋势(
p = 0.0562,图13c),且GLP1/2-Fc施用组中的小肠显著长于其他组(图13d)。然而,在结肠中没有观察到所述效果(图13e)。当以高剂量施用时,证实了强的效果(图14b)。作为对空肠和回肠的冷冻切片的组织学分析的结果,GLP1/2-Fc施用组具有更厚的上皮层并且充满了绒毛(图13f)。进行了回肠中的Ki-67蛋白的免疫染色以确定GLP1/2-Fc是否增加了肠体积。如所预期的,Ki-67蛋白表达主要在实验组中的GLP1/2-Fc施用组中检测到(图13g)。与阴性对照组相比,GLP1/2-Fc施用组中的所有三个冷冻切片(cry-sections)在肠中都显示出更深的隐窝深度(图13h至13j)。在GLP1/2-Fc和GLP2-Fc施用组两者中,十二指肠和回肠中的绒毛长度都是长的,但在GLP1-Fc施用组中没有观察到这种变化。在空肠中,GLP1/2-Fc施用组显示出比阴性对照组更长的绒毛,尽管差异不显著(图13k到13m)。实验组间结肠中隐窝深度中几乎没有差异(图14e)。这些结果表明GLP1/2-Fc可以通过增加肠上皮再生和恢复受损组织来保护小肠环境。
实验例8:双特异性蛋白改善肠环境的机制的分析
由于GLP1/2-Fc增加了肠中的微绒毛和隐窝深度,所以本发明人测量了肠透性。结果,如所预期的,与GLP2-Fc施用组和阴性对照组相比,GLP1/2-Fc施用组有效地降低了肠透性(图15a)。这些结果与肠的组织学分析结果一致。令人惊讶地,在GLP1/2-Fc施用组中,血清中的毒素水平也显著更低(图15b)。为了研究不同水平的透性是否归因于紧密连接的变化,本发明人对Zo-1紧密连接蛋白进行了免疫组织化学分析。与肠透性分析的结果一致,与其他实验组相比,GLP1/2-Fc施用组中Zo-1蛋白最丰富地表达(图15c)。此外,为了确认肠环境中的细胞再生,本发明人分别测量了肠中的黏蛋白层的厚度和杯形细胞的数目。与阴性对照组相比,在所有三个实验组中都显示出厚的黏蛋白层(图15d和15e)。然而,其在GLP1/2-Fc施用组中最有效。此外,确认了在GLP1/2-Fc施用组和GLP2-Fc施用组中增加的杯形细胞数目(图15d、15f和15g)。
实验例9:双特异性融合蛋白对肠道微生物菌群影响的研究
本发明人已经观察到GLP1/2-Fc可以通过改变肠结构和肠环境来影响肠道微生物菌群概况的各种证据。为此,本发明人分析了粪便微生物组(microbiome)的组成。PCoA和UPGMA树数据表明,GLP1/2-Fc施用组被放置在与其他实验组明显分开的集簇中(图16a和16b)。当以百分比表示时,发现分类学分配结果在门和属水平两者上都是丰富的(图16c和16d)。结果,本发明人确认了8门中的118属。在门水平上,GLP1/2-Fc施用组显著增加了疣微菌门(Verrucomicrobia)(与阴性对照组25%差异,
p < 0.0005),并减少了变形杆菌门(Proteobacteria)(与阴性对照组10.5%差异,
p < 0.005)。在属水平上,与阴性对照组相比,阿克曼菌属(
Akkermansia)、 普雷沃氏菌属(
Prevotellamassilia)、
Mailhela和
Faecalibaculun在GLP1/2-Fc施用组中最显著地改变(图16c和16d)。本发明人进一步在物种水平上分析了微生物组的分类学组成,且证实了与肥胖症或代谢功能异常相关的18个物种显著地改变(图16e)。特别地,在这些物种中,肠中最丰富的优势物种之一嗜黏蛋白阿克曼菌因其代谢健康益处而众所周知(图16f)。此外,发现在GLP-1/2-Fc施用组中,
Mailhella
massiliensis最被抑制(图16g)。此外,
Alistipes senegalensis、
Lactobacillus
integralis和
Prevotellamassilia timonensis在健康的肠环境中增加且发现(图16h至16j)。有趣的是,本发明人已发现
Faecalibaculum rhodium和
Acetatifactor muris已显著减少(图16k和16l),从而表明GLP1/2-Fc改变了肠道微生物菌群的组成。
如上所述,根据本发明实施方案的双特异性融合蛋白与小肠中的GLP-1和GLP-2受体结合以通过增加小肠中的绒毛长度和隐窝深度并改善肠道微生物菌群来改善小肠中的环境。此外,通过本发明的双特异性融合蛋白改善小肠环境可以影响肠-肝轴并导致非酒精性脂肪肝或非酒精性脂肪性肝炎症状的改善。此外,根据本发明实施方案的双特异性融合蛋白表现出连同胰岛素抵抗的降低的体重减轻的效果。因此,根据本发明实施例的双特异性融合蛋白可以有效地用于治疗慢性代谢性肝病,例如肥胖症、2型糖尿病、非酒精性脂肪肝和由非酒精性脂肪肝进展发展而来的肝纤维化。
尽管已经参考上述实施例和实验例描述了本发明,但是将理解的是,本领域技术人员可以使得由此得出的各种修改和等同的其他实例是可能的。因此,本发明真正的技术保护范围应由所附权利要求的技术精神确定。
工业适用性
根据本发明实施方案的组合物可以有用地用于诸如2型糖尿病、肥胖症、非酒精性脂肪肝疾病、非酒精性脂肪性肝炎和肝纤维化的代谢病的治疗剂的开发中。
序列表
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<120> 用于治疗代谢综合征及与其相关疾病的新药物组合物
<130> PT21-5223
<150> KR 10-2020-0030728
<151> 2020-03-12
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Ser Gly Ala Pro Pro Pro Ser
35
<210> 6
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 利西拉来
<400> 6
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 7
<211> 905
<212> PRT
<213> 人工序列
<220>
<223> 毒蜥外泌肽4-XTEN
<400> 7
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Ser Pro Ala Gly Ser Pro Thr
35 40 45
Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro
50 55 60
Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala
65 70 75 80
Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu
85 90 95
Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
100 105 110
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro
115 120 125
Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly
130 135 140
Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu
145 150 155 160
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr
165 170 175
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu
180 185 190
Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu
195 200 205
Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr
210 215 220
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro
225 230 235 240
Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
245 250 255
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro
260 265 270
Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Thr Glu Pro Ser Glu
275 280 285
Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
290 295 300
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu
305 310 315 320
Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr
325 330 335
Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro
340 345 350
Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu
355 360 365
Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu
370 375 380
Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
385 390 395 400
Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr
405 410 415
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu
420 425 430
Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
435 440 445
Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr
450 455 460
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro
465 470 475 480
Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro
485 490 495
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro
500 505 510
Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro
515 520 525
Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
530 535 540
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala
545 550 555 560
Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr
565 570 575
Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu
580 585 590
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr
595 600 605
