CN112566655A - 具有优化的活性比率的fgf21化合物/glp-1r激动剂组合 - Google Patents
具有优化的活性比率的fgf21化合物/glp-1r激动剂组合 Download PDFInfo
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Abstract
本发明涉及包含FGF21(成纤维细胞生长因子21)化合物和GLP‑1R(胰高血糖素样肽‑1受体)激动剂的组合、药物组合物和融合分子，其具有优化的GLP‑1R激动剂/FGF21化合物活性比率。本发明还涉及所述组合、药物组合物和融合分子作为特定用于治疗肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和/或动脉粥样硬化的药物的用途。
Description
技术领域
本发明涉及包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂的组合、药物组合物和融合分子，其具有优化的GLP-1R激动剂/FGF21化合物活性比率。本发明还涉及所述组合、药物组合物和融合分子作为特定地用于治疗以下疾病的药物的用途：肥胖症、超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和/或动脉粥样硬化。
发明背景
施用成纤维细胞生长因子21(FGF21)化合物(例如重组产生的FGF21多肽)导致体重、血糖和血脂的显著降低以及胰岛素敏感度的改善，如例如由Gaich等(2013)Cell Metab18(3):333-340和Dong等(2015)Br J Clin Pharmacol 80(5):1051-1063所证明的。胰高血糖素样肽-1受体(GLP-1R)激动剂在人类中有效降低葡萄糖和体重，如例如由Astrup等(2012)Int J Obes(Lond)36(6):843-854和Nauck等(2013)Diabetes Obes Metab 15(3):204-212所示的。将施用FGF21的有益效应与GLP-1受体激动剂的降糖效应组合出人意料地产生协同效应(参见，例如WO 2011/089203 A1和WO 2014/037373 A1)，所述协同效应提供对如肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和/或动脉粥样硬化等疾病/病症的更全面的治疗。
发明概述
FGF21化合物和GLP-1R激动剂的组合(例如以融合蛋白的形式组合)可例如用于改善具有2型糖尿病的体重超重至肥胖症血脂异常患者中的血糖控制。
值得注意的是，FGF21和GLP-1(作为主要的GLP-1R激动剂)在不同血浆浓度下发挥其药理学效应。更特别地，与GLP-1效用相比，FGF21效应以更高的血浆水平开始作用。此外，已知在较高水平下，GLP-1具有不良效应，例如恶心和呕吐。总之，这意味着当施用FGF21化合物和GLP-1R激动剂的组合(例如以融合蛋白形式)时，存在潜在的GLP-1介导的不良效应的风险。
因此，本发明的目的是确定优化的GLP-1R激动剂/FGF21化合物活性比率，以便达到有益效应，同时避免潜在的不良效应(例如恶心和呕吐)。本发明的另一目的是提供具有优化的GLP-1R激动剂/FGF21化合物活性比率的相应组合、药物组合物和融合分子。
在一方面中，本发明涉及一种组合，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比，降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂的GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/531至1/9(或1/531.0至1/9.449)。
在一个实施方案中，所述FGF21活性是指FGF21受体的激活。在一个实施方案中，该术语是指体外活性。在一个实施方案中，FGF21受体的激活是通过测量FGF21受体在体外与所述FGF21化合物接触时的自身磷酸化来确定的。在一个实施方案中，FGF21活性是通过使用In-Cell Western(ICW)测定法来确定的，例如基本上如实施例3中所述的。
在一个实施方案中，所述GLP-1R激动活性是指GLP-1受体的激活。在一个实施方案中，该术语是指体外激动活性。在一个实施方案中，GLP-1受体的激活是通过测定稳定表达GLP-1受体的细胞在体外与所述激动剂接触时的cAMP反应来确定的。在一个实施方案中，所述GLP-1受体的激活是基本上如实施例4中所测定的。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/482至1/9(或1/482.396至1/9.449)或1/319至1/9至(或1/319.311至1/9.449)或1/121至1/9(或1/121.189至1/9.449)。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/319至1/9。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至多1/9.4或至多1/9.45或至多1/9.5。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至多1/10。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至少1/482.4或至少1/482.35。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至少1/482。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/482至1/10。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/319至1/10。
在一个实施方案中，所述GLP-1R激动剂的GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/100至1/90。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至多1/18(或至多1/18.268)。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/501至1/18(或1/500.686至1/18.268)或1/469至1/18(或1/468.679至1/18.268)或1/313至1/18(或1/313.214至1/18.268)或1/123至1/18(或1/123.466至1/18.268)。
在一个实施方案中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/313至1/18。
在上述实施方案之一中，所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为至多1/18.2倍或至多1/18.3。
在一个实施方案中，所述FGF21变体与天然FGF21的氨基酸序列具有至少80％或至少90％或至少95％氨基酸序列同一性。
在一个实施方案中，所述FGF21变体包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63和64。
在一个实施方案中，所述GLP-1R激动剂包含以下氨基酸序列或由以下氨基酸序列组成
H-G-E-G-T-F-T-S-D-X10-S-X12-Q-X14-X15-E-E-X18-V-X20-X21-F-I-E-W-L-X27-X28-X29-X30(SEQ ID NO:37)，
其中
X10是L或K；
X12是K或I；
X14是L或M；
X15是E或D；
X18是A或R；
X20是R或Q；
X21是L或E；
X27是L、E、K或V；
X28是A、N或K；
X29是T或G；
X30是G或R；
其中，任选地，所述氨基酸序列在其N末端包含至少一个额外的氨基酸残基；并且
其中，任选地，所述氨基酸序列在其C末端包含由多至12、11或10个氨基酸残基组成的肽延伸。
在一个实施方案中，所述GLP-1R激动剂包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:9、10、12、14、15、16、17、19和20。
在一个实施方案中，X14是L且X28是A。
在一个实施方案中，所述GLP-1R激动剂包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:9、10、12、14、16、17、19和20。
在另一方面中，本发明涉及一种药物组合物，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂以及药学上可接受的载体和/或赋形剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比降低为1/531至1/9(或1/531.0至1/9.449)。
在又一方面中，本发明涉及一种融合分子，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比降低为1/531至1/9(或1/531.0至1/9.449)。
在一个实施方案中，所述融合分子还包含杂合Fc域，所述杂合Fc域包含不同免疫球蛋白的部分Fc区/域的组合。
在一个实施方案中，所述GLP-1R激动剂和/或所述FGF21化合物是如上所定义的。
在另一方面中，本发明涉及一种核酸分子，其编码如上所定义的融合分子。
在另一方面中，本发明涉及一种宿主细胞，其含有如上所定义的核酸分子。
在另一方面中，本发明涉及一种试剂盒，其包含如上所定义的组合、如上所定义的药物组合物、如上所定义的融合分子、如上所定义的核酸分子或如上所定义的宿主细胞。
在另一方面中，本发明涉及如上所定义的组合、如上所定义的药物组合物、如上所定义的融合分子、如上所定义的核酸分或如上所定义的宿主细胞，其用作药物。
在另一方面中，本发明涉及如上所定义的组合、如上所定义的药物组合物、如上所定义的融合分子、如上所定义的核酸分子或如上所定义的宿主细胞，其用于治疗选自下组的疾病或病症：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化。
在一个实施方案中，所述疾病或病症是糖尿病。在一个实施方案中，所述糖尿病是1型糖尿病或2型糖尿病。
在另一方面中，本发明涉及如上所定义的组合、如上所定义的药物组合物、如上所定义的融合分子、如上所定义的核酸分子或如上所定义的宿主细胞在制备用于治疗选下组的疾病或病症的药物中的用途：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化。
在一个实施方案中，所述疾病或病症是糖尿病。在一个实施方案中，所述糖尿病是1型糖尿病或2型糖尿病。
在另一方面中，本发明涉及一种治疗选自下组的疾病或病症的方法：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化，所述方法包括向有此需要的受试者施用如上所定义的组合、如上所定义的药物组合物、如上所定义的融合分子、如上所定义的核酸分子或如上所定义的宿主细胞。
在一个实施方案中，所述疾病或病症是糖尿病。在一个实施方案中，所述糖尿病是1型糖尿病或2型糖尿病。
附图说明
图1是显示根据GLP-1衰减因子(12个月模拟)的不良效应(胃排空(GE)率)和药效学(即，HbA1c、甘油三酯、脂肪酸、非HDL、脂肪量)的EC50的图：
·对于大于9.449(可圆整至9)的GLP-1衰减因子，GLP-1介导的胃肠道不良效应(胃排空；GE率)的EC50大于药效学效应(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)的EC50。
·通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为121.189；即，在121.189(可圆整至121)处，在GLP-1介导的效应(HbA1c)与FGF21介导的平均效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离处，存在药效学效应(HbA1c)的最大值与不良效应(GE率)之间的最大距离(参见图2)；
·药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为319.311(可圆整至319)；
·平均药效学(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)与不良效应(GE率)之间的最大距离为482.396(参见图2；可圆整至482)；
·胃排空率的最大值在531.0；
(所有：竖直线)。
图2是显示根据GLP-1衰减因子(12个月模拟)的胃排空(GE)率和平均药效学效应(即，HbA1c、甘油三酯、脂肪酸、非HDL、脂肪量)的EC50的图：
·平均药效学(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)与不良效应(GE率)之间的最大距离为482.396(右侧竖直线；可圆整至482)；
·通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为121.189(左侧竖直线；可圆整至121)。曲线“(最大值-GE率)/范围”代表HbA1c与GE率之间的最大距离相对于HbA1c与FGF21介导的平均效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离的比率。在“(最大值-GE率)/范围”曲线的最小值处(即，在121.189处)，在GLP-1介导的效应(HbA1c)与FGF21介导的效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离处，存在药效学效应(HbA1c)的最大值与不良效应(GE率)之间的最大距离。
图3是显示根据GLP-1衰减因子(3个月模拟)的不良效应(胃排空(GE)率)和药效学(HbA1c、甘油三酯、脂肪酸、非HDL、脂肪量)的EC50的图：
·对于大于18.268(可圆整至18)的GLP-1衰减因子，GLP-1介导的胃肠不良效应(胃排空；GE率)的EC50大于药效学效应(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)的EC50；
·通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为123.466；即，在123.466(可圆整至123)处，在GLP-1介导的效应(HbA1c)与FGF21介导的平均效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离处，存在药效学效应(HbA1c)的最大值与不良效应(GE率)之间的最大距离(参见图4)；
·药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为313.214(可舍入为313)；
·平均药效学(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)与不良效应(GE率)之间的最大距离为468.679(参见图4；可圆整至469)；
·胃排空率的最大值在500.686(可圆整至501)
(所有：竖直线)。
图4是显示根据GLP-1衰减因子(3个月模拟)的胃排空(GE)率和平均药效学效应(即，HbA1c、甘油三酯、脂肪酸、非HDL、脂肪量)的EC50的图：
·平均药效学(即，HbA1c、脂肪量、非HDL、脂肪酸、甘油三酯)与不良效应(GE率)之间的最大距离为468.679(右侧竖直线；可圆整至469)；
·通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应(GE率)之间的最大距离为123.466(左侧竖直线；可圆整至123)。曲线“(最大值-GE率)/范围”代表HbA1c与GE率之间的最大距离相对于HbA1c与FGF21介导的平均效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离的比率。在“(最大值-GE率)/范围”曲线的最小值处(即在123.466处)，在GLP-1介导的效应(HbA1c)与FGF21介导的效应(即，脂肪量、非HDL、脂肪酸、甘油三酯)之间的最小距离处，存在药效学效应(HbA1c)的最大值与不良效应(GE率)之间的最大距离。
图5显示在用成熟人FGF21(SEQ ID NO:2)刺激后，在过表达人FGFR1c和β-klotho的CHO细胞中，通过In-Cell Western测量的(A)FGFR自身磷酸化或(B)ERK1/2-磷酸化的剂量反应曲线。
发明详述
虽然下文详细描述本发明，但应理解，本发明并不限于本文所述的特定方法、方案和试剂，因为这些可变。还应理解，本文所用术语仅用于描述特定实施方案的目的，并且并不旨在限制本发明的范围，本发明的范围仅受所附权利要求书限制。除非另有定义，否则本文所用的所有技术和科学术语都具有与本领域普通技术人员通常所理解的相同的意义。
在下文中，将描述本发明的某些要素。这些要素可用具体实施方案来列举，然而应理解，其可以任一方式和任一数目组合以产生其他实施方案。差异性描述的实施例和优选的实施方案不应视为将本发明限制于仅明确描述的实施方案。本说明书应理解为支持并涵盖组合明确描述的实施方案与任一数目的所公开和/或优选要素的实施方案。此外，除非上下文另有指示，否则应考虑本申请的说明书公开本申请中所有所述要素的任何排列和组合。
本文所用术语是如“A multilingual glossary of biotechnological terms:(IUPAC Recommendations)”,H.G.W.Leuenberger、B.Nagel和H.
