CN115485292A - 新的双特异性蛋白及其用途 - Google Patents
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- CN115485292A CN115485292A CN202180034304.8A CN202180034304A CN115485292A CN 115485292 A CN115485292 A CN 115485292A CN 202180034304 A CN202180034304 A CN 202180034304A CN 115485292 A CN115485292 A CN 115485292A
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Abstract
本发明涉及一种新的双特异性融合蛋白及其用途。更具体地,本发明涉及:其中GLP‑1类似物和GLP‑2类似物融合的双特异性融合蛋白,或包含其中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区的第二融合蛋白的双特异性融合蛋白,其中所述双特异性融合蛋白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;以及包含其作为活性成分的药物组合物,用于治疗需要肠生长的疾病或症状或代谢疾病,如肥胖症、2型糖尿病和非酒精性脂肪性肝炎。
Description
技术领域
本发明涉及一种新的双特异性蛋白及其用途,且更具体地,涉及一种包含GLP-1类似物和GLP-2类似物的双特异性蛋白及其用途。
背景技术
GLP-1和GLP-2是肽激素,它们作为称为胰高血糖素原(proglucagons)的前体表达,并通过一系列组织特异性蛋白切割过程产生。具体而言,GLP-1是由脑干孤束核中的特定神经细胞和小肠中的肠内分泌L-细胞在摄入食物时产生和分泌的,其中初始产物GLP-1(1-37)容易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))。由于活性GLP-1以葡萄糖依赖性方式发挥作用以降低血糖水平,所以它已被开发并用作2型糖尿病的治疗剂。此外,GLP-2是一种在也释放GLP-1的过程中由胰高血糖素原的特定翻译后蛋白酶剪切产生的具有33个氨基酸的肽,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。在养分摄食时,肠GLP-2与GLP-1一同共分泌。当外部施用时,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(neuroprotection),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。
如上所述,GLP-1之前因其在治疗2型糖尿病患者中对葡萄糖稳态的有益作用而引起注意(Gutniak等人, N. Engl. J. Med. 326: 1316-1322, 1992)。然而,与GLP-2类似,其在治疗短肠综合征中的作用已从表明减少的胃肠分泌和动力的研究发现中得到暗示(Kunkel等人, Neurogastroenterol. Motil. 23: 739-e328, 2011)。此外,已报道通过GLP-1激活GLP1R信号传导系统促进肠的生长和隐窝细胞的融合(Koehler等人, Cell Metabol. 21(3): 379-391, 2015)。基于这一机制,Naia Pharmaceuticals Inc.正在使用GLP-1-XTEN进行短肠综合征的1期临床试验,所述GLP-1-XTEN具有与GLP-1连接的半衰期延长肽XTEN。此外,已报道,与当单独施用每种肽时相比,GLP-1和GLP-2的共同施用显示出对肠吸收的加性效应(Madsen等人, Regul. Pept. 184: 30-39, 2013)。
另一方面,非酒精性脂肪肝疾病(NAFLD)不是单一疾病,而是包括范围从无炎症的单纯性脂肪肝一直到慢性肝炎和肝硬变的各种类型的肝病,并且已知与肥胖和与之有关的胰岛素抵抗有紧密联系。非酒精性脂肪肝疾病的疾病严重程度可能不同,范围从没有肝细胞损伤的轻度脂肪肝一直到有严重和持续性肝细胞损伤的脂肪性肝炎(steatohepatitis),且甚至到伴有腹水或脓病的肝纤维化或肝硬变,并且已知如果进一步进展的话则进展为肝癌,并且是由于西式饮食的流行而发病率迅速增加的西方疾病(Western disease)。大多数非酒精性脂肪肝疾病是轻度的疾病,但不是可以安全忽视的症状,这是因为如果使其不治疗的话,四分之一的具有严重脂肪肝的患者随着时间的过去逐渐发展为肝硬变(或肝纤维化),这是严重的肝病。非酒精性脂肪肝疾病的流行根据群体特征而不同,且据报道在正常人中为10-24%,而在肥胖人中为58-74%。然而,目前还没有药物被批准作为非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的治疗剂,且因此,用于非酒精性脂肪肝疾病的治疗剂的开发被认为是一项非常紧迫的任务。
此外,还没有开发出使用GLP-1R和GLP-2R的双重激动剂的对于诸如非酒精性脂肪性肝炎的代谢综合征的治疗药物,所述双重激动剂与单一激动剂GLP-1R相比表现出更好的效果。
发明内容
技术问题
为了解决包括上述问题在内的各种问题,本发明的目的是提供一种新的双特异性蛋白,所述蛋白能够处理传统GLP-2类似物和GLP-1类似物的缺点,同时保留GLP-1和GLP-2的功能,且在治疗诸如非酒精性脂肪肝疾病的代谢综合征中有效。然而,本发明的保护范围不受上述目的的限制。
技术方案
根据本发明的一个方面,提供了一种具有彼此融合的GLP-1类似物和GLP-2类似物的双特异性融合蛋白。
根据本发明的另一个方面,提供了一种双特异性融合蛋白,其包含具有与抗体Fc区连接的GLP-1类似物的第一融合蛋白,和具有与抗体Fc区连接的GLP-2类似物的第二融合蛋白,其中所述双特异性融合蛋白由第一融合蛋白和第二融合蛋白的二聚化产生。
根据本发明的另一个方面,提供了一种包含所述双特异性融合蛋白的药物组合物。
根据本发明的另一个方面,提供了一种用于治疗非酒精性脂肪性肝炎的药物组合物,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据本发明的另一个方面,提供了一种用于治疗代谢综合征的药物组合物,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据本发明的另一个方面,提供了一种在患有需要肠增殖的疾病的主体中治疗需要肠增殖的疾病或症状的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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代谢综合征的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据本发明的另一个方面,提供了一种在患有非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的主体中治疗非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
有利效果
本发明的双特异性融合蛋白在体内施用时可显著增加肠增殖,且因此可极其有效地用于治疗需要肠增殖的疾病,例如,疾病如短肠综合征,或代谢病如代谢综合征,肥胖症,2型糖尿病,非酒精性脂肪肝疾病和肝纤维化。
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3c是显示了在还原和非还原条件中根据本发明实施方案的MG12-6的SDS-PAGE分析结果的一系列凝胶图像(左)和显示了纯化的蛋白的HPLC结果的层析谱(右)。
M:大小标记;
1:MG12-6;和
