CN114174348A - 胰岛素类似物及其使用方法 - Google Patents
胰岛素类似物及其使用方法 Download PDFInfo
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- CN114174348A CN114174348A CN202080054344.4A CN202080054344A CN114174348A CN 114174348 A CN114174348 A CN 114174348A CN 202080054344 A CN202080054344 A CN 202080054344A CN 114174348 A CN114174348 A CN 114174348A
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Abstract
公开了胰岛素(INS)类似物,其包括与天然人INS相比的修饰,所述修饰增加半衰期、维持对胰岛素受体(IR)的选择性和提供体外和体内稳定性以改善成药性和降低免疫原性。还公开了药物组合物,其包括在药学上可接受的载体中的一种或多种本文所述的INS类似物。还公开了制备和使用INS类似物的方法,特别是用于治疗代谢病症、疾病或障碍,尤其是治疗疾病诸如糖尿病和肥胖。
Description
本公开内容总体上涉及生物学和医学,且更具体地它涉及胰岛素(INS)类似物,尤其是长效单链INS(SCI)类似物,其可以结合INS受体(IR),从而作为IR激动剂起作用。本公开内容进一步涉及包含它们的组合物以及它们在治疗代谢病症、疾病或障碍诸如糖尿病和肥胖中的用途。
INS是一种由胰腺β(β)细胞分泌的肽激素,其生理作用是通过促进细胞葡萄糖摄取和通过伴随地抑制肝糖原异生来维持正常血糖水平,从而调节碳水化合物、脂质和蛋白代谢。此外,INS促进进食状态下的细胞分裂和生长。
在结构上,INS是通过两个链间二硫键连接的21个和30个氨基酸(分别为A链和B链)的两条肽链的异源二聚体,其中A链还具有一个链内二硫键。INS从它的激素原胰岛素原通过从其裂解C肽而产生。参见,例如,De Meyts (2004) Bioessays 26:1351-1362;和Wilcox (2005) Clin. Biochem. Rev. 26:19-39。
在治疗上,存在六种主要类型的INS,包括:(1)速效INS,(2)短效(膳食)INS,(3)中效INS,(4)长效(基础)INS,(5)组合/预混合INS和(6)吸入INS。用于患有糖尿病的个体的有效INS疗法通常是两种类型的外源INS制剂的组合——在进餐时施用的短效(膳食)INS和每天施用一次或两次的长效(基础)INS,以控制餐间的血糖水平。
存在许多与天然INS相比具有延长的t½的INS类似物,因此它们可以作为长效(基础)INS施用。例如,国际专利申请公开号WO 1995/007931和WO 2018/217573描述了INS类似物,其包括与脂肪酸部分连接(即,酰化)以改善t½的INS及其变体。美国专利号5,656,722描述了INS类似物,其包括A链的Asp21Gly突变和两个Arg残基的B链的羧基端延伸。国际专利申请公开号WO 2005/012347描述了INS类似物,其是通过将十六烷二酸添加到在B链的第29位的Lys而产生的六聚体。Duttaroy等人描述了类似物,其包括与人血清白蛋白连接以改善t½的人INS (参见,Duttaroy等人(2005) Diabetes 54:251-258)。中国专利号103509118和国际专利申请公开号WO 2016/178905描述了INS类似物,它们是A链和/或B链的融合体,其进一步包括Fc部分以改善t½。
尽管有大量的INS类似物,但仍需要具有改善的t½的其它INS类似物,尤其是用作长效(基础)INS的类似物。
为了满足这种需要,本公开内容首先描述了对IR具有活性的SCI类似物,其由此可以充当IR激动剂。这样的SCI类似物包括以下的从氨基端(N-端)至羧基端(C-端)的基础结构:
VHH-L1-A-L2-B,
VHH-L1-B-L2-A,
A-L2-B-L1-VHH,或者
B-L2-A-L1-VHH,
其中VHH是充当药代动力学增强剂的部分,A是INS A链,B是INS B链,L1是第一接头,且L2是第二接头。
在某些情况下,VHH部分可以具有SEQ ID NO:7、8或9的氨基酸序列。在其它情况下,VHH部分可以是具有一个或多个添加、缺失、插入或置换的变体,使得VHH部分具有与SEQID NO:7、8或9具有至少约90%至约99%序列相似性的氨基酸序列。
在某些情况下,A链可以具有SEQ ID NO:3的氨基酸序列。在其它情况下,A链可以是具有一个或多个添加、缺失、插入或置换的变体,使得A链具有与SEQ ID NO:3中的任一个具有至少约90%至约99%序列相似性的氨基酸序列。例如,A链可以包括SEQ ID NO:3的E4Q突变、T8H突变、Y14E突变或N21G突变。
在某些情况下,B链可以具有SEQ ID NO:4的氨基酸序列。在其它情况下,B链可以是具有一个或多个添加、缺失、插入或置换的变体,使得B链具有与SEQ ID NO:4中的任一个具有至少约90%至约99%序列相似性的氨基酸序列。例如,B链可以包括SEQ ID NO:4的N3D突变、N3K突变、N3S突变、S9A突变、Y16E突变、Y16F突变、Y16H突变、Y16R突变、Y16W突变、E21Q突变或F25H突变。
在某些情况下,L1可以具有(GGGGQ)n (SEQ ID NO:10)、(GGGQ)n (SEQ ID NO:11)、(GGGGS)n (SEQ ID NO:12)、(PGPQ)n (SEQ ID NO:13)、(PGPA)n (SEQ ID NO:14)、(GGE)nGG(SEQ ID NO:15)、(GGGGE)nGGGG (SEQ ID NO:16)、(GGGGK)nGGGG (SEQ ID NO:17)、GGGG(AP)nGGGG (SEQ ID NO:18)、GGGG(EP)nGGGG (SEQ ID NO:19)、GGGG(KP)nGGGG (SEQ IDNO:20)、(PGPE)nPGPQ (SEQ ID NO:21)、(PGPK)nPGPQ (SEQ ID NO:22)的氨基酸序列,其中n可以是1-10。在其它情况下,L1可以具有SEQ ID NO:23至33中的任一个的氨基酸序列。在其它情况下,L1可以是具有一个或多个添加、缺失、插入或置换的变体,使得L1具有与SEQ IDNO:23至33中的任一个具有至少约90%至约99%序列相似性的氨基酸序列。
在某些情况下,L2可以具有SEQ ID NO:34至36中的任一个的氨基酸序列。在其它情况下,L2可以是具有一个或多个添加、缺失、插入或置换的变体,使得L2具有与SEQ ID NO:34至36中的任一个具有至少约90%至约99%序列相似性的氨基酸序列。
在某些情况下,INS类似物可以具有这样的氨基酸序列,其包括:SEQ ID NO:7或8的VHH;SEQ ID NO:3或其变体的A链;SEQ ID NO:4或其变体的B链;SEQ ID NO:23至33中的任一个的L1和SEQ ID NO:34至36中的任一个的L2。可替换地,INS类似物可以具有这样的氨基酸序列,其与包括以下内容的氨基酸序列具有至少约90%至约99%序列相似性:SEQ IDNO:7或8的VHH;SEQ ID NO:3或其变体的A链;SEQ ID NO:4或其变体的B链;SEQ ID NO:23至33中的任一个的L1;和SEQ ID NO:34至36中的任一个的L2。
在特定情况下,INS类似物可以具有SEQ ID NO:37至81中的任一个的氨基酸序列。可替换地,INS类似物可以具有与SEQ ID NO:37至81中的任一个的氨基酸序列具有至少约90%至约99%序列相似性的氨基酸序列。
在某些情况下,VHH部分可以结合血清白蛋白,尤其是人血清白蛋白,且可以包括互补性决定区1 (CDR1)、互补性决定区2 (CDR2)和互补性决定区3 (CDR3),其中CDR1可以具有SEQ ID NO:84、85或86的氨基酸序列,其中CDR2可以具有SEQ ID NO:87、88或89的氨基酸序列,且CDR3可以具有SEQ ID NO:90、91或92的氨基酸序列。在某些情况下,VHH部分可以包括SEQ ID NO:84的CDR1、SEQ ID NO:87的CDR2和SEQ ID NO:90的CDR3;SEQ ID NO:84的CDR1、SEQ ID NO:88的CDR2和SEQ ID NO:90的CDR3;SEQ ID NO:85的CDR1、SEQ ID NO:89的CDR2和SEQ ID NO:91的CDR3;或SEQ ID NO:86的CDR1、SEQ ID NO:89的CDR2和SEQ ID NO:92的CDR3。
在某些情况下,INS类似物对IR具有的结合亲和力与天然人INS (SEQ ID NO:3和4)的结合亲和力相当。在其它情况下,INS类似物对IR具有的结合亲和力大于天然人INS(SEQ ID NO:3和4)的结合亲和力。在其它情况下,INS类似物对IR具有的结合亲和力弱于天然人INS (SEQ ID NO:3和4)的结合亲和力。
在某些情况下,INS类似物具有的t½长于天然人INS (SEQ ID NO:3和4)的t½,包括当施用给人类时长高达约20天至约30天。
以上组合物可替换地可以是编码本文中的氨基酸序列的核酸序列,以及用于表达本文中的VHH部分或INS类似物的载体和包含其的宿主细胞。
第二,描述了药物组合物,其包含本文中的INS类似物或其药学上可接受的盐(例如,三氟乙酸盐、乙酸盐或盐酸盐)和药学上可接受的载体。在某些情况下,药学上可接受的载体是缓冲液,例如,生理盐水、磷酸盐-缓冲盐水、柠檬酸盐-缓冲盐水或组氨酸-缓冲盐水。在某些情况下,缓冲液是组氨酸、组氨酸缓冲液或组氨酸-缓冲盐水。在其它情况下,药物组合物还可以包含载体、稀释剂和/或赋形剂。
此外,药物组合物可以包含至少一种另外的治疗剂,例如,用作代谢病症、疾病或障碍中的护理标准的药剂。在某些情况下,至少一种另外的治疗剂可以是二肽基肽酶4(DPP-IV)抑制剂、天然胰淀素或其类似物、短效(膳食) INS类似物、天然肠降血糖素或其类似物、天然胰岛素样生长因子(IGF)或其类似物、二甲双胍、钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂、抑制素、磺酰脲(SU)、噻唑烷二酮(TZD)和/或其它抗血糖剂或其它抗肥胖剂。
第三,描述了使用本文中的INS类似物的方法,尤其是使用INS类似物治疗代谢病症、疾病或障碍的方法。所述方法至少包括向有此需要的个体施用有效量的INS类似物或其药学上可接受的盐的步骤。
在某些情况下,可以通过任何标准施用途径(例如,肌肉内、静脉内、胃肠外、皮下或透皮)施用INS类似物。在某些情况下,皮下(SQ)、肌肉内(IM)或静脉内(IV)施用INS类似物。在特定情况下,可以将INS类似物皮下或静脉内施用给个体。
同样地,且在某些情况下,可以每天、每隔一天、每周三次、每周两次、每周一次(即,每周)、每两周(即,每隔一周)、每个月一次(即,每月),每两个月(即,每隔一个月)或甚至每三个月施用INS类似物。在某些情况下,可以每隔一天皮下、每周三次皮下、每周两次皮下、每周一次皮下、每隔一周皮下或每月一次皮下施用INS类似物。在特定情况下,每周一次(QW)皮下施用INS类似物。
可替换地,可以将INS类似物静脉内施用给个体。如上,可以每天、每隔一天、每周三次、每周两次、每周一次(即,每周)、每两周(即,每隔一周)或每月施用INS类似物。在某些情况下,可以每隔一天静脉内、每周三次静脉内、每周两次静脉内、每周一次静脉内、每隔一周静脉内或每个月一次静脉内施用INS类似物。在特定情况下,每周一次静脉内施用INS类似物。
所述方法还可以包括将INS类似物与有效量的至少一种另外的治疗剂组合施用的步骤。简而言之,本文中许多病症/疾病/障碍的护理标准包括DPP-IV抑制剂、天然胰淀素或其类似物、短效(膳食) INS类似物、天然肠降血糖素或其类似物、天然IGF或其类似物、二甲双胍、SGLT2抑制剂、抑制素、SU、TZD和/或其它抗血糖剂或其它抗肥胖剂,以及控制并存病(包括、但不限于,高胆固醇和高血压)的其它治疗剂。在某些情况下,可以与INS类似物同时、分开或依次施用另外的治疗剂。
例如,可以以与INS类似物相同的频率(即,每隔一天、每周两次、每周或甚至每月)施用另外的治疗剂。在其它情况下,可以以与INS类似物不同的频率施用另外的治疗剂。在其它情况下,可以皮下或静脉内施用另外的治疗剂。在其它情况下,皮下施用INS类似物,且可以口服或静脉内施用另外的治疗剂。可替换地,静脉内施用INS类似物,且皮下施用另外的治疗剂。
在某些情况下,个体患有糖尿病和/或肥胖。
所述方法还可以包括诸如测量或获得血糖、HbA1c、胆固醇、甘油三酯和/或体重和将这样的测量/获得的值与一个或多个基线值或先前测量/获得的值进行对比以评估治疗/疗法的有效性的步骤。
所述方法还可以与饮食和锻炼相组合,和/或可以与除以上讨论的那些之外的另外的治疗剂相组合。
第四,描述了包括本文中的INS类似物的用途。例如,可以提供INS类似物用于治疗,尤其是治疗代谢病症、疾病或障碍,尤其是糖尿病和/或肥胖。INS类似物任选地可以与至少一种另外的治疗剂同时、分开或依次(即,组合)施用。同样地,可以提供INS类似物用于制备用于治疗代谢病症、疾病或障碍的药物,其中所述药物任选地可以进一步包括一种或多种上面指出的另外的治疗剂。
第五,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:37)。在某些情况下,所述化合物可以具有与SEQ ID NO:37具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:38)。在某些情况下,所述化合物可以具有与SEQ ID NO:38具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:39)。在某些情况下,所述化合物可以具有与SEQ ID NO:39具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:40)。在某些情况下,所述化合物可以具有与SEQ ID NO:40具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:41)。在某些情况下,所述化合物可以具有与SEQ ID NO:41具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:42)。在某些情况下,所述化合物可以具有与SEQ ID NO:42具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:43)。在某些情况下,所述化合物可以具有与SEQ ID NO:43具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:44)。在某些情况下,所述化合物可以具有与SEQ ID NO:44具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:45)。在某些情况下,所述化合物可以具有与SEQ ID NO:45具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:46)。在某些情况下,所述化合物可以具有与SEQ ID NO:46具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:47)。在某些情况下,所述化合物可以具有与SEQ ID NO:47具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:48)。在某些情况下,所述化合物可以具有与SEQ ID NO:48具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:49)。在某些情况下,所述化合物可以具有与SEQ ID NO:49具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:50)。在某些情况下,所述化合物可以具有与SEQ ID NO:50具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:51)。在某些情况下,所述化合物可以具有与SEQ ID NO:51具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:52)。在某些情况下,所述化合物可以具有与SEQ ID NO:52具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:53)。在某些情况下,所述化合物可以具有与SEQ ID NO:53具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:54)。在某些情况下,所述化合物可以具有与SEQ ID NO:54具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:55)。在某些情况下,所述化合物可以具有与SEQ ID NO:55具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:56)。在某些情况下,所述化合物可以具有与SEQ ID NO:56具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:57)。在某些情况下,所述化合物可以具有与SEQ ID NO:57具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:58)。在某些情况下,所述化合物可以具有与SEQ ID NO:58具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:59)。在某些情况下,所述化合物可以具有与SEQ ID NO:59具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:60)。在某些情况下,所述化合物可以具有与SEQ ID NO:60具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:61)。在某些情况下,所述化合物可以具有与SEQ ID NO:61具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:62)。在某些情况下,所述化合物可以具有与SEQ ID NO:62具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:63)。在某些情况下,所述化合物可以具有与SEQ ID NO:63具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:64)。在某些情况下,所述化合物可以具有与SEQ ID NO:64具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:65)。在某些情况下,所述化合物可以具有与SEQ ID NO:65具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:66)。在某些情况下,所述化合物可以具有与SEQ ID NO:66具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:67)。在某些情况下,所述化合物可以具有与SEQ ID NO:67具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:68)。在某些情况下,所述化合物可以具有与SEQ ID NO:68具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:69)。在某些情况下,所述化合物可以具有与SEQ ID NO:69具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:70)。在某些情况下,所述化合物可以具有与SEQ ID NO:70具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:71)。在某些情况下,所述化合物可以具有与SEQ ID NO:71具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:72)。在某些情况下,所述化合物可以具有与SEQ ID NO:72具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:73)。在某些情况下,所述化合物可以具有与SEQ ID NO:73具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:74)。在某些情况下,所述化合物可以具有与SEQ ID NO:74具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:75)。在某些情况下,所述化合物可以具有与SEQ ID NO:75具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:76)。在某些情况下,所述化合物可以具有与SEQ ID NO:76具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:77)。在某些情况下,所述化合物可以具有与SEQ ID NO:77具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:78)。在某些情况下,所述化合物可以具有与SEQ ID NO:78具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:79)。在某些情况下,所述化合物可以具有与SEQ ID NO:79具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:80)。在某些情况下,所述化合物可以具有与SEQ ID NO:80具有至少约90%至约99%序列相似性的氨基酸序列。
可替换地,提供了包括以下氨基酸序列的化合物:
(SEQ ID NO:81)。在某些情况下,所述化合物可以具有与SEQ ID NO:81具有至少约90%至约99%序列相似性的氨基酸序列。
本文中的INS类似物的一个优点是,它们可以化学或重组合成为单链多肽(即,单体),且因此不需要内切蛋白水解加工即可获得生物活性。但是,考虑在某些情况下,VHH部分不仅可以缀合至单链INS,而且还可以缀合至双链INS(例如,天然的)。在VHH部分上,不仅可以缀合至N-和C-端,而且可以缀合至VHH的任何表面暴露的氨基酸(前提条件是,这样的缀合不会完全消除VHH部分的白蛋白结合或INS部分的IR信号传递)。
本文中的INS类似物的一个优点是,VHH部分不仅可以与天然A链和B链序列一起使用,而且可以与其修饰的序列一起使用。此外,可以进一步修饰VHH部分以具有增强的或额外的功能,其通过附着于VHH部分的其它肽/蛋白融合物或小分子来实现。
本文中的INS类似物的一个优点是,VHH部分在哺乳动物诸如人类中提供延长的作用持续时间,并且可以具有约20天至约30天的t½,从而与天然人INS、尤其是天然人INS(SEQ ID NO:3和4)相比允许至少每周或每2周施用,这可以提高顺应性。
本文中的INS类似物的一个优点是,与天然人INS (SEQ ID NO:3和4)相比,它们对IR具有类似的或更好的选择性、亲和力和/或效能。
本文中的INS类似物的一个优点是,它们具有可调的药代动力学,这通过改变VHH部分的白蛋白亲和力而实现。
本文中的INS类似物的一个优点是,与天然人INS (SEQ ID NO:3和4)或未与本文中的VHH部分之一融合的INS类似物相比,它们在制剂中具有改善的稳定性,尤其是在保存制剂中。
本文中的VHH部分的一个优点是,它们不仅对人血清白蛋白而且对狗、猴、小鼠、猪和大鼠血清白蛋白具有类似的结合,这使得药效动力学、药代动力学和毒理学研究更容易地从这些物种转化至人类或上面列出的其它物种。
本文中的VHH部分的一个优点是,它们不仅可以用于与天然人INS (SEQ ID NO:3和4)相比改善本文中的INS类似物的t½,而且可以用于改善其它生物活性肽和蛋白(例如,生长分化因子15 (GDF-15)、葡萄糖依赖性促胰岛素肽1 (GLP-1)或松弛素(RLN))的t½。
除非另外定义,否则在本文中使用的所有技术和科学术语具有与本公开内容所属领域的技术人员通常理解的相同的含义。尽管在INS类似物、药物组合物和方法的实践或测试中可以使用与本文描述的那些相似或等效的任何方法和材料,但本文描述了优选的方法和材料。
此外,不定冠词“一个/种”对要素的提及不排除存在超过一个/种要素的可能性,除非上下文清楚地要求存在一个/种且仅一个/种要素。因此,不定冠词“一个/种”通常是指“至少一个/种”。
定义
如本文中使用的,“约”是指在一个或多个值例如所述的浓度、长度、分子量、pH、序列相似性、时间范围、温度、体积等的统计上有意义的范围内。这样的值或范围可以是在一个数量级以内,通常在给定值或范围的20%以内,更通常在10%以内,和甚至更通常在5%以内。“约”所涵盖的允许变化将取决于所研究的特定系统,并且本领域技术人员可以容易地理解。
如本文中使用的并且就一种或多种受体而言,“活性”、“激活”、“活化”等是指化合物诸如本文中的INS类似物的结合受体并诱导受体处的应答的能力,如使用本领域已知的测定法(诸如下文所述的体外测定法)测量的。
本文中使用的“氨基酸”是指这样的分子:从化学观点来看,其特征在于存在一个或多个胺基团和一个或多个羧酸基团并且可以含有其它官能团。如本领域已知的,存在一组二十种氨基酸,其被指定为标准氨基酸并且其可以用作任何生物产生的肽/蛋白的结构单元。本公开内容中的氨基酸序列含有二十种天然存在的氨基酸的标准单字母或三字母代码。
本文中使用的“类似物”是指激活靶受体并引发至少一种由该受体的天然激动剂引发的体内或体外效应的化合物,诸如合成肽、多肽或蛋白。
本文中使用的“激动剂”是指结合受体并激活受体的受体配体。
本文中使用的“保守置换”是指,除了在其氨基酸序列中具有一个或多个保守氨基酸置换以外,与参照分子相同的参照肽、多肽或蛋白的变体。一般而言,保守修饰的变体包括与参考氨基酸序列具有至少约70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。更具体地,保守置换表示将一个氨基酸用具有相似特征(例如,电荷、侧链大小、疏水性/亲水性、主链构象和刚度等)并且对得到的被置换的肽、多肽或蛋白的生物活性具有最小影响的氨基酸置换。在功能上相似的氨基酸的保守置换是本领域众所周知的,且因此无需在本文中详尽描述。
本文中使用的“有效量”是指一种或多种本文中的INS类似物或其药学上可接受的盐的量或剂量,其在向有此需要的个体施用单剂量或多剂量后,在这样的接受诊断或治疗的个体中提供所需的效果(即,可能在个体的状况中产生临床上可测量的差异,例如,降低的血糖、降低的HbA1c、降低的胆固醇、降低的甘油三酯或减轻体重)。通过使用已知技术和通过观察在类似情况下获得的结果,本领域技术人员可以容易地确定有效量。在确定个体的有效量时,考虑许多因素,包括但不限于哺乳动物的物种、其大小、年龄和一般健康、所涉及的特定疾病或障碍、疾病或障碍的程度或涉入度或严重程度、个体的应答、施用的特定INS类似物、施用模式、施用的制剂的生物利用度特征、所选择的剂量方案、伴随药物的使用和其它有关的情况。
本文中使用的“延长的作用持续时间”是指,本文中的INS类似物的结合和活性持续比天然INS、尤其是天然人INS (SEQ ID NO:3和4)更长的时间段,从而允许至少如每天一次或甚至每周三次、每周两次或每周一次较不频繁地给药。使用已知的药代动力学试验方法,诸如在以下实施例中使用的那些,可以测量INS类似物的时间作用特性。
本文中使用的“半衰期”或“t½”是指通过生物学过程从个体的流体或其它生理空间(诸如血清或血浆)除去化合物(诸如本文中的天然INS或INS类似物)的量的一半所花费的时间。可替换地,t½也可以是指一定量的这样的化合物失去其药理学、生理学或放射学活性的一半所花费的时间。
本文中使用的“半数最大有效浓度”或“EC50”是指导致测定终点诸如剂量-响应曲线(例如,IRS-PI3K-Akt和IRS-Raf/Ras/MEK/MAPK信号传递途径)的50%活化/刺激的化合物的浓度。
本文中使用的“与……组合”是指与一种或多种另外的治疗剂同时、依次或在单一组合制剂中施用至少一种本文中的INS类似物。
本文中使用的“胰岛素”或“INS”是指从任何物种(诸如哺乳动物物种,尤其是人)获得或衍生的胰岛素,其中天然形式是具有通过两个二硫键连接的两条肽链(例如,A链和B链)的异源二聚体肽,并且其中A链进一步具有单个分子内二硫键。在人类中,INS加工从前胰岛素原(SEQ ID NO:1;也参见, UniProt/SwissProt数据库登记号P01308)开始,其被加工成胰岛素原(包括A链、B链和C肽;天然INS具有B-C-A的结构),其中天然人胰岛素原的序列在SEQ ID NO:2中列出。胰岛素原经过进一步加工,其中C肽被裂解以得到INS。天然人INS的A链的序列在SEQ ID NO:3中列出。同样地,天然人INS的B链的序列在SEQ ID NO:4中列出。
INS信号传递通过IR发生,IR是具有酪氨酸激酶活性的两条α链和两条β(αβ)2链的同源二聚体。例如,已经在脂肪组织、脑、红细胞、成纤维细胞、粒细胞、心脏、肾、单核细胞、肺泡、胰腺腺泡、胎盘、血管内皮和骨骼肌中发现了IR。在人类中,存在两种IR亚型- IR-A(SEQ ID NO:5;也参见, UniProt/SwissProt数据库登记号P06213)和IR-B (SEQ ID NO:6;也参见, UniProt/SwissProt数据库登记号P06213)。此外,IR-A和IR-B在组织表达、配体结合亲和力、受体内化、再循环时间和细胞内信号传递方面存在已知差异。参见,例如,Belfiore等人(2009) Endocr. Rev. 30:586-6923;Benyoucef (2007) Biochem. J. 403:603-613;Frasca (1999) Mol. Cell. Biol. 19:3278-3288;Seino等人(1989) Proc. Natl. Acad. Sci. USA 86:114-118;和Yamaguchi等人(1993) Endocrinology 132:1132-1138。刺激IR会激活涉及酪氨酸激酶、PI3K或Ras的信号转导网络。
本文中使用的“胰岛素类似物”或“INS类似物”等是指这样的化合物,诸如肽或多肽:其引起天然INS在IR的一种或多种作用,但是由于一个或多个添加、缺失、插入和/或置换,与天然INS相比在氨基酸序列方面以某种方式变化。INS类似物也可以包括这些化合物的变体,其在功能上与天然INS等效,但具有为片段或为完整序列的序列,但它们本身具有进一步的添加、缺失、插入和/或置换。除非另外指出,否则本文描述的未修饰的或修饰的INS中的氨基酸位置的所有提及均基于天然人INS的SEQ ID NO:3的A链或SEQ ID NO:4的B链中的相应位置。在某些情况下,与天然INS、尤其是天然人INS (SEQ ID NO:3和4)相比,本文中的INS类似物可以以更高或更低的亲和力结合IR,但在体内或在体外表现出更长的t½。以此方式,本文中的INS类似物是充当IR激动剂的合成化合物。
本文中使用的“胰岛素抗性”是指这样的生理状况:其中正常的或升高的INS水平在个体中产生减弱的生物应答。
本文中使用的“有此需要的个体”是指具有需要治疗或疗法的病症、疾病、障碍或症状的哺乳动物,诸如人,包括例如本文所列的那些。特别是,优选的待治疗个体是人。
本文中使用的“长效”是指,本文中的INS类似物的结合亲和力和活性持续比天然人INS (SEQ ID NO:3和4)更长的时间段,从而允许至少如每天一次或甚至每周三次、每周两次、每周一次或每月一次较不频繁地给药。使用已知的药代动力学试验方法,诸如在以下实施例中描述的那些,可以测量本文中的INS类似物的时间作用特性。
本文中使用的“非标准氨基酸”是指可天然存在于细胞中但不参与肽合成的氨基酸。非标准氨基酸可以是肽的组分,且经常通过修饰肽、多肽或蛋白中的标准氨基酸(即通过翻译后修饰)而产生。非标准氨基酸可以包括D-氨基酸,其具有与上述标准氨基酸相反的绝对手性。
本文中使用的“药学上可接受的缓冲液”是指本领域技术人员已知的标准药用缓冲液中的任一种。
本文中使用的“序列相似性”是指生物化合物的两个或更多个核酸序列或氨基酸序列的定量特性,例如,两个或更多个序列在整个长度或对比窗上的对应性。通过(1)同一性百分比或(2)相似性百分比,可以测量序列相似性。同一性百分比测量两种生物化合物之间相同的残基除以最短序列的长度的百分比;而相似性百分比测量同一性,并此外在评价中包括序列间隙和残基相似性。用于确定序列相似性的方法和算法是本领域众所周知的,且因此无需在本文中详尽描述。相同核苷酸或氨基酸位置的指定百分比为至少约75%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高。
本文中使用的“单链胰岛素”、“scINS”、“SCI”等是指这样的INS多肽:其中A链和B链通过非天然接头(即,L2)彼此连接,如在A-L2-B或B-L2-A中。此外,SCI可以包括天然链间和/或链内二硫键中的至少一种以维持正确的结构折叠。
本文中使用的“双链胰岛素”、“tcINS”、“TCI”等是指这样的INS多肽:其中A链和B链通过一个或多个链间和/或链内二硫键、但不通过任何接头彼此连接,以维持正确的结构折叠,诸如天然INS。
本文中使用的“治疗”是指管理和护理具有病症、疾病、障碍或症状的个体,针对所述病症、疾病、障碍或症状,指示INS类似物施用,以实现减弱、抑制、逆转、减缓或停止病症、疾病、障碍或症状的进展或严重程度的目的。治疗包括给个体施用本文中的INS类似物或含有本文中的INS类似物的组合物,以预防症状或并发症的发作,减轻症状或并发症,或消除病症、疾病、障碍或症状。治疗包括给个体施用INS类似物或含有本文中的INS类似物的组合物以导致例如降低的血糖、降低的HbA1c、降低的胆固醇、降低的甘油三酯或降低的体重。待治疗的个体是哺乳动物,尤其是人。
本文中使用的“患者”、“对象”和“个体”在本文中可互换地使用,并且是指哺乳动物,尤其是人。在某些情况下,所述个体进一步的特征在于具有将受益于施用本文中的INS类似物的病症、疾病、障碍或症状。
本文中使用的“VHH”或“VHH部分”是指单结构域抗体的一种形式,尤其是仅重链抗体(HcAb)的单个单体可变区的抗体片段,其具有非常小的约15 kDa的大小。本文已发现,VHH部分可以用作药代动力学增强剂以延长本文中的INS类似物的作用持续时间和/或改善其t½。本文中的VHH部分结合血清白蛋白,尤其是人血清白蛋白;但是,VHH部分可替换地可以用于结合IgG (包括Fc结构域)、新生儿Fc受体(FcRn)或其它持久的血清蛋白。尽管本文中的VHH部分用于改善INS的t½,但它们同样可以用于改善其它生物活性肽/蛋白例如GDF-15、GLP-1或RLN的t½。
因为VHH部分是单结构域重链抗体,它们具有三个CDR,其包括与抗原(例如,人血清白蛋白)形成特异性相互作用的残基。将残基分配给各种CDR可以通过算法例如Chothia、IMBT、Kabat或North来完成。North CDR定义是基于具有大量晶体结构的近邻传播聚类(affinity propagation clustering)(North等人(2011) J. Mol. Bio. 406:228-256)。在本文中,CDR最好由序列表中列出的序列定义,所述序列是基于包括North和Kabat在内的多个定义的组合。
在某些情况下,VHH部分至少可以包括互补性决定区(CDR) 1 (CDR1)、CDR2和CDR3,其中CDR1可以是SEQ ID NO:84、85和86之一,其中CDR2可以是SEQ ID NO:87、88和89之一,且CDR3可以是SEQ ID NO:90、91和92之一。
某些缩写定义如下:“ACR”表示尿白蛋白/尿肌酸酐比率;“amu”表示原子质量单位;“AUC”表示曲线下面积;“BHI”表示生物合成的人胰岛素;“Boc”表示叔丁氧基羰基;“cAMP”表示环磷酸腺苷;“CMV”表示巨细胞病毒;“DNA”表示脱氧核糖核酸;“DMF”表示二甲基甲酰胺;“DMSO”表示二甲亚砜;“EDC”表示1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐;“EDTA”表示乙二胺四乙酸;“EIA/RIA”表示酶免疫测定/放射免疫测定;“ETA”表示乙醇胺;“GS”表示谷氨酰胺合成酶;“HIC”表示疏水相互作用色谱法;“hr”表示小时;“HTRF”表示均相时间分辨荧光;“IV”表示静脉内;“kDa”表示千道尔顿;“LC-MS”表示液相色谱法-质谱法;“min”表示分钟;“MS”表示质谱法;“MSX”表示甲硫氨酸亚砜亚胺;“NHS”表示N-羟基琥珀酰亚胺;“OtBu”表示O-叔丁基;“Pbf”表示NG-2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基;“PEI”表示聚乙烯亚胺;“RP-HPLC”表示反相高效液相色谱法;“sec”表示秒;“NaOAc”表示醋酸钠;“RU”是指共振单位;“SPA”表示闪烁迫近测定;“SEC”表示尺寸排阻色谱法;“SEM”表示平均值的标准误差;“SPR”表示表面等离子体共振;“SQ”表示皮下的;“TFA”表示三氟乙酸;和“Trt”表示三苯甲基。
胰岛素类似物
本文中的INS类似物与天然人INS (SEQ ID NO:3和4)具有结构相似性,但有许多结构差异。例如,当与天然人INS (SEQ ID NO:3和4)相比时,本文中的INS类似物与天然人INS中存在的氨基酸相比包括至少一个变异,包括在A链和B链之间的肽接头,并包括药代动力学增强剂诸如结合白蛋白的VHH部分。本文中的INS类似物在IR产生足够的活性,并因此具有与其作为治疗性治疗的可开发性相关的有益属性,包括改善的在水溶液中的溶解度、改善的化学和物理制剂稳定性、延长的药代动力学特性(其可以基于VHH对血清白蛋白的亲和力进行调整),以及最小化的免疫原性的可能性。
简而言之,本文中的INS类似物包括从氨基端至羧基端具有以下结构之一的氨基酸序列:
VHH-L1-A-L2-B,
VHH-L1-B-L2-A,
A-L2-B-L1-VHH, 或者
B-L2-A-L1-VHH,
其中VHH是充当药代动力学增强剂的部分,A是INS A链,B是INS B链,L1是第一肽接头且L2是第二肽接头,其中L1和L2彼此不同(即,各自具有不同的氨基酸序列)。在某些情况下,INS类似物具有从氨基端至羧基端为B-L2-A-L1-VHH的氨基酸序列。
关于A链,它可以是天然INS A链,诸如天然人INS A链(SEQ ID NO:3)。可替换地,A链可以是其变体。例如,A链变体可以具有这样的氨基酸序列,当与SEQ ID NO:3相比时,其包括:E4Q突变、T8H突变、Y14E突变、N21G突变或它们的组合(例如,T8H和N21G;或T8H、Y14E和N21G)。可替换地,A链可以是其截短体。例如,A链可以是缺少SEQ ID NO:3的残基1-3(desA1-3)或缺少残基21 (desA21)的INS A链。
同样地,关于B链,它可以是天然INS链,诸如天然人INS B链(SEQ ID NO:4)。可替换地,B链可以是其变体。例如,B链变体可以具有这样的氨基酸序列,其包括:SEQ ID NO:4的N3D突变、N3K突变、N3S突变、S9A突变、Y16E突变、Y16F突变、Y16H突变、Y16R突变、Y16W突变、E21Q突变、F25H突变或它们的组合(例如,N3S和Y16F;N3S和Y16H;N3S和Y16R;N3S和Y16W;N3S和F25H;N3S和Y16R;N3S、Y16H和F25H;或N3S、Y16R和F25H)。可替换地,B链可以是其截短体。例如,B链可以是缺少SEQ ID NO:4的残基1-3 (desB1-3)或缺少残基27-30(desB27-30)的INS B链。
考虑到以上,A链可以是天然人INS A链(SEQ ID NO:3)且B链可以是天然人INS B链(SEQ ID NO:4)。在其它情况下,A链可以是SEQ ID NO:3的变体且B链可以是SEQ ID NO:4。可替换地,A链可以是SEQ ID NO:3且B链可以是SEQ ID NO:4的变体。仍然可替换地,A链可以是SEQ ID NO:3的变体且B链可以是SEQ ID NO:4的变体。在再其它情况下,A链可以是SEQ ID NO:3的截短体且B链可以是SEQ ID NO:4。可替换地,A链可以是SEQ ID NO:3的截短体且B链可以是SEQ ID NO:4的变体或SEQ ID NO:4的截短体。在再其它情况下,A链可以是SEQ ID NO:3且B链可以是SEQ ID NO:4的截短体。可替换地,A链可以是SEQ ID NO:3的变体或SEQ ID NO:3的截短体且B链可以是SEQ ID NO:4的截短体。
可用在本文中的INS类似物中的其它A和B链描述于,例如,国际专利申请公开号WO1996/034882、WO 2005/054291、WO 2006/097521、WO 2007/096332、WO 2007/104734、WO2007/104736、WO 2007/104737、WO 2007/104738、WO 2011/031622、WO 2011/159895、WO2014/071405、WO 2016/057529、WO 2017/052305、WO 2018/165290、WO 2018/217573和WO2019/066570;也参见, Glidden等人(2018) J. Biol. Chem. 293:47-68;Hua等人(2008)J. Biol. Chem. 283:14703-14716;Kaur等人(2013) ACS Chem. Biol. 8:1822-1829;Mao等人(2017) Appl. Microbiol. Biotechnol. 101:3259-3271;Mao等人(2019) Appl. Microbiol. Biotechnol. 103:1-15;Sanlioglu等人(2013) Islets 5:67-78。
关于L1,它可以是约1至约50个氨基酸的肽。可替换地,L1可以是约1个、约5个、约10个、约15个、约20个、约25个、约30个、约35个、约40个、约45个或约50个氨基酸。仍然可替换地,L1可以是约5至约10个氨基酸、约10至约15个氨基酸、约15至约20个氨基酸、约20至约25个氨基酸、约25至约30个氨基酸、约30至约35个氨基酸、约35至约40个氨基酸、约40至约45个氨基酸、或约45至约50个氨基酸。在某些情况下,L1可以被省略,使得A链或B链直接缀合至VHH部分。在某些情况下,L1可以包括(GGGGQ)n (SEQ ID NO:10)的重复序列,其中n可以是约1至约10,尤其是5 (即,(GGGGQ)5;SEQ ID NO:23)。在其它情况下,L1可以包括(PGPQ)n(SEQ ID NO:13)的重复序列,其中n可以是约1至约10,尤其是8 (即,(PGPQ)8;SEQ ID NO:24)。在其它情况下,L1可以包括(PGPA)n (SEQ ID NO:14)的重复序列,其中n可以是约1至约10,尤其是8 (即,(PGPA)8;SEQ ID NO:25)。在其它情况下,L1可以包括(GGE)nGG (SEQ IDNO:15)的重复序列,其中n可以是约1至约10,尤其是7 (即,(GGE)7GG;SEQ ID NO:26)。在其它情况下,L1可以包括(GGGGE)nGGGG (SEQ ID NO:16)的重复序列,其中n可以是约1至约10,尤其是4 (即,(GGGGE)4GGGG;SEQ ID NO:27)。在其它情况下,L1可以包括(GGGGK)nGGGG(SEQ ID NO:17)的重复序列,其中n可以是约1至约10,尤其是4 (即,(GGGGK)4GGGG;SEQ IDNO:28)。在其它情况下,L1可以包括GGGG(AP)nGGGG (SEQ ID NO:18)的重复序列,其中n可以是约1至约10,尤其是10 (即,GGGG(AP)10GGGG;SEQ ID NO:29)。在其它情况下,L1可以包括GGGG(EP)nGGGG (SEQ ID NO:19)的重复序列,其中n可以是约1至约10,尤其是10 (即,GGGG(EP)10GGGG;SEQ ID NO:30)。在其它情况下,L1可以包括GGGG(KP)nGGGG (SEQ ID NO:20)的重复序列,其中n可以是约1至约10,尤其是10 (即,GGGG(KP)10GGGG;SEQ ID NO:31)。在其它情况下,L1可以包括(PGPE)nPGPQ (SEQ ID NO:21)的重复序列,其中n可以是约1至约10,尤其是7 (即,(PGPE)7PGPQ;SEQ ID NO:32)。在其它情况下,L1可以包括(PGPK)nPGPQ (SEQ IDNO:22)的重复序列,其中n可以是约1至约10,尤其是7 (即,(PGPK)7PGPQ;SEQ ID NO:33)。