编辑，HelveticaChimica Acta,CH-4010Basel,Switzerland,(1995)中所述来定义的。
除非另有指示，否则本发明的实践将采用化学、生物化学、细胞生物学、免疫学和重组DNA技术的常规方法，其解释于本领域的文献中(Sambrook,J.等(2001)MolecularCloning:A Laboratory Manual，第3版，Cold Spring Harbor Laboratory Press,ColdSpring Harbor,NY)。
在本说明书和所附权利要求书的全文中，除非上下文另有要求，否则词语“包含(comprise)”和如“包含(comprises)”和“包含(comprising)”的变化形式将理解为暗示包括所述成员、整数或步骤，或成员、整数或步骤的组，但不排除任何其他成员、整数或步骤或成员、整数或步骤的组，但是在一些实施方案中，可排除此类其他成员、整数或步骤或成员、整数或步骤的组，即主题在于包括所述成员、整数或步骤或成员、整数或步骤的组。除非本文另有指示或根据上下文明显矛盾，否则在描述本发明的上下文中(尤其在权利要求书的上下文中)所用的术语“一个/一种(a/an)”和“所述”和类似参考应视为同时覆盖单数和复数。本文中列举值的范围仅旨在用作个别提及落在所述范围内的每一单独值的速记法。除非本文另有指示，否则将每一单独的值并入说明书中，如同在本文中单独列举所述值一样。除非本文中另有指示或与上下文明确矛盾，否则本文所述的所有方法都能以任何合适的顺序来进行。本文中提供的任何和所有实例或示例性语言(例如，“如”)的使用都仅旨在更好地说明本发明，并且不对以其他方式要求保护的本发明的范围施加限制。本说明书中的所有语言都不应视为指示任何未要求保护的要素为本发明实践所必需。
在本说明书的正文中，全文引用若干文件。本文在上文或下文中引用的每篇文件(包括所有专利、专利申请、科学出版物、制造商说明书、指导等)都是通过引用以其全文特此并入。本文中的任何内容都不应被解释为承认本发明无权早于在先发明的所述公开内容。
通过使用在糖尿病病理生理学情况下整合GLP-1受体信号传导与FGF21产生和作用的关键组分的系统药理学方法，本发明人成功确定最佳GLP-1R激动剂/FGF21化合物活性比率，以实现两种活性剂的有益效果(例如，在体重、脂质、血糖控制方面)，同时避免潜在的不良效应(例如，恶心和呕吐)。
如本文所用的术语“组合”意欲包括以下方式：允许通过向患者单独施用FGF21化合物和GLP-1R激动剂或以其中存在FGF21化合物和GLP-1R激动剂的组合产物的形式(例如在一种药物组合物中)或以融合分子/蛋白形式来施加包含FGF21化合物和GLP-1R激动剂的组合。在单独施用时，施用可同时或以任一顺序按顺序进行。FGF21化合物和GLP-1R激动剂的量以及施用的相对时机会经选择以实现合意的组合治疗效果。组合的施用可以如下形式并行进行：(1)单一药物组合物，包括所有活性药物成分；或(2)单独的药物组合物，各自包括至少一种活性药物成分。可替代地，组合可以按顺序方式单独施用，其中首先施用一种治疗剂，之后施用另一种治疗剂，或反之亦然。这种按顺序的施用可在时间上相隔较近或相隔较远。在一个实施方案中，组合是以试剂盒形式来提供，例如如本文所定义的试剂盒。
如本文所用的术语“成纤维细胞生长因子21”或“FGF21”是指本领域中已知的任何FGF21蛋白，并且特定地是指人FGF21。在一个实施方案中，人FGF21具有SEQ ID NO:1的氨基酸序列。
如本文所用的术语“FGF21化合物”通常是指具有FGF21活性的化合物。
在一个实施方案中，FGF21化合物是肽化合物，即，肽或蛋白质。
如本文所用的术语“肽”是指任何长度的氨基酸的聚合形式，例如，包含两个或更多个、或3个或更多个、或4个或更多个、或6个或更多个、或8个或更多个、或9个或更多个、或10个或更多个、或13个或更多个、或16个或更多个、或21个或更多个通过肽键共价连接的氨基酸。肽可例如由多达100个氨基酸组成。术语“多肽”是指大型肽，优选地具有多于100个氨基酸残基的肽。术语“多肽”和“蛋白质”在本文中可互换使用。
在一个实施方案中，FGF21化合物是天然FGF21或FGF21变体，所述FGF21变体与天然FGF21的氨基酸序列具有至少80％或至少90％或至少91％或至少92％或至少93％或至少94％或至少95％或至少96％或至少97％或至少98％氨基酸序列同一性。
如本文所用的术语“天然FGF21”是指天然存在的FGF21，例如，具有SEQ ID NO:1的氨基酸序列的人野生型FGF21(也称为“全长人野生型FGF21”)。如本文所用的术语“天然FGF21”还包括成熟FGF21，即缺少天然信号序列(也称为信号肽)的天然存在的FGF21。在一个实施方案中，天然FGF21是缺少SEQ ID NO:1的氨基酸1至28(M1至A28)的成熟人野生型FGF21，并且由SEQ ID NO:2表示。
两个氨基酸序列之间的“序列同一性”指示序列之间相同的氨基酸的百分比。除了手动方式以外，还可借助Smith和Waterman(1981,Ads App.Math.2,482)的局部同源性算法，借助Neddleman和Wunsch(1970,J.Mol.Biol.48,443)的局部同源性算法，借助Pearson和Lipman(1988,Proc.Natl Acad.Sci.USA 85,2444)的相似性检索方法，或借助使用这些算法的电脑程序(Wisconsin Genetics软件包中的GAP、BESTFIT、FASTA、BLAST P、BLAST N和TFASTA，Genetics Computer Group,575Science Drive,Madison,Wis.)产生序列的最佳比对以供比较。
FGF21变体可以是基于天然FGF21(例如，SEQ ID NO:1或2)中至少一个氨基酸残基的缺失、添加和/或取代。
这种缺失、添加和/或取代可促成变体与天然FGF21(例如，SEQ ID NO:1或2)相比提高的稳定性，例如蛋白水解稳定性和/或热稳定性。这可例如通过在经取代氨基酸处或其附近阻止蛋白酶裂解或通过形成一个或多个额外二硫桥来实现。
如本文所用的术语“氨基酸”或“氨基酸残基”是指天然存在的氨基酸、以与天然存在的氨基酸类似的方式起作用的非天然氨基酸、氨基酸类似物和氨基酸模拟物，如果其结构允许其D和L立体异构形式，那么其都呈此类立体异构体。氨基酸在本文中是以其名称、其众所周知的三字母符号或以IUPAC-IUB生物化学命名委员会建议的单字母符号来指称。
在结合氨基酸使用时，术语“天然存在的”是指20种常规氨基酸(即，丙氨酸(A)、半胱氨酸(C)、天冬氨酸(D)、谷氨酸(E)、苯丙氨酸(F)、甘氨酸(G)、组氨酸(H)、异亮氨酸(I)、赖氨酸(K)、亮氨酸(L)、甲硫氨酸(M)、天冬酰胺(N)、脯氨酸(P)、谷氨酰胺(Q)、精氨酸(R)、丝氨酸(S)、苏氨酸(T)、缬氨酸(V)、色氨酸(W)和酪氨酸(Y))，以及硒代半胱氨酸(selenocysteine)、吡咯赖氨酸(PYL)和吡咯啉-羧基赖氨酸(PCL)。
如本文所用的术语“非天然氨基酸”意指并非以任何生物体的遗传代码编码或未在任何生物体中发现的氨基酸。其可为例如纯合成化合物。非天然氨基酸的实例包括但不限于羟脯氨酸、γ-羧基谷氨酸、O-磷酸丝氨酸、氮杂环丁烷羧酸(azetidinecarboxylicacid)、2-氨基己二酸、3-氨基己二酸、β-丙氨酸、氨基丙酸、2-氨基丁酸、4-氨基丁酸、6-氨基己酸、2-氨基庚酸、2-氨基异丁酸、3-氨基异丁酸、2-氨基庚二酸、叔丁基甘氨酸、2,4-二氨基异丁酸、锁链素(desmosine)、2,2'-二氨基庚二酸、2,3-二氨基丙酸、N-乙基甘氨酸、N-甲基甘氨酸、N-乙基天冬酰胺、高脯氨酸、羟赖氨酸、别-羟赖氨酸、3-羟脯氨酸、4-羟脯氨酸、异锁链素、别-异亮氨酸、N-甲基丙氨酸、N-甲基甘氨酸、N-甲基异亮氨酸、N-甲基戊基甘氨酸、N-甲基缬氨酸、萘丙氨酸、正缬氨酸、正亮氨酸、鸟氨酸、D-鸟氨酸、D-精氨酸、对氨基苯丙氨酸、戊基甘氨酸、哌啶酸(pipecolic acid)和硫代脯氨酸。
如本文所用的术语“氨基酸类似物”是指与天然存在的氨基酸具有相同的基础化学结构的化合物。氨基酸类似物包括天然和非天然氨基酸，其经可逆或不可逆地化学封阻，或其C末端羧基、其N末端氨基和/或其侧链官能团经化学修饰。此类类似物包括但不限于甲硫氨酸亚砜、甲硫氨酸砜、S-(羧甲基)-半胱氨酸、S-(羧甲基)-半胱氨酸亚砜、S-(羧甲基)-半胱氨酸砜、天冬氨酸-(β甲基酯)、N-乙基甘氨酸、丙氨酸羧酰胺(alanine carboxamide)、高丝氨酸、正亮氨酸和甲硫氨酸甲基锍。
如本文所用的术语“氨基酸模拟物”是指具有与氨基酸的通用化学结构不同的结构，但以与天然存在的氨基酸类似的方式起作用的化学化合物。
在一些实施方案中，变体在其N末端包含至少一个额外氨基酸。在一个实施方案中，至少一个额外氨基酸选自除了脯氨酸以外的天然存在的氨基酸、非天然氨基酸、氨基酸类似物和氨基酸模拟物。在一个实施方案中，至少一个额外氨基酸选自G、A、N和C。在特定实施方案中，至少一个额外氨基酸为G。
用于本发明的适合的FGF21变体描述于例如WO 2016/114633 A1、WO 2017/093465A1、WO 2017/074117 A1、WO 2017/074123 A1和WO 2018/088838 A1中，其通过引用并入本文中。
在一个实施方案中，FGF21化合物是FGF21变体，所述FGF21变体包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:3、4、5和6。
在一个实施方案中，所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变。
给定的FGF21变体的免疫原性可以通过本领域已知的常规方法来预测。例如，可以通过使用例如iTopeTM和/或TCEDTM方法来筛选蛋白质的潜在免疫原性。此外，可以通过本领域已知的常规方法设计用于使免疫原性最小化的突变。例如，当通过进行EpiScreenTM分析以评估潜在的免疫原性而观察到免疫原性时，可以通过T细胞表位作图鉴定诱导免疫原性的氨基酸序列，并可以通过计算机预测设计免疫原性最小化的突变体。
在一个实施方案中，所述FGF21化合物是FGF21变体，所述FGF21变体包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63和64。
包含于本发明的组合、药物组合物和融合分子中的FGF21化合物展现的FGF21活性与天然FGF21(例如，SEQ ID NO:2)的FGF21活性相同或基本上相同。在一个实施方案中，FGF21活性是指FGF21化合物在不包含于如本文所定义的融合分子中(不是其组分)时和/或在未经进一步修饰时的FGF21活性(参见下文)。
如本文所用的术语“基本上相同”是指在天然FGF21(例如，SEQ ID NO:2)的FGF21活性的50％至150％或60％至140％或65％至135％范围内的FGF21活性。
在一个实施方案中，如本文所用的术语“FGF21活性”(或“FGF21效力”)是指FGF21受体(FGFR，例如，FGFR1c)的激活。在一个实施方案中，FGF21受体是人FGF21受体。在一个实施方案中，所述术语是指在体外的活性/效力。在另一实施方案中，所述术语是指在体内的活性/效力。在一个实施方案中，FGF21受体的激活是通过测量FGF21受体在体外与FGF21化合物接触时的自身磷酸化来确定。在一个实施方案中，FGF21活性/效力是通过使用In-CellWestern(ICW)测定法来确定。在一个实施方案中，活性/效力是通过确定EC50值来定量。
如本文所用的术语“In-Cell Western(ICW)测定法”是指免疫细胞化学测定法，更特定为定量免疫荧光测定法，通常在微板中(例如，在96孔或384孔形式中)进行。其组合蛋白质印迹法的特异性与ELISA的再现性和通量(参见，例如，Aguilar H.N.等(2010)PLoSONE 5(4):e9965)。适当的ICW测定系统是商业上可得到的(例如，来自LI-CORBiosciences,USA)。在一个实施方案中，在ICW测定法中使用抗pFGFR和/或抗pERK。在一个实施方案中，进行pFGFR ICW测定法。在一个实施方案中，ICW测定是基本上如实施例3中所述进行。
在一个实施方案中，具有与天然FGF21的FGF21活性相同或基本上相同的FGF21活性的FGF21化合物可根据其FGF21受体激活的EC50值来定义。例如，具有在天然FGF21(例如，SEQ ID NO:2)的FGF21活性的50％至150％或60％至140％或65％至135％范围内的FGF21活性的FGF21化合物在本文中也可分别称为在pFGFR ICW测定中以2.40至7.20nmol/L或2.88至6.72nmol/L或3.12至6.48nmol/L的EC50激活FGF21受体的FGF21化合物，例如，如基本上于实施例3中所述。在一个实施方案中，EC50值是作为EC50±SD给出的。在一个实施方案中，SD是测定依赖性标准偏差。在一个实施方案中，在pFGFR ICW测定中，EC50分别为2.40±SD至7.20±SD nmol/L或2.88±SD至6.72±SD nmol/L或3.12±SD至6.48±SD nmol/L，例如，如基本上于实施例3中所述。在一个实施方案中，SD为1.8nmol/L。
根据本发明，FGF21化合物可进一步经修饰，例如，融合/缀合至另一实体/分子，如聚合物(例如，PEG)或肽/多肽，如人血清白蛋白(HSA)或免疫球蛋白的Fc区/结构域或其变体，例如，如下文进一步描述。在一个实施方案中，本文中提到的FGF21化合物的FGF21活性是不具有所述进一步修饰的FGF21化合物的FGF21活性，在本文中也称为“纯FGF21化合物”。
如本文所用的术语“融合至”特定地是指遗传融合，例如，通过重组DNA技术融合。可在变体氨基酸序列内的任一位置引入(聚)肽半衰期延长模块的氨基酸序列，并且可例如在所编码蛋白质结构内呈环形形状，或其可为N末端或C末端融合。
如本文所用的术语“缀合至”特定地是指化学和/或酶缀合，其导致(聚-)肽与另一分子(例如，变体和半衰期延长模块)之间的稳定共价连接。此类缀合可发生在(聚-)肽的N末端或C末端处或特定侧链处，例如，在赖氨酸、半胱氨酸、酪氨酸或非天然氨基酸残基处。
如本文所用的术语“GLP-1R激动剂”(简写：“GLP-1RA”)通常是指结合至并激活GLP-1受体的化合物，如GLP-1(作为主要GLP-1R激动剂)。
在一个实施方案中，GLP-1R激动剂是肽化合物，即，肽或蛋白质。在另一实施方案中，GLP-1R激动剂是小分子，即，分子量小于900Da的有机化合物。
包含于本发明的组合、药物组合物和融合分子中的GLP-1R激动剂展现如本文所定义的与天然GLP-1(7-36)相比降低的GLP-1R激动活性。如本文所用的表述“降低x倍”中的值“x”在本文中可是指“衰减因子”或“降低因子”。在一个实施方案中，如本文所定义的与天然GLP-1(7-36)相比降低的GLP-1R激动活性是在GLP-1R激动剂是如本文所定义的融合分子的组分时展现的。
如本文所用的术语“天然GLP-1(7-36)”是指具有SEQ ID NO:7的氨基酸序列的肽，所述序列任选地在其C末端包含酰胺基团。
在一个实施方案中，如本文所用的术语“GLP-1R激动活性”(或“GLP-1R激动效力”)是指GLP-1受体的激活。在一个实施方案中，所述术语是指在体外的激动活性/效力。在另一实施方案中，所述术语是指在体内的激动活性/效力。在一个实施方案中，GLP-1受体的激活是通过测量稳定表达GLP-1受体的细胞在体外与激动剂接触时的cAMP反应来确定。在一个实施方案中，细胞来自HEK-293细胞系。在一个实施方案中，GLP-1受体是人GLP-1受体。在一个实施方案中，GLP-1受体的激活是基本上如实施例4中所述来确定。在一个实施方案中，活性/效力是通过确定EC50值来定量。
在一个实施方案中，具有与天然GLP-1(7-36)的GLP-1R激动活性相比降低的GLP-1R激动活性的GLP-1R激动剂可根据其GLP-1受体激活的EC50值来定义，例如，如表4中所指示。例如，具有与天然GLP-1(7-36)的GLP-1R激动活性相比降低为1/531至1/9的GLP-1R激动活性的GLP-1R激动剂在本文中还可称为以6.93至408.87pmol/L的EC50激活GLP-1受体的GLP-1R激动剂等。在一个实施方案中，EC50值是如上文所述来确定。在一个实施方案中，EC50值是作为EC50±SD给出的。在一个实施方案中，SD是测定依赖性标准偏差。
具有与天然GLP-1(7-36)的GLP-1R激动活性相比降低的GLP-1R激动活性的适合的GLP-1R激动剂可通过本文针对确定GLP-1R激动活性所述的测定来鉴别，例如，如实施例4中或Xiao等(2001)Biochemistry.40(9):2860-9或Gault等(2013)J Biol Chem.288(49):35581-91中所述的测定，例如，对GLP-1R激动剂诱导的细胞溶质cAMP的产生、β细胞保存作用(细胞凋亡)或葡萄糖刺激的胰岛素分泌(GSIS)的分析等。上述适合的GLP-1R激动剂可例如通过以下来鉴别：例如通过随机或定点诱变或化学合成产生已知肽类GLP-1R激动剂(如天然GLP-1(7-36))的变体(参见，例如，实施例5)，且随后如本文所述使用天然GLP-1(7-36)作为对照确定其GLP-1R激动活性。可替代地，上述适合的GLP-1R激动剂可通过使用天然GLP-1(7-36)作为对照，根据GLP-1R激动活性筛选小分子文库来鉴别。这些测定都可以以高通量测定的形式来进行。
已知肽类GLP-1R激动剂(例如，天然GLP-1(7-36))的变体可以是基于已知肽类GLP-1R激动剂的氨基酸序列中至少一个氨基酸残基的缺失、添加和/或取代/对所述氨基酸序列进行至少一个氨基酸残基的缺失、添加和/或取代。
在一个实施方案中，变体包含氨基酸残基的多达15、14、13、12、11、10、9、8、7、6或5个取代。
在一个实施方案中，GLP-1R激动剂是天然GLP-1(7-36)的变体，其包含天然GLP-1(7-36)序列中的氨基酸残基的多达15、14、13、12、11、10、9、8、7、6或5个取代。在一个实施方案中，所述取代选自下组，所述组包含以下各项或由以下各项组成：A8G、V16L、V16K、S18K、S18I、Y19Q、L20M、E21D、G22E、Q23E、A24R、A25V、K26R、K26Q、E27L、A30E、V33K、V33L、V33E、K34N、K34A、G35T和R36G和/或如表5中所列的取代(参见SEQ ID NO:8至20的说明)。
在一些实施方案中，变体在其N末端包含至少一个额外氨基酸残基。在一个实施方案中，至少一个额外氨基酸残基选自除了脯氨酸以外的天然存在的氨基酸、非天然氨基酸、氨基酸类似物和氨基酸模拟物。在一个实施方案中，至少一个额外氨基酸残基选自下组：G、A、N和C。在特定实施方案中，至少一个额外氨基酸残基是(单一)G。
在一些实施方案中，变体在其C末端包含肽延伸部分。肽延伸部分可例如由多达12、11或10个氨基酸残基组成。在一个实施方案中，肽延伸部分具有选自下组的氨基酸序列：PSSGAPPPS(SEQ ID NO:38)、PVSGAPPPS(SEQ ID NO:39)、PSSGEPPPES(SEQ ID NO:40)、PSSGEPPPE(SEQ ID NO:41)、PKKQRLS(SEQ ID NO:42)和PKKIRYS(SEQ ID NO:43)。
在一个实施方案中，具有如本文所定义的与天然GLP-1(7-36)的GLP-1R激动活性相比降低的GLP-1R激动活性的GLP-1R激动剂包含以下氨基酸序列或由以下氨基酸序列组成：
H-G-E-G-T-F-T-S-D-X10-S-X12-Q-X14-X15-E-E-X18-V-X20-X21-F-I-E-W-L-X27-X28-X29-X30(SEQ ID NO:37)
其中
X10是任一氨基酸，例如L或K；
X12是任一氨基酸，例如K或I；
X14是任一氨基酸，例如L或M；
X15是任一氨基酸，例如E或D；
X18是任一氨基酸，例如A或R；
X20是任一氨基酸，例如R或Q；
X21是任一氨基酸，例如L或E；
X27是任一氨基酸，例如L、E、K或V；
X28是任一氨基酸，例如A、N或K；
X29是任一氨基酸，例如T或G；
X30是任一氨基酸，例如G或R；
其中，任选地，所述氨基酸序列在其N末端包含至少一个额外氨基酸残基；并且
其中，任选地，所述氨基酸序列在其C末端包含由多达12、11或10个氨基酸残基组成的肽延伸部分。
在一个实施方案中，X27是L、E或V，例如，L。在一个实施方案中，X28是A或K，例如，A。
在一个实施方案中，至少一个额外氨基酸残基选自下组：G、A、N和C。在特定实施方案中，至少一个额外氨基酸残基是(单一)G。