C:对照(3 μg)-赫赛汀(Herceptin)。
图3d是显示了在还原和非还原条件中根据本发明实施方案的MG12-7和MG12-8的SDS-PAGE分析结果的一系列凝胶图像(左)和显示了纯化的蛋白的HPLC结果的层析谱(右)。
M:大小标记;
1:MG12-7;
2:MG12-8;和
3:对照(3 μg)-赫赛汀。
图3e是显示了在还原和非还原条件中根据本发明实施方案的MG12-9的SDS-PAGE分析结果的凝胶图像(顶部)和显示了纯化的蛋白的HPLC结果的层析谱(底部)。层析谱的顶部显示大小标记:
1:还原MG12-9;
2:非还原MG12-9;和
3:对照(3 μg)-BSA。
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是显示如通过萤光素酶报道基因测定所分析的根据本发明的实施方案的GLP-1-Fc同二聚体的GLP-1活性的图。
图6b是显示如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6c是显示如通过萤光素酶报道基因测定所分析的根据本发明的实施方案的MG12-2蛋白的GLP-1活性的图。
图6d是显示如通过荧光光谱学所分析的根据本发明的实施方案的MG12-2蛋白的GLP-2活性的图。
图7a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7b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8a是显示将根据本发明的实施方案的各种蛋白二聚体(GLP-2-2G、GLP-2-Fc同二聚体和MG12-5)施用于模型动物之后的肠重量的图。
图8b是显示将根据本发明的实施方案的各种蛋白二聚体(GLP-2-2G、GLP-2-Fc同二聚体和MG12-5)施用于模型动物之后12天期间的体重变化的图。
图8c是显示如在将根据本发明的实施方案的各种蛋白二聚体(GLP-2-2G、GLP-2-Fc同二聚体和MG12-5)施用于模型动物之前所测量的能量吸收的图。
图8d是显示如在将根据本发明的实施方案的各种蛋白二聚体(GLP-2-2G、GLP-2-Fc同二聚体和MG12-5)施用于模型动物后1周所测量的能量吸收的图。
图8d是显示如在将根据本发明的实施方案的各种蛋白二聚体(GLP-2-2G、GLP-2-Fc同二聚体和MG12-5)施用于模型动物后2周所测量的能量吸收的图。
图9a是显示将根据本发明的实施方案的各种双特异性蛋白(MG12-1和MG12-4)和对照组(GLP-1-Fc同二聚体和GLP-2-Fc同二聚体)施用于模型动物后13天小肠重量变化的图。
图9b是显示将根据本发明的实施方案的各种双特异性融合蛋白(MG12-1和MG12-4)和对照组(GLP-1-Fc同二聚体和GLP-2-Fc同二聚体)施用于模型动物后13天测量的体重变化的图。
图10是显示施用根据本发明的实施方案的各种双特异性融合蛋白(MG12-1和MG12-4)和对照组(GLP-1-Fc同二聚体)后的模型动物的脑、小肠和大肠中荧光强度结果的图。
图11是显示在施用于模型动物后根据本发明的实施方案的各种双特异性融合蛋白(MG12-1、MG12-4和MG12-5)和对照组(仅Fc、GLP-1-Fc同二聚体和GLP-2-Fc同二聚体)在肝、小肠和大肠中如通过PET-MRI所分析的分布的一系列图。
图12a是显示在将根据本发明的实施方案的各种双特异性融合蛋白(MG12-1、MG12-3、MG12-4和MG12-5)以及毒蜥外泌肽4(Ex-4)、GLP-2-2G和毒蜥外泌肽4与GLP-2-2G的组合(Ex-4 +GLP-2-2G)施用于实验动物达12天后的小肠重量测量结果的图。
图12b是显示在将根据本发明的实施方案的各种双特异性融合蛋白(MG12-1、MG12-3、MG12-4和MG12-5)以及毒蜥外泌肽4(Ex-4)、GLP-2-2G和毒蜥外泌肽4与GLP-2-2G的组合(Ex-4 +GLP-2-2G)施用于实验动物达12天后的体重增加对饲料摄入测量结果的图。
图12c是显示在施用根据本发明的实施方案的各种双特异性融合蛋白(MG12-1、MG12-3、MG12-4和MG12-5)以及毒蜥外泌肽4(Ex-4)、GLP-2-2G和毒蜥外泌肽4与GLP-2-2G的组合(Ex-4 +GLP-2-2G)达12天后从实验动物取出的十二指肠中黏膜深度和绒毛高度测量结果的图。
图12d是显示在施用根据本发明的实施方案的各种双特异性融合蛋白(MG12-1、MG12-3、MG12-4和MG12-5)以及毒蜥外泌肽4(Ex-4)、GLP-2-2G和毒蜥外泌肽4与GLP-2-2G的组合(Ex-4 +GLP-2-2G)达12天后从实验动物取出的空肠中黏膜深度和绒毛高度测量结果的图。
图13a是示意性地显示了用于胆碱缺乏的高脂肪饮食代谢综合征模型动物的根据本发明的实施方案的MG12给药方案的示意图。
图13b是显示在根据图13a中所示的实验方案进行的动物实验中随着时间的过去体重变化的图。
图13c是显示在根据图13a中所示的实验方案进行的动物实验中在药物施用后随着时间的过去体重中的相对变化的图。
图13d是显示在根据图13a中所示的实验方案进行的动物实验中饲料摄入量的测量结果的图。
图14a是显示对于分别用于根据图13a中所示的实验方案进行的动物实验中的实验组进行的腹膜内葡萄糖耐量试验结果的图,且显示了在限饲(feed restriction)12小时后以2 g/kg的剂量腹膜内施用葡萄糖后以一定时间间隔测量总共3小时的血糖水平的记录。
图14b是显示作为血糖变化的曲线下面积(area under the curve)(AUC)测量图14a的实验结果的结果的图。
图15a是从分别在根据图13a中所示的实验方案进行的动物实验结束时处死的实验组的实验动物切除的肝组织的照片。
图15b是显示分别在图15a中的实验组的实验动物的肝组织重量的图。
图15c是显示分别在图15a中的实验组中的实验动物的血液AST水平的测量结果的图表。
图16a显示了显示制备严重NASH-诱导的模型动物的方法和用于动物实验以施用根据本发明的实施方案的MG-12、阴性对照组(媒介物)和作为阳性对照组的奥贝胆酸(obeticholic acid)(OCA)的给药方案的图。
图16b是显示在根据图16a中所举例说明的实验方案进行的动物实验中,在第8周之后每个实验组随着时间的过去体重变化的测量结果的图。
图16c是显示从分别在根据图16a中所举例说明的实验方案进行的动物实验结束时处死的实验组中的实验动物切除的肝组织的重量测量结果的图。
图16d是一系列图,其显示了在根据图16a中所举例说明的实验方案进行的动物实验中每个实验组的血液AST(左)和ALT(右)水平的测量结果。
图16e是显示在根据图16a中所举例说明的实验方案进行的动物实验中每个实验组的NAFLD活动性分数的测量结果的图。
具体实施方式
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”指在生物学上发挥GLP-1的功能并可以通过与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”指在生物学上发挥GLP-2的功能并可以通过与GLP-2受体结合介导下游信号传导的蛋白,且也称为“GLP-2受体激动剂”。
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。
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,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。