可以作为L1用在INS类似物中的其它接头包括但不限于(GGGQ)n (SEQ ID NO:11)或(GGGGS)n (SEQ ID NO:12)。
关于L2,它可以是约1至约15个氨基酸的肽。可替换地,L2可以是约1个、约2个、约3个、约4个、约5个、约6个、约7个、约8个、约9个、约10个、约11个、约12个、约13个、约14个或约15个氨基酸。仍然可替换地,L2可以是约1至约5个氨基酸、约5至约10个氨基酸、约10至约15个氨基酸,尤其是10-15个氨基酸。在某些情况下,L2可以包括Ala/A、Gln/Q、Gly/G、Pro/P和Ser/S残基的混合物。在其它情况下,L2可以是SEQ ID NO:34、35或36。
关于VHH,它可以是约50至约200个氨基酸,尤其是约125至约150个氨基酸的多肽,其可以结合血清白蛋白或具有长t½的另一种血清蛋白。在某些情况下,VHH可以是SEQ IDNO:7、8或9中的任一个。这些VHH部分的结构特征导致与天然INS、尤其是天然人INS (SEQID NO:3和4)相比具有更长t½的INS类似物。鉴于本文中的VHH部分靶向血清白蛋白,因此可以预期本文中的INS类似物的t½与给其施用INS类似物的物种的血清白蛋白的t½相似(考虑任何靶标介导的药物处置)。
除了本文所述的变化之外,INS类似物可以包括一个或多个另外的氨基酸修饰,尤其是保守置换,但前提是INS类似物仍然能够结合并激活IR。
综合起来,示例性的INS类似物如下:
INS类似物1,其从N-端至C-端包括INS的B链、6个残基的L2 (粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物2,其从N-端至C-端包括具有N3D突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物3,其从N-端至C-端包括具有S9A突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物4,其从N-端至C-端包括具有Y16E突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物5,其从N-端至C-端包括具有Y16H突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物6,其从N-端至C-端包括具有F25H突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物7,其从N-端至C-端包括具有N3S突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物8,其从N-端至C-端包括具有N3S和F25H突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物9,其从N-端至C-端包括具有N3S和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物10,其从N-端至C-端包括具有N3S和Y16H突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物11,其从N-端至C-端包括具有N3S和Y16H突变的INS的B链、6个残基的L2(粗体)、具有T8H、Y14E和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物12,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物13,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H、Y14E和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物14,其从N-端至C-端包括具有N3S和Y16R突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物15,其从N-端至C-端包括具有N3S和Y16F突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物16,其从N-端至C-端包括具有N3S和Y16W突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物17,其从N-端至C-端包括具有N3S和Y16R突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物18,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPA)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物19,其从N-端至C-端包括具有N3S突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物20,其从N-端至C-端包括具有N3S突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物21,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物22,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物23,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有Y14E和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物24,其从N-端至C-端包括具有N3S、Y16H和F25H突变的INS的B链、6个残基的L2(粗体)、具有Y14E和N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物25,其从N-端至C-端包括具有N3S和Y16R突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物26,其从N-端至C-端包括具有N3S和Y16R突变的INS的B链、6个残基的L2(粗体)、具有N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物27,其从N-端至C-端包括具有N3S和Y16R突变的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物28,其从N-端至C-端包括具有N3S和Y16R突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物29,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物30,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPQ)8 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物31,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G2E)7G2 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物32,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4E)4G4 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物33,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4K)4G4 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物34,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、G4(AP)10G4 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物35,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、G4(EP)10G4 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物36,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、G4(KP)10G4 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物37,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPE)7PGPQ L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物38,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(PGPK)7PGPQ L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物39,其从N-端至C-端包括具有N3K、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物40,其从N-端至C-端包括具有N3S、Y16R、E21Q和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物41,其从N-端至C-端包括具有N3K、Y16R、E21Q和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物42,其从N-端至C-端包括具有N3S、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物43,其从N-端至C-端包括具有N3K、Y16R和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物44,其从N-端至C-端包括具有N3K、Y16R、E21Q和F25H突变的INS的B链、6个残基的L2(粗体)、具有T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
INS类似物45,其从N-端至C-端包括具有N3K、Y16R和F25Q突变的INS的B链、6个残基的L2(粗体)、具有E4Q、T8H和N21G突变的INS的A链、(G4Q)5 L1 (斜体)和VHH部分(有下划线),具有以下氨基酸序列:
(SEQ ID NO:81)。
使用本领域已知的方法,包括例如以下实施例中描述的那些,可以测量本文中的INS类似物的半衰期。同样地,使用本领域已知的用于测量结合亲和力的方法,例如在以下实施例中描述的那些,可以测量本文中的INS类似物对不同物种的白蛋白的亲和力,并且通常表示为平衡解离常数(KD)值。此外,使用本领域已知的方法,包括例如下面描述的体外活性测定,可以测量本文中的INS类似物对IR或胰岛素样生长因子1受体(IGF-1R)的活性,并且通常表示为EC50值。
作为上述修饰的结果,当施用于哺乳动物、尤其是人类时,本文中的INS类似物具有比天然INS、尤其是天然人INS (SEQ ID NO:3和4)更长的t½。如上面所指出的,本文中的VHH部分靶向血清白蛋白;因此,可以预期本文中的INS类似物的t½与给其施用INS类似物的物种的血清白蛋白的t½相似。在某些情况下,INS类似物可以具有约1天至约31天、约5天至约25天、约10天至约20天或甚至约15天的t½。在其它情况下,当施用给人类时,INS类似物可以具有约1至约5天、约6至约10天、约11至约15天、约16至约20天、约21至约25天、或甚至约26至约31天的t½。在其它情况下,INS类似物可以具有约1天、约2天、约3天、约4天、约5天、约6天、约7天、约8天、约9天、约10天、约11天、约12天、约13天、约14天、约15天、约16天、约17天、约18天、约19天、约20天、约21天、约22天、约23天、约24天、约25天、约26天、约27天、约28天、约29天、约30天或甚至约31天或更长的t½。在特定情况下,当施用给人类时,INS类似物可以具有约20天的t½。
同样地,在某些情况下,当施用给人类时,本文中的INS类似物对IR (诸如天然的人IR-A或人IR-B;分别为SEQ ID NO:5和6)的效能是在例如天然人INS (SEQ ID NO:3和4)的约10倍至约1000倍内。在其它情况下,当施用给人类时,本文中的INS类似物对IR (诸如天然的人IR-A或人IR-B;分别为SEQ ID NO:5和6)的效能是在例如天然人INS (SEQ ID NO:3和4)的约25倍至约975倍、约50倍至约950倍、约75倍至约925倍、约100倍至约900倍、约125倍至约875倍、150倍至约850倍、约175倍至约825倍、约200倍至约800倍、约225倍至约775倍、约250倍至约750倍、约275倍至约725倍、约300倍至约700倍、约325倍至约675倍、约350倍至约650倍、约375倍至约625倍、约375倍至约600倍、约400倍至约575倍、约425倍至约550倍、约450倍至约500倍或约475倍内。在其它情况下,当施用给人类时,本文中的INS类似物对IR (诸如天然的人IR-A或人IR-B;分别为SEQ ID NO:5和6)的效能是在例如天然人INS(SEQ ID NO:3和4)的约10倍、约25倍、约50倍、约75倍、约100倍、约125倍、约150倍、约175倍、约200倍、约225倍、约250倍、约275倍、约300倍、约325倍、约350倍、约375倍、约400倍、约425倍、约450倍、约475倍、约500倍、约525倍、约550倍、约575倍、约600倍、约625倍、约650倍、约675倍、约700倍、约725倍、约750倍、约775倍、约800倍、约825倍、约850倍、约875倍、约900倍、约925倍、约950倍、约975倍或约1000倍内。
药物组合物和试剂盒
本文中的INS类似物可以配制成药物组合物,其可以通过胃肠外途径(例如,静脉内、腹膜内、肌肉内、皮下或透皮)施用。这样的药物组合物及其制备技术是本领域众所周知的。参见,例如,Remington, “The Science and Practice of Pharmacy”(D.B. Troy编,第21版, Lippincott, Williams & Wilkins, 2006)。在特定情况下,皮下或静脉内施用INS类似物。但是,可替换地,可以将INS类似物配制成用于其它药学上可接受的途径的形式,例如,用于口服施用的片剂或其它固体,限时释放胶囊剂和目前使用的任何其它形式,包括乳膏剂、洗剂、吸入剂等。
为了改善它们的体内相容性和有效性,本文中的INS类似物可以与多种无机和有机酸/碱中的任一种反应以形成药学上可接受的酸/碱加成盐。药学上可接受的盐和制备它们的常用技术是本领域众所周知的(参见,例如,Stahl等人, “Handbook ofPharmaceutical Salts:Properties, Selection and Use”(第2次修订版,Wiley-VCH,2011))。用于本文的药学上可接受的盐包括钠盐、三氟乙酸盐、盐酸盐和乙酸盐。
本文中的INS类似物可以由医师施用或使用注射剂自我施用。应当理解,本领域技术人员可以容易地确定规格尺寸和注射体积的量。但是,注射体积的量可以≤约2 ml或甚至≤约1 ml,并且针头规格可以≥约27 G或甚至≥约29 G。可替换地,可以通过泵系统施用本文中的INS类似物。
本公开内容还提供并因此涵盖可用于合成本文中的INS类似物或其药学上可接受的盐的新型中间体和方法。通过本领域众所周知的多种技术,可以制备中间体和INS类似物。例如,在以下实施例中说明了使用重组合成的方法。所描述的每种技术的具体步骤可以以不同方式组合以制备本文中的INS类似物。试剂和起始原料对于本领域技术人员来说是容易获得的。
本文中的INS类似物通常在宽剂量范围内是有效的。INS类似物或包含它们的药物组合物的示例性剂量可以是每千克(kg)个体的毫克(mg)或微克(µg)、纳克(ng)或皮克(pg)量。以此方式,每日剂量可以是约1 μg至约100 mg。
在这里,药物组合物中的INS类似物的有效量可以是约0.25 mg至约5.0 mg的剂量。但是,本领域技术人员理解,在某些情况下,有效量(即剂量/用量)可能低于上述范围的下限并绰绰有余,而在其它情况下,有效量可能是更大的剂量并且可以在可接受的副作用下使用。
除了INS类似物之外,药物组合物还可以包含至少一种另外的治疗剂,尤其是通常用作代谢病症、疾病和障碍的护理标准的治疗剂。
以此方式,药物组合物可以包含有效量的至少一种SEQ ID NO:37-81的INS类似物、药学上可接受的载体和任选的至少一种另外的治疗剂。例如,药物组合物可以包含有效量的SEQ ID NO:37的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:38的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:39的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:40的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:41的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:42的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:43的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:44的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:45的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:46的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:47的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:48的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:49的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:50的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:51的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:52的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:53的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:54的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:55的INS类似物和药学上可接受的载体、有效量的SEQ IDNO:56的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:57的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:58的INS类似物和药学上可接受的载体、有效量的SEQID NO:59的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:60的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:61的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:62的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:63的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:64的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:65的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:66的INS类似物和药学上可接受的载体、和有效量的SEQ ID NO:67的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:68的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:69的INS类似物和药学上可接受的载体、和有效量的SEQ ID NO:70的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:71的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:72的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:73的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:74的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:75的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:76的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:77的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:78的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:79的INS类似物和药学上可接受的载体、有效量的SEQ ID NO:80的INS类似物和药学上可接受的载体、或有效量的SEQ IDNO:81的INS类似物和药学上可接受的载体。