在一个实施方案中，肽延伸部分具有选自下组的氨基酸序列：PSSGAPPPS(SEQ IDNO:38)、PVSGAPPPS(SEQ ID NO:39)、PSSGEPPPES(SEQ ID NO:40)、PSSGEPPPE(SEQ ID NO:41)、PKKQRLS(SEQ ID NO:42)和PKKIRYS(SEQ ID NO:43)。
如本文所公开的修饰，如在N末端引入G或X12＝I，导致GLP-1R激动活性的适当降低。
在一个实施方案中，具有如本文所定义的与天然GLP-1(7-36)的GLP-1R激动活性相比降低的GLP-1R激动活性的GLP-1R激动剂包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:9、10、12、14、15、16、17、19和20。
在一个实施方案中，X14是L且X28是A。
在一个实施方案中，GLP-1R激动剂包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:9、10、12、14、16、17、19和20。
根据本发明，GLP-1R激动剂可例如如上文结合FGF21化合物所述进一步经修饰。例如，它可以与免疫球蛋白的Fc区/结构域或其变体融合，例如本文所述的免疫球蛋白的Fc区/结构域或其变体。
根据本发明的药物组合物包含一种或多种载体和/或赋形剂，所有所述载体和/或赋形剂都是药学上可接受的。如本文所用的术语“药学上可接受的”是指材料无毒性，所述材料优选地不与药物组合物的活性剂的作用相互作用。
术语“载体”是指天然或合成性质的有机或无机组分，其中组合活性组分以促进、增强或实现应用。根据本发明，术语“载体”还包括一种或多种适于施用至受试者的相容的固体或液体填充剂、稀释剂或囊封物质。
可能用于肠胃外施用的载体物质是例如无菌水、林格氏溶液、乳酸林格氏溶液、生理盐水、抑菌盐水(例如，含有0.9％苯甲醇的盐水)、磷酸盐缓冲盐水(PBS)、汉克氏溶液、聚亚烷基二醇、氢化萘和特定是生物相容性丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯/聚氧丙烯共聚物。
如本文所用的术语“赋形剂”旨在包括可存于药物组合物中并且并非活性成分的所有物质，如盐、粘合剂(例如，乳糖、右旋糖、蔗糖、海藻糖、山梨醇、甘露醇)、填充剂、润滑剂、增稠剂、表面活性剂、防腐剂、乳化剂、缓冲物质、调味剂或着色剂。
并非药学上可接受的盐可用于制备药学上可接受的盐并且被包括于本发明中。这种药学上可接受的盐以非限制性方式包含从以下酸制备的那些盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、乙酸、水杨酸、柠檬酸、甲酸、丙二酸、琥珀酸等。药学上可接受的盐也可制备为碱金属盐或碱土金属盐，如钠盐、钾盐或钙盐。可添加盐以调节离子强度或张力。
用于药物组合物的适合的防腐剂包括抗氧化剂、柠檬酸、柠檬酸钠、苯扎氯铵、氯丁醇、半胱氨酸、甲硫氨酸、羟基苯甲酸酯类(parabens)、硫柳汞、酚、甲酚和其混合物。
用于药物组合物的适合的缓冲物质包括盐中的乙酸、盐中的柠檬酸、盐中的硼酸、盐中的磷酸和三(羟甲基)氨基甲烷(Tris，THAM，氨丁三醇)。
根据本发明的药物组合物优选为无菌的。药物组合物可以按统一剂型提供并且可以本身已知的方式来制备。药物组合物可例如呈溶液或悬浮液形式。
还可将药物组合物配制为用适当稀释剂重构的稳定冻干产物，其任选地包含如上文所定义的一种或多种赋形剂。
根据本发明的药物组合物可进一步包含至少一种其他活性药物成分。
如本文所用的术语“活性药物成分”(API)包括任何药物活性化学或生物化合物和其任何药学上可接受的盐和其任何混合物，其提供一些药理学效应并且用于治疗或预防病症，例如，如本文所定义的疾病或病症。示例性药学上可接受的盐包括盐酸、硫酸、硝酸、磷酸、氢溴酸、顺丁烯二酸、苹果酸、抗坏血酸、柠檬酸、酒石酸、双羟萘酸、月桂酸、硬脂酸、棕榈酸、油酸、肉豆蔻酸、月桂基硫酸、萘磺酸、亚油酸、亚麻酸等(的盐)。如本文所用的术语“活性药物成分”、“活性剂”、“活性成分”、“活性物质”、“治疗活性化合物”和“药物”意欲为同义词，即具有相同含义。
根据本发明，活性药物成分任选地选自：
-Rote Liste 2014中提到的所有药物，例如Rote Liste 2014第12章中提到的所有抗糖尿病药、Rote Liste 2014第06章中提到的所有减重药或食欲抑制药、Rote Liste2014第58章中提到的所有降脂药、Rote Liste 2014第17章中提到的所有抗高血压药、RoteListe中提到的所有保肾药或Rote Liste 2014第36章中提到的所有利尿药；
-胰岛素和胰岛素衍生物，例如：甘精胰岛素(例如
)、浓度高于100U/mL的甘精胰岛素，例如270-330U/mL的甘精胰岛素或300U/mL的甘精胰岛素(如EP 2387989中所公开的)、赖谷胰岛素(例如
)、地特胰岛素(例如
)、赖脯胰岛素(例如
)、德谷胰岛素(例如
IdegLira(NN9068))、门冬胰岛素和门冬胰岛素配制物(例如
)、基础胰岛素和类似物(例如LY2605541、LY2963016、NN1436)、聚乙二醇化赖脯胰岛素(例如LY-275585)、长效胰岛素(例如NN1436、Insumera(PE0139)、AB-101、AB-102、Sensulin LLC)、中度作用胰岛素(例如
)、速效和短效胰岛素(例如
PH20胰岛素、NN1218、
)、预混胰岛素、
NN1045、胰岛素加
PE-0139、ACP-002水凝胶胰岛素和口服、可吸入、经皮和含服或舌下胰岛素(例如
特果匹胰岛素、TPM-02胰岛素、
口服胰岛素、ORMD-0801、Oshadi口服胰岛素、NN1953、NN1954、NN1956、
)。那些通过双功能接头键合至白蛋白或另一蛋白质的胰岛素衍生物也是适合的；
-胰高血糖素样肽1(GLP-1)、GLP-1类似物和GLP-1受体激动剂，例如：GLP-1(7-37)、GLP-1(7-36)酰胺、利西那肽(lixisenatide)(例如
)、艾塞那肽(例如毒蜥外泌肽-4、rExendin-4、
艾塞那肽NexP)、艾塞那肽-LAR、利拉鲁肽(例如
)、索马鲁肽、他司鲁肽、阿必鲁肽、杜拉鲁肽、Albugon、胃泌酸调节素、栀子苷(geniproside)、ACP-003、CJC-1131、CJC-1134-PC、GSK-2374697、PB-1023、TTP-054、兰勒那肽(HM-11260C)、CM-3、GLP-1Eligen、AB-201、ORMD-0901、NN9924、NN9926、NN9927、Nodexen、Viador-GLP-1、CVX-096、ZYOG-1、ZYD-1、ZP-3022、CAM-2036、DA-3091、DA-15864、ARI-2651、ARI-2255、艾塞那肽-XTEN(VRS-859)、艾塞那肽-XTEN+胰高血糖素-XTEN(VRS-859+AMX-808)以及聚合物结合的GLP-1和GLP-1类似物；
-双重GLP-1/GIP激动剂(例如RG-7697(MAR-701)、MAR-709、BHM081、BHM089、BHM098)；双重GLP-1/胰高血糖素受体激动剂(例如BHM-034、OAP-189(PF-05212389、TKS-1225)、TT-401/402、ZP2929、LAPS-HMOXM25、MOD-6030)；
-双重GLP-1/胃泌素激动剂(例如ZP-3022)；
-胃肠肽，如肽YY3-36(PYY3-36)或其类似物和胰腺多肽(PP)或其类似物；
-胰高血糖素受体激动剂或拮抗剂、葡萄糖依赖性促胰岛素多肽(GIP)受体激动剂或拮抗剂、胃饥饿素拮抗剂或反向激动剂、类爪蟾肽和其类似物；
-二肽基肽酶-IV(DPP-4)抑制剂，例如：阿格列汀(例如
)、利格列汀(例如
)、萨格列汀(例如
Komboglyze
)、西格列汀(例如
Janumet
)、安奈格列汀、替格列汀(例如
)、曲格列汀、维格列汀(例如
)、吉格列汀、奥格列汀、依格列汀、度格列汀、DA-1229、MK-3102、KM-223、KRP-104、PBL-1427、盐酸哌诺沙星和Ari-2243；
-钠依赖性葡萄糖转运蛋白2(SGLT-2)抑制剂，例如：卡格列净、达格列净、瑞格列净、依碳酸瑞格列净、舍格列净、恩格列净、伊格列净、托格列净、鲁格列净、埃格列净、EGT-0001442、LIK-066、SBM-TFC-039和KGA-3235(DSP-3235)；
-SGLT-2和SGLT-1的双重抑制剂(例如LX-4211、LIK066)；
-SGLT-1抑制剂(例如LX-2761、KGA-3235)或SGLT-1抑制剂与抗肥胖症药物的组合，所述抗肥胖症药物如回肠胆汁酸转运体(IBAT)抑制剂(例如GSK-1614235+GSK-2330672)；
-双胍类(例如二甲双胍、丁双胍、苯乙双胍)；
-噻唑烷二酮(例如吡格列酮、罗格列酮)、格列酮类似物(例如洛贝格列酮)；
-过氧化物酶体增殖子激活受体(PPAR-)(α、γ或α/γ)激动剂或调节剂(例如沙格列扎(例如
)、GFT-505)或PPARγ部分激动剂(例如lnt-131)；
-磺酰脲类(例如甲苯磺丁脲、格列本脲、格列美脲、
格列吡嗪)和氯茴苯酸(例如那格列奈、瑞格列奈、米格列奈)；
-α-葡糖苷酶抑制剂(例如阿卡波糖、米格列醇、伏格列波糖)；
-胰淀素和胰淀素类似物(例如普兰林肽、
)；
-G-蛋白偶联受体119(GPR119)激动剂(例如GSK-1292263、PSN-821、MBX-2982、APD-597、ARRY-981、ZYG-19、DS-8500、HM-47000、YH-Chem1)；
-GPR40激动剂(例如TUG-424、P-1736、P-11187、JTT-851、GW9508、CNX-011-67、AM-1638、AM-5262)；
-GPR120激动剂和GPR142激动剂；
-系统或低吸收性TGR5(GPBAR1＝G-蛋白偶联胆汁酸受体1)激动剂(例如INT-777、XL-475、SB756050)；
-糖尿病免疫治疗剂，例如：口服C-C趋化因子受体2型(CCR-2)拮抗剂(例如CCX-140、JNJ-41443532)、白介素1β(IL-1β)拮抗剂(例如AC-201)或口服单克隆抗体(MoA)(例如醋甲唑胺、VVP808、PAZ-320、P-1736、PF-05175157、PF-04937319)；
-用于治疗代谢综合征和糖尿病的抗炎剂，例如：核因子κB抑制剂(例如
)；
-单磷酸腺苷激活的蛋白质激酶(AMPK)刺激剂，例如：Imeglimin(PXL-008)、Debio-0930(MT-63-78)、R-118；
-11-β-羟类固醇脱氢酶1(11-β-HSD-1)抑制剂(例如LY2523199、BMS770767、RG-4929、BMS816336、AZD-8329、HSD-016、BI-135585)；
-葡糖激酶的激活剂(例如PF-04991532、TTP-399(GK1-399)、GKM-001(ADV-1002401)、ARRY-403(AMG-151)、TAK-329、TMG-123、ZYGK1)；
-二酰甘油O-酰基转移酶(DGAT)的抑制剂(例如pradigastat(LCQ-908))、蛋白质酪氨酸磷酸酶1抑制剂(例如trodusquemine)、葡萄糖-6-磷酸酶抑制剂、果糖-1,6-二磷酸酶抑制剂、糖原磷酸化酶抑制剂、磷酸烯醇丙酮酸羧激酶抑制剂、糖原合酶激酶抑制剂、丙酮酸脱氢酶激酶抑制剂；
-葡萄糖转运蛋白-4的调节剂、生长抑素受体3激动剂(例如MK-4256)；
-一种或多种降脂剂也适合作为组合配偶体，例如：3-羟基-3-甲基戊二酰基-辅酶-A-还原酶(HMG-CoA-还原酶)抑制剂，如斯伐他汀(例如
)、阿托伐他汀(例如
)、瑞舒伐他汀(例如
)、普伐他汀(例如
)、氟伐他汀(例如
)、匹伐他汀(例如
)、洛伐他汀(例如
)、美伐他汀(例如
)、立伐他汀、西立伐他汀
贝特类药物(如苯扎贝特(例如
延迟剂)、环丙贝特(例如
)、非诺贝特(例如
)、吉非贝齐(例如
)、依托贝特、双贝特、氯烟贝特、克利贝特)、氯贝胺、烟酸和其衍生物(例如尼克酸，包括尼克酸的缓释配制物)、烟酸受体1激动剂(例如GSK-256073)、PPAR-δ激动剂、乙酰基-CoA-乙酰基转移酶(ACAT)抑制剂(例如阿伐麦布)、胆固醇吸收抑制剂(例如依折麦布、
S-556971)、胆汁酸结合物质(例如考来烯胺、考来维仑)、回肠胆汁酸转运(IBAT)抑制剂(例如GSK-2330672、LUM-002)、微粒体甘油三酯转移蛋白(MTP)抑制剂(例如洛美他派(AEGR-733)、SLx-4090、格兰他派)、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的调节剂(例如阿利珠单抗(REGN727/SAR236553)、AMG-145、LGT-209、PF-04950615、MPSK3169A、LY3015014、ALD-306、ALN-PCS、BMS-962476、SPC5001、ISIS-394814、1B20、LGT-210、1D05、BMS-PCSK9Rx-2、SX-PCK9、RG7652)、LDL受体上调剂(例如肝选择性甲状腺激素受体β激动剂(例如伊罗替罗(KB-2115)、MB07811、苏比替罗(QRX-431)、VIA-3196、ZYT1))、HDL升高化合物，如：胆固醇酯转移蛋白(CETP)抑制剂(例如安塞曲匹(MK0859)、达塞曲匹、依塞曲匹、JTT-302、DRL-17822、TA-8995、R-1658、LY-2484595、DS-1442)、或双重CETP/PCSK9抑制剂(例如K-312)、ATP结合盒(ABC1)调节剂、脂质代谢调节剂(例如BMS-823778、TAP-301、DRL-21994、DRL-21995)、磷脂酶A2(PLA2)抑制剂(例如达雷拉地、
伐瑞拉地、瑞拉帕地)、ApoA-l增强剂(例如RVX-208、CER-001、MDCO-216、CSL-112)、胆固醇合成抑制剂(例如ETC-1002)、脂质代谢调节剂(例如BMS-823778、TAP-301、DRL-21994、DRL-21995)和ω-3脂肪酸和其衍生物(例如二十碳五烯酸乙酯(AMR101)、
AKR-063、NKPL-66、PRC-4016、CAT-2003)；
-溴隐亭(例如
)、芬特明和芬特明配制物或组合(例如Adipex-P、苯丁胺、
)、苄非他明(例如
)、安非拉酮(例如
)、苯甲曲秦(例如
)、安非他酮和组合(例如
Wellbutrin
)、西布曲明(例如
)、托吡酯(例如
)、唑尼沙胺(例如
)、特索芬辛、阿片样物质拮抗剂(如纳曲酮(例如
纳曲酮+安非他酮))、大麻类物质受体1(CB1)拮抗剂(例如TM-38837)、黑色素浓集激素(MCH-1)拮抗剂(例如BMS-830216、ALB-127158(a))、MC4受体激动剂和部分激动剂(例如AZD-2820、RM-493)、神经肽Y5(NPY5)或NPY2拮抗剂(例如韦利贝特、S-234462)、NPY4激动剂(例如PP-1420)、β-3-肾上腺素能受体激动剂、瘦素或瘦素模拟物、5-羟色胺2c(5HT2c)受体激动剂(例如罗卡西林、
)、普兰林肽/美曲普汀、脂肪酶抑制剂(如新利司他(例如
)、奥利司他(例如
))、血管发生抑制剂(例如ALS-L1023)、β组氨酸和组胺H3拮抗剂(例如HPP-404)、AgRP(刺鼠相关蛋白)抑制剂(例如TTP-435)、血清素再摄取抑制剂(如氟西汀(例如
)、度洛西汀(例如
))、双重或三重单胺摄取抑制剂(多巴胺、去甲肾上腺素和血清素再摄取)(如舍曲林(例如
)、特索芬辛)、甲硫氨酸氨肽酶2(MetAP2)抑制剂(例如贝洛拉尼)和针对成纤维细胞生长因子受体4(FGFR4)产生的反义寡核苷酸(例如ISIS-FGFR4Rx)或抑制素靶向肽-1(例如
)；
-一氧化氮供体、AT1拮抗剂或血管紧张肽II(AT2)受体拮抗剂(如替米沙坦(例如
)、坎地沙坦(例如
)、缬沙坦(例如
)、氯沙坦(例如
)、依普罗沙坦(例如
)、厄贝沙坦(例如
)、奥美沙坦(例如
)、他索沙坦、阿齐沙坦(例如
))、双重血管紧张肽受体阻断剂(双重ARB)、血管紧张肽转化酶(ACE)抑制剂、ACE-2激活剂、肾素抑制剂、肾素原抑制剂、内皮缩血管肽转化酶(ECE)抑制剂、内皮缩血管肽受体(ET1/ETA)阻断剂、内皮缩血管肽拮抗剂、利尿药、醛甾酮拮抗剂、醛甾酮合酶抑制剂、α-阻断剂、α-2肾上腺素能受体拮抗剂、β-阻断剂、混合α-/β-阻断剂、钙拮抗剂、钙通道阻断剂(CCB)、钙通道阻断剂地尔硫卓的鼻用配制物(例如CP-404)、双重盐皮质激素/CCB、中枢作用性抗高血压药、中性肽链内切酶抑制剂、氨肽酶-A抑制剂、血管肽抑制剂、双重血管肽抑制剂(如肾胰岛素残基溶酶-ACE抑制剂或肾胰岛素残基溶酶-ECE抑制剂、双效AT受体-肾胰岛素残基溶酶抑制剂、双重AT1/ETA拮抗剂)、晚期糖化终产物(AGE)分解剂、重组肾酶、血压疫苗(如抗RAAS(肾素-血管紧张肽-醛甾酮-系统)疫苗、AT1-疫苗或AT2-疫苗)、基于高血压药物基因组学的药物(如具有抗高血压反应的遗传多态性的调节剂、凝血细胞聚集抑制剂和其他)或其组合是适合的。
术语“融合分子”通常是指通过以下方式产生的分子：连接(特别是共价连接)两个或更多个不同分子(例如，蛋白质和/或肽)，得到具有衍生自每一原始分子的功能性质的单一分子。在蛋白质和/或肽的情形中，融合分子被称为“融合蛋白”。融合分子可通过遗传融合(例如，通过重组DNA技术)或通过化学和/或酶缀合来生成。两个或更多个不同分子也可通过适合的接头分子来连接，例如，肽接头或非肽类聚合物，例如聚乙二醇(PEG)。
通常，肽接头设计为提供柔性和蛋白酶抗性。在一个实施方案中，肽接头具有1至30、1至25或1至20个氨基酸残基的长度。在一个实施方案中，肽接头包含至少5个氨基酸残基。在一个实施方案中，肽接头是富含甘氨酸-丝氨酸的接头，其中至少50％、优选至少60％、更优选至少70％、更优选至少80％、甚至更优选至少85％的氨基酸分别是甘氨酸或丝氨酸残基。在一个实施方案中，肽接头在其C末端包含丙氨酸残基。在另一实施方案中，氨基酸选自甘氨酸和丝氨酸，即，肽接头仅由甘氨酸和丝氨酸构成(称为甘氨酸-丝氨酸接头)。在一个实施方案中，肽接头包含SEQ ID NO:22或SEQ ID NO:23的氨基酸序列或由所述氨基酸序列组成。肽接头可进一步包含一个或多个特异性蛋白酶裂解位点。
在一个实施方案中，融合分子是融合蛋白。在根本本发明的融合蛋白那个，融合蛋白的组成可以按顺序(从N末端到C末端)A–B–C或C–B–A排列，其中A是GLP-1R激动剂，B是接头分子，且C是FGF21化合物。
在一个实施方案中，融合蛋白进一步包含免疫球蛋白(例如，IgG1、IgG2、IgG3、IgG4或IgD)的Fc区/结构域或其变体。在一个实施方案中，与Fc区/结构域的野生型序列相比，Fc区/结构域的变体包含多达5、4或3个突变。在一个实施方案中，所述突变选自氨基酸取代和缺失，例如，N-或C末端缺失。在一个实施方案中，IgG4的Fc区/结构域的变体(也称为“IgG4 Fc变体”)包含SEQ ID NO:21的氨基酸序列或由所述氨基酸序列组成。
在一个实施方案中，Fc区/结构域的变体是杂合Fc区/结构域。此类杂合Fc区/结构域描述于例如WO 2016/114633 A1、WO 2017/074117 A1、WO 2017/074123 A1和WO 2018/088838 A1，其通过引用并入本文。在一个实施方案中，杂合Fc区/结构域包含不同免疫球蛋白(例如，IgG1、IgG2、IgG3、IgG4或IgD)的部分Fc区/结构域的组合。在一个实施方案中，杂合Fc区/结构域包含IgG4和IgD的部分Fc区/结构域(也称为“IgG4/IgD杂合Fc区/结构域”)，优选为人IgG4和IgD。在一个实施方案中，杂合Fc区/结构域包含IgD Fc区/结构域的部分铰链序列和CH2，以及IgG4 Fc区/结构域的CH2和CH3序列。在一个实施方案中，杂合Fc区/结构域包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:65、66、67、68、69和70。
在一个实施方案中，FGF21化合物和GLP-1R激动剂通过免疫球蛋白的Fc区/结构域或其变体连接。在一个实施方案中，FGF21化合物和GLP-1R激动剂通过包含选自下组的结构的接头分子连接：L–Fc、Fc–L、L1–Fc–L2和Fc，其中L、L1和L2是如本文所定义的肽接头(L1和L2相同或不同)，并且Fc是免疫球蛋白的Fc区/结构域或其变体。
在一个实施方案中，融合蛋白包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:25、26、28、30、31、32、33、35和36。
根据本发明的融合蛋白的其他特征描述于例如WO 2014/037373 A1和WO 2017/093465 A1中，其是通过引用并入本文中。
根据本发明，“核酸分子”优选为脱氧核糖核酸(DNA)或核糖核酸(RNA)。根据本发明，核酸分子可以是单链的或双链的线性或共价闭合以形成环的分子的形式。