如本文所用的,术语“吸收障碍”指由肠道,特别是小肠中的养分的部分或完全不吸收引起的疾病。首先,吸收障碍的主要原因可能包括原发性先天性异常,如二糖分解酶的缺乏,如乳糖和糖,胰和小肠中消化酶缺乏等,以及小肠黏膜中对于葡萄糖和维生素B12的传递障碍等,且其次,吸收障碍的次要原因可能包括由肠疾病等引起的持续性吸收障碍以及其他原因,例如肠道中酶的缺乏,正常肠道细菌中的变化,由于胰、肝、胆囊等中疾病的消化不足,由于寄生物、胃痛等的肠道中的疾病,以及由于肠切除外科手术的减少的吸收表面等。危险因素包括过度酒精消费、肠切除、吸收障碍或囊性纤维化的家族史以及使用矿物油或其他缓泻药等。
本文所用的术语“炎性肠病”指特征在于经历反复缓和和复发的肠道异常慢性炎症的疾病,且常见的例子包括溃疡性结肠炎和克罗恩病,且其确切发病机理尚未阐明。炎性肠病的诊断是通过考虑各种发现来进行的,包括临床症状、内窥镜和组织病理学发现、血液试验发现和放射学发现。炎性肠病是一种特征在于症状反复缓和和复发的慢性疾病,且其治疗目标是调节症状、预防并发症和提高生活质量,而不是疾病的完全恢复。
如本文所用的,术语“溃疡性结肠炎”是诸如克罗恩病和Behcet氏病的炎性肠病之一,且指特征在于大肠中未知原因的慢性炎症或溃疡的疾病。溃疡性结肠炎的确切原因仍不知道。在大多数病例中,症状反复经历复发和缓和,且因此被认为是用现代医学难以治疗的不能医治的疾病。
如本文所用的,术语“Bechete氏病”是一种自身免疫病,其特征在于体内的黏膜,尤其是胃肠道的黏膜通过身免疫而破坏。Bechet氏病被认为是一种不能医治的疾病,其表现各种症状,其中病变位置取决于个体而不同,且如果病变出现在诸如神经系统、胃肠系统、眼系统和血管系统中的区域,则可能是致命的。目前,对于Bechet氏病没有根本的治疗。
如本文所用的,“短肠综合征(SBS)”是一种吸收障碍病症,其可由外科手术去除部分小肠或肠节段的功能异常引起。例如,大多数病症是由克罗恩病、消化道的炎性病症、肠扭转、由于血液供给中断导致组织死亡的小肠自发扭转、小肠中的肿瘤、小肠中的伤口或创伤、坏死性肠结肠炎、用于肥胖症治疗的旁路外科手术和用于小肠疾病的外科手术或小肠受损部分的去除引起的。同样地,一些婴儿天生具有短的肠。
如本文所用的,术语“代谢综合征”是推测由胰岛素抵抗引起的疾病,并且指特征在于胆固醇、血压和血糖的两种或更多种异常水平的症状。代谢综合征是心血管疾病和2型糖尿病的一组危险因素,被概念化为一个疾病组。这是可以综合解释胰岛素抵抗(IR)和相关的复杂和各种代谢异常和临床特征的有用的概念。如果未被注意,则已知代谢综合征增加发展诸如动脉硬化、心肌梗死和卒中的心血管疾病或2型糖尿病的危险。
发明详述:
根据本发明的一个方面,提供了一种具有彼此融合的GLP-1类似物和GLP-2类似物的双特异性融合蛋白。
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。
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。
根据一个方面,提供了双特异性融合蛋白,其包含具有与抗体fc区连接的GLP-1类似物的第一融合蛋白和具有与抗体fc区连接的GLP-2类似物的第二融合蛋白,并且通过第一融合蛋白和第二融合蛋白的二聚化形成。
在双特异性融合蛋白中,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。
此外,在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。
在双特异性融合蛋白中,GLP-1可以包含由SEQ ID NO: 1或2表示的氨基酸序列。
在双特异性融合蛋白中,毒蜥外泌肽3可以包含由SEQ ID NO: 3表示的氨基酸序列。
在双特异性融合蛋白中,毒蜥外泌肽4可以包含由SEQ ID NO: 4表示的氨基酸序列。
在双特异性融合蛋白中,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。
在双特异性融合蛋白中,利西拉来可以包含由SEQ ID NO: 6表示的氨基酸序列。
在双特异性融合蛋白中,毒蜥外泌肽4-XTEN可以包含由SEQ ID NO: 7表示的氨基酸序列。
在双特异性融合蛋白中,阿必鲁肽可以包含由SEQ ID NO: 8表示的氨基酸序列。
在双特异性融合蛋白中,利拉鲁肽可以包含由SEQ ID NO: 9表示的氨基酸序列。
在双特异性融合蛋白中,他司鲁泰可以包含由SEQ ID NO: 10表示的氨基酸序列。
在双特异性融合蛋白中,GLP-1串联重复可以包含由SEQ ID NO: 11表示的氨基酸序列。
在双特异性融合蛋白中,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SEQ ID 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 ID NO: 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、glepaglutide或GLP-2类似物10。
在双特异性融合蛋白中,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-2 A2G、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SEQ ID NO: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。
在双特异性融合蛋白中,Glepaglutide可以包含由SEQ ID NO: 21表示的氨基酸序列。
在双特异性融合蛋白中,GLP-2类似物10可以包含由SEQ ID NO: 22表示的氨基酸序列。
在双特异性融合蛋白中,第一融合蛋白可以包含选自SEQ ID NOs:23至30的氨基酸序列。
在双特异性融合蛋白中,第二融合蛋白包含选自SEQ ID NOs:31至36的氨基酸序列。
在双特异性融合蛋白中,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。
在双特异性融合蛋白中,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,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,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)。
根据本发明的另一个方面,提供了一种包含双特异性融合蛋白的药物组合物。
所述药物组合物可用于治疗需要肠增殖的疾病或症状。
需要肠增殖的疾病或症状可以是吸收障碍、炎性肠病或短肠综合征。
在药物组合物中,炎性肠病可以是溃疡性结肠炎、Behcet氏病或克罗恩病。
根据本发明实施方案的双特异性融合蛋白在体内施用时具有显著改善小肠中绒毛长度和隐窝深度以及增加胃肠道特别是小肠长度的效果,且因此可以有效地用于治疗需要肠增殖和功能改善的疾病,例如短肠综合征。
根据本发明的另一个方面,提供了一种用于治疗非酒精性脂肪性肝炎的药物组合物,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据本发明的另一个方面,提供了一种用于治疗代谢综合征的药物组合物,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
根据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,其包含一种或多种这样的双特异性融合蛋白作为活性成分。
作为GLP-1受体激动剂的毒蜥外泌肽-4已在临床试验中证明在控制患有2型糖尿病的患者的血糖水平和体重中有效(DeFronzo等人, Diabetes Care 28: 1092-1100,2005),根据本发明实施方案的双特异性融合蛋白可用于治疗肥胖症相关疾病,例如代谢综合征,以及肥胖症和2型糖尿病。