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro
610 615 620
Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro
625 630 635 640
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro
645 650 655
Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro
660 665 670
Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro
675 680 685
Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu
690 695 700
Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly
705 710 715 720
Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro
725 730 735
Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala
740 745 750
Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu
755 760 765
Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro
770 775 780
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu
785 790 795 800
Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly
805 810 815
Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro
820 825 830
Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr
835 840 845
Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu
850 855 860
Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro
865 870 875 880
Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr
885 890 895
Glu Pro Ser Glu Gly Ser Ala Pro Gly
900 905
<210> 8
<211> 645
<212> PRT
<213> 人工序列
<220>
<223> 阿必鲁肽
<400> 8
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg His Gly
20 25 30
Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala
35 40 45
Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Asp Ala His Lys
50 55 60
Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
65 70 75 80
Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
85 90 95
Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
100 105 110
Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
115 120 125
Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
130 135 140
Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
145 150 155 160
Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
165 170 175
Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
180 185 190
Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
195 200 205
Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
210 215 220
Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
225 230 235 240
Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
245 250 255
Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
260 265 270
Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
275 280 285
Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
290 295 300
Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
305 310 315 320
Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
325 330 335
Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
340 345 350
Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
355 360 365
Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
370 375 380
Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
385 390 395 400
Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
405 410 415
Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
420 425 430
Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
435 440 445
Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
450 455 460
Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
465 470 475 480
Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
485 490 495
Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
500 505 510
Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
515 520 525
Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
530 535 540
Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
545 550 555 560
Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
565 570 575
Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
580 585 590
Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
595 600 605
Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
610 615 620
Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
625 630 635 640
Ala Ala Leu Gly Leu
645
<210> 9
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 利拉鲁肽
<400> 9
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly
20 25 30
<210> 10
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 他司鲁泰
<220>
<221> MOD_RES
<222> (2)
<223> 甲基化,
<220>
<221> MOD_RES
<222> (29)
<223> 甲基化,
<400> 10
His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Xaa Arg
20 25 30
<210> 11
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> GLP-1串联重复
<400> 11
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
50 55 60
Gly Gly Gly Gly Ser His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser
65 70 75 80
Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val
85 90 95
Lys Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
100 105
<210> 12
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 杂种Fc区
<400> 12
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 13
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 杂种Fc臼
<400> 13
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 14
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 杂种Fc杵
<400> 14
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 15
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 杂种Fc杵