可替换地,本文中的INS类似物可以作为试剂盒的一部分提供。在某些情况下,试剂盒包括用于给个体施用至少一种INS类似物或包含其(和任选的至少一种另外的治疗剂)的组合物的装置。在某些情况下,试剂盒包括用于施用INS类似物或包含其(和任选的至少一种另外的治疗剂)的组合物的注射器和针头。在特定情况下,将INS类似物或包含其(和任选的至少一种另外的治疗剂)的组合物在注射器内预先配制在水溶液中。
制备和使用胰岛素类似物的方法
通过本领域已知的任何数量的标准重组DNA方法或标准化学肽合成方法,可以制备本文中的INS类似物。关于重组DNA方法,可以使用标准重组技术构建具有编码本文中的INS类似物的氨基酸序列的核酸序列的多核苷酸,将该多核苷酸掺入重组表达载体,并将该载体引入宿主细胞诸如细菌、酵母和哺乳动物细胞,以产生本文中的INS类似物。参见,例如,Green和Sambrook, “Molecular Cloning:A Laboratory Manual”(Cold SpringHarbor Laboratory Press, 2012年第4版)。
关于重组DNA方法,可以通过使用重组DNA技术产生蛋白或前体蛋白分子来制备本文的化合物。DNA,包括cDNA和合成的DNA,可以是双链的或单链的,并且其中编码本文中的化合物的编码序列可能由于遗传密码的冗余或简并性而变化。简而言之,将编码本文中的化合物的DNA序列引入宿主细胞以产生化合物或其前体。宿主细胞可以是细菌细胞诸如大肠杆菌的K12或B株,真菌细胞诸如酵母细胞,或哺乳动物细胞诸如中国仓鼠卵巢(CHO)细胞。
将适当的宿主细胞用表达系统诸如表达载体瞬时或稳定转染或转化,以产生本文的化合物或其前体。表达载体通常可作为附加体或作为宿主染色体DNA的组成部分在宿主生物中复制。通常,表达载体将含有选择标志物例如四环素、新霉素、G418和二氢叶酸还原酶,以允许选择用期望的DNA序列转化的那些细胞。
可以使用、不使用或以不同方式组合本文描述的每个步骤的具体生物合成或合成步骤以制备本文中的化合物。
关于化学肽合成方法,可以使用标准的手动或自动化固相合成程序。例如,自动化的肽合成仪可从例如Applied Biosystems (Foster City, CA)和Protein TechnologiesInc. (Tucson, AZ)商购获得。用于固相合成的试剂容易从商业来源获得。可以根据生产商的说明书使用固相合成仪阻断干扰基团、在反应过程中保护氨基酸、偶联、去保护和将未反应氨基酸加帽。制备合成的INS的额外细节可以参见例如Arai等人(2018) Comm. Chem. 1:26;Belgi等人(2011) Immun. Endoc. & Metab. Agents in Med. Chem. 11:40-47;Hossain和Wade (2017) Acc. Chem. Res. 50:2116-2127;和Liu等人(2016) J. Pept. Sci. 22:260-270。也参见,国际专利申请公开号WO 2011/031622。
本文中的INS类似物的一种用途是用于治疗代谢病症、疾病和/或障碍。示例性的病症、疾病和障碍包括但不限于代谢综合征、糖尿病和肥胖。
本文中的INS类似物的另一种用途是用于治疗心脏和/或肾脏病症、疾病和/或障碍。示例性的心脏和/或肾脏病症、疾病和障碍包括但不限于血脂异常、中风、肾病和视网膜病变。
所述方法可以包括本文所述的步骤,并且这些步骤可以但不一定按照所述的顺序进行。但是,其它顺序也是可以想到的。此外,单个或多个步骤可以并行地和/或在时间上重叠地和/或单独地或以多次重复的步骤进行。此外,所述方法可以包括另外的、未指定的步骤。
因此,这样的方法可以包括选择具有代谢病症、疾病或障碍或易患它们的个体。可替换地,所述方法可以包括选择患有糖尿病或易患糖尿病的个体。可替换地,所述方法可以包括选择肥胖或易于肥胖的个体。在某些情况下,所述方法可以包括选择患有糖尿病和肥胖或易患它们的个体。
所述方法也可以包括给个体施用有效量的至少一种本文中的INS类似物,其可以是也如本文所述的药物组合物的形式。在某些情况下,INS类似物/药物组合物可以包含另外的治疗剂,诸如DPP-IV抑制剂、天然胰淀素或其类似物、短效(膳食)INS类似物、天然肠降血糖素或其类似物、天然IGF或其类似物、二甲双胍、SGLT2抑制剂、抑制素、SU、TZD和/或其它抗血糖剂或其它抗肥胖剂,以及控制并存病(包括但不限于,高胆固醇、高甘油三酯、高血压、心房颤动和糖尿病)的其它治疗剂。
在本文别处讨论INS类似物和任选的另外的治疗剂的浓度/剂量/用量。
关于施用途径,INS类似物或包含其的药物组合物可以按照已知方法施用,例如口服;通过注射(即,动脉内、静脉内、腹膜内、大脑内、脑室内、肌肉内、眼内、门静脉内或病灶内);通过持续释放系统,或通过植入装置。在某些情况下,可以通过快速推注或连续地皮下施用INS类似物或包含其的药物组合物。
关于给药频率,可以每天、每隔一天、每周三次、每周两次、每周一次(即,每周)、每两周(即,每隔一周)或每个月施用INS类似物或包含其的药物组合物。在某些情况下,每隔一天皮下、每周三次皮下、每周两次皮下、每周一次皮下、每隔一周皮下或每月皮下施用INS类似物或包含其的药物组合物。在特定情况下,每周一次(QW)皮下施用INS类似物或包含其的药物组合物。
关于其中将INS类似物或包含其的药物组合物与有效量的至少一种另外的治疗剂组合施用的那些情况,另外的治疗剂可以与INS类似物或包含其的药物组合物同时、分开或依次施用。
此外,可以以与INS类似物或包含其的药物组合物相同的频率(即,每隔一天、每周两次或甚至每周)施用另外的治疗剂。可替换地,可以以与INS类似物或包含其的药物组合物不同的频率施用另外的治疗剂。在其它情况下,可以皮下施用另外的治疗剂。在其它情况下,可以静脉内施用另外的治疗剂。在其它情况下,可以口服施用另外的治疗剂。
进一步考虑,所述方法可以与饮食和锻炼结合,和/或可以与除上述那些之外的另外的治疗剂组合。
实施例
提供以下非限制性实施例用于举例说明而非限制的目的。
多肽表达
实施例1:INS类似物1的重组表达
实施例1是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:37)。
在这里,使用CHOK1细胞衍生物在哺乳动物细胞表达系统中产生SEQ ID NO:37的INS类似物。将编码SEQ ID NO:37的cDNA序列亚克隆到含有GS的表达质粒主链(基于pEE12.4的质粒)中。cDNA序列与信号肽序列METDTLLLWVLLLWVPGSTG (SEQ ID NO:82)的编码序列发生框架内融合以增强INS类似物向组织培养基中的分泌。该表达由病毒CMV启动子驱动。
为了通过瞬时转染生成INS类似物,使用基于PEI的方法用重组表达质粒转染CHOK1细胞。简而言之,将密度为4 x 106个细胞/ml的适当体积的CHOK1悬浮细胞转移到摇瓶中,并将PEI和重组质粒DNA加入细胞中。将细胞在悬浮培养物中在32℃温育6天。在温育时段结束时,通过低速离心除去细胞,并从条件培养基中纯化INS类似物。
可替换地,并为了通过稳定转染产生INS类似物,使用电穿孔和适当量的重组表达质粒稳定转染CHOK1细胞,并将转染的细胞以适当细胞密度维持在悬浮培养物中。通过在25µM含有MSX的无血清培养基中生长并在35℃-37℃和5%-7%CO2下温育来完成转染的细胞的选择。
将从CHO细胞分泌到培养基中的INS类似物通过蛋白A亲和色谱法和随后的离子交换、疏水相互作用或尺寸排阻色谱法进行纯化。具体而言,将来自收获的培养基的INS类似物捕获到Mab Select Protein A树脂(GE)上。然后将树脂用运行缓冲液诸如磷酸盐缓冲盐水(PBS;pH 7.4)或含有Tris的运行缓冲液短暂洗涤,以除去非特异性地结合的物质。使用低pH溶液(诸如10 mM柠檬酸, 150 mM NaCl pH 3)从树脂洗脱蛋白。将含有INS类似物的级分合并,然后用20 mM NaOAc pH 5进行1:1稀释。使用1 M NaOH将最终pH调节至pH 5,并且可以将溶液保持在低pH以灭活潜在病毒。可以通过添加碱(诸如0.1 M Tris pH 8.0)来中和pH,用于后续的尺寸排阻色谱法。可以通过离子交换色谱法使用树脂诸如POROS 50 HS(ThermoFisher)进一步纯化INS类似物。使用在20 mM NaOAc(pH 5.0)中的0 mM至500 mMNaCl梯度经15个柱体积从柱洗脱INS类似物。
可以使用Capto Phenyl ImpRes HIC柱(GE Healthcare)通过疏水相互作用色谱法进一步纯化INS类似物。通过将柱装载溶液调节至约0.5 M Na2SO4并使用10个柱体积(CV)的在20 mM Tris pH 8溶液中的从0.5 M至0 M Na2SO4的梯度洗脱进行纯化。在HIC后,甚至可以通过SEC进一步纯化INS类似物,其中将浓缩的Capto Phenyl ImpRes合并物(pool)加载到Superdex200 (GE Healthcare)上,在PBS pH 7.4中或在20 mM组氨酸、50mM NaCl pH6.0中等度洗脱。
可以将纯化的INS类似物通过病毒截留过滤器,诸如Planova 20N (Asahi KaseiMedical),然后在再生纤维素膜(Millipore)上使用切向流超滤浓缩/渗滤到20 mM组氨酸、20 mM NaCl pH 6中。
因此,以这种方式或以本领域技术人员容易确定的类似方式制备INS类似物。
实施例2:INS类似物2的重组表达
实施例2是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:38)。
在这里,基本上如关于实施例1所述产生实施例2,除了将编码SEQ ID NO:38的cDNA序列用在表达质粒中。
实施例3:INS类似物3的重组表达
实施例3是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:39)。
在这里,基本上如关于实施例1所述产生实施例3,除了将编码SEQ ID NO:39的cDNA序列用在表达质粒中。
实施例4:INS类似物4的重组表达
实施例4是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:40)。
在这里,基本上如关于实施例1所述产生实施例4,除了将编码SEQ ID NO:40的cDNA序列用在表达质粒中。
实施例5:INS类似物5的重组表达
实施例5是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:41)。
在这里,基本上如关于实施例1所述产生实施例5,除了将编码SEQ ID NO:41的cDNA序列用在表达质粒中。
实施例6:INS类似物6的重组表达
实施例6是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:42)。
在这里,基本上如关于实施例1所述产生实施例6,除了将编码SEQ ID NO:42的cDNA序列用在表达质粒中。
实施例7:INS类似物7的重组表达
实施例7是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:43)。
在这里,基本上如关于实施例1所述产生实施例7,除了将编码SEQ ID NO:43的cDNA序列用在表达质粒中。
实施例8:INS类似物8的重组表达
实施例8是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:44)。
在这里,基本上如关于实施例1所述产生实施例8,除了将编码SEQ ID NO:44的cDNA序列用在表达质粒中。
实施例9:INS类似物9的重组表达
实施例9是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:45)。
在这里,基本上如关于实施例1所述产生实施例9,除了将编码SEQ ID NO:45的cDNA序列用在表达质粒中。
实施例10:INS类似物10的重组表达
实施例10是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:46)。
在这里,基本上如关于实施例1所述产生实施例10,除了将编码SEQ ID NO:46的cDNA序列用在表达质粒中。
实施例11:INS类似物11的重组表达
实施例11是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:47)。
在这里,基本上如关于实施例1所述产生实施例11,除了将编码SEQ ID NO:47的cDNA序列用在表达质粒中。
实施例12:INS类似物12的重组表达
实施例12是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:48)。
在这里,基本上如关于实施例1所述产生实施例12,除了将编码SEQ ID NO:48的cDNA序列用在表达质粒中。
实施例13:INS类似物13的重组表达
实施例13是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:49)。
在这里,基本上如关于实施例1所述产生实施例13,除了将编码SEQ ID NO:49的cDNA序列用在表达质粒中。
实施例14:INS类似物14的重组表达
实施例14是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:50)。
在这里,基本上如关于实施例1所述产生实施例14,除了将编码SEQ ID NO:50的cDNA序列用在表达质粒中。
实施例15:INS类似物15的重组表达
实施例15是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:51)。
在这里,基本上如关于实施例1所述产生实施例15,除了将编码SEQ ID NO:51的cDNA序列用在表达质粒中。
实施例16:INS类似物16的重组表达
实施例16是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:52)。
在这里,基本上如关于实施例1所述产生实施例16,除了将编码SEQ ID NO:52的cDNA序列用在表达质粒中。
实施例17:INS类似物17的重组表达
实施例17是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:53)。
在这里,基本上如关于实施例1所述产生实施例17,除了将编码SEQ ID NO:53的cDNA序列用在表达质粒中。
实施例18:INS类似物18的重组表达
实施例18是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:54)。
在这里,基本上如关于实施例1所述产生实施例18,除了将编码SEQ ID NO:54的cDNA序列用在表达质粒中。
实施例19:INS类似物19的重组表达
实施例19是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:55)。
在这里,基本上如关于实施例1所述产生实施例19,除了将编码SEQ ID NO:55的cDNA序列用在表达质粒中。
实施例20:INS类似物20的重组表达
实施例20是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:56)。
在这里,基本上如关于实施例1所述产生实施例20,除了将编码SEQ ID NO:56的cDNA序列用在表达质粒中。
实施例21:INS类似物21的重组表达
实施例21是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:57)。
在这里,基本上如关于实施例1所述产生实施例21,除了将编码SEQ ID NO:57的cDNA序列用在表达质粒中。
实施例22:INS类似物22的重组表达
实施例22是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:58)。
在这里,基本上如关于实施例1所述产生实施例22,除了将编码SEQ ID NO:58的cDNA序列用在表达质粒中。
实施例23:INS类似物23的重组表达
实施例23是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:59)。
在这里,基本上如关于实施例1所述产生实施例23,除了将编码SEQ ID NO:59的cDNA序列用在表达质粒中。
实施例24:INS类似物24的重组表达
实施例24是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:60)。
在这里,基本上如关于实施例1所述产生实施例24,除了将编码SEQ ID NO:60的cDNA序列用在表达质粒中。
实施例25:INS类似物25的重组表达
实施例25是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:61)。
在这里,基本上如关于实施例1所述产生实施例25,除了将编码SEQ ID NO:61的cDNA序列用在表达质粒中。
实施例26:INS类似物26的重组表达
实施例26是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:62)。
在这里,基本上如关于实施例1所述产生实施例26,除了将编码SEQ ID NO:62的cDNA序列用在表达质粒中。
实施例27:INS类似物27的重组表达
实施例27是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:63)
在这里,基本上如关于实施例1所述产生实施例27,除了将编码SEQ ID NO:63的cDNA序列用在表达质粒中。
实施例28:INS类似物28的重组表达
实施例28是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:64)。
在这里,基本上如关于实施例1所述产生实施例28,除了将编码SEQ ID NO:64的cDNA序列用在表达质粒中。
实施例29:INS类似物29的重组表达
实施例29是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:65)。
在这里,基本上如关于实施例1所述产生实施例29,除了将编码SEQ ID NO:65的cDNA序列用在表达质粒中。
实施例30:INS类似物30的重组表达
实施例30是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:66)。
在这里,基本上如关于实施例1所述产生实施例30,除了将编码SEQ ID NO:66的cDNA序列用在表达质粒中。
实施例31:INS类似物31的重组表达
实施例31是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:67)。
在这里,基本上如关于实施例1所述产生实施例31,除了将编码SEQ ID NO:67的cDNA序列用在表达质粒中。
实施例32:INS类似物32的重组表达
实施例32是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:68)。
在这里,基本上如关于实施例1所述产生实施例32,除了将编码SEQ ID NO:68的cDNA序列用在表达质粒中。
实施例33:INS类似物33的重组表达
实施例33是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:69)。
在这里,基本上如关于实施例1所述产生实施例33,除了将编码SEQ ID NO:69的cDNA序列用在表达质粒中。
实施例34:INS类似物34的重组表达
实施例34是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:70)。
在这里,基本上如关于实施例1所述产生实施例34,除了将编码SEQ ID NO:70的cDNA序列用在表达质粒中。
实施例35:INS类似物35的重组表达
实施例35是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:71)。
在这里,基本上如关于实施例1所述产生实施例35,除了将编码SEQ ID NO:71的cDNA序列用在表达质粒中。
实施例36:INS类似物36的重组表达
实施例36是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:72)。
在这里,基本上如关于实施例1所述产生实施例36,除了将编码SEQ ID NO:72的cDNA序列用在表达质粒中。
实施例37:INS类似物37的重组表达
实施例37是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:73)。
在这里,基本上如关于实施例1所述产生实施例37,除了将编码SEQ ID NO:73的cDNA序列用在表达质粒中。
实施例38:INS类似物38的重组表达
实施例38是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:74)。
在这里,基本上如关于实施例1所述产生实施例38,除了将编码SEQ ID NO:74的cDNA序列用在表达质粒中。
实施例39:INS类似物39的重组表达
实施例39是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:75)。
在这里,基本上如关于实施例1所述产生实施例39,除了将编码SEQ ID NO:75的cDNA序列用在表达质粒中。
实施例40:INS类似物40的重组表达
实施例40是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:76)。