术语“DNA”是指包含脱氧核糖核苷酸残基并且优选完全或基本上由脱氧核糖核苷酸残基构成的分子。“脱氧核糖核苷酸”是指在β-D-呋喃核糖基的2'-位置缺少羟基的核苷酸。术语“DNA”包含分离的DNA，如部分或完全纯化的DNA、基本上纯的DNA、合成的DNA和重组生成的DNA，并且包括修饰的DNA，其与天然存在的DNA相差一个或多个核苷酸的添加、缺失、取代和/或改变。此类改变可包括添加非核苷酸材料，如添加至DNA的一个或多个末端或添加至内部，例如在DNA的一个或多个核苷酸处添加。DNA分子中的核苷酸还可包含非标准核苷酸，如非天然存在的核苷酸或化学合成的核苷酸。这些经改变的DNA可被称为类似物或天然存在的DNA的类似物。在结合核苷酸使用时，术语“天然存在的”是指碱基腺嘌呤(A)、胞嘧啶(C)、鸟嘌呤(G)、胸腺嘧啶(T)和尿嘧啶(U)。
术语“RNA”是指包含核糖核苷酸残基并且优选完全或基本上由核糖核苷酸残基构成的分子。“核糖核苷酸”是指在β-D-呋喃核糖基的2'-位置具有羟基的核苷酸。术语“RNA”包含经分离的RNA，如部分或完全纯化的RNA、基本上纯的RNA、合成RNA和重组生成的RNA，并且包括经修饰的RNA，其与天然存在的RNA相差一个或多个核苷酸的添加、缺失、取代和/或改变。此类改变可包括添加非核苷酸材料，如添加至RNA的一个或多个末端或添加至内部，例如在RNA的一个或多个核苷酸处添加。RNA分子中的核苷酸还可包含非标准核苷酸，如非天然存在的核苷酸或化学合成的核苷酸或脱氧核苷酸。这些经改变的RNA可被称为类似物或天然存在的RNA的类似物。根据本发明，“RNA”是指单链RNA或双链RNA。在一个实施方案中，RNA是mRNA，例如，体外经转录的RNA(IVT RNA)或合成RNA。RNA还可经修饰，例如，具有一个或多个提高RNA稳定性(例如，半衰期)的修饰。此类修饰为本领域技术人员已知，并且包括例如5'-帽或5'帽类似物。
根据本发明的核酸分子可含于/包含于载体中。如本文所用的术语“载体”包括所有技术人员已知的载体，包括质粒载体、粘粒载体、噬菌体载体(如λ噬菌体)、病毒载体(如腺病毒或杆状病毒载体)或人工染色体载体(如细菌人工染色体(BAC)、酵母人工染色体(YAC)或P1人工染色体(PAC))。所述载体包括表达以及克隆载体。表达载体包含质粒以及病毒载体，并且通常含有所期望的编码序列和用于在特定宿主生物体(例如，细菌、酵母、植物、昆虫或哺乳动物)中或在体外表达系统中表达可操作连接的编码序列所需的适当DNA序列。克隆载体通常用于工程化和扩增某一所期望的DNA片段，并且可能缺少表达所期望的DNA片段所需的功能性序列。
可替代地，可将根据本发明的核酸分子整合至基因组(例如，宿主细胞的基因组)中。将特定核酸分子整合至基因组中的手段和方法是本领域技术人员已知的。
术语“细胞”或“宿主细胞”优选涉及完整细胞，即，具有完整膜并且尚未释放其正常细胞内组分(如酶、细胞器或遗传物质)的细胞。完整细胞优选是活细胞，即，能实施其正常代谢功能的活细胞。优选地，根据本发明，所述术语涉及可经外源核酸转染或转化的任何细胞。优选地，在经外源核酸转染或转化并转移至接受者时，细胞可在所述接受者中表达所述核酸。术语“细胞”包括原核细胞，如细菌细胞，以及真核细胞，如酵母细胞、真菌细胞或哺乳动物细胞。适合的细菌细胞包括来自以下各项的细胞：革兰氏阴性细菌株系，如大肠杆菌(Escherichia coli)、变形杆菌属(Proteus)和假单胞菌属(Pseudomonas)的株系，以及革兰氏阳性细菌株系，如芽孢杆菌属(Bacillus)、链霉菌属(Streptomyces)、葡萄球菌属(Staphylococcus)和乳球菌属(Lactococcus)的株系。适合的真菌细胞包括来自以下物种的细胞：木霉属(Trichoderma)、脉孢菌属(Neurospora)和曲霉属(Aspergillus)。适合的酵母细胞包括来自以下物种的细胞：酵母属(Saccharomyces)(例如，酿酒酵母(Saccharomyces cerevisiae))、裂殖酵母属(Schizosaccharomyces)(例如，粟酒裂殖酵母(Schizosaccharomyces pombe))、毕赤酵母属(Pichia)(例如，巴斯德毕赤酵母(Pichiapastoris)和甲醇毕赤酵母(Pichia methanolica))和汉逊酵母属(Hansenula)。适合的哺乳动物细胞包括例如CHO细胞、BHK细胞、HeLa细胞、COS细胞、HEK293等。在一个实施方案中，使用HEK293细胞。然而，也可使用两栖动物细胞、昆虫细胞、植物细胞和本领域中用于表达异源蛋白质的任何其他细胞。哺乳动物细胞特别优选地用于过继转移，如来自人、小鼠、仓鼠、猪、山羊和灵长类动物的细胞。所述细胞可源自众多种组织类型，并且包括原代细胞和细胞系，如免疫系统的细胞，特别是抗原呈递细胞，如树突细胞和T细胞；干细胞，如造血干细胞和间质干细胞；和其他细胞类型。抗原呈递细胞是在其表面上的主要组织相容性复合物环境中展示抗原的细胞。T细胞可使用其T细胞受体(TCR)识别此复合物。“细胞”或“宿主细胞”可为经分离的细胞或组织或生物体(特别是“非人生物体”)的部分。
如本文所用的术语“非人生物体”意欲包括非人灵长类动物或其他动物，特别是哺乳动物，如牛、马、猪、绵羊、山羊、狗、猫、兔或啮齿类动物，例如小鼠、大鼠、豚鼠和仓鼠。
如本文所用的术语“部件试剂盒(简写：试剂盒)”是指包含一个或多个容器以及任选地数据载体的制品。所述一个或多个容器可填充有一种或多种上文所提到的药剂(试剂)。试剂盒中可包括其他容器，所述其他容器含有例如稀释剂、缓冲液和其他试剂。所述数据载体可为非电子数据载体，例如，图形数据载体，如信息传单、信息页、条形码或存取码；或电子数据载体，如光盘(CD)、数字多功能盘(DVD)、微芯片或另一基于半导体的电子数据载体。存取码可容许访问数据库，例如，互联网数据库、集中式数据库或分布式数据库。所述数据载体可包含使用本发明药剂的说明，所述药剂例如如本文所述的组合、药物组合物和融合分子以及相关药剂，如核酸分子和宿主细胞。
本文所述的药剂和组合物可通过任何常规途径来施用，例如，经口、经肺、通过吸入或肠胃外，包括通过注射或输注。在一个实施方案中，使用肠胃外施用，例如，静脉内、动脉内、皮下、真皮内或肌内。本文所述的药剂和组合物还可通过持续释放施用来施用。
适用于肠胃外施用的药物组合物通常包含活性化合物的无菌水性或非水性制剂，其优选地与接受者的血液是等渗的。相容载体/溶剂/稀释剂的实例是无菌水、林格氏溶液、乳酸林格氏溶液、生理盐水、抑菌盐水(例如，含有0.9％苯甲醇的盐水)、磷酸盐缓冲盐水(PBS)和汉克氏溶液。另外，通常可使用无菌非挥发油作为溶液或悬浮液介质。
本文所述的药剂和组合物通常是以治疗有效量来给予。“治疗有效量”是指单独或与其他剂量一起实现所期望的治疗反应或所期望的治疗效应、优选地不引起不可接受的副作用的量。在治疗特定疾病或特定病况的情形中，所期望的反应优选地与抑制病程相关。这包含减慢疾病进程，以及特别是中断或逆转疾病进程。疾病或病况的治疗中的所期望的反应也可为延迟所述疾病或所述病况的发作，或预防所述疾病或所述病况的发作。本文所述的药剂或组合物的有效量将取决于要治疗的病况、疾病严重程度、受试者的个别参数(包括年龄、生理状况、体型和体重)、治疗持续时间、伴随治疗(如果存在)的类型、具体施用途径和类似因素。因此，施用本文所述的药剂的剂量可取决于多个此类参数。在初始剂量引起的受试者反应不足的情形中，可使用较高剂量(或通过不同的、更局部的施用途径实现的有效较高的剂量)。
根据本发明，术语“疾病或病症”是指任何病理性或不健康状态，特别是肥胖症、超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和/或动脉粥样硬化。
术语“肥胖症”是指其中已积累过多体脂，达到可对健康造成负面影响的程度的医学病况。对于人(成年)受试者，肥胖症可定义为体质指数(BMI)大于或等于30kg/m2(BMI≥30kg/m2)。
术语“超重”是指其中体脂的量高于最佳健康状态的医学病况。对于人(成年)受试者，肥胖症可定义为体质指数(BMI)大于或等于25kg/m2(例如，25kg/m2≤BMI<30kg/m2)。
BMI是体重对身高的简单指数，常用于归类成人的超重和肥胖症。其定义为个人体重(千克)除以其身高(米)的平方(kg/m2)。
“代谢综合征”可定义为以下医学病况中至少三种的聚集：腹部(中央型)肥胖症(例如，定义为对于欧洲男性腰围≥94cm，以及对于欧洲女性腰围≥80cm，对于其他族群具有种族特异性值)、血压升高(例如，130/85mmHg或更高)、空腹血糖升高(例如，至少100mg/dL)、高血清甘油三酯(例如，至少150mg/dL)和低高密度脂蛋白(HDL)水平(例如，对于男性低于40mg/dL，以及对于女性低于50mg/dL)。
“糖尿病(Diabetes mellitus)”(也简称为“糖尿病(diabetes)”)是指一组代谢疾病，其特征为由于胰岛素产生、胰岛素作用或二者的缺陷所致的高血糖水平。在一个实施方案中，糖尿病选自以下项：1型糖尿病、2型糖尿病、妊娠糖尿病、成人迟发型自身免疫性糖尿病(LADA)、青年的成年发病型糖尿病(MODY)和由于特殊遗传病况、药物、营养不良、感染和其他疾病所致的其他类型的糖尿病。
糖尿病的当前WHO诊断标准如下：空腹血糖≥7.0mmol/l(126mg/dL)或2-h血糖≥11.1mmol/l(200mg/dL)。
“1型糖尿病”(也称为“胰岛素依赖性糖尿病(IDDM)”或“青少年糖尿病”)是特征为由完全缺乏胰岛素引起的高血糖水平的病况。这在身体的免疫系统攻击胰腺中产生胰岛素的β细胞并破坏所述细胞时发生。之后胰腺产生极少胰岛素或不产生胰岛素。胰腺移除或疾病也可导致产生胰岛素的β细胞的损失。1型糖尿病占糖尿病病例的5％-10％。
“2型糖尿病”(也称为“非胰岛素依赖性糖尿病(NIDDM)”或“成年发作型糖尿病”)是特征如下的病况：虽然可获得胰岛素，但仍产生过多葡萄糖，并且由于葡萄糖清除(胰岛素作用)不足，循环葡萄糖水平保持过高。2型糖尿病可占所有经诊断糖尿病病例的约90％至95％。
“妊娠糖尿病”是其中先前未诊断出糖尿病的女性在妊娠期间(尤其在妊娠末三个月期间)展现高血糖水平的病况。取决于所研究的群体，妊娠糖尿病影响3％-10％的妊娠。
“成人迟发型自身免疫性糖尿病(LADA)”(也称为“缓发型1型糖尿病”)是在成人中发生的1型糖尿病形式，通常具有较慢发作过程。
“青年的成年发病型糖尿病(MODY)”是指由常染色体显性基因中破坏胰岛素产生的突变引起的糖尿病的遗传性形式。
“糖尿病视网膜病变”是由糖尿病患者体内发生的代谢紊乱诱导的眼部疾病，并且导致视力的进行性损失。
术语“高血糖症”是指血液中的过多糖(葡萄糖)。
术语“血脂异常”是指脂蛋白代谢障碍，包括脂蛋白过度产生(“高脂血症”)或缺乏(“低脂血症”)。血脂异常可表现为血液中的总胆固醇、低密度脂蛋白(LDL)胆固醇和/或甘油三酯浓度升高，和/或高密度脂蛋白(HDL)胆固醇浓度降低。
非酒精性脂肪性肝炎(NASH)是特征为脂肪(脂滴)积累以及肝细胞的降解和炎症的肝病。一旦发生，所述疾病伴随高硬化风险，这是一种肝功能改变并且可进展至肝功能不全的状态。此后，NASH通常进展至肝癌。
“动脉粥样硬化”是特征如下的血管疾病：称为斑块的脂质沉积物不规则分布于大型和中型动脉的内膜中，其可引起动脉管腔狭窄并且进展至纤维化和钙化。病灶通常是局部的并且缓慢且间接性进展。有时发生斑块破裂，导致血流阻塞，从而引起远离阻塞处的组织死亡。血流受限解释大多数临床表现，所述临床表现随阻塞的分布和严重程度而变。
如本文所用的术语“药物”是指用于疗法，即用于治疗疾病或病症的物质/组合物。
“治疗”意指向所述受试者施用化合物或组合物或化合物或组合物的组合，以预防或消除疾病或病症；阻止或减慢受试者的疾病或病症；抑制或减慢新生疾病或病症在受试者中的进展；在目前患有或先前曾患有疾病或病症的受试者中降低症状和/或复发的频率或严重程度；和/或延长(即增加)受试者的寿命。
特定地，术语“治疗(treating)/治疗(treatment)疾病或病症”包括治愈疾病或病症或其症状、缩短其持续时间、改善、预防、减慢或抑制疾病或病症或其症状的进程或恶化，或预防或延迟疾病或病症或其症状的发作。
根据本发明，术语“受试者”意指用于治疗的受试者，特别是患病的受试者(也称为“患者”)，包括人、非人灵长类动物或其他动物，特别是哺乳动物，如牛、马、猪、绵羊、山羊、狗、猫、兔或啮齿类动物，例如小鼠、大鼠、豚鼠和仓鼠。在一个实施方案中，受试者/患者是人。
现在参考以下实施例进一步描述本发明，所述实施例旨在说明而不是限制本发明的范围。
实施例
实施例1：通过系统药理学建模确定最佳GLP-1RA/FGF21活性比率
使用改进的对GLP-1RA/FGF21融合蛋白在人体中的药理学效应的机理了解来鉴定最佳GLP-1RA/FGF21效力比。开发了机理系统药理学模型来描述GLP-1和FGF21在人体中对葡萄糖、脂质和能量代谢的效应(Cuevas-Ramos等(2009)Curr Diabetes Rev 5(4):216-220；Deacon等(2011)Rev Diabet Stud 8(3):293-306；Kim等(2008)Pharmacol Rev 60(4):470-512；Kharitonenkov等(2014)Mol Metab 3(3):221-229)。
所述模型代表GLP-1和FGF21作用的相关路径。捕获血糖控制(即，HbA1c、空腹血糖、餐后血糖)、脂质参数(即，血浆甘油三酯、脂肪酸、胆固醇)和能量平衡(即，体重、食物摄入、能量消耗)以评价对模拟药物治疗(例如，GLP-1RA/FGF21融合蛋白、利拉鲁肽、FGF21类似物LY2405319)的治疗反应。对于LY2405319，参见Kharitonenkov等(2013)PLoS ONE 8(3):e58575。
所述模型覆盖受激素胰岛素、胰高血糖素和肠降血糖素(GLP-1、GIP)控制的葡萄糖内稳态的关键方面。关于血糖控制的主要模型终点是HbA1c。HbA1c是常用于估计在先前数月期间的平均血糖浓度的临床终点。HbA1c是在模型中使用平均血糖与HbA1c之间的线性关系来估计，如Nathan等(2008)Diabetes Care 31(8):1473-1478中所报道的。
所述模型以适于操作基础脂质代谢(包括胆固醇的代表)的水平并入甘油三酯和脂肪酸代谢。HDL和非HDL(即，LDL加VLDL胆固醇)是循环脂蛋白。脂质代谢的代表允许模拟FGF21化合物对脂质的影响和与他汀类药物的相互作用。FGF21化合物对脂质浓度具有显著效应(Gaich等(2013)Cell Metab 18(3):333-340；Fisher等(2011)Endocrinology 152(8):2996-3004)。
测量模型中的体重减轻或增加作为身体脂肪量的变化。脂肪量与体重之间存在直接联系(Broyles等(2011)Br J Nutr 105(8):1272-1276)。食物摄入是基于基础和静息代谢率(Amirkalali等(2008)Indian J Med Sci 62(7):283-290)。在能量消耗等于热量摄入时，身体脂肪量保持恒定。在模型中使用(Gobel等(2014)Obesity(Silver Spring)22(10):2105-2108)的配制物来实现对食物摄入的治疗效应。
将食物视为碳水化合物(葡萄糖当量)、脂肪(脂肪酸当量)和蛋白质(氨基酸当量)。所有营养物都进入胃中，穿过延迟结，然后经过三室胃肠道。胃肠道设计是基于(Bastianelli等(1996)J Anim Sci 74(8):1873-1887；Worthington(1997)Med Inform(Lond)22(1):35-45)进行的工作及食物消化和吸收。
营养物、激素、药物和疾病状况可引起胃排空的延迟。在健康状况下，胃排空率取决于膳食量、其能量密度以及胃中营养物的量(Achour等(2001)Eur J Clin Nutr 55(9):769-772；Fouillet等(2009)Am J Physiol Regul Integr Comp Physiol 297(6):R1691-1705)。患有糖尿病的个体通常具有葡萄糖吸收延迟，如通过口服葡萄糖耐量测试或膳食测试所见(Bharucha等(2009)Clin Endocrinol(Oxf)70(3):415-420；Chang等(2012)Diabetes Care 35(12):2594-2596)。此延迟归因于胃排空的减慢。在模型中增加胃与小肠之间的延迟以解释糖尿病受试者中延迟的胃排空。药物和激素(GLP-1)可影响胃的迷走紧张，其减少机械混合和/或蠕动，并且这也减慢胃排空(Jelsing等(2012)Diabetes ObesMetab 14(6):531-538；Little等(2006)J Clin Endocrinol Metab 91(5):1916-1923；Nauck等(2011)Diabetes 60(5):1561-1565；van Can等(2013)Int J Obes(Lond)38(6):784-93)。
这项研究的一个目的是预防GLP-1相关的不良效应，即恶心和呕吐(Lean等(2014)Int J Obes(Lond)38(5):689-697)。胃排空测量提供对如恶心和呕吐的不良事件的估计，其与低胃排空速率有关。因此，模型中胃不良事件的标志是胃排空率的和。
在模型平台中实现代表健康的和不同疾病阶段的2型糖尿病患者的不同虚拟患者。而且，虚拟患者覆盖不同程度的肥胖症和血脂异常。虚拟患者代表疾病严重程度和病理生理学的变异性以及在诊所观察到的表型变异性。
在模型中实现若干种疗法，即，GLP-1RA/FGF21融合蛋白、利拉鲁肽、FGF21类似物LY2405319、二甲双胍、阿托伐他汀、西格列汀、人胰岛素。可在模拟中开启或关闭这些疗法。假定虚拟患者在施用GLP-1RA/FGF21融合蛋白时具有二甲双胍和阿托伐他汀背景。
在模型中实现虚拟GLP-1RA/FGF21融合蛋白。融合蛋白同时含有FGF21和GLP-1激动活性，并且其具有与FGF21和GLP-1受体激动剂二者相同的作用。假定虚拟融合蛋白的药代动力学谱与杜拉鲁肽相似(Geiser等(2016)Clin Pharmacokinet 55(5):625-34)。
通过与多个数据集比较来验证所述模型。模拟结果在性质上与相关数据和知识一致，例如，Hellerstein等(1997)J Clin Invest 100(5):1305-1319；Muscelli等(2008)Diabetes 57(5):1340-1348。所述模型与相关定量测试数据相匹配，例如，Aschner等(2006)Diabetes Care 29(12):2632-2637；Dalla Man,Caumo等(2005)Am J PhysiolEndocrinol Metab 289(5):E909-914；Dalla Man等(2005)Diabetes 54(11):3265-3273；Fiallo-Scharer(2005)J Clin Endocrinol Metab 90(6):3387-3391；Hahn等(2011)TheorBiol Med Model 8:12；Herman等(2005)Clin Pharmacol Ther 78(6):675-688；Herman等(2006)J Clin Pharmacol 46(8):876-886和J Clin Endocrinol Metab 91(11):4612-4619；Hojlund等(2001)Am J Physiol Endocrinol Metab 280(1):E50-58；Monauni等(2000)Diabetes 49(6):926-935；Nauck等(2009)Diabetes Care 32(1):84-90；Nauck等(1993)J Clin Invest 91(1):301-307；Nauck等(2004)Regul Pept 122(3):209-217；Tzamaloukas等(1989)West J Med 150(4):415-419；Sikaris(2009)J Diabetes SciTechnol 3(3):429-438；Vicini和Cobelli(2001)Am J Physiol Endocrinol Metab 280(1):E179-186；Vollmer等(2008)Diabetes 57(3):678-687。