<400> 15
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 16
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 杂种Fc臼
<400> 16
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 17
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人GLP-2突变体(A2G)
<400> 17
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 18
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人GLP-2野生型
<400> 18
His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 19
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人GLP-2突变体(A2G, N16G, L17Q)
<400> 19
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Gly
1 5 10 15
Gln Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 20
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人GLP-2突变体(A2G, L17Q)
<400> 20
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Gln Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 21
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> Glepaglutide
<400> 21
His Gly Glu Gly Thr Phe Ser Ser Glu Leu Ala Thr Ile Leu Asp Ala
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Ala Trp Leu Ile Ala Thr Lys Ile Thr
20 25 30
Asp Lys Lys Lys Lys Lys Lys
35
<210> 22
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> GLP-2类似物10
<220>
<221> MOD_RES
<222> (11)
<223> 经由第11个和第18个氨基酸半胱氨酸的硫醇基与脂化的交联剂连接的
<220>
<221> MOD_RES
<222> (18)
<223> 经由第11个和第18个氨基酸半胱氨酸的硫醇基与脂化的交联剂连接的
<400> 22
His Gly Asp Gly Ser Phe Ser Asp Glu Met Cys Thr Ile Leu Asp Asn
1 5 10 15
Leu Cys Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Pro Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 23
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 23
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Ala
20 25 30
Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly
35 40 45
Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu
50 55 60
Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe
65 70 75 80
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
85 90 95
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
100 105 110
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
115 120 125
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
130 135 140
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
145 150 155 160
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
165 170 175
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
180 185 190
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
195 200 205
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
210 215 220
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
225 230 235 240
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
245 250 255
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
260 265 270
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
275 280 285
<210> 24
<211> 301
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 24
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Lys
35 40 45
Asn Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Thr Arg Gly Gly Glu
50 55 60
Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Thr His
65 70 75 80
Thr Cys Pro Pro Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu
85 90 95
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
100 105 110
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
115 120 125
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
130 135 140
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
145 150 155 160
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
165 170 175
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
180 185 190
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys
195 200 205
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
210 215 220
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
225 230 235 240
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
245 250 255
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
260 265 270
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
275 280 285
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
290 295 300
<210> 25
<211> 279
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 25
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Lys
35 40 45
Glu Lys Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro Cys Pro
50 55 60
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
65 70 75 80
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
85 90 95
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
100 105 110
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
115 120 125
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
130 135 140
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
145 150 155 160
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
165 170 175
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
180 185 190
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
195 200 205
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
210 215 220
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
225 230 235 240
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
245 250 255
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
260 265 270
Leu Ser Leu Ser Leu Gly Lys
275