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 Pharmaceutical Sciences,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。
根据本发明的另一个方面,提供了一种在患有需要肠增殖的疾病的主体中治疗需要肠增殖的疾病或症状的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
在治疗方法中,需要肠增殖的疾病或症状可以是吸收障碍、炎性肠病或短肠综合征,且可以优选是短肠综合征。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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代谢综合征的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据本发明的另一个方面,提供了一种在患有非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的主体中治疗非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的方法,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
根据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,所述方法包括向所述主体施用治疗有效量的双特异性融合蛋白。
在治疗方法中,肝纤维化可以是由慢性非酒精性脂肪性肝炎引起的肝纤维化。
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和MG12-9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5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。
此外,本发明人合成了编码MG12-6至MG12-9的多核苷酸,且然后使用用于在动物细胞中暂时表达的N293F载体系统(YBiologics)转染HEK293F细胞,以进行质粒DNA转染。对于核酸制备,将25 μg质粒DNA与3 ml培养基混合,且然后与25 μg的2 mg/ml PEI(聚乙烯亚胺,PolyPlus,美国)混合。将反应溶液于室温放置15分钟,然后放入80-1000 ml以1×10 6个细胞/ml培养的培养溶液中,并在120 rpm、37℃和8%CO2温育24小时。DNA转染后24小时,添加营养补料培养基组分(Soytone, BD,美国)至10 g/L的终浓度。培养7天后,将细胞培养基以5,000 rpm离心10分钟,且收集上清液。然后,将A蛋白树脂填充到柱中并通过用1xDPBS洗涤来制备,且收集的上清液于4℃以 0.5 ml/分钟的速率与树脂结合,且蛋白用 0.1M甘氨酸洗脱。为了更换缓冲液,将洗脱的溶液放入透析管(GeBAflex tube, Geba,以色列)中并用1x DPBS于4℃透析,并将由此获得的材料在PBS(pH 7.4)缓冲液中配制。
如此获得的MG12-6至MG12-9也在如上文所述的还原和非还原条件下经受SDS凝胶电泳。结果,如图3c至3e所示的,证实了根据本发明实施方案的异二聚体融合蛋白正常表达。
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:MG12-2的体外GLP-1和GLP-2活性分析
本发明人研究了在实施例1、3和4的含有添加到GLP-1和杂种Fc区之间的铰链部分的聚糖链的融合蛋白和进行设计从而使得聚糖链添加到GLP-2和杂种Fc区之间的铰链部分而含有GLP-1的融合蛋白不含聚糖链的实施例2的双特异性融合蛋白(MG12-2)的情况下,与GLP-1-Fc同二聚体和GLP-2-Fc同二聚体相比,GLP-1和GLP-2活性怎样不同。
结果,如表4和图6a至6d中所示的,对于GLP-1和GLP-2活性,本发明实施例2的双特异性融合蛋白(MG12-2)分别显示出与GLP-1-Fc同二聚体相比约11.2%的活性和与GLP-2-Fc同二聚体相比约17.5%的活性。这表明GLP-1活性与MG12-1的水平相似,但GLP-2活性是其他 MG12-2变体的约1/5-1/4。
表4
根据本发明实施例2的双特异性融合蛋白的体外GLP-1和GLP-2活性
实验例4: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5和6以及图7a和7b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5
实施例 | C<sub>max </sub>(ng/mL) | T<sub>max </sub>(h) | 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6
实施例 | C<sub>max </sub>(ng/mL) | T<sub>max </sub>(h) | 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5:体内活性的确认
5-1:实验动物中小肠变化及养分吸收变化的分析
为了观察物质施用后小肠和养分吸收能力的变化,在B6正常小鼠中进行了实验。PBS和GLP-2-2G每天施用两次,且GLP-2-Fc同二聚体和MG12-5每三天施用一次达2周。对于GLP-2-Fc同二聚体和MG12-5组,在不施用药物的时间段期间,如在其他施用组中那样,每天施用两次PBS。以3-天时间间隔监控体重和饮食摄入,并在施用前、施用后第5-6天和施用后第11-12天收集粪便,并使用弹式量热器进行热量测定法,且同样,在所述时间段此期间摄食的饲料也通过相同的分析经受热量测定法。能量吸收率被定义为通过从摄食的饲料的热值减去粪便的热值而获得的值。药物施用后第14天,处死实验动物,并称重小肠(幽门回肠)。
结果,如图8a中所示的,在给药时间段期间,与对照组相比,在其他实验组中观察到小肠重量增加,其中MG12-5施用组显示最显著的小肠重量增加,且如图8b、8d和8e中所示的,所述发现与在体重增加和能量吸收率变化中观察到的趋势一致。特别地,如图8d中所示的,就施用一周后能量吸收率的变化而论,只有根据本发明实施方案的MG12-5施用组显示了显著的渐增趋势。另一个方面,如图8c中所示的,在施用每种测试物质之前进行的实验中没有观察到能量吸收率的变化。然而,在含有GLP-2的药物施用组中有增加的体重的倾向,且发现MG12-5组与阴性对照组(媒介物施用组)相比显示出显著的增加。发现施用前所有组的能量吸收率相似,且在第 1周,其是在第二次给药后,在施用含GLP-2的药物的组中有渐增趋势,但只有MG12-5显示与媒介物施用组(媒介物)相比统计学显著的增加,并且在第四次给药后的第2周显示出比GLP-2-Fc同二聚体(homo)甚至更显著的增加。在所有药物施用结束后,测量各组的小肠重量。与能量吸收相似,与对照组相比,在施用含有GLP-2的药物的组中观察到显著增加,且尤其是MG12-5与其他两个药物施用组相比显示出统计学显著的增加。
总之,发现MG12-5具有比GLP-2-2G和GLP-2-Fc同二聚体更好的增加小肠重量的效果,且这被认为使得能够更有效地吸收摄食的饲料的卡路里,从而导致与其他药物施用组相比统计学显著的体重增加。
此外,本发明人在仅仅改变施用的物质的情况下进行了与上述相同的实验,以确认以除MG12-5以外的形式设计的双特异性融合蛋白(MG12-1和MG12-4)是否也增加实验动物的小肠重量和能量吸收率。具体而言,皮下施用PBS、10 nmol/kg GLP-1-Fc同二聚体、10nmol/kg GLP-2-Fc同二聚体、20 nmol/kg MG12-1和20 nmol/kg MG12-4。所述药物每周施用两次,达总共4次2周。4次给药后,在尸体剖检前测量体重,且在尸体剖检后切除小肠并称重。在尸体剖检后,将小鼠的整个胃肠道分离,切除肠系膜和胰,并切割回肠和盲肠会合的区域以将小肠和大肠分离。分离的小肠用10%的中性福尔马林灌注和洗涤以去除内容物,且在用吸水毛巾除去中性福尔马林后称重。