在模型中实现现有疗法以供直接比较，包括FGF21类似物和GLP-1受体激动剂。用临床数据验证FGF21类似物的效应，例如，Gaich等2013。GLP-1受体激动剂利拉鲁肽是针对靶的直接竞争剂，并且将其实施与多种临床数据相比，例如，Jacobsen等(2009)Br J ClinPharmacol 68(6):898-905；Elbrond等(2002)Diabetes Care 25(8):1398-1404；Chang等(2003)Diabetes52(7):1786-1791；Kolterman等(2003)J Clin Endocrinol Metab 88(7):3082-3089；Degn等(2004)Diabetes53(5):1 187-1 194；Kolterman等(2005)Am J HealthSyst Pharm 62(2):173-181；Vilsboll等(2008)Diabet Med 25(2):152-156；Buse等(2009)Lancet 374(9683):39-47；Jelsing等(2012)Diabetes Obes Metab 14(6):531-538；Hermansen等(2013)Diabetes Obes Metab 15(11):1040-1048；Suzuki等(2013)Intern Med 52(10):1029-1034；van Can等(2013)Int J Obes(Lond)38(6):784-93)；Zinman等(2009)Diabetes Care 32(7):1224-1230；Russell-Jones等(2009)Diabetologia52(10):2046-2055；Pratley等(2011)Int J Clin Pract 65(4):397-407；Nauck等(2013)Diabetes Obes Metab 15(3):204-212；Flint等(2011)Adv Ther 28(3):213-226；Kapitza等(2011)Adv Ther 28(8):650-660；Astrup等(2012)Int J Obes(Lond)36(6):843-854。
所述模型平台容许以变化的活性比率模拟虚拟GLP-1RA/FGF21融合蛋白的有益和不良效应。将有效的FGF21介导的EC50值设定为恒定值，源自Gaich等(2013)Cell Metab 18(3):333-340。相对于内源GLP-1，有效的GLP-1介导的EC50值通过2至600增量为1的因子减小(表1)。
表1：GLP-1R激动剂/FGF21融合蛋白药效学(EC50值)。
*相对于内源GLP-1
**FGF21 EC50值是根据Gaich等(2013)Cell Metab 18(3):333-340假定半最大效应来设定。
对于每一虚拟融合蛋白，针对相关药效学终点(即，HbA1c、甘油三酯、脂肪酸、非HDL胆固醇和脂肪量)模拟暴露-反应关系。使用胃排空率作为GLP-1介导的不良事件的标志。针对宽剂量范围模拟用GLP-1RA/FGF21融合蛋白对普通肥胖型血脂异常2型糖尿病虚拟患者的52周治疗。在治疗52周后，预期所有相关药效学终点都达到稳态。对于每一终点，根据暴露-反应曲线来确定半最大有效浓度(EC50值)。尤其对于主要GLP-1介导的终点HbA1c和胃排空率，EC50值随活性比率而变。图1描绘取决于GLP-1衰减因子的EC50值。增加的GLP-1衰减因子指示GLP-1R激动活性降低。
此程序容许鉴别相关活性比率，对于所述活性比率，与药效学效应相比，不良效应在较高血浆水平下起作用。对于大于9的GLP-1衰减因子，GLP-1介导的胃肠不良效应的EC50大于药效学效应的EC50。因此，胃不良效应在高于药效学效应的血浆水平下起作用。有可能发现提供所有所期望的药效学效应同时避免GLP-1介导的胃肠不良效应的剂量。因此，低于1:10的活性比率是不相关的。
在衰减因子531处达到胃排空率的最大EC50值。在衰减因子482处达到不良效应与平均药效学效应之间的最大距离(图2)。因此，超出1:482的活性比率是不相关的。药效学(HbA1c)的最大值与不良效应之间的最大距离为319。通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应之间的最大距离为121。
预测效力比为1:10-1:482的GLP-1RA/FGF21融合蛋白在改进脂质分布、体重和葡萄糖代谢方面最有益，并且基于胃排空反应，可能不引起严重不良事件。基于其所预测的对胃排空的强抑制以及不良事件的可能性，较低效力比可能并非良好候选者。较高效力比可能不足够有效并且因此无竞争性。
此外，针对宽剂量范围模拟用GLP-1RA/FGF21融合蛋白对普通肥胖型血脂异常2型糖尿病虚拟患者的12周治疗，因为主要GLP-1介导的参数HbA1c在12周治疗后在临床上达到稳态。
图3描绘取决于12周模拟的GLP-1衰减因子的EC50值。对于大于18的GLP-1衰减因子，GLP-1介导的胃肠不良效应的EC50大于药效学效应的EC50。在衰减因子501处达到胃排空率的最大EC50值。在衰减因子469处达到不良效应与平均药效学效应之间的最大距离(图4)。药效学(HbA1c)的最大值与不良效应之间的最大距离为313。通过扩展FGF21-(脂质)和GLP-1介导的效应(HbA1c)归一化的药效学(HbA1c)的最大值与不良效应之间的最大距离为123。
借助所述系统药理学方法来研究具有不同活性比率的GLP-1RA/FGF21融合蛋白对不良事件的功效和潜力。鉴别具有推测计算的理想效力比的融合蛋白，预测其在改进脂质分布、体重和血糖控制方面是有益的，同时基于胃排空反应，可能不会引起严重的不良GLP-1RA相关效应。因此，预测具有所选的模型告知效力比的化合物提供良好的功效对风险特征。
实施例2：GLP1RA-FGF21融合蛋白在HEK293细胞中的表达
将SEQ ID NO:2的FGF21蛋白直接融合至GLP1RA，或将接头序列插入GLP1RA与FGF21序列之间。在所有构建体中，FGF21构建体以C末端融合至GLP1RA序列。如果插入接头，则GLP1RA以N末端融合至接头序列，并且FGF21以C末端融合至接头序列。GLP1RA-FGF21融合蛋白的DNA序列以N末端融合至IL2信号序列，之后是富含组氨酸的序列(His标签)和Tev裂解位点。GLP1RA-FGF21融合蛋白是通过瞬时转染HEK293细胞来产生的。将所期望的融合蛋白分泌至培养基中需要信号序列。使用固定化金属离子亲和色谱(IMAC)从培养上清液纯化所期望的融合蛋白。在从IMAC柱洗脱后，可通过添加Tev蛋白酶来裂解N末端His标签。出于构建体筛选目的，通过将Tev蛋白酶直接添加至用于GLP1RA活性测定的温育培养基中来裂解His标签。开始测定之前的温育时间为10-60分钟，以确保His标签完全裂解。具有在所期望的范围内的GLP1RA活性的构建体是以较大规模产生。GLP1RA-Fc-FGF21融合蛋白是通过在HEK293细胞中瞬时转染来产生的。使用IMAC和完全His标签纯化树脂(Roche)从培养上清液纯化所期望的融合蛋白。在His标签裂解后，使裂解反应溶液第二次经过IMAC柱(cOmpleteTM His标签纯化树脂(Roche))，从而收集(无his标签)流过物级分。使用凝胶过滤柱以磷酸盐缓冲盐水(PBS,Gibco)作为运行缓冲液进一步纯化融合蛋白。收集含有所期望的融合蛋白的级分，合并，浓缩并储存于-80℃直至进一步使用为止。
实施例3：对CHO细胞中的人FGF21受体功效的体外细胞测定(胞内Western)
使用具有特异性和高灵敏度的In-Cell Western(ICW)测定来测量成熟人FGF21(SEQ ID NO:2)或FGF21变体的细胞体外功效。ICW测定是免疫细胞化学测定，通常以微量板形式来进行。使用稳定表达人FGFR1c(＝FGF受体1c同种型)以及人β-Klotho(KLB)的CHOFlp-ln细胞(Invitrogen,Darmstadt,Germany)使用In-Cell Western进行FGF21受体自身磷酸化测定(Aguilar H.N.等(2010)PLoS ONE 5(4):e9965)。为了确定MAP激酶ERK1/2的受体自身磷酸化水平或下游激活，将2x104个细胞/孔接种至96孔板中并使其生长48小时。用具有GlutaMAX的无血清培养基Ham氏F-12营养混合物(Gibco,Darmstadt,Germany)将细胞血清饥饿3-4小时。随后用递增浓度的成熟人FGF21(SEQ ID NO:2)将细胞在37℃处理5分钟。在温育后，弃去培养基，并将细胞在3.7％新鲜制备的低聚甲醛中固定20分钟。用PBS中的0.1％Triton-X-100将细胞渗透化处理20分钟。用Odyssey封闭缓冲液(LICOR,BadHomburg,Germany)在室温进行封闭2小时。添加一抗(抗pFGFR Tyr653/654(New EnglandBiolabs,Frankfurt,Germany)或抗pERK磷酸p44/42MAP激酶Thr202/Tyr204(细胞信号传导))并在4℃温育过夜。在温育一抗后，用PBS加0.1％Tween20洗涤细胞。将第二抗小鼠800CW抗体(LICOR,Bad Homburg,Germany)在室温下温育1小时。随后，用PBS加0.1％Tween20再次洗涤细胞，并且用Odyssey成像仪(LICOR,Bad Homburg,Germany)对红外染料信号进行定量。通过用TO-PRO3染料(Invitrogen,Karlsruhe,Germany)对DNA进行定量来将结果归一化。以任意单位(AU)获得数据，并从剂量反应曲线获得EC50值并且归纳于表2中。图5显示来自使用过表达人FGFR1c加KLB的CHO细胞的ICW的结果。
表2：通过ICW pFGFR或ICW pERK在过表达人FGFR1c和KLB的CHO细胞中测量的成熟人FGF21(SEQ ID NO:2)的EC50值。
实施例4：人GLP-1受体功效的体外细胞测定
通过测量稳定表达人GLP-1受体的HEK-293细胞系中的cAMP反应的功能测定来确定化合物对人胰高血糖素样肽-1(GLP-1)受体的激动作用。
使用来自Cisbio Corp.的试剂盒(目录号62AM4PEC)基于HTRF(均相时间分辨荧光)来确定细胞的cAMP含量。对于制备，将细胞分配至T175培养烧瓶中并在培养基(DMEM/10％FBS)中生长过夜至接近汇合。然后移除培养基并用缺少钙和镁的PBS洗涤细胞，之后用Accutase(Sigma-Aldrich目录号A6964)进行蛋白酶处理。洗涤脱离的细胞并将其重悬于测定缓冲液(1xHBSS；20mM HEPES,0.1％BSA,2mM IBMX)中，并确定细胞密度。然后将其稀释至4x105个细胞/mL，并将25μL等份试样分配至96孔板的孔中。对于测量，将25μL于测定缓冲液中的测试化合物添加至孔，之后在室温下温育30分钟。在添加稀释于裂解缓冲液(试剂盒组分)中的HTRF试剂后，将板温育1小时，之后测量665/620nm处的荧光比。通过确定引起最大反应的50％激活的浓度(EC50)来对激动剂的体外效力进行定量。结果归纳于表3中。
表3：通过在稳定表达人GLP-1受体的HEK-293细胞系中检测cAMP反应而测量的GLP-1受体激动剂(SEQ ID NO:7和24-36)的EC50值。还显示GLP-1R激动活性的相应比率(天然GLP-1(7-36)/GLP-1R激动剂)。比率X意指GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/X。
表4：GLP-1R激动活性的所选比率(天然GLP-1(7-36)/GLP-1R激动剂)和相应的计算EC50值(基于上文所获得的结果)。比率X意指GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/X。
实施例5：肽化合物的合成
融合蛋白是通过重组方法产生的(参见实施例2)，而经分离肽类GLP-1R激动剂是化学合成的。
更特定地，肽是通过以下人工合成程序来合成：
将0.3g烘干的Rink酰胺MBHA树脂(0.66mmol/g)置于配备有聚丙烯过滤器的聚乙烯容器中。使树脂在DCM(15ml)中溶胀1小时，并在DMF(15ml)中溶胀1小时。通过用20％(v/v)哌啶/DMF溶液将其处理两次(5分钟和15分钟)来使树脂上的Fmoc基团去保护。用DMF/DCM/DMF(各自6:6:6倍)洗涤树脂。使用Kaiser测试(定量方法)确认Fmoc从固体载体的移除。将在干燥DMF中的C末端Fmoc-氨基酸(对应于树脂载量为5当量过量)添加至去保护树脂，并用在DMF中的5当量过量的DIC和HOBT起始下一Fmoc-氨基酸的偶连。反应混合物中每一反应物的浓度为约0.4M。将混合物在旋转器上在室温下旋转2小时。过滤树脂并用DMF/DCM/DMF(各自6:6:6倍)洗涤。在偶连完成后对肽树脂等份试样的Kaiser测试为阴性(树脂上无颜色)。在第一个氨基酸附接后，使用乙酸酐/吡啶/DCM(1:8:8)对树脂中的未反应氨基(如果存在的话)加帽/封端20分钟以避免序列的任何缺失。在加帽/封端后，用DCM/DMF/DCM/DMF(各自6/6/6/6倍)洗涤树脂。通过将其用20％(v/v)哌啶/DMF溶液处理两次(5分钟和15分钟)使肽基树脂附接的C末端氨基酸上的Fmoc基团去保护。用DMF/DCM/DMF(各自6:6:6倍)洗涤树脂。在Fmoc去保护完成后，对肽树脂等份试样的Kaiser测试为阳性。
使用Fmoc AA/DIC/HOBt方法，使用对应于DMF中树脂载量的5当量过量，按顺序偶连Rink酰胺MBHA树脂上的靶序列中的其余氨基酸。反应混合物中每一反应物的浓度为约0.4M。将混合物在旋转器上在室温下旋转2小时。过滤树脂并用DMF/DCM/DMF(各自6:6:6倍)洗涤。在每一偶连步骤和Fmoc去保护步骤后，实施Kaiser测试以确认反应的完成。
在线性序列完成后，通过使用DMF中的2.5％水合肼(hydrazine hydrate)，经15分钟x2将用作分支点或修饰点的赖氨酸的ε氨基去保护，并用DMF/DCM/DMF(各自6:6:6倍)洗涤。使用Fmoc-Glu(OH)-OtBu及DIC/HOBt方法(相对于树脂载量为5当量过量)在DMF中将谷氨酸的γ羧基端附接至Lys的ε氨基。使混合物在旋转器上在室温下旋转2小时。过滤树脂并用DMF/DCM/DMF(各自6x30ml)洗涤。通过将其用20％(v/v)哌啶/DMF溶液处理两次5分钟和15分钟(各25ml)使谷氨酸上的Fmoc基团去保护。用DMF/DCM/DMF(各自6:6:6倍)洗涤树脂。在Fmoc去保护完成后，对肽树脂等份试样的Kaiser测试为阳性。
如果侧链分支还含有另一个γ-谷氨酸，则用DIC/HOBt方法(相对于树脂载量为5当量过量)在DMF中使用第二Fmoc-Glu(OH)-OtBu附接至γ-谷氨酸的游离氨基。使混合物在旋转器上在室温下旋转2小时。过滤树脂并用DMF/DCM/DMF(各自6x30ml)洗涤。通过将其用20％(v/v)哌啶/DMF溶液处理两次5分钟和15分钟(25mL)使γ-谷氨酸上的Fmoc基团去保护。用DMF/DCM/DMF(各自6:6:6倍)洗涤树脂。在Fmoc去保护完成后，对肽树脂等份试样的Kaiser测试为阳性。
肽从树脂的最终裂解：
用DCM(6x10ml)、MeOH(6x10ml)和醚(6x10ml)洗涤通过人工合成而合成的肽基树脂，并在真空干燥器中干燥过夜。将肽从固体载体裂解是通过如下实现的：在室温用试剂混合剂(80％TFA/5％苯甲硫醚/5％苯酚/2.5％EDT/2.5％DMS/5％DCM)处理肽-树脂3小时。通过过滤收集裂解混合物，并用TFA(2ml)和DCM(2x5ml)洗涤树脂。在氮气下将过量TFA和DCM浓缩至小体积，并将少量DCM(5-10ml)添加至残余物并在氮气下蒸发。重复所述过程3-4次以移除大部分挥发性杂质。使残余物冷却至0℃，并添加无水醚以使肽沉淀。将沉淀的肽离心并移除上清液中的醚，并将新鲜醚添加至肽并再次离心。将粗制样品用制备型HPLC纯化并冻干。通过LCMS确认肽的身份。
表5：序列表
序列表
<110> 赛诺菲(Sanofi)
<120> 具有优化的活性比率的FGF21化合物/GLP-1R激动剂组合
<130> 589-264 PCT2
<150> EP 18 305 784.3
<151> 2018年6月21日
<160> 70
<170> PatentIn版本3.5
<210> 1
<211> 209
<212> PRT
<213> 人(Homo sapiens)
<400> 1
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro
20 25 30
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
35 40 45
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
50 55 60
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
65 70 75 80
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
85 90 95
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
100 105 110
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
115 120 125
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
130 135 140
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
145 150 155 160
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu
165 170 175
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
195 200 205
Ser
<210> 2
<211> 181
<212> PRT
<213> 人(Homo sapiens)
<400> 2
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 3
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21(His29-Ser209) A59C,G71C
<400> 3
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Cys His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Cys Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 4
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21(His29-Ser209) Q55C,N149C,G198Y
<400> 4
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Tyr Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 5
<211> 180
<212> PRT
<213> 人工序列
<220>
<223> FGF21(His29-Ser209) Q55C,P147C,delP199
<400> 5
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Cys Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser Gln Gly Arg Ser Pro
165 170 175
Ser Tyr Ala Ser
180
<210> 6
<211> 180
<212> PRT
<213> 人工序列
<220>
<223> FGF21(His29-Ser209) Q55C,N149C,delP199
<400> 6
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser Gln Gly Arg Ser Pro
165 170 175
Ser Tyr Ala Ser
180
<210> 7
<211> 30
<212> PRT
<213> 人(Homo sapiens)
<400> 7
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 Lys Gly Arg
20 25 30
<210> 8
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,L20M,G22E,Q23E,A25V,K26R,E27L,A30E,V33K,K34N,R
36G,insPSSGAPPPS
<400> 8
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
35
<210> 9
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G,insPSSGAPPPS
<400> 9
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 10