<210> 26
<211> 309
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 26
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Lys Asn Thr Thr Ala Pro Ala Thr Thr
50 55 60
Arg Asn Thr Thr Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys
65 70 75 80
Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro Cys Pro Ser His
85 90 95
Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
100 105 110
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
115 120 125
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
130 135 140
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
145 150 155 160
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
165 170 175
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
180 185 190
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
195 200 205
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
210 215 220
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
225 230 235 240
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
245 250 255
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
260 265 270
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
275 280 285
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
290 295 300
Leu Ser Leu Gly Lys
305
<210> 27
<211> 310
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 27
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser Gly Gly Gly Gly Ser Ala Lys Asn Thr Thr Ala Pro Ala Thr
50 55 60
Thr Arg Asn Thr Thr Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu
65 70 75 80
Lys Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro Cys Pro Ser
85 90 95
His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
100 105 110
Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
115 120 125
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
130 135 140
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
145 150 155 160
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
165 170 175
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
180 185 190
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
195 200 205
Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn
210 215 220
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
225 230 235 240
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
245 250 255
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
260 265 270
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
275 280 285
Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
290 295 300
Ser Leu Ser Leu Gly Lys
305 310
<210> 28
<211> 287
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 28
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg
50 55 60
Thr His Thr Cys Pro Pro Cys Pro Ser His Thr Gln Pro Leu Gly Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr
85 90 95
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
100 105 110
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
115 120 125
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
130 135 140
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
145 150 155 160
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
165 170 175
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
180 185 190
Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
195 200 205
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
210 215 220
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
225 230 235 240
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
245 250 255
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
275 280 285
<210> 29
<211> 309
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 29
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Lys Asn Thr Thr Ala Pro Ala Thr Thr
50 55 60
Arg Asn Thr Thr Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys
65 70 75 80
Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro Cys Pro Ser His
85 90 95
Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln
100 105 110
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
115 120 125
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
130 135 140
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
145 150 155 160
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
165 170 175
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
180 185 190
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
195 200 205
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
210 215 220
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
225 230 235 240
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
245 250 255
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
260 265 270
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
275 280 285
Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
290 295 300
Leu Ser Leu Gly Lys
305
<210> 30
<211> 353
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-1类似物的双特异性融合蛋白的第一融合蛋白
<400> 30
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
50 55 60
Gly Gly Gly Gly Ser His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser
65 70 75 80
Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val
85 90 95
Lys Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
115 120 125