在这里,基本上如关于实施例1所述产生实施例40,除了将编码SEQ ID NO:76的cDNA序列用在表达质粒中。
实施例41:INS类似物41的重组表达
实施例41是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:77)。
在这里,基本上如关于实施例1所述产生实施例41,除了将编码SEQ ID NO:77的cDNA序列用在表达质粒中。
实施例42:INS类似物42的重组表达
实施例42是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:78)。
在这里,基本上如关于实施例1所述产生实施例42,除了将编码SEQ ID NO:78的cDNA序列用在表达质粒中。
实施例43:INS类似物43的重组表达
实施例43是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:79)。
在这里,基本上如关于实施例1所述产生实施例43,除了将编码SEQ ID NO:79的cDNA序列用在表达质粒中。
实施例44:INS类似物44的重组表达
实施例44是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:80)。
在这里,基本上如关于实施例1所述产生实施例44,除了将编码SEQ ID NO:80的cDNA序列用在表达质粒中。
实施例45:INS类似物45的重组表达
实施例45是具有以下氨基酸序列的INS类似物:
(SEQ ID NO:81)。
在这里,基本上如关于实施例1所述产生实施例45,除了将编码SEQ ID NO:81的cDNA序列用在表达质粒中。
体外功能
实施例46:通过SPR进行的INS类似物白蛋白结合研究
通过SPR确定各种INS类似物与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的体外结合。特别是,实施例23至30对这些物种的血清白蛋白的亲和力总结在下表1-8中。
在Biacore 8K仪器上进行实施例23至30的INS类似物与各种血清白蛋白的结合。根据生产商的说明书(Amine Coupling Kit BR-1000-50)将血清白蛋白固定到S系列传感器芯片CM5表面。简而言之,通过以10µL/min注射70µL含有75 mg/ml EDC和11.5 mg/ml NHS的混合物,活化在传感器芯片表面(流动池1和2)上的羧基基团。将人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白以1、1、3、1、1、1、1和1 μg/mL在10 mM NaOAc pH 4.0 (BR-1003-49)中稀释,然后以10 µL/min注射到活化的芯片表面(流动池2, 通道1-7)上90秒(人、小鼠、大鼠、猪和牛血清白蛋白得自Sigma Aldrich (St. Louis, MO);食蟹猴血清白蛋白得自Hölzel Diagnostika (Cologne,德国);狗血清白蛋白得自Molecular Innovations(Novi, MI);和兔血清白蛋白得自Fitzgerald Industries International (Acton,MA))。将各种血清白蛋白通过游离胺共价地固定到羧甲基葡聚糖包被的传感器芯片CM5上,目标表面密度平均值为约77 (58-98) RU。通过以10 μL/min注射70µL 1 M ETA HCl-NaOHpH 8.5,使表面(流动池1和2)上的过量反应基团失活。
将实施例23-30以1000、333.33、111.11、37.04、12.35、4.12、1.37、0.457、0.152、0.051和0.017 nM的浓度在HBS-EP+ 缓冲液(10 mM HEPES pH 7.6, 150 mM NaCl, 3 mMEDTA, 0.05%聚山梨酯20)中稀释。将150 μL样品单独地依次注射经过固定化血清白蛋白表面,然后在25℃以50 μL/min流速解离600秒。通过以50 μL/min注射10 mM甘氨酸-HCl pH1.5 (BR-1003-54) 100秒使表面再生。使用Biacore 8K Insight评价软件(版本2.0.15.12933)1:1结合动力学或稳态亲和模型拟合分析所得的传感图,以计算结合动力学参数结合速率(ka)、解离速率(kd)和平衡解离常数(KD)。
表1:在25℃实施例23与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例23的结合,将KD分别确定为0.73、6.8、76、53、130、23和590 nM。
表2:在25℃实施例24与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例24的结合,将KD分别确定为0.91、5.5、49、40、100、16和430 nM。
表3:在25℃实施例25与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例25的结合,将KD分别确定为0.32、3.5、42、34、90、16和390 nM。
表4:在25℃实施例26与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例26的结合,将KD分别确定为0.49、3.9、35、32、87、13和400 nM。
表5:在25℃实施例27与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例27的结合,将KD分别确定为0.75、4.7、45、32、90、17和390 nM。
表6:在25℃实施例28与人、食蟹猴、小鼠、大鼠、猪、狗、牛和兔血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例28的结合,将KD分别确定为0.73、4.1、37、26、75、12和400 nM。
表7:在25℃实施例29与人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例29的结合,将KD分别确定为0.74、4.4、48、32、86、16、380 nM。
表8:在25℃实施例30与人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白的结合动力学
对于人、食蟹猴、小鼠、大鼠、猪、狗和牛血清白蛋白与实施例30的结合,将KD分别确定为0.73、4.3、39、30、80、13和370 nM。
实施例47:INS类似物在IR-A和IR-B的体外效能
制备膜:从用含有C-末端C9标签(TETSQVAPA;SEQ ID NO:83)的人IR-A (hIR-A;SEQ ID NO:5)和人IR-B (hIR-B;SEQ ID NO:6)稳定转染的HEK293细胞制备细胞膜。通常,细胞沉淀物来自第6至12代细胞,取决于受体。将冷冻的细胞沉淀物在冰冷的匀浆化/重悬浮缓冲液(50 mM Tris-HCl, pH 7.5)中融化,所述缓冲液在每50 mL缓冲液中含有1片Complete®蛋白酶抑制剂和EDTA (Roche Diagnostics)。将细胞用高架电机驱动的Teflon®-玻璃Potter-Elvehjem匀浆器匀浆化,使用15至20次冲程,然后在4℃在1100 x g离心10min。将上清液保存在冰上,并像以前一样将沉淀物重新匀浆化,并在4℃在1100 x g离心10min。将所有上清液合并,随后在4℃在35,000 x g离心60 min。将沉淀物重新悬浮在含有蛋白酶抑制剂的缓冲液(4-5 ml/g的起始细胞糊)中,并在-80℃储存之前在液氮中快速冷冻。使用BCA试剂盒(ThermoScientific)以牛血清白蛋白(BSA)作为标准确定蛋白浓度。
受体结合测定方案:通过竞争性放射性配体结合测定用均得自Perkin Elmer(Waltham, MA)的人重组(3-[125I]-碘酪氨酰-A14)-胰岛素(2200 Ci/mmol)或人重组[125I]-胰岛素样生长因子-1 (1680-2800 Ci/mmol)确定受体结合亲合力(Ki)。使用聚乙烯基甲苯(PVT)麦胚凝集素偶联的SPA珠子(Perkin Elmer)用SPA方法进行测定。测定缓冲液含有50 mM Tris-HCl(pH 7.5)、150 mM NaCl和以下任一种:A) 0.1%w/v不含脂肪酸的BSA;B) 0.1%w/v不含脂肪酸的人血清白蛋白(HSA);C) 0.1%w/v大鼠血清白蛋白(RSA);或D)0.001%Nonidet P-40 Substitute (NP-40, Roche Diagnostics)。使用Freedom/Evo机器人(Tecan)在测定缓冲液中制备使用试验样品或对照的三倍系列稀释液的十点浓度响应曲线。使用TeMO机器人(Tecan)将50 μL化合物稀释液添加到96孔白色透明底微孔板(Corning, 3632)中,然后使用Multiflo F/X (Biotek)批量分配仪器加入放射性配体(50µL, 最终约40 pM)、膜(50µL, 0.1-0.4µg/孔)和SPA珠子(50µL, 0.1-0.15 mg/孔)。试验化合物和对照的最高最终测定浓度如下表所示:
表9:受体结合测定浓度/对照
最高最终测定浓度(nM) | |
化合物或对照 | IR-A/IR-B结合 |
化合物X | 10000 - 15000 |
BHI | 100 |
IGF-1 | 1000 |
AspB10 INS | 40 |
在室温温育10小时和珠子沉降后,使用Microbeta™ Trilux闪烁计数器(PerkinElmer)测定放射性并表示为每分钟计数(CPM)。
在三个不同天运行的三个独立测定中测试样品(n = 3)。对于每次运行,将样品用每个平板上包括的BHI (SEQ ID NO:3和4)、IGF-1 (PeproTech, Inc.;Rocky Hill, NJ)和AspB10 INS (SEQ ID NO:4的His10Asp)对照随机化。
IR测定的数据分析:每个实验用单个重复浓度响应曲线测试每种化合物。仅使用测定缓冲液以8孔/板确定最大结合应答(MAX),并使用100 nM BHI在每个孔中确定最小结合或非特异性应答(MIN)。所有试验样品浓度应答都标准化至该对照应答,并在校正非特异性结合后计算为特异性抑制百分比,如下所示:
%特异性抑制= 100 - [(CPM - MIN)/(MAX - MIN) x 100]。
将特异性抑制百分比(y-轴)相对于化合物的对数浓度(x轴)作图。由四参数逻辑非线性回归分析(Analyzer,第15版,GeneData Screener)确定导致50%结合抑制的浓度(IC50)。基于方程式Ki = IC50/(1 + L/Kd)从IC50值计算亲和常数(Ki),其中L等于在实验中使用的放射性配体的浓度,且Kd等于从饱和结合分析确定的放射性配体的平衡结合亲和常数。将报告的Ki值显示为几何平均值和标准误差(Delta方法标准误差),并将独立重复测定的数量用于计算由n指示的几何平均值。
表10:实施例1-30对IR-A的体外效能
表11:实施例1-30对IR-B的体外效能
体内功能
实施例48:INS类似物在链脲霉素(STZ)处理的小鼠中降低葡萄糖
STZ小鼠:允许来自Envigo RSM Inc. (Indianapolis, IN)的11-12周龄雄性C57Bl/6NHsd小鼠适应至少3天。将小鼠单独圈养在带有玉米穗轴垫料和小鼠饮水器的鞋盒笼中。环境条件如下:12小时光照和12小时黑暗的光周期(可能因研究相关活动而中断),20℃至26℃的温度,和30%至70%的相对湿度。
如下制备STZ:将媒介物添加到预先称重的STZ中,以达到16.67 mg/mL的给药浓度。轻轻涡旋以混合直至粉末溶解。将溶液保存在湿冰上,避光并在制备后3小时内使用。在给药前阶段的第5天和第9天,在每次STZ施用之前,在禁食过夜(不超过16小时)之后,基于最近的体重以6 mL/kg (100 mg/kg)的剂量体积对动物腹膜内给药。任何低于19克体重的动物都不施用STZ。
在第二次STZ处理后10天,使用旨在实现血糖仪值(250 mg/dL至500 mg/dL纳入标准)和体重平衡的区组随机分配工具(BRAT),将动物分配到研究中。以10 mL/kg的剂量体积向肩胛骨之间的皮下空间(肩胛间)施用单剂量的预先配制的试验物。记录任何可能的给药错误。
在试验物治疗之后,每天早晨监测体重。在第1天(三次:0至4小时、4至12小时和12至24小时)、第2、3、4、5、6、7和8天监测食物摄入。在给药后0、4、12、24、36、48、72、96、120、144和168小时,使用血糖仪(一式两份地)通过尾部取血(tail clip)测量葡萄糖。在给药后4、12、24、36、48和72小时,收集另外40µL全血用于测定化合物浓度。
将所有数据表示为每组5只动物的平均值±SEM。如下计算每个时间点的葡萄糖变化百分比:在给药后X小时的变化百分比= ((X时间点的葡萄糖- 动物在给药后时间0的葡萄糖) x 100) - 100。
如下表12所示,在单次300 nmol/kg注射后,实施例1至6的INS类似物表现出全血葡萄糖水平的持续降低。同样地,如下表13和14所示,在单次200 nmol/kg注射后,实施例7至18的INS类似物表现出全血葡萄糖水平的持续降低。
实施例49:INS类似物在STZ处理的大鼠中降低葡萄糖
允许来自Envigo RMS Inc. (Indianapolis, IN)的390-425 g雄性SpragueDawley大鼠适应至少3天。将大鼠单独圈养在鞋盒笼中,所述鞋盒笼带有玉米穗轴垫料和随意提供水的饮水器。给大鼠饲喂Teklad Global Diets的Rodent 2014饲料。环境条件如下:12小时光照和12小时黑暗的光周期(可能因研究相关活动而中断),20℃至26℃的温度,和30%至70%的相对湿度。
如下制备STZ:将19 mL冷的无菌盐水加入STZ瓶(Zanosar®, Teva ParenteralMedicines, Inc., Irvine, CA)并轻轻混合直至粉末溶解。用第二瓶STZ重复,将两者放在湿冰上,并避光。这些溶液在所述条件下保持良好3小时。在给药前阶段的第8天,在禁食6小时后,基于最近的体重以0.8 mL/kg (40 mg/kg)的剂量体积对动物静脉内给药。在异氟醚麻醉下进行STZ给药。观察大鼠直至完全清醒。
在STZ处理后三天,使用旨在实现血糖仪值(450 mg/dL至550 mg/dL纳入标准)和体重平衡的BRAT将动物分配到研究中。60只大鼠中的50只接受研究。以5 mL/kg的剂量体积将单剂量的预先配制的试验物(在20 mM组氨酸、50 mM NaCl pH 6.0中的50、100、200和400nmol/kg的INS类似物)施用至皮下空间中。
在试验物治疗之后,每天早上(给药阶段的第1-11天)监测体重和食物摄入。使用血糖仪(AccuChek® Aviva®, Roche, Indianapolis, IN) (一式两份地)在给药后0、2、4、6、8、10、12、18、24、36、48、72、96、120、144、168、192、216和240小时通过尾部取血测量葡萄糖。
将所有数据表示为每组4-5只动物的平均值±SEM。如下计算每个时间点的葡萄糖变化百分比:在给药后X小时的变化百分比= ((X时间点的葡萄糖- 动物在给药后时间0的葡萄糖) x 100) - 100。
如下表15所示,在单次注射后,所有四种INS类似物表现出全血葡萄糖水平的剂量依赖性(50、100、200和400 nmol/kg)降低。
实施例50:INS类似物在STZ处理的大鼠中的药代动力学
在STZ诱导的糖尿病大鼠模型中测试了本文中的INS类似物的药代动力学。给STZ处理的雄性大鼠以50、100、200或400 nmol/kg(5 mL/kg剂量,在20 mM组氨酸、50 mM NaClpH 6.0中)施用单次皮下剂量的各种INS类似物。在给药前和给药后2、4、6、8、10、12、18、24、36、48、72、96、120、144、168、192、216和240小时从每只动物收集血液。将血液样品处理成K3EDTA血浆,并在约-70℃冷冻储存。在Eli Lilly and Company (Indianapolis, IN)测量血浆中的INS类似物浓度,并使用浓度-时间数据计算药代动力学参数(参见,表12)。
使用与Dionex Ultimate 3000 UPLC系统偶联的Thermo orbitrap质谱仪(Q/Exactive或Fusion Lumos)通过免疫亲和-LC/MS测量动物的血浆类似物浓度。使用固定化至链霉亲和素包被的磁珠(Dynal M-280, Thermo E2017-02)的抗-骆驼科-VHH-生物素单克隆抗体(Eli Lilly and Company, 克隆96A3F5)从K3EDTA大鼠血浆中免疫沉淀类似物。在除去非特异性地结合的蛋白的洗涤步骤之后,将变体还原(三乙基膦, Aldrich 245275-5G),烷基化(2-碘乙醇, Aldrich 176850-25G),并消化(Trypsin Gold,Promega E2019-12)。通过LC/MS在0.293 nM至150 nM的范围内测量来自变体的不同区域的后续胰蛋白酶肽,作为完整类似物的替代测量。
实施例29和30的药代动力学在测试的剂量范围(50-400 nmol/kg皮下)内大约呈线性。两种类似物的表观清除率范围为2.9 mL/hr/kg至4.7 mL/hr/kg,且它们的消除半衰期范围为25小时至42小时(参见,表17)。
表17:在对STZ处理的雄性大鼠的单次50、100、200或400 nmol/kg皮下剂量后实施例29和30的INS类似物的平均药代动力学参数
平均值±(SD), N=5
缩写:AUC0-∞=从时间0小时至无穷大的曲线下面积,CL/F = 清除率/生物利用度,Tmax = 达到最大浓度的时间,Cmax/剂量=观察到的最大血浆浓度除以剂量,t1/2 = 半衰期。
序列
以下核酸和/或氨基酸序列在本公开内容中提及并在下面提供用于参考。
SEQ ID NO:1 - 人前胰岛素原(110个氨基酸;NCBI Ref. No. NP_001278826.1)
SEQ ID NO:2 - 人胰岛素原(86个氨基酸;NCBI Ref. No. NP_001278826.1的25-110)
SEQ ID NO:3 - 人INS A链(21个氨基酸;NCBI Ref. No. NP_001278826.1的90-110)
SEQ ID NO:4 - 人INS B链(30个氨基酸;NCBI Ref. No. NP_001278826.1的25-54)
SEQ ID NO:5–具有C-端C9标签的人INS受体-A (1370个氨基酸;NCBI Ref. No.NP_001073285.1)
SEQ ID NO:6–具有C-端C9标签的人INS受体-B (1382个氨基酸;NCBI Ref. No.NP_000199.2)
SEQ ID NO:7 - VHH部分#1 (MC6.1C22.43)
SEQ ID NO:8 - VHH部分#2 (MC6.1)
SEQ ID NO:9 - VHH部分#3 (MC6.1C80.43)
SEQ ID NO:10 - L1 ((GGGGQ)n的基本序列)
SEQ ID NO:11 - L1 ((GGGQ)n的基本序列)
SEQ ID NO:12 - L1 ((GGGGS)n的基本序列)
SEQ ID NO:13 - L1 ((PGPQ)n的基本序列)
SEQ ID NO:14 - L1 ((PGPA)n的基本序列)
SEQ ID NO:15- L1 ((GGE)nGG的基本序列)
SEQ ID NO:16 - L1 ((GGGGE)nGGGG的基本序列)
SEQ ID NO:17 - L1 ((GGGGK)nGGGG的基本序列)
SEQ ID NO:18 - L1 ((GGGG(AP)nGGGG的基本序列)
SEQ ID NO:19 - L1 (GGGG(EP)n的基本序列)
SEQ ID NO:20 - L1 (GGGG(KP)nGGGG的基本序列)
SEQ ID NO:21 - L1 ((PGPE)nPGPQ的基本序列)
SEQ ID NO:22 - L1 ((PGPK)nPGPQ的基本序列)
SEQ ID NO:23 - L1 #1 ((GGGGQ)5)
SEQ ID NO:24 - L1 #2 ((PGPQ)8)
SEQ ID NO:25 - L1 #3 ((PGPA)8)
SEQ ID NO:26 - L1 #4 (G2E)7G2
SEQ ID NO:27 - L1 #5 (G4E)4G4
SEQ ID NO:28 - L1 #6 (G4K)4G4
SEQ ID NO:29 - L1 #7 (G4(AP)10G4)
SEQ ID NO:30 - L1 #7 (G4(EP)10G4)
SEQ ID NO:31 - L1 #8 (G4(KP)10G4)
SEQ ID NO:32 - L1 #9 ((PGPE)7PGPQ)
SEQ ID NO:33 - L1 #10 ((PGPK)7PGPQ)
SEQ ID NO:34 - L2 #1
SEQ ID NO:35 - L2 #2
SEQ ID NO:36 - L2 #3
SEQ ID NO:37 - INS类似物#1 (SCI(A21G)-(PGPA)8-MC6.1)
SEQ ID NO:38 - INS类似物#2 (SCI(B3D,A21G)-(PGPA)8-MC6.1)
SEQ ID NO:39 - INS类似物#3 (SCI(B9A,A21G)-(PGPA)8-MC6.1)
SEQ ID NO:40 - INS类似物#4 (SCI(B16E,A21G)-(PGPA)8-MC6.1)
SEQ ID NO:41 - INS类似物#5 (SCI(B16H,A21G)-(PGPA)8-MC6.1)
SEQ ID NO:42 - INS类似物#6 (SCI(B25H,A21G)-(PGPA)8-MC6.1)
SEQ ID NO:43 - INS类似物#7 (SCI(B3S,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:44 - INS类似物#8 (SCI(B3S,B25H,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:45 - INS类似物#9 (SCI(B3S,B25H,A8H,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:46 - INS类似物#10 (SCI(B3S,B16H,A21G)-(PGPA)8-MC6.1C22.43)(SCIv5-(PGPA)8-C22.43)