作为实验的结果,如在图9a和9b中所示的,与阴性对照组相比,在GLP-1-Fc同二聚体和GLP-2-Fc同二聚体施用组中观察到小肠重量增加,并且在GLP-2-Fc同二聚体施用组中观察到统计学显著的增加。MG12-1和MG12-4施用组显示出比GLP-2-Fc同二聚体施用组更大的小肠重量增加,且与阴性对照组相比,两组都显示统计学显著的小肠重量增加。就在尸体剖检前的重量变化而论,与阴性对照组相比,在GLP-1-Fc同二聚体中有数值减少,且在GLP-2-Fc同二聚体中没有变化,而在MG12-1和MG12-4施用组两者中均观察到体重的数值增加。在所有药物施用组中均未观察到统计学显著的变化。
总之,发现当施用于正常小鼠时,MG12-1和MG12-4施用组与GLP-1-Fc同二聚体和GLP-2-Fc同二聚体相比显示出更好的增加小肠重量和增加体重的效果。
5-2:荧光光谱测定法
然后,本发明人在B6正常小鼠中进行了实验,以观察根据本发明实施方案的双特异性融合蛋白的施用在各组织和器官中的分布。Cy5.5用作荧光团,用于跟踪每种物质施用后的分布。使用硼酸缓冲液(pH 8.5)对每种待施用的物质MG12-1、MG12-4和GLP-1Fc同二聚体进行缓冲液更换,并参考Cy5.5标记试剂盒(GE,#PA15605)的规程使其在冷藏条件下与合适量的Cy5.5反应过夜。通过PBS置换过程除去反应完成的物质中未反应的Cy5.5,并通过最终的SDS-PAGE确认Cy5.5是否充分反应。在施用前将每种施用的物质用10%DMSO/PBS稀释至使用能够测量荧光强度的ELISA平板读出器具有相同的荧光强度。药物施用后,在24小时后进行尸体剖检和灌注,估计为Tmax,以比较和评价每种施用的药物在脑、小肠和大肠中的分布。
结果,如在表7和图10中所示的,三种施用的药物在脑中的分布没有显示出显著差异,并且发现MG12-1和MG12-4在小肠和大肠中的分布与GLP-1-Fc同二聚体相比更大,且这是统计学显著的差异。
总之,当将Cy5.5-缀合的GLP-1-Fc同二聚体、MG12-1、MG12-4施用于正常小鼠时,发现MG12-1和MG12-4在小肠和大肠中与GLP-1-Fc同二聚体相比以更大的量分布。
表7
各器官中的平均荧光强度
5-3:PET-MRI分析
然后,本发明人在Balb/c-裸鼠中进行了实验,以观察物质施用后在每种组织器官中的分布。Zr89用作放射性示踪元素,用于跟踪每种物质施用后的分布。每种待施用的物质都用Zr89作为反应条件和通过初步测试选择的螯合剂进行标记。使用PD-10柱纯化标记的Zr89-蛋白,并使用Radio TLC和SEC-HPLC确认Zr89标记效率和纯度。90%或更高的Zr89-蛋白的标记效率和80%或更高的纯度被确定为适当的,且标记的蛋白以0.2 mCi/0.2 cc皮下施用。将每种施用物质施用于三只动物,并在注射后1小时、6小时、24小时、48时和168小时使用PET-MRI获得20分钟的静态图像。通过图像分析,药物在肝、小肠和大肠中随时间而变的分布被表示为SUV(标准化摄入值(Standardized Uptake Value))并进行比较分析。
作为分析的结果,如在图11中所示的,当仅施用Fc时,在三种器官之间没有特别可区别的分布特征。对于GLP-1-Fc同二聚体和GLP-2-Fc同二聚体,在所有三种器官中SUV值均与Fc相比增加,且特别地在小肠和大肠中的增加略微更大。在MG12-1、MG12-4和MG12-5的情况下,与Fc相比,向肝的分布减少或没有差异,且与GLP-1-Fc同二聚体和GLP-2-Fc同二聚体相比,向小肠和大肠的分布显著更高。所述趋势在MG12-1和MG12-4中更为普遍。
总之,在对Balb/c-裸鼠施用Zr89-附着的Fc、GLP-1-Fc同二聚体、GLP-2-Fc同二聚体、MG12-1、MG12-4和MG12-5后观察到MG12-1、MG12-4和MG12-5的分布。结果,在 MG12-1、MG12-4和MG12-5中,发现物质向小肠和大肠的分布与Fc、GLP-1-Fc同二聚体和GLP-2-Fc同二聚体相比增加。
实验例6:MG12对GLP-1和GLP-2组合的显著效果
本发明人努力比较根据本发明实施方案的双特异性融合蛋白与GLP-1和GLP-2的简单共同施用的效果。
特别地,为了观察物质施用后体重和小肠的变化,在B6正常小鼠中进行了实验。进行了PBS(媒介物),10 nmol/kg 毒蜥外泌肽4(Ex-4),33.3 nmol/kg GLP-2-2G,Ex-4 +GLP-2-2G,33.3 nmol/kg MG12-1,33.3 nmol/kg MG12-3、33.3 nmol/kg MG12-4和33.3nmol/kg MG12-5的皮下施用。对于Ex-4、GLP-2-2G和Ex-4+GLP-2-2G,药物每天施用2次达总共24次12天,且对于其他组,药物每周施用2次达总共4次12天。在测试时间段期间开始每周两次药物施用后,测量饲料摄入并表示为累积饲料摄入,并测量尸体剖检前体重以计算体重对饲料摄入。尸体剖检后,测量小肠重量,以及十二指肠和空肠的黏膜深度和绒毛高度。更具体地,在尸体剖检后,将小鼠的整个胃肠道分离,切除肠系膜和胰,并切割回肠和盲肠会合的区域以分离小肠和大肠。将分离的小肠用10%中性福尔马林灌注以除去内容物,且在用吸水毛巾除去中性福尔马林后称重。从称重的小肠中,适当切割十二指肠和空肠部分,并用10%中性福尔马林固定,且用于组织病理学检查。
结果,与对照组(媒介物)相比,Ex-4和GLP-2-2G施用组显示小肠重量的增加,且除Ex-4之外的所有其他实验组与对照组相比都显示小肠重量的统计学显著的增加(图12a)。对于Ex-4+GLP-2-2G施用组,小肠重量的增加在数值上大于当每种物质单独施用时,并且在根据本发明实施方案的MG12的情况下,与共同施用组相比,观察到小肠重量的数值上更大的增加。特别地,与共同施用组相比,MG12-5显示小肠中统计学显著的增加。在十二指肠和空肠的黏膜深度和绒毛高度的测量结果中观察到了类似的趋势(图12C和12D)。为了确认来自小肠形态增加的体重增加,通过相对于累积饲料摄入归一化来比较体重增加趋势。结果,如在图12b中所示的,与对照组相比,在Ex-4和共同施用组中略有增加,且MG12与共同施用组相比显示了数值上更大的体重增加,且特别地,MG12-3、MG12-4和MG12-5与共同施用组相比显示出统计学显著的体重增加。
总之,当对正常小鼠施用时,用根据本发明实施方案的双特异性融合蛋白(MG12)施用的组与Ex-4 + GLP-2-2G相比在小肠重量、组织病理学变化和相对于饲料摄入归一化的体重变化方面显示出优异的效果。
实验例7:MG12蛋白对代谢综合征的治疗作用
本发明人努力以确认根据本发明实施方案的MG12是否对除了短肠综合征之外的各种代谢综合征具有治疗作用。
为此,特别地,关于通过高脂肪饮食诱发脂肪肝和脂肪性肝炎的实验动物,如图13a和表8中所示的,本发明人使用8-周龄的C57BL/6J雄性小鼠进行12周的胆碱缺乏高脂肪饮食(CD-HFD),且然后连同CD-HFD饮食每周两次皮下施用20 nmol/kg的MG12-5和MG12-8以及各10 nmol/kg的GLP-1和GLP-2组合(combo)达4周,并进行各种血清学和组织学分析。
表8
每个实验组的饮食条件、施用的物质和剂量
7-1:体重变化和食物摄入变化分析
首先,本发明人记录了在实验时间段期间实验动物的体重和食物摄入的变化。结果,如图13b和13c中所示的,当施用本发明的MG12时,实验动物的体重显著降低,且特别地,施用根据本发明实施方案的MG12-5和MG12-8的组与正常饮食组(NCD+PBS)和GLP-1和GLP-2组合施用组相比显示出更大的相对体重减轻效果,且如图13D中所示的,与正常饮食组或combo-施用组相比,显示更低的饲料摄入。这提示根据本发明实施方案的双特异性融合蛋白具有优于GLP-1和GLP-2的简单共同施用的效果。