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ser His Thr Gln Pro Leu
130 135 140
Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
165 170 175
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
340 345 350
Lys
<210> 31
<211> 288
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 31
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg
35 40 45
Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu
50 55 60
Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly
65 70 75 80
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
85 90 95
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
100 105 110
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
115 120 125
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
130 135 140
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
145 150 155 160
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
165 170 175
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
180 185 190
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
195 200 205
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
210 215 220
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
225 230 235 240
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
245 250 255
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
260 265 270
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
275 280 285
<210> 32
<211> 281
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 32
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro
50 55 60
Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys
65 70 75 80
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
85 90 95
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
100 105 110
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
115 120 125
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
130 135 140
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
145 150 155 160
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
165 170 175
Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met
180 185 190
Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro
195 200 205
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
210 215 220
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
225 230 235 240
Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
245 250 255
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
260 265 270
Lys Ser Leu Ser Leu Ser Leu Gly Lys
275 280
<210> 33
<211> 303
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 33
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Ala Lys Asn Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Thr Arg Gly
50 55 60
Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg
65 70 75 80
Thr His Thr Cys Pro Pro Cys Pro Ser His Thr Gln Pro Leu Gly Val
85 90 95
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
100 105 110
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
115 120 125
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
130 135 140
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
145 150 155 160
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
165 170 175
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
180 185 190
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
195 200 205
Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
210 215 220
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
225 230 235 240
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
245 250 255
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
260 265 270
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
275 280 285
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
290 295 300
<210> 34
<211> 281
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 34
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro
50 55 60
Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys
65 70 75 80
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
85 90 95
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
100 105 110
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
115 120 125
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
130 135 140
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
145 150 155 160
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
165 170 175
Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met
180 185 190
Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro
195 200 205
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
210 215 220
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
225 230 235 240
Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
245 250 255
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
260 265 270
Lys Ser Leu Ser Leu Ser Leu Gly Lys
275 280
<210> 35
<211> 304
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 35
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Ala Lys Asn Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Thr Arg
50 55 60
Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu
65 70 75 80
Arg Thr His Thr Cys Pro Pro Cys Pro Ser His Thr Gln Pro Leu Gly
85 90 95
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg
100 105 110
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