SEQ ID NO:47 - INS类似物#11 (SCI(B3S,B16H,A8H,A14E,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:48 - INS类似物#12 (SCI(B3S,B16H,B25H,A8H,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:49 - INS类似物#13 (SCI(B3S,B16H,B25H,A8H,A14E,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:50 - INS类似物#14 (SCI(B3S,B16R,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:51 - INS类似物#15 (SCI(B3S,B16F,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:52 - INS类似物#16 (SCI(B3S,B16W,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:53 - INS类似物#17 (SCI(B3S,B16R,A8H,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:54 - INS类似物#18 (SCI(B3S,B16R,B25H,A8H,A21G)-(PGPA)8-MC6.1C22.43)
SEQ ID NO:55 - INS类似物#19 (SCI(B3S,A21G)-(G4Q)5-MC6.1C22.43)
SEQ ID NO:56 - INS类似物#20 (SCI(B3S,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:57 - INS类似物#21 (SCI(B3S,B16H,B25H,A8H,A21G)-(G4Q)5-C22.43)
SEQ ID NO:58 - INS类似物#22 (SCI(B3S,B16H,B25H,A8H,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:59 - INS类似物#23 (SCI(B3S,B16H,B25H,A8H,A14E,A21G)-(G4Q)5-MC6.1C22.43)
SEQ ID NO:60 - INS类似物#24 (SCI(B3S,B16H,B25H,A8H,A14E,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:61 - INS类似物#25 SCI(B3S,B16R,A21G)-(G4Q)5-MC6.1C22.43)
SEQ ID NO:62 - INS类似物#26 SCI(B3S,B16R,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:63 - INS类似物#27 (SCI(B3S,B16R,A8H,A21G)-(G4Q)5-MC6.1C22.43)
SEQ ID NO:64 - INS类似物#28 (SCI(B3S,B16R,A8H,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:65 - INS类似物#29 (SCI(B3S,B16R,B25H,A8H,A21G)-(G4Q)5-MC6.1C22.43)
SEQ ID NO:66 - INS类似物#30 (SCI(B3S,B16R,B25H,A8H,A21G)-(PGPQ)8-MC6.1C22.43)
SEQ ID NO:67 - INS类似物#31 (SCI(B3S,B16R,B25H,A8H,A21G)-(G2E)7G2-MC6.1C22.43)
SEQ ID NO:68 - INS类似物#32 (SCI(B3S,B16R,B25H,A8H,A21G)-(G4E)4G4-MC6.1C22.43)
SEQ ID NO:69 - INS类似物#33 (SCI(B3S,B16R,B25H,A8H,A21G)-(G4K)4G4-MC6.1C22.43)
SEQ ID NO:70 - INS类似物#34 (SCI(B3S,B16R,B25H,A8H,A21G)-G4(AP)10G4-MC6.1C22.43)
SEQ ID NO:71 - INS类似物#35 (SCI(B3S,B16R,B25H,A8H,A21G)-G4(EP)10G4-MC6.1C22.43)
SEQ ID NO:72 - INS类似物#36 (SCI(B3S,B16R,B25H,A8H,A21G)-G4(KP)10G4-MC6.1C22.43)
SEQ ID NO:73 - INS类似物#37 (SCI(B3S,B16R,B25H,A8H,A21G)-(PGPE)7PGPQ-MC6.1C22.43)
SEQ ID NO:74 - INS类似物#38 (SCI(B3S,B16R,B25H,A8H,A21G)-(PGPK)7PGPQ-MC6.1C22.43)
SEQ ID NO:75 - INS类似物#39 (SCI(B3K,B16R,B25H,A8H,A21G)-G4Q)5-MC6.1C22.43)
SEQ ID NO:76 - INS类似物#40 (SCI(B3K,B16R,B21Q,B25H,A8H,A21G)-G4Q)5-MC6.1C22.43)
SEQ ID NO:77 - INS类似物#41
(SCI(B3K,B16R,B21Q,B25H,A4Q,A8H,A21G)-G4Q)5- MC6.1C22.43)
SEQ ID NO:78 - INS类似物#42
(SCI(B3S,B16R,B25H,A8H,A21G)-(G4Q)5-MC6.1C80.43)
SEQ ID NO:79 - INS类似物#43
(SCI(B3K,B16R,B25H,A8H,A21G)-(G4Q)5-MC6.1C80.43)
SEQ ID NO:80 - INS类似物#44
(SCI(B3K,B16R,B21Q,B25H,A8H,A21G)-(G4Q)5-MC6.1C80.43)
SEQ ID NO:81 - INS类似物#45
(SCI(B3K,B16R,B21Q,B25H,A4Q,A8H,A21G)-(G4Q)5-MC6.1C80.43)
SEQ ID NO:82 - 信号肽
SEQ ID NO:83 - C-末端C9标签
SEQ ID NO:84 (CDR1 #1)
SEQ ID NO:85 (CDR1 #2)
SEQ ID NO:86 (CDR1 #3)
SEQ ID NO:87 (CDR2 #1)
SEQ ID NO:88 (CDR2 #2)
SEQ ID NO:89 (CDR2 #3)
SEQ ID NO:90 (CDR3 #1)
SEQ ID NO:91 (CDR3 #2)
SEQ ID NO:92 (CDR3 #3)
序列表
<110> Eli Lilly and Company
<120> 胰岛素类似物及其使用方法
<130> X22580
<160> 92
<170> PatentIn version 3.5
<210> 1
<211> 110
<212> PRT
<213> 智人
<400> 1
Met Ala Leu Trp Met Arg Leu Leu Pro Leu Leu Ala Leu Leu Ala Leu
1 5 10 15
Trp Gly Pro Asp Pro Ala Ala Ala Phe Val Asn Gln His Leu Cys Gly
20 25 30
Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe
35 40 45
Phe Tyr Thr Pro Lys Thr Arg Arg Glu Ala Glu Asp Leu Gln Val Gly
50 55 60
Gln Val Glu Leu Gly Gly Gly Pro Gly Ala Gly Ser Leu Gln Pro Leu
65 70 75 80
Ala Leu Glu Gly Ser Leu Gln Lys Arg Gly Ile Val Glu Gln Cys Cys
85 90 95
Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
100 105 110
<210> 2
<211> 86
<212> PRT
<213> 智人
<400> 2
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg
20 25 30
Glu Ala Glu Asp Leu Gln Val Gly Gln Val Glu Leu Gly Gly Gly Pro
35 40 45
Gly Ala Gly Ser Leu Gln Pro Leu Ala Leu Glu Gly Ser Leu Gln Lys
50 55 60
Arg Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln
65 70 75 80
Leu Glu Asn Tyr Cys Asn
85
<210> 3
<211> 21
<212> PRT
<213> 智人
<400> 3
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu
1 5 10 15
Glu Asn Tyr Cys Asn
20
<210> 4
<211> 30
<212> PRT
<213> 智人
<400> 4
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr
20 25 30
<210> 5
<211> 1383
<212> PRT
<213> 智人
<400> 5
Met Ala Thr Gly Gly Arg Arg Gly Ala Ala Ala Ala Pro Leu Leu Val
1 5 10 15
Ala Val Ala Ala Leu Leu Leu Gly Ala Ala Gly His Leu Tyr Pro Gly
20 25 30
Glu Val Cys Pro Gly Met Asp Ile Arg Asn Asn Leu Thr Arg Leu His
35 40 45
Glu Leu Glu Asn Cys Ser Val Ile Glu Gly His Leu Gln Ile Leu Leu
50 55 60
Met Phe Lys Thr Arg Pro Glu Asp Phe Arg Asp Leu Ser Phe Pro Lys
65 70 75 80
Leu Ile Met Ile Thr Asp Tyr Leu Leu Leu Phe Arg Val Tyr Gly Leu
85 90 95
Glu Ser Leu Lys Asp Leu Phe Pro Asn Leu Thr Val Ile Arg Gly Ser
100 105 110
Arg Leu Phe Phe Asn Tyr Ala Leu Val Ile Phe Glu Met Val His Leu
115 120 125
Lys Glu Leu Gly Leu Tyr Asn Leu Met Asn Ile Thr Arg Gly Ser Val
130 135 140
Arg Ile Glu Lys Asn Asn Glu Leu Cys Tyr Leu Ala Thr Ile Asp Trp
145 150 155 160
Ser Arg Ile Leu Asp Ser Val Glu Asp Asn Tyr Ile Val Leu Asn Lys
165 170 175
Asp Asp Asn Glu Glu Cys Gly Asp Ile Cys Pro Gly Thr Ala Lys Gly
180 185 190
Lys Thr Asn Cys Pro Ala Thr Val Ile Asn Gly Gln Phe Val Glu Arg
195 200 205
Cys Trp Thr His Ser His Cys Gln Lys Val Cys Pro Thr Ile Cys Lys
210 215 220
Ser His Gly Cys Thr Ala Glu Gly Leu Cys Cys His Ser Glu Cys Leu
225 230 235 240
Gly Asn Cys Ser Gln Pro Asp Asp Pro Thr Lys Cys Val Ala Cys Arg
245 250 255
Asn Phe Tyr Leu Asp Gly Arg Cys Val Glu Thr Cys Pro Pro Pro Tyr
260 265 270
Tyr His Phe Gln Asp Trp Arg Cys Val Asn Phe Ser Phe Cys Gln Asp
275 280 285
Leu His His Lys Cys Lys Asn Ser Arg Arg Gln Gly Cys His Gln Tyr
290 295 300
Val Ile His Asn Asn Lys Cys Ile Pro Glu Cys Pro Ser Gly Tyr Thr
305 310 315 320
Met Asn Ser Ser Asn Leu Leu Cys Thr Pro Cys Leu Gly Pro Cys Pro
325 330 335
Lys Val Cys His Leu Leu Glu Gly Glu Lys Thr Ile Asp Ser Val Thr
340 345 350
Ser Ala Gln Glu Leu Arg Gly Cys Thr Val Ile Asn Gly Ser Leu Ile
355 360 365
Ile Asn Ile Arg Gly Gly Asn Asn Leu Ala Ala Glu Leu Glu Ala Asn
370 375 380
Leu Gly Leu Ile Glu Glu Ile Ser Gly Tyr Leu Lys Ile Arg Arg Ser
385 390 395 400
Tyr Ala Leu Val Ser Leu Ser Phe Phe Arg Lys Leu Arg Leu Ile Arg
405 410 415
Gly Glu Thr Leu Glu Ile Gly Asn Tyr Ser Phe Tyr Ala Leu Asp Asn
420 425 430
Gln Asn Leu Arg Gln Leu Trp Asp Trp Ser Lys His Asn Leu Thr Ile
435 440 445
Thr Gln Gly Lys Leu Phe Phe His Tyr Asn Pro Lys Leu Cys Leu Ser
450 455 460
Glu Ile His Lys Met Glu Glu Val Ser Gly Thr Lys Gly Arg Gln Glu
465 470 475 480
Arg Asn Asp Ile Ala Leu Lys Thr Asn Gly Asp Gln Ala Ser Cys Glu
485 490 495
Asn Glu Leu Leu Lys Phe Ser Tyr Ile Arg Thr Ser Phe Asp Lys Ile
500 505 510
Leu Leu Arg Trp Glu Pro Tyr Trp Pro Pro Asp Phe Arg Asp Leu Leu
515 520 525
Gly Phe Met Leu Phe Tyr Lys Glu Ala Pro Tyr Gln Asn Val Thr Glu
530 535 540
Phe Asp Gly Gln Asp Ala Cys Gly Ser Asn Ser Trp Thr Val Val Asp
545 550 555 560
Ile Asp Pro Pro Leu Arg Ser Asn Asp Pro Lys Ser Gln Asn His Pro
565 570 575
Gly Trp Leu Met Arg Gly Leu Lys Pro Trp Thr Gln Tyr Ala Ile Phe
580 585 590
Val Lys Thr Leu Val Thr Phe Ser Asp Glu Arg Arg Thr Tyr Gly Ala
595 600 605
Lys Ser Asp Ile Ile Tyr Val Gln Thr Asp Ala Thr Asn Pro Ser Val
610 615 620
Pro Leu Asp Pro Ile Ser Val Ser Asn Ser Ser Ser Gln Ile Ile Leu
625 630 635 640
Lys Trp Lys Pro Pro Ser Asp Pro Asn Gly Asn Ile Thr His Tyr Leu
645 650 655
Val Phe Trp Glu Arg Gln Ala Glu Asp Ser Glu Leu Phe Glu Leu Asp
660 665 670
Tyr Cys Leu Lys Gly Leu Lys Leu Pro Ser Arg Thr Trp Ser Pro Pro
675 680 685
Phe Glu Ser Glu Asp Ser Gln Lys His Asn Gln Ser Glu Tyr Glu Asp
690 695 700
Ser Ala Gly Glu Cys Cys Ser Cys Pro Lys Thr Asp Ser Gln Ile Leu
705 710 715 720
Lys Glu Leu Glu Glu Ser Ser Phe Arg Lys Thr Phe Glu Asp Tyr Leu
725 730 735
His Asn Val Val Phe Val Pro Arg Pro Ser Arg Lys Arg Arg Ser Leu
740 745 750
Gly Asp Val Gly Asn Val Thr Val Ala Val Pro Thr Val Ala Ala Phe
755 760 765
Pro Asn Thr Ser Ser Thr Ser Val Pro Thr Ser Pro Glu Glu His Arg
770 775 780
Pro Phe Glu Lys Val Val Asn Lys Glu Ser Leu Val Ile Ser Gly Leu
785 790 795 800
Arg His Phe Thr Gly Tyr Arg Ile Glu Leu Gln Ala Cys Asn Gln Asp
805 810 815
Thr Pro Glu Glu Arg Cys Ser Val Ala Ala Tyr Val Ser Ala Arg Thr
820 825 830
Met Pro Glu Ala Lys Ala Asp Asp Ile Val Gly Pro Val Thr His Glu
835 840 845
Ile Phe Glu Asn Asn Val Val His Leu Met Trp Gln Glu Pro Lys Glu
850 855 860
Pro Asn Gly Leu Ile Val Leu Tyr Glu Val Ser Tyr Arg Arg Tyr Gly
865 870 875 880
Asp Glu Glu Leu His Leu Cys Val Ser Arg Lys His Phe Ala Leu Glu
885 890 895
Arg Gly Cys Arg Leu Arg Gly Leu Ser Pro Gly Asn Tyr Ser Val Arg
900 905 910
Ile Arg Ala Thr Ser Leu Ala Gly Asn Gly Ser Trp Thr Glu Pro Thr
915 920 925
Tyr Phe Tyr Val Thr Asp Tyr Leu Asp Val Pro Ser Asn Ile Ala Lys
930 935 940
Ile Ile Ile Gly Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val Ile
945 950 955 960
Gly Ser Ile Tyr Leu Phe Leu Arg Lys Arg Gln Pro Asp Gly Pro Leu
965 970 975
Gly Pro Leu Tyr Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser Asp
980 985 990
Val Phe Pro Cys Ser Val Tyr Val Pro Asp Glu Trp Glu Val Ser Arg
995 1000 1005
Glu Lys Ile Thr Leu Leu Arg Glu Leu Gly Gln Gly Ser Phe Gly
1010 1015 1020
Met Val Tyr Glu Gly Asn Ala Arg Asp Ile Ile Lys Gly Glu Ala
1025 1030 1035
Glu Thr Arg Val Ala Val Lys Thr Val Asn Glu Ser Ala Ser Leu
1040 1045 1050
Arg Glu Arg Ile Glu Phe Leu Asn Glu Ala Ser Val Met Lys Gly
1055 1060 1065
Phe Thr Cys His His Val Val Arg Leu Leu Gly Val Val Ser Lys
1070 1075 1080
Gly Gln Pro Thr Leu Val Val Met Glu Leu Met Ala His Gly Asp
1085 1090 1095
Leu Lys Ser Tyr Leu Arg Ser Leu Arg Pro Glu Ala Glu Asn Asn