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18I,Y19Q,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,G
35T,R36G,insPVSGAPPPS
<400> 10
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Val
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 11
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18I,Y19Q,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33E,K34A,G
35T,R36G,insPVSGAPPPS
<400> 11
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Glu Ala Thr Gly Pro Val
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 12
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,R
36G,insPSSGAPPPS
<400> 12
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 13
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,G
35T,R36G,insPSSGAPPPS
<400> 13
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 14
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,E21D,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G
35T,R36G,insPSSGEPPPES
<400> 14
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Glu Pro Pro Pro Glu Ser
35 40
<210> 15
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,L20M,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33K,K
34N,R36G
<400> 15
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
20 25 30
<210> 16
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G
<400> 16
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly
20 25 30
<210> 17
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G,insPSSGEPPPE
<400> 17
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Glu Pro Pro Pro Glu
35
<210> 18
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18K,Y19Q,G22E,Q23E,A24R,A25V,K26Q,A30E,insPSSGAPPP
S
<400> 18
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu
1 5 10 15
Glu Glu Arg Val Gln Glu Phe Ile Glu Trp Leu Val Lys Gly Arg Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 19
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33E,K34A,G35T,R
36G,insPSSGAPPPS
<400> 19
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Glu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 20
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,R
36G,insPKKQRLS
<400> 20
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro
20 25 30
Lys Lys Gln Arg Leu Ser
35
<210> 21
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc变体, IGHG4_人(Glu99-Gly326)
<400> 21
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly
225
<210> 22
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> (G7S)(G4S)(G4S)A接头(19GS)
<400> 22
Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Ala
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> (G3S)(GS)A接头(7GS)
<400> 23
Gly Gly Gly Ser Gly Ser Ala
1 5
<210> 24
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,L20M,G22E,Q23E,A25V,K26R,E27L,A30E,V33K,K34N,R
36G,insPSSGAPPPS_[19GS]_IgG4 Fc_变体[7GS]_
FGF21(His29-Ser209)_A59C,G71C
<400> 24
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 Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln
305 310 315 320
Gln Thr Glu Cys His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Cys
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 25
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G,insPSSGAPPPS_[19GS] _IgG4 Fc
变体_[7GS]_FGF21(His29-Ser209)Q55C,N149C,G198Y
<400> 25
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys
305 310 315 320
Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Tyr Pro
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 26
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18I,Y19Q,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,G
35T,R36G,insPVSGAPPPS_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,P147C,delP199
<400> 26
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Val
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys
305 310 315 320
Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Cys Gly Asn Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser
450 455 460
Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 27
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18I,Y19Q,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33E,K34A,G
35T,R36G,insPVSGAPPPS_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,delP199
<400> 27
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Glu Ala Thr Gly Pro Val
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys
305 310 315 320
Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser
450 455 460
Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 28
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,R
36G,insPSSGAPPPS_[19GS] _IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,delP199
<400> 28
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly
50 55 60
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
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 Gly
275 280 285
Gly Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Cys Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 29
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,G
35T,R36G,insPSSGAPPPS_[19GS]_Ig4G Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,P147C,delP199
<400> 29
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly
50 55 60
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
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 Gly
275 280 285
Gly Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Cys Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Cys Gly Asn Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 30
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,E21D,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G
35T,R36G,insPSSGEPPPES_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,G198Y
<400> 30
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Glu Pro Pro Pro Glu Ser Gly Gly Gly Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly
50 55 60
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
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 Gly
275 280 285
Gly Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Cys Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Tyr
450 455 460
Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470 475
<210> 31
<211> 465
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,L20M,E21D,G22E,Q23E,A25V,K26R,E27L,A30E,V33K,K
34N,R36G_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,G198Y
<400> 31
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 Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
50 55 60
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
65 70 75 80
Thr 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 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
180 185 190
Gln Val Ser Leu Thr Cys Leu 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 Tyr 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 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
260 265 270
Ser Leu Ser Leu Gly Gly Gly Gly Ser Gly Ser Ala His Pro Ile Pro
275 280 285
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
290 295 300
Leu Tyr Thr Asp Asp Ala Cys Gln Thr Glu Ala His Leu Glu Ile Arg
305 310 315 320
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
325 330 335
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
340 345 350
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
355 360 365
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
370 375 380
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
385 390 395 400
His Leu Pro Gly Cys Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
405 410 415
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu
420 425 430
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
435 440 445
Pro Leu Ser Met Val Tyr Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
450 455 460
Ser
465
<210> 32
<211> 465
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G_[19GS]_IgG4 Fc_变体[7GS]
FGF21(His29-Ser209)Q55C,N149C,G198Y
<400> 32
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
50 55 60
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
65 70 75 80
Thr 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 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
180 185 190
Gln Val Ser Leu Thr Cys Leu 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 Tyr 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 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
260 265 270
Ser Leu Ser Leu Gly Gly Gly Gly Ser Gly Ser Ala His Pro Ile Pro
275 280 285
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
290 295 300
Leu Tyr Thr Asp Asp Ala Cys Gln Thr Glu Ala His Leu Glu Ile Arg
305 310 315 320
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
325 330 335
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
340 345 350
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
355 360 365
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
370 375 380
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
385 390 395 400
His Leu Pro Gly Cys Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
405 410 415
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu
420 425 430
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
435 440 445