115 120 125
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
130 135 140
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
145 150 155 160
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
165 170 175
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
180 185 190
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu
195 200 205
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys
210 215 220
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
225 230 235 240
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
245 250 255
Ser Asp Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser
260 265 270
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
275 280 285
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
290 295 300
<210> 36
<211> 278
<212> PRT
<213> 人工序列
<220>
<223> 含有GLP-2类似物的双特异性融合蛋白的第二融合蛋白
<400> 36
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Gly
1 5 10 15
Gln Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ser
50 55 60
His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
65 70 75 80
Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
85 90 95
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
100 105 110
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
115 120 125
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
130 135 140
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
145 150 155 160
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
165 170 175
Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
180 185 190
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
195 200 205
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
210 215 220
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Arg
225 230 235 240
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
245 250 255
Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
260 265 270
Ser Leu Ser Leu Gly Lys
275
<210> 37
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 37
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 38
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 38
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 39
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 39
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
<210> 40
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 40
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
<210> 41
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 41
Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly
1 5 10 15
Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg
20 25 30
Glu Thr Lys Thr Pro Glu Cys Pro
35 40
<210> 42
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 42
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Lys Glu Lys Glu Glu Gln Glu Glu Arg Thr His Thr Cys Pro Pro Cys
20 25 30
Pro
<210> 43
<211> 55
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 43
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
Lys Asn Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Thr Arg Gly Gly
20 25 30
Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Thr
35 40 45
His Thr Cys Pro Pro Cys Pro
50 55
<210> 44
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 44
Ala Ala Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 45
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 46
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 46
Gly Gly Ser Gly Gly
1 5
<210> 47
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 47
Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 48
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 48
Gly Gly Gly Ser Gly Gly
1 5
<210> 49
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头肽单位序列
<400> 49
Gly Gly Gly Gly Ser
1 5
<210> 50
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 接头肽单位序列
<400> 50
Gly Ser Ser Gly Gly Ser
1 5
<210> 51
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 51
Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser
1 5 10 15
Leu Asp
<210> 52
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 52
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr
1 5 10
<210> 53
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 53
Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe
1 5 10
<210> 54
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头肽单位序列
<400> 54
Glu Ala Ala Ala Lys
1 5
<210> 55
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 55
Cys Arg Arg Arg Arg Arg Arg Glu Ala Glu Ala Cys
1 5 10
<210> 56
<211> 46
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 56
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
35 40 45
<210> 57
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 57
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 58
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 58
Gly Gly Gly Gly Gly Gly
1 5
<210> 59
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 59
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Ala Lys Ala
1 5 10
<210> 60
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 60
Pro Ala Pro Ala Pro
1 5
<210> 61
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 61
Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp
1 5 10 15
Val
<210> 62