1100 1105 1110
Pro Gly Arg Pro Pro Pro Thr Leu Gln Glu Met Ile Gln Met Ala
1115 1120 1125
Ala Glu Ile Ala Asp Gly Met Ala Tyr Leu Asn Ala Lys Lys Phe
1130 1135 1140
Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Val Ala His Asp
1145 1150 1155
Phe Thr Val Lys Ile Gly Asp Phe Gly Met Thr Arg Asp Ile Tyr
1160 1165 1170
Glu Thr Asp Tyr Tyr Arg Lys Gly Gly Lys Gly Leu Leu Pro Val
1175 1180 1185
Arg Trp Met Ala Pro Glu Ser Leu Lys Asp Gly Val Phe Thr Thr
1190 1195 1200
Ser Ser Asp Met Trp Ser Phe Gly Val Val Leu Trp Glu Ile Thr
1205 1210 1215
Ser Leu Ala Glu Gln Pro Tyr Gln Gly Leu Ser Asn Glu Gln Val
1220 1225 1230
Leu Lys Phe Val Met Asp Gly Gly Tyr Leu Asp Gln Pro Asp Asn
1235 1240 1245
Cys Pro Glu Arg Val Thr Asp Leu Met Arg Met Cys Trp Gln Phe
1250 1255 1260
Asn Pro Lys Met Arg Pro Thr Phe Leu Glu Ile Val Asn Leu Leu
1265 1270 1275
Lys Asp Asp Leu His Pro Ser Phe Pro Glu Val Ser Phe Phe His
1280 1285 1290
Ser Glu Glu Asn Lys Ala Pro Glu Ser Glu Glu Leu Glu Met Glu
1295 1300 1305
Phe Glu Asp Met Glu Asn Val Pro Leu Asp Arg Ser Ser His Cys
1310 1315 1320
Gln Arg Glu Glu Ala Gly Gly Arg Asp Gly Gly Ser Ser Leu Gly
1325 1330 1335
Phe Lys Arg Ser Tyr Glu Glu His Ile Pro Tyr Thr His Met Asn
1340 1345 1350
Gly Gly Lys Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn
1355 1360 1365
Pro Ser Ala Ala Ala Gly Thr Glu Thr Ser Gln Val Ala Pro Ala
1370 1375 1380
<210> 6
<211> 1395
<212> PRT
<213> 智人
<400> 6
Met Ala Thr Gly Gly Arg Arg Gly Ala Ala Ala Ala Pro Leu Leu Val
1 5 10 15
Ala Val Ala Ala Leu Leu Leu Gly Ala Ala Gly His Leu Tyr Pro Gly
20 25 30
Glu Val Cys Pro Gly Met Asp Ile Arg Asn Asn Leu Thr Arg Leu His
35 40 45
Glu Leu Glu Asn Cys Ser Val Ile Glu Gly His Leu Gln Ile Leu Leu
50 55 60
Met Phe Lys Thr Arg Pro Glu Asp Phe Arg Asp Leu Ser Phe Pro Lys
65 70 75 80
Leu Ile Met Ile Thr Asp Tyr Leu Leu Leu Phe Arg Val Tyr Gly Leu
85 90 95
Glu Ser Leu Lys Asp Leu Phe Pro Asn Leu Thr Val Ile Arg Gly Ser
100 105 110
Arg Leu Phe Phe Asn Tyr Ala Leu Val Ile Phe Glu Met Val His Leu
115 120 125
Lys Glu Leu Gly Leu Tyr Asn Leu Met Asn Ile Thr Arg Gly Ser Val
130 135 140
Arg Ile Glu Lys Asn Asn Glu Leu Cys Tyr Leu Ala Thr Ile Asp Trp
145 150 155 160
Ser Arg Ile Leu Asp Ser Val Glu Asp Asn Tyr Ile Val Leu Asn Lys
165 170 175
Asp Asp Asn Glu Glu Cys Gly Asp Ile Cys Pro Gly Thr Ala Lys Gly
180 185 190
Lys Thr Asn Cys Pro Ala Thr Val Ile Asn Gly Gln Phe Val Glu Arg
195 200 205
Cys Trp Thr His Ser His Cys Gln Lys Val Cys Pro Thr Ile Cys Lys
210 215 220
Ser His Gly Cys Thr Ala Glu Gly Leu Cys Cys His Ser Glu Cys Leu
225 230 235 240
Gly Asn Cys Ser Gln Pro Asp Asp Pro Thr Lys Cys Val Ala Cys Arg
245 250 255
Asn Phe Tyr Leu Asp Gly Arg Cys Val Glu Thr Cys Pro Pro Pro Tyr
260 265 270
Tyr His Phe Gln Asp Trp Arg Cys Val Asn Phe Ser Phe Cys Gln Asp
275 280 285
Leu His His Lys Cys Lys Asn Ser Arg Arg Gln Gly Cys His Gln Tyr
290 295 300
Val Ile His Asn Asn Lys Cys Ile Pro Glu Cys Pro Ser Gly Tyr Thr
305 310 315 320
Met Asn Ser Ser Asn Leu Leu Cys Thr Pro Cys Leu Gly Pro Cys Pro
325 330 335
Lys Val Cys His Leu Leu Glu Gly Glu Lys Thr Ile Asp Ser Val Thr
340 345 350
Ser Ala Gln Glu Leu Arg Gly Cys Thr Val Ile Asn Gly Ser Leu Ile
355 360 365
Ile Asn Ile Arg Gly Gly Asn Asn Leu Ala Ala Glu Leu Glu Ala Asn
370 375 380
Leu Gly Leu Ile Glu Glu Ile Ser Gly Tyr Leu Lys Ile Arg Arg Ser
385 390 395 400
Tyr Ala Leu Val Ser Leu Ser Phe Phe Arg Lys Leu Arg Leu Ile Arg
405 410 415
Gly Glu Thr Leu Glu Ile Gly Asn Tyr Ser Phe Tyr Ala Leu Asp Asn
420 425 430
Gln Asn Leu Arg Gln Leu Trp Asp Trp Ser Lys His Asn Leu Thr Ile
435 440 445
Thr Gln Gly Lys Leu Phe Phe His Tyr Asn Pro Lys Leu Cys Leu Ser
450 455 460
Glu Ile His Lys Met Glu Glu Val Ser Gly Thr Lys Gly Arg Gln Glu
465 470 475 480
Arg Asn Asp Ile Ala Leu Lys Thr Asn Gly Asp Gln Ala Ser Cys Glu
485 490 495
Asn Glu Leu Leu Lys Phe Ser Tyr Ile Arg Thr Ser Phe Asp Lys Ile
500 505 510
Leu Leu Arg Trp Glu Pro Tyr Trp Pro Pro Asp Phe Arg Asp Leu Leu
515 520 525
Gly Phe Met Leu Phe Tyr Lys Glu Ala Pro Tyr Gln Asn Val Thr Glu
530 535 540
Phe Asp Gly Gln Asp Ala Cys Gly Ser Asn Ser Trp Thr Val Val Asp
545 550 555 560
Ile Asp Pro Pro Leu Arg Ser Asn Asp Pro Lys Ser Gln Asn His Pro
565 570 575
Gly Trp Leu Met Arg Gly Leu Lys Pro Trp Thr Gln Tyr Ala Ile Phe
580 585 590
Val Lys Thr Leu Val Thr Phe Ser Asp Glu Arg Arg Thr Tyr Gly Ala
595 600 605
Lys Ser Asp Ile Ile Tyr Val Gln Thr Asp Ala Thr Asn Pro Ser Val
610 615 620
Pro Leu Asp Pro Ile Ser Val Ser Asn Ser Ser Ser Gln Ile Ile Leu
625 630 635 640
Lys Trp Lys Pro Pro Ser Asp Pro Asn Gly Asn Ile Thr His Tyr Leu
645 650 655
Val Phe Trp Glu Arg Gln Ala Glu Asp Ser Glu Leu Phe Glu Leu Asp
660 665 670
Tyr Cys Leu Lys Gly Leu Lys Leu Pro Ser Arg Thr Trp Ser Pro Pro
675 680 685
Phe Glu Ser Glu Asp Ser Gln Lys His Asn Gln Ser Glu Tyr Glu Asp
690 695 700
Ser Ala Gly Glu Cys Cys Ser Cys Pro Lys Thr Asp Ser Gln Ile Leu
705 710 715 720
Lys Glu Leu Glu Glu Ser Ser Phe Arg Lys Thr Phe Glu Asp Tyr Leu
725 730 735
His Asn Val Val Phe Val Pro Arg Lys Thr Ser Ser Gly Thr Gly Ala
740 745 750
Glu Asp Pro Arg Pro Ser Arg Lys Arg Arg Ser Leu Gly Asp Val Gly
755 760 765
Asn Val Thr Val Ala Val Pro Thr Val Ala Ala Phe Pro Asn Thr Ser
770 775 780
Ser Thr Ser Val Pro Thr Ser Pro Glu Glu His Arg Pro Phe Glu Lys
785 790 795 800
Val Val Asn Lys Glu Ser Leu Val Ile Ser Gly Leu Arg His Phe Thr
805 810 815
Gly Tyr Arg Ile Glu Leu Gln Ala Cys Asn Gln Asp Thr Pro Glu Glu
820 825 830
Arg Cys Ser Val Ala Ala Tyr Val Ser Ala Arg Thr Met Pro Glu Ala
835 840 845
Lys Ala Asp Asp Ile Val Gly Pro Val Thr His Glu Ile Phe Glu Asn
850 855 860
Asn Val Val His Leu Met Trp Gln Glu Pro Lys Glu Pro Asn Gly Leu
865 870 875 880
Ile Val Leu Tyr Glu Val Ser Tyr Arg Arg Tyr Gly Asp Glu Glu Leu
885 890 895
His Leu Cys Val Ser Arg Lys His Phe Ala Leu Glu Arg Gly Cys Arg
900 905 910
Leu Arg Gly Leu Ser Pro Gly Asn Tyr Ser Val Arg Ile Arg Ala Thr
915 920 925
Ser Leu Ala Gly Asn Gly Ser Trp Thr Glu Pro Thr Tyr Phe Tyr Val
930 935 940
Thr Asp Tyr Leu Asp Val Pro Ser Asn Ile Ala Lys Ile Ile Ile Gly
945 950 955 960
Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val Ile Gly Ser Ile Tyr
965 970 975
Leu Phe Leu Arg Lys Arg Gln Pro Asp Gly Pro Leu Gly Pro Leu Tyr
980 985 990
Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser Asp Val Phe Pro Cys
995 1000 1005
Ser Val Tyr Val Pro Asp Glu Trp Glu Val Ser Arg Glu Lys Ile
1010 1015 1020
Thr Leu Leu Arg Glu Leu Gly Gln Gly Ser Phe Gly Met Val Tyr
1025 1030 1035
Glu Gly Asn Ala Arg Asp Ile Ile Lys Gly Glu Ala Glu Thr Arg
1040 1045 1050
Val Ala Val Lys Thr Val Asn Glu Ser Ala Ser Leu Arg Glu Arg
1055 1060 1065
Ile Glu Phe Leu Asn Glu Ala Ser Val Met Lys Gly Phe Thr Cys
1070 1075 1080
His His Val Val Arg Leu Leu Gly Val Val Ser Lys Gly Gln Pro
1085 1090 1095
Thr Leu Val Val Met Glu Leu Met Ala His Gly Asp Leu Lys Ser
1100 1105 1110
Tyr Leu Arg Ser Leu Arg Pro Glu Ala Glu Asn Asn Pro Gly Arg
1115 1120 1125
Pro Pro Pro Thr Leu Gln Glu Met Ile Gln Met Ala Ala Glu Ile
1130 1135 1140
Ala Asp Gly Met Ala Tyr Leu Asn Ala Lys Lys Phe Val His Arg
1145 1150 1155
Asp Leu Ala Ala Arg Asn Cys Met Val Ala His Asp Phe Thr Val
1160 1165 1170
Lys Ile Gly Asp Phe Gly Met Thr Arg Asp Ile Tyr Glu Thr Asp
1175 1180 1185
Tyr Tyr Arg Lys Gly Gly Lys Gly Leu Leu Pro Val Arg Trp Met
1190 1195 1200
Ala Pro Glu Ser Leu Lys Asp Gly Val Phe Thr Thr Ser Ser Asp
1205 1210 1215
Met Trp Ser Phe Gly Val Val Leu Trp Glu Ile Thr Ser Leu Ala
1220 1225 1230
Glu Gln Pro Tyr Gln Gly Leu Ser Asn Glu Gln Val Leu Lys Phe
1235 1240 1245
Val Met Asp Gly Gly Tyr Leu Asp Gln Pro Asp Asn Cys Pro Glu
1250 1255 1260
Arg Val Thr Asp Leu Met Arg Met Cys Trp Gln Phe Asn Pro Lys
1265 1270 1275
Met Arg Pro Thr Phe Leu Glu Ile Val Asn Leu Leu Lys Asp Asp
1280 1285 1290
Leu His Pro Ser Phe Pro Glu Val Ser Phe Phe His Ser Glu Glu
1295 1300 1305
Asn Lys Ala Pro Glu Ser Glu Glu Leu Glu Met Glu Phe Glu Asp
1310 1315 1320
Met Glu Asn Val Pro Leu Asp Arg Ser Ser His Cys Gln Arg Glu
1325 1330 1335
Glu Ala Gly Gly Arg Asp Gly Gly Ser Ser Leu Gly Phe Lys Arg
1340 1345 1350
Ser Tyr Glu Glu His Ile Pro Tyr Thr His Met Asn Gly Gly Lys
1355 1360 1365
Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn Pro Ser Ala
1370 1375 1380
Ala Ala Gly Thr Glu Thr Ser Gln Val Ala Pro Ala
1385 1390 1395
<210> 7
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 7
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp Glu Thr
20 25 30
Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp Leu
100 105 110
Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro Pro
115 120 125
<210> 8
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 8
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Ser Thr
20 25 30
Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Gly Gly Ser Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Arg Pro Gly Arg Pro Leu Ile Thr Ser Arg Asp Ala Asn Leu
100 105 110
Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 9
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 9
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp Glu Thr
20 25 30
Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val
35 40 45
Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp Leu
100 105 110
Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro Pro
115 120 125
<210> 10
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Gly Gly Gly Gly Gln
1 5
<210> 11
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 11
Gly Gly Gly Gln
1
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 12
Gly Gly Gly Gly Ser
1 5
<210> 13
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 13
Pro Gly Pro Gln
1
<210> 14
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 14
Pro Gly Pro Ala
1
<210> 15
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 15
Gly Gly Glu Gly Gly