Pro Leu Ser Met Val Tyr Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
450 455 460
Ser
465
<210> 33
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33L,K34A,G35T,R
36G,insPSSGEPPPE_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,G198Y
<400> 33
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Leu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Glu Pro Pro Pro Glu Gly Gly Gly Gly Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys
305 310 315 320
Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Tyr Pro
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 34
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18K,Y19Q,G22E,Q23E,A24R,A25V,K26Q,A30E,insPSSGAPPP
S_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,delP199
<400> 34
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu
1 5 10 15
Glu Glu Arg Val Gln Glu Phe Ile Glu Trp Leu Val Lys Gly Arg Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly
50 55 60
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser
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 Gly
275 280 285
Gly Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Cys Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly
450 455 460
Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 35
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
A8G,V16L,S18K,Y19Q,G22E,Q23E,A25V,K26Q,E27L,A30E,V33E,K34A,G35T,R
36G,insPSSGAPPPS_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,delP199
<400> 35
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Gln Leu Phe Ile Glu Trp Leu Glu Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly
35 40 45
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
50 55 60
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
65 70 75 80
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 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 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 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 Met His Glu Ala Leu
260 265 270
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
275 280 285
Gly Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln
290 295 300
Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys
305 310 315 320
Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly
325 330 335
Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys
340 345 350
Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys
355 360 365
Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu
370 375 380
Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr
385 390 395 400
Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser
405 410 415
Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu
420 425 430
Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro
435 440 445
Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser
450 455 460
Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 36
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> GLP1(7-36)
insG,A8G,V16L,S18I,Y19Q,G22E,Q23E,A25V,K26R,E27L,A30E,V33L,K34A,R
36G,insPKKQRLS_[19GS]_IgG4 Fc_变体
[7GS]_FGF21(His29-Ser209)Q55C,N149C,delP199
<400> 36
Gly His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ile Gln Leu Glu
1 5 10 15
Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Leu Ala Gly Gly Pro
20 25 30
Lys Lys Gln Arg Leu Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly
35 40 45
Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro
50 55 60
Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser 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 Gly Gly Gly
275 280 285
Ser Gly Ser Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe
290 295 300
Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Cys Gln
305 310 315 320
Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala
325 330 335
Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro
340 345 350
Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln
355 360 365
Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala
370 375 380
Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln
385 390 395 400
Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Cys Lys Ser Pro
405 410 415
His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro
420 425 430
Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln
435 440 445
Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ser Gln
450 455 460
Gly Arg Ser Pro Ser Tyr Ala Ser
465 470
<210> 37
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> GLP-1RA，通用序列
<220>
<221> misc_特征
<222> (10)..(10)
<223> Xaa是任一氨基酸，例如，L或K
<220>
<221> misc_特征
<222> (12)..(12)
<223> Xaa是任一氨基酸，例如，K或I
<220>
<221> misc_特征
<222> (14)..(14)
<223> Xaa是任一氨基酸，例如，L或M
<220>
<221> misc_特征
<222> (15)..(15)
<223> Xaa是任一氨基酸，例如，E或D
<220>
<221> misc_特征
<222> (18)..(18)
<223> Xaa是任一氨基酸，例如，A或R
<220>
<221> misc_特征
<222> (20)..(20)
<223> Xaa是任一氨基酸，例如，R或Q
<220>
<221> misc_特征
<222> (21)..(21)
<223> Xaa是任一氨基酸，例如，L或E
<220>
<221> misc_特征
<222> (27)..(27)
<223> Xaa是任一氨基酸，例如，L、E、K或V
<220>
<221> misc_特征
<222> (28)..(28)
<223> Xaa是任一氨基酸，例如，A、N或K
<220>
<221> misc_特征
<222> (29)..(29)
<223> Xaa是任一氨基酸，例如，T或G
<220>
<221> misc_特征
<222> (30)..(30)
<223> Xaa是任一氨基酸，例如，G或R
<400> 37
His Gly Glu Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Gln Xaa Xaa Glu
1 5 10 15
Glu Xaa Val Xaa Xaa Phe Ile Glu Trp Leu Xaa Xaa Xaa Xaa
20 25 30
<210> 38
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸I
<400> 38
Pro Ser Ser Gly Ala Pro Pro Pro Ser
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸II
<400> 39
Pro Val Ser Gly Ala Pro Pro Pro Ser
1 5
<210> 40
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸III
<400> 40
Pro Ser Ser Gly Glu Pro Pro Pro Glu Ser
1 5 10
<210> 41
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸IV
<400> 41
Pro Ser Ser Gly Glu Pro Pro Pro Glu
1 5
<210> 42
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸V
<400> 42
Pro Lys Lys Gln Arg Leu Ser
1 5
<210> 43
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> C末端肽延伸VI
<400> 43
Pro Lys Lys Ile Arg Tyr Ser
1 5
<210> 44
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 44
Glu Ile Arg Pro
1
<210> 45
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 45
Thr Gly Leu Glu Ala Val
1 5
<210> 46
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 46
Thr Gly Leu Glu Ala Asn
1 5
<210> 47
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 47
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 48
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 48
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Val Arg
165 170 175
Ser Pro Ser Tyr Ala Ser
180
<210> 49
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 49
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Asn Arg
165 170 175
Ser Pro Ser Tyr Ala Ser
180
<210> 50
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 50
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Asn Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 51
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 51
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Asn Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 52
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 52
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Val Arg
165 170 175
Ser Pro Ser Tyr Ala Ser
180
<210> 53
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 53
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Asn Arg
165 170 175
Ser Pro Ser Tyr Ala Ser
180
<210> 54
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 54
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Asn Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 55
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 55
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Asn Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 56
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 56
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 57
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 57
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Val Arg
165 170 175
Ser Pro Ser Tyr Glu Ser
180
<210> 58
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 58
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Asn Arg
165 170 175
Ser Pro Ser Tyr Glu Ser
180
<210> 59
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 59
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Asn Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 60
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 60
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Asn Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 61
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 61
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Val Arg
165 170 175
Ser Pro Ser Tyr Glu Ser
180
<210> 62
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 62
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly Leu Glu Ala Asn Arg
165 170 175
Ser Pro Ser Tyr Glu Ser
180
<210> 63
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 63
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Asn Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 64
<211> 181
<212> PRT
<213> 人工序列
<220>
<223> FGF21变体
<400> 64