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 62
Pro Leu Gly Leu Trp Ala
1 5
<210> 63
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 63
Thr Arg His Arg Gln Pro Arg Gly Trp Glu
1 5 10
<210> 64
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 64
Ala Gly Asn Arg Val Arg Arg Ser Val Gly
1 5 10
<210> 65
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 65
Arg Arg Arg Arg Arg Arg Arg Arg
1 5
<210> 66
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 66
Gly Phe Leu Gly
1
<210> 67
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 67
Gly Ser Ser Gly Gly Ser Gly Ser Ser Gly Gly Ser Gly Gly Gly Asp
1 5 10 15
Glu Ala Asp Gly Ser Arg Gly Ser Gln Lys Ala Gly Val Asp Glu
20 25 30
<210> 68
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头肽
<400> 68
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
1 5 10 15
<210> 69
<211> 103
<212> PRT
<213> 人工序列
<220>
<223> IgG1 CH3结构域
<400> 69
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
1 5 10 15
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
20 25 30
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
35 40 45
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
50 55 60
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
65 70 75 80
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
85 90 95
Leu Ser Leu Ser Pro Gly Lys
100
Claims (38)
1.用于治疗代谢综合征的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
2.用于治疗肥胖症的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
3.用于治疗2型糖尿病的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
4.用于治疗非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
5.用于治疗肝纤维化的药物组合物,其包含作为活性成分的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
6.根据权利要求1-5任一项所述的药物组合物,其中所述i)的双特异性融合蛋白包含半衰期延长部分。
7.根据权利要求6所述的药物组合物,其中所述半衰期延长部分插入所述GLP-1类似物和所述GLP-2类似物之间或添加到总融合蛋白的N-末端或C-末端。
8.根据权利要求6所述的药物组合物,其中所述半衰期延长部分是抗体Fc区、PEG、XTEN、PAS(Pro-Ala-Ser)、ELP(弹性蛋白样肽)、富甘氨酸HAP(同型氨基酸聚合物)、GLP(明胶样蛋白)或血清清蛋白。
9.根据权利要求1-5任一项所述的药物组合物,其中所述GLP-1类似物是GLP-1、毒蜥外泌肽3、毒蜥外泌肽4、GLP-1/毒蜥外泌肽4杂种肽、GLP-1-XTEN、毒蜥外泌肽4-XTEN、利西拉来、阿必鲁肽、利拉鲁肽或他司鲁泰。
10.根据权利要求1-5任一项所述的药物组合物,其中所述GLP-1包含由SEQ ID NO: 1或2表示的氨基酸序列。
11.根据权利要求9所述的药物组合物,其中所述毒蜥外泌肽3包含由SEQ ID NO: 3表示的氨基酸序列。
12.根据权利要求9所述的药物组合物,其中所述毒蜥外泌肽4包含由SEQ ID NO: 4表示的氨基酸序列。
13.根据权利要求9所述的药物组合物,其中所述GLP-1/毒蜥外泌肽4杂合体包含由SEQID NO: 5表示的氨基酸序列。
14.根据权利要求9所述的药物组合物,其中所述GLP-1/毒蜥外泌肽4杂合体包含由SEQID NO: 5表示的氨基酸序列。
15.根据权利要求9所述的药物组合物,其中所述利西拉来包含由SEQ ID NO: 6表示的氨基酸序列。
16.根据权利要求9所述的药物组合物,其中所述毒蜥外泌肽4-XTEN包含由SEQ ID NO:7表示的氨基酸序列。
17.根据权利要求9所述的药物组合物,其中所述阿必鲁肽包含由SEQ ID NO: 8表示的氨基酸序列。
18.根据权利要求9所述的药物组合物,其中所述利拉鲁肽包含由SEQ ID NO: 9表示的氨基酸序列。
19.根据权利要求9所述的药物组合物,其中所述他司鲁泰包含由SEQ ID NO: 10表示的氨基酸序列。
20.根据权利要求9所述的药物组合物,其中所述GLP-1串联重复可以包含由SEQ IDNO: 11表示的氨基酸序列。
21.根据权利要求1-5任一项所述的药物组合物,其中所述抗体Fc区是杂种抗体Fc区。
22.根据权利要求21所述的药物组合物,其中所述杂种抗体Fc区是其中至少两种或更多种同种型的至少两个或更多个部分组合的抗体Fc区。
23.根据权利要求21所述的药物组合物,其中所述杂种抗体Fc区由选自SEQ ID NO:12至16的氨基酸序列组成。
24.根据权利要求1-5任一项所述的药物组合物,其中所述GLP-2类似物可以是GLP-2、替度鲁肽、Glepaglutide或GLP-2类似物10。
25.根据权利要求24所述的药物组合物,其中所述GLP-2包含SEQ ID NO:17至20中任一项的氨基酸序列。
26.根据权利要求24所述的药物组合物,其中所述Glepaglutide包含由SEQ ID NO: 21表示的氨基酸序列。
27.根据权利要求24所述的药物组合物,其中所述GLP-2类似物10包含由SEQ ID NO:22表示的氨基酸序列。
28.根据权利要求1-5任一项所述的药物组合物,其中所述第一融合蛋白包含选自SEQID NOs:23至30的氨基酸序列。
29.根据权利要求1-5任一项所述的药物组合物,其中所述第二融合蛋白包含选自SEQID NOs:31至36的氨基酸序列。
30.根据权利要求1-5任一项所述的药物组合物,其中在所述GLP-1类似物和所述GLP-2类似物之间、或在所述GLP-1类似物和所述抗体Fc区之间、或在所述GLP-2类似物和所述抗体Fc区之间插入接头肽。
31.根据权利要求29所述的药物组合物,其中所述接头肽含有或不含N-糖基化位点。
32.根据权利要求31所述的药物组合物,其中所述第一融合蛋白不包含与接头肽的N-糖基化位点,且所述第二融合蛋白包含与接头肽的N-糖基化位点。
33.根据权利要求30所述的药物组合物,其中所述接头肽是EPKSSDKTHTCPPCP(SEQ IDNO: 37)、 EPKSCDKTHTCPPCP(SEQ ID NO: 38)、GGGGSGGGGSGGGGSEPKSSDKTHTCPPCP(SEQ IDNO: 39)、GGGGSGGGGSGGGGSEPKSCDKTHTCPPCP(SEQ ID NO: 40)、AKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECP(SEQ ID NO: 41)、GGGGSGGGGSGGGGSEKEKEEQEERTHTCPPCP(SEQ IDNO: 42)、GGGGSGGGGSGGGGSAKNTTAPATTRNTTRGGEEKKKEKEKEEQEERTHTCPPCP(SEQ ID NO:43)、AAGSGGGGGSGGGGSGGGGS(SEQ ID NO: 44)、GGGGSGGGGSGGGGS(SEQ ID NO: 45)、GGSGG(SEQ ID NO: 46)、GGSGGSGGS(SEQ ID NO: 47)、GGGSGG(SEQ ID NO: 48)、SEQ ID NO:(G4S)n(亚单位:SEQ ID NO: 49,n是1-10的整数)、(GGS)n(n是1-10的整数)、(GS)n(n是1-10的整数)、(GSSGGS)n(亚单位:SEQ ID NO: 50,n是1-10的整数)、KESGSVSSEQLAQFRSLD(SEQID NO: 51)、EGKSSGSGSESKST(SEQ ID NO: 52)、GSAGSAAGSGEF(SEQ ID NO: 53)、(EAAAK)n(亚单位:SEQ ID NO: 54,n是1-10的整数)、CRRRRRREAEAC(SEQ ID NO: 55)、A(EAAAK)4ALEA(EAAAK)4A(SEQ ID NO: 56)、GGGGGGGG(SEQ ID NO: 57)、GGGGGG(SEQ ID NO: 58)、AEAAAKEAAAAKA(SEQ ID NO: 59)、PAPAP(SEQ ID NO: 60)、(Ala-Pro)n(n是1-10的整数)、VSQTSKLTRAETVFPDV(SEQ ID NO: 61、PLGLWA(SEQ ID NO: 62)、TRHRQPRGWE(SEQ ID NO:63)、AGNRVRRSVG(SEQ ID NO: 64)、RRRRRRRR(SEQ ID NO: 65)、GFLG(SEQ ID NO: 66)、GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE(SEQ ID NO: 67)或GSTSGSGKPGSGEGS(SEQ ID NO:68)。
34.在患有代谢综合征的主体中治疗代谢综合征的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
35.在患有肥胖症的主体中治疗肥胖症的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
36.在患有2型糖尿病的主体中治疗2型糖尿病的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
37.在患有NAFLD或NASH的主体中治疗NAFLD或NASH的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
38.在患有肝纤维化的主体中治疗肝纤维化的方法,包括向所述主体施用治疗有效量的i)其中GLP-1类似物和GLP-2类似物彼此融合的双特异性融合蛋白;或ii)双特异性融合蛋白,其包含包含与抗体Fc区连接的GLP-1类似物的第一融合蛋白和包含与抗体Fc区连接的GLP-2类似物的第二融合蛋白并通过所述第一融合蛋白和所述第二融合蛋白的二聚化产生。
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