7-2:血糖降低效果分析
然后,本发明人研究了根据本发明的实施方案的MG-12的除体重减轻效果之外的血糖降低效果。
如上所述,在CD-HFD上16周后,在限制食物12小时后,每周两次用药物(MG12-5、MG12-8 和GLP-1和GLP-2 combo)治疗达4周的小鼠以2 g/kg的剂量腹膜内施用葡萄糖,并以一定时间间隔测量血糖水平的变化达总共3小时。结果,如图14a中所示的,与正常饮食组相比,在CD-HFD饮食组中观察到更高的血糖水平升高。另一方面,与仅施用媒介物的阴性对照组(CD-HFD+PBS)相比,在根据本发明的实施方案的MG12-5和MG12-8施用组中观察到血糖水平的统计学显著的降低。与GLP-1和GLP-2共同施用相比,在MG12中观察到统计学显著的更高功效。图14b是显示与血糖水平变化相关的曲线下面积的图。通过施用GLP-1和GLP-2,由CD-HFD增加的血糖水平变化的曲线下面积减少到正常范围,且特别地,发现通过MG12-5和MG12-8减少到1/2或更小。
7-3:肝组织检查
本发明人将已结束了如上所述的药物施用实验的小鼠处死并从其提取肝组织,且拍摄其照片以检查肝组织的大小和颜色的变化,并测量提取的肝组织的重量以及ALT血液水平,这是肝脏毒性水平的量度。
结果,如图15a中所示的,在MG12-5施用组、MG12-8施用组以及GLP-1和GLP-2共同施用组中观察到与正常饮食组相似的肝颜色,且发现通过药物减少了肝组织中的脂肪累积。另外,如图15b中所示的,正常饮食组和CD-HFD-饲养组之间的肝重量相似,且通过MG12-5以及GLP-1和GLP-2共同施用降低了肝重量,且在MG12-8施用组中观察到肝重量的最大降低。另外,如图15c中所示的,作为在CD-HFD饮食16周后测量表明肝毒性的血液ALT水平的结果,通过CD-HFD饮食ALT水平增加到约两倍,但MG12-5施用组和MG12-8施用组显示出ALT 水平下降到与正常饮食组相似的水平。另一方面,GLP-1和GLP-2共同施用组显示出与阴性对照组相似的高血液ALT水平。所述结果表明,虽然GLP-1和GLP-2的简单共同施用没有保肝作用,但根据本发明实施方案的MG12在施用时显示保肝作用。
实验例8:MG12蛋白对非酒精性脂肪性肝炎的治疗作用
基于上述结果,本发明人利用严重NASH-诱导的动物模型进行了动物实验,以确定根据本发明实施方案的MG12对严重非酒精性脂肪性肝炎(NASH)是否具有治疗作用,这是一种脂肪肝的更晚期形式。
为此,特别如图16a中所举例说明的,2-日龄C57BL/6小鼠腹膜内施用200 mg/kg链脲佐菌素(STZ)一次,且从第4周开始饲喂60%高脂肪饮食达4周,且然后饲喂60%高脂肪饮食达3周,且PBS(媒介物)作为阴性对照组,且以10、30和90 nmol /kg的剂量每周3次皮下(s.c.)施用根据本发明实施方案的MG12-8药物。在第11周处死小鼠以获得肝和血液,并进行分析。作为阳性对照组,从第8周开始以30 mg/kg的浓度每天口服施用OCA(奥贝胆酸)达3周。
首先,如图16b中所示的体重变化的测量结果显示,与阴性对照组相比,阳性对照组和用根据本发明实施方案的MG12-8处理的实验组均显示出相似的体重变化。
此外,本发明人在实验动物中测量了作为肝损伤量度的血液AST和ALT浓度。结果,如图16d中所示的,与阴性对照组相比,阳性对照组显示相似水平的AST表达,以及与阴性对照组相比对于ALT颇为升高的水平。另一方面,发现根据本发明的实施方案的MG12-8无论浓度如何都统计学显著地降低血液中的AST和ALT水平。这表明根据本发明实施方案的MG12是对严重NASH具有治疗作用的物质。
然后,本发明人努力以通过NAFLD活动性指数分析根据本发明实施方案的MG12对非酒精性脂肪肝疾病(NAFLD)的治疗效果。NAFLD活动性指数是通过综合分析肝内脂肪累积、炎症反应和肝细胞形状变化而表示的指数。脂肪累积以浅绿色表示,炎症反应以灰色表示,且肝细胞的变化(膨胀)以粉红色表示。结果,如图16e中所示的,与阴性对照组相比,阳性对照组略微减少了肝中的脂肪累积,但未能抑制炎症反应,因而显示与阴性对照组相当的总指数。另一方面,确认了根据本发明的实施方案的MG12-8以剂量依赖性方式降低NAFLD活动性指数,且特别地,在以30 nmol/kg和90 nmol/kg施用的组中,显示出将指数降低至0.5点或更低的显著效果,其为阴性对照组的1/8或更低。所述结果表明,根据本发明的实施方案的MG12是具有极其有效的NASH药物候选物的物质。
基于以上结果,可以看出,与GLP-1和GLP-2的简单共同施用相比,根据本发明实施方案的MG12是用于治疗诸如短肠综合征、肥胖症、2型糖尿病和非酒精性脂肪性肝炎的代谢病的非常有效的药物候选物。因此,根据本发明实施方案的异二聚体融合蛋白可以非常有用地用作先前已经用GLP-1和/或GLP-2治疗的各种疾病例如短肠综合征和代谢病的治疗剂。
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利地用作包括肥胖症、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、肝纤维化等的代谢病的治疗药物。
序列表
<110> SL METAGEN
<120> 新的双特异性蛋白及其用途
<130> PT21-5222
<150> KR 10-2020-0030727
<151> 2020-03-12
<160> 69
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His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
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Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
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Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
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Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
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Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
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Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
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<222> (2)
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<222> (29)
<223> 甲基化,
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Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
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Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