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Glu Ile Arg Pro Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Asn Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 65
<211> 223
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 65
Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
35 40 45
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
100 105 110
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 66
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 66
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys
1 5 10 15
Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His
20 25 30
Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
35 40 45
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
50 55 60
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
65 70 75 80
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
85 90 95
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
100 105 110
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
115 120 125
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
130 135 140
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
145 150 155 160
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
165 170 175
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
180 185 190
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
195 200 205
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
210 215 220
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
225 230 235 240
Leu Ser Leu Gly Lys
245
<210> 67
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 67
Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu
1 5 10 15
Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys
20 25 30
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
35 40 45
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
65 70 75 80
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
85 90 95
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
100 105 110
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
115 120 125
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
130 135 140
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
165 170 175
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
180 185 190
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
195 200 205
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
210 215 220
Lys Ser Leu Ser Leu Ser Leu Gly Lys
225 230
<210> 68
<211> 255
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 68
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 Ser His Thr Gln Pro Leu Gly Val
35 40 45
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
50 55 60
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
65 70 75 80
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
85 90 95
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
100 105 110
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
115 120 125
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
130 135 140
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
145 150 155 160
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
165 170 175
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
180 185 190
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
195 200 205
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
210 215 220
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
225 230 235 240
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
245 250 255
<210> 69
<211> 264
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 69
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro
1 5 10 15
Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu
20 25 30
Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys
35 40 45
Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro
50 55 60
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
65 70 75 80
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
85 90 95
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
100 105 110
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
115 120 125
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
130 135 140
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
145 150 155 160
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
165 170 175
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
180 185 190
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
195 200 205
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
210 215 220
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
225 230 235 240
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
245 250 255
Ser Leu Ser Leu Ser Leu Gly Lys
260
<210> 70
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> 杂合Fc变体
<400> 70
Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
35 40 45
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
100 105 110
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala
210 215 220
Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly
225 230 235 240
Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu
245 250
Claims (20)
1.一种组合，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/531至1/9。
2.根据权利要求1所述的组合，其中所述GLP-1R激动剂的GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/482至1/9或1/319至1/9或1/121至1/9。
3.根据权利要求1所述的组合，其中所述GLP-1R激动剂的GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/501至1/18或1/469至1/18或1/313至1/18或1/123至1/18。
4.根据权利要求1至3中任一项所述的组合，其中所述FGF21变体与天然FGF21的氨基酸序列具有至少80％或至少90％或至少95％氨基酸序列同一性。
5.根据权利要求1至4中任一项所述的组合，其中所述FGF21变体包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63和64。
6.根据权利要求1至5中任一项所述的组合，其中所述GLP-1R激动剂包含以下氨基酸序列或由以下氨基酸序列组成
H-G-E-G-T-F-T-S-D-X10-S-X12-Q-X14-X15-E-E-X18-V-X20-X21-F-I-E-W-L-X27-X28-X29-X30(SEQ ID NO:37)，
其中
X10是L或K；
X12是K或I；
X14是L或M；
X15是E或D；
X18是A或R；
X20是R或Q；
X21是L或E；
X27是L、E、K或V；
X28是A、N或K；
X29是T或G；
X30是G或R；
其中，任选地，所述氨基酸序列在其N末端包含至少一个额外的氨基酸残基；并且
其中，任选地，所述氨基酸序列在其C末端包含由多至12、11或10个氨基酸残基组成的肽延伸。
7.根据权利要求1至6中任一项所述的组合，其中所述GLP-1R激动剂包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成：SEQ ID NO:9、10、12、14、15、16、17、19和20。
8.根据权利要求6或7所述的组合，其中X14是L且X28是A。
9.一种药物组合物，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂以及药学上可接受的载体和/或赋形剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；和
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/531至1/9。
10.一种融合分子，其包含FGF21(成纤维细胞生长因子21)化合物和GLP-1R(胰高血糖素样肽-1受体)激动剂，
其中所述FGF21化合物具有与天然FGF21的FGF21活性相同或基本相同的FGF21活性，并且所述FGF21化合物是FGF21变体，所述FGF21变体包含至少一个选自下组的突变：
-以氨基酸序列EIRP(SEQ ID NO:44)取代来自SEQ ID NO:2的天然FGF21的N末端的位置98至101处的氨基酸残基；
-以氨基酸序列TGLEAV(SEQ ID NO:45)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸序列TGLEAN(SEQ ID NO:46)取代来自SEQ ID NO:2的天然FGF21的N末端的位置170至174处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置170处的氨基酸残基；
-以氨基酸N取代来自SEQ ID NO:2的天然FGF21的N末端的位置174处的氨基酸残基；
-以氨基酸E取代来自SEQ ID NO:2的天然FGF21的N末端的位置180处的氨基酸残基以及一个或多个如以上定义的突变；以及
-与SEQ ID NO:2的天然FGF21相比降低所述FGF21变体的免疫原性的1至10个氨基酸残基的突变，并且
其中所述GLP-1R激动剂具有GLP-1R激动活性，所述GLP-1R激动活性与天然GLP-1(7-36)的GLP-1R激动活性相比，降低为1/531至1/9。
11.根据权利要求10所述的融合分子，其中所述融合分子还包含杂合Fc域，所述杂合Fc域包含不同免疫球蛋白的部分Fc区/域的组合。
12.根据权利要求9所述的药物组合物或根据权利要求10或11所述的融合分子，其中所述GLP-1R激动剂和/或所述FGF21化合物是如权利要求2至8中任一项定义的。
13.一种核酸分子，其编码根据权利要求10至12中任一项所述的融合分子。
14.一种宿主细胞，其含有根据权利要求13所述的核酸分子。
15.一种试剂盒，其包含根据权利要求1至8中任一项所述的组合、根据权利要求9或12所述的药物组合物、根据权利要求10至12中任一项所述的融合分子、根据权利要求13所述的核酸分子或根据权利要求14所述的宿主细胞。
16.根据权利要求1至8中任一项所述的组合、根据权利要求9或12所述的药物组合物、根据权利要求10至12中任一项所述的融合分子、根据权利要求13所述的核酸分子或根据权利要求14所述的宿主细胞，其用作药物。
17.根据权利要求1至8中任一项所述的组合、根据权利要求9或12所述的药物组合物、根据权利要求10至12中任一项所述的融合分子、根据权利要求13所述的核酸分子或根据权利要求14所述的宿主细胞，其用于治疗选自下组的疾病或病症：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化。
18.根据权利要求1至8中任一项所述的组合、根据权利要求9或12所述的药物组合物、根据权利要求10至12中任一项所述的融合分子、根据权利要求13所述的核酸分子或根据权利要求14所述的宿主细胞在制备用于治疗选自下组的疾病或病症的药物中的用途：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化。
19.一种治疗选自下组的疾病或病症的方法：肥胖症、体重超重、代谢综合征、糖尿病、糖尿病视网膜病变、高血糖症、血脂异常、非酒精性脂肪性肝炎(NASH)和动脉粥样硬化，所述方法包括向有此需要的受试者施用根据权利要求1至8中任一项所述的组合、根据权利要求9或12所述的药物组合物、根据权利要求10至12中任一项所述的融合分子、根据权利要求13所述的核酸分子或根据权利要求14所述的宿主细胞。
20.根据权利要求17所述的用于所述用途的组合、药物组合物、融合分子、核酸分子或宿主细胞、根据权利要求18所述的用途或根据权利要求19所述的方法，其中所述糖尿病是1型糖尿病或2型糖尿病。
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| WO2021221482A1 (ko) * | 2020-04-29 | 2021-11-04 | 주식회사 원진바이오테크놀로지 | 신규한 단백질 결합체, 및 이의 비알콜성 지방간염, 비만 및 당뇨 질환의 예방 또는 치료 용도 |
| US11981718B2 (en) | 2020-05-27 | 2024-05-14 | Ampsource Biopharma Shanghai Inc. | Dual-function protein for lipid and blood glucose regulation |
| EP4175660A1 (en) * | 2020-07-02 | 2023-05-10 | Sanofi | Glp-1r agonist / fgf21 fusion proteins |
| US20230250147A1 (en) * | 2020-07-02 | 2023-08-10 | Sanofi | Glp-1r agonistic peptides with reduced activity |
| US12054551B2 (en) | 2020-07-02 | 2024-08-06 | Sanofi | FGFR1/KLB targeting agonistic antigen-binding proteins and conjugates thereof with GLP-1R agonistic peptides |
| AU2020204470B1 (en) * | 2020-07-03 | 2021-05-27 | Ampsource Biopharma Shanghai Inc. | Dual-function protein for lipid and blood glucose regulation |
| WO2024165571A2 (en) | 2023-02-06 | 2024-08-15 | E-Therapeutics Plc | Inhibitors of expression and/or function |
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| WO2019243557A1 (en) | 2019-12-26 |
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| US20210275643A1 (en) | 2021-09-09 |
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