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Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
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Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
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Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
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Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
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Leu Ser Leu Ser Leu Gly Lys
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Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
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Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
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Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
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Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
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Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
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Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys
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Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
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Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
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Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
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Leu Ser Leu Ser Leu Gly Lys
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Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
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Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
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Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
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Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
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Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
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Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
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Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
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Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
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Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
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Leu Ser Leu Ser Leu Gly Lys
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His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
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Asp
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His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
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Asp
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His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Gly
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Asp
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His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
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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 (47)
1.包含彼此融合的GLP-1类似物和GLP-2类似物的双特异性融合蛋白。
2.根据权利要求1所述的双特异性融合蛋白,其进一步包含半衰期延长部分。
3.根据权利要求2所述的双特异性融合蛋白,其中所述半衰期延长部分插入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。
4.根据权利要求2所述的双特异性融合蛋白,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。
5.双特异性融合蛋白,其包含具有与抗体Fc区连接的GLP-1类似物的第一融合蛋白和具有与抗体Fc区连接的GLP-2类似物的第二融合蛋白,其中所述双特异性融合蛋白通过所述第一融合蛋白和所述第二融合蛋白的二聚化生成。
6.根据权利要求1-5任一项所述的双特异性融合蛋白,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杂合体、GLP-1-XTEN、利西拉来、阿必鲁肽、利拉鲁肽、Dulaglutide、Extenatide、他司鲁泰、利西拉来或GLP-1串联重复。
7.根据权利要求5所述的双特异性融合蛋白,其中所述GLP-1类似物和所述GLP-2类似物中的至少一个是串联重复,并且所述GLP-1类似物和所述GLP-2类似物具有不同数目的重复。
8.根据权利要求6所述的双特异性融合蛋白,其中所述GLP-1包含由SEQ ID NO: 1或2表示的氨基酸序列。
9.根据权利要求6所述的双特异性融合蛋白,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。
10.根据权利要求6所述的双特异性融合蛋白,其中所述毒蜥外泌肽4包含由SEQ IDNO: 4表示的氨基酸序列。
11.根据权利要求6所述的双特异性融合蛋白,其中所述GLP-1/毒蜥外泌肽4杂合体包含由SEQ ID NO: 5表示的氨基酸序列。
12.根据权利要求6所述的双特异性融合蛋白,其中所述利西拉来包含由SEQ ID NO: 6表示的氨基酸序列。
13.根据权利要求6所述的双特异性融合蛋白,其中所述毒蜥外泌肽4-XTEN包含由SEQID NO: 7表示的氨基酸序列。
14.根据权利要求6所述的双特异性融合蛋白,其中所述阿必鲁肽包含由SEQ ID NO: 8表示的氨基酸序列。
15.根据权利要求6所述的双特异性融合蛋白,其中所述利拉鲁肽包含由SEQ ID NO: 9表示的氨基酸序列。
16.根据权利要求6所述的双特异性融合蛋白,其中所述他司鲁泰包含由SEQ ID NO:10表示的氨基酸序列。
17.根据权利要求6所述的双特异性融合蛋白,其中所述GLP-1串联重复包含由SEQ IDNO: 11表示的氨基酸序列。
18.根据权利要求4或5所述的双特异性融合蛋白,其中所述抗体Fc区是杂种抗体Fc区。
19.根据权利要求18所述的双特异性融合蛋白,其中所述杂种抗体Fc区是其中两种或更多种同种型的至少两个部分混合的Fc区。
20.根据权利要求4或5所述的双特异性融合蛋白,
其中所述第一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,且所述第二融合蛋白包含修饰的杂种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,或者
其中所述第一融合蛋白包含修饰的杂种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,且所述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。
21.根据权利要求18所述的双特异性融合蛋白,其中所述杂种抗体Fc区包含选自SEQID NO:12至16的氨基酸序列。
22.根据权利要求1-5任一项所述的双特异性融合蛋白,其中所述GLP-2类似物是GLP-2、glepaglutide或GLP-2类似物10。
23.根据权利要求22所述的双特异性融合蛋白,其中所述GLP-2包含选自SEQ ID NO:17至20的氨基酸序列。
24.根据权利要求22所述的双特异性融合蛋白,其中所述Glepaglutide包含由SEQ IDNO: 21表示的氨基酸序列。
25.根据权利要求22所述的双特异性融合蛋白,其中所述GLP-2类似物10包含由SEQ IDNO: 22表示的氨基酸序列。
26.根据权利要求5所述的双特异性融合蛋白,其中所述第一融合蛋白包含选自SEQ IDNOs:23至30的氨基酸序列。
27.根据权利要求5所述的双特异性融合蛋白,其中所述第二融合蛋白包含选自SEQ IDNOs:31至36的氨基酸序列。
28.根据权利要求5所述的双特异性融合蛋白,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Fc区之间、或在所述GLP-2类似物和所述Fc区之间插入接头肽。
29.根据权利要求28所述的双特异性融合蛋白,其中所述接头肽包含或不包含N-糖基化位点。
30.根据权利要求29所述的双特异性融合蛋白,其中所述第一融合蛋白不包含接头肽中的N-糖基化位点,且所述第二融合蛋白包含接头肽中的N-糖基化位点。
31.根据权利要求29所述的双特异性融合蛋白,其中所述第一融合蛋白包含接头肽中的N-糖基化位点,且所述第二融合蛋白不包含接头肽中的N-糖基化位点。
32.根据权利要求28所述的双特异性融合蛋白,其中所述接头肽是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)。
33.包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分的药物组合物。
34.根据权利要求33所述的药物组合物,其用于治疗需要肠增殖的疾病或症状。
35.根据权利要求34所述的药物组合物,其中所述需要肠增殖的疾病或症状是吸收障碍、炎性肠病或短肠综合征。
36.根据权利要求35所述的药物组合物,其中所述炎性肠病是溃疡性结肠炎、Behcet氏病或短肠综合征。
37.用于治疗非酒精性脂肪性肝炎的药物组合物,其包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分。
38.用于治疗代谢综合征的药物组合物,其包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分。
39.用于治疗肥胖症的药物组合物,其包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分。
40.用于治疗2型糖尿病的药物组合物,其包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分。
41.用于治疗肝纤维化的药物组合物,其包含根据权利要求1-32任一项的双特异性融合蛋白作为活性成分。
42.在患有需要肠增殖的疾病的主体中治疗需要肠增殖的疾病或症状的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
43.在患有代谢综合征的主体中治疗代谢综合征的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
44.在患有肥胖症的主体中治疗肥胖症的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
45.在患有2型糖尿病的主体中治疗2型糖尿病的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
46.在患有非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的主体中治疗非酒精性脂肪肝疾病或非酒精性脂肪性肝炎的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
47.在患有非酒精性肝纤维化的主体中治疗肝纤维化的方法,所述方法包括向所述主体施用治疗有效量的根据权利要求1-32任一项的双特异性融合蛋白。
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