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 16
Gly Gly Gly Gly Glu Gly Gly Gly Gly
1 5
<210> 17
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 17
Gly Gly Gly Gly Lys Gly Gly Gly Gly
1 5
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 18
Gly Gly Gly Gly Ala Pro Gly Gly Gly Gly
1 5 10
<210> 19
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 19
Gly Gly Gly Gly Glu Pro Gly Gly Gly Gly
1 5 10
<210> 20
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 20
Gly Gly Gly Gly Lys Pro Gly Gly Gly Gly
1 5 10
<210> 21
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 21
Pro Gly Pro Glu Pro Gly Pro Gln
1 5
<210> 22
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 22
Pro Gly Pro Lys Pro Gly Pro Gln
1 5
<210> 23
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 23
Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly
1 5 10 15
Gly Gly Gly Gln Gly Gly Gly Gly Gln
20 25
<210> 24
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 24
Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln
1 5 10 15
Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln
20 25 30
<210> 25
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 25
Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala
1 5 10 15
Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala
20 25 30
<210> 26
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 26
Gly Gly Glu Gly Gly Glu Gly Gly Glu Gly Gly Glu Gly Gly Glu Gly
1 5 10 15
Gly Glu Gly Gly Glu Gly Gly
20
<210> 27
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 27
Gly Gly Gly Gly Glu Gly Gly Gly Gly Glu Gly Gly Gly Gly Glu Gly
1 5 10 15
Gly Gly Gly Glu Gly Gly Gly Gly
20
<210> 28
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 28
Gly Gly Gly Gly Lys Gly Gly Gly Gly Lys Gly Gly Gly Gly Lys Gly
1 5 10 15
Gly Gly Gly Lys Gly Gly Gly Gly
20
<210> 29
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 29
Gly Gly Gly Gly Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro Ala Pro Ala Pro Gly Gly Gly Gly
20 25
<210> 30
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 30
Gly Gly Gly Gly Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 10 15
Glu Pro Glu Pro Glu Pro Glu Pro Gly Gly Gly Gly
20 25
<210> 31
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 31
Gly Gly Gly Gly Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 10 15
Lys Pro Lys Pro Lys Pro Lys Pro Gly Gly Gly Gly
20 25
<210> 32
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 32
Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro Glu
1 5 10 15
Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro Gln
20 25 30
<210> 33
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 33
Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro Lys
1 5 10 15
Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro Gln
20 25 30
<210> 34
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 34
Gly Gly Gly Gly Gly Gly
1 5
<210> 35
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 35
Gly Gly Gly Ser Gly Gly Ser Gly Gly Gly
1 5 10
<210> 36
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 36
Gly Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Gly
1 5 10
<210> 37
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 37
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 38
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 38
Phe Val Asp Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 39
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 39
Phe Val Asn Gln His Leu Cys Gly Ala His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 40
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 40
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Glu
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 41
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 41
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 42
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 42
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Ser Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Arg Asp Ala Asn Leu Tyr Asp Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser
210 215
<210> 43
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 43
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 44
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 44
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 45
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 45
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 46
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 46
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 47
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 47
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Glu Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 48
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 48
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 49
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 49
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Glu Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 50
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 50
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 51
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 51
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Phe
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 52
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 52
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Trp
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 53
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 53
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 54
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 54
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Ala Pro Gly Pro
50 55 60
Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro Ala Pro Gly Pro
65 70 75 80
Ala Pro Gly Pro Ala Pro Gly Pro Ala Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 55
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 55
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 56
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 56
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 57
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 57
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 58
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 58
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 59
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 59
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Glu Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 60
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 60
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Glu Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 61
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 61
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 62
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 62
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 63
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 63
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 64
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 64
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 65
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 65
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 66
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 66
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Gln Pro Gly Pro
50 55 60
Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro Gln Pro Gly Pro
65 70 75 80
Gln Pro Gly Pro Gln Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 67
<211> 208
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 67
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Glu Gly Gly Glu Gly
50 55 60
Gly Glu Gly Gly Glu Gly Gly Glu Gly Gly Glu Gly Gly Glu Gly Gly
65 70 75 80
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
85 90 95
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp Glu Thr
100 105 110
Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
115 120 125
Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val
130 135 140
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
145 150 155 160
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
165 170 175
Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp Leu
180 185 190
Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro Pro
195 200 205
<210> 68
<211> 209
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 68
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Glu Gly Gly
50 55 60
Gly Gly Glu Gly Gly Gly Gly Glu Gly Gly Gly Gly Glu Gly Gly Gly
65 70 75 80
Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
85 90 95
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp Glu
100 105 110
Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
115 120 125
Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser
130 135 140
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
145 150 155 160
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
165 170 175
Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp
180 185 190
Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro
195 200 205
Pro
<210> 69
<211> 209
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 69
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Lys Gly Gly
50 55 60
Gly Gly Lys Gly Gly Gly Gly Lys Gly Gly Gly Gly Lys Gly Gly Gly
65 70 75 80
Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
85 90 95
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp Glu
100 105 110
Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
115 120 125
Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser
130 135 140
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
145 150 155 160
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
165 170 175
Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp
180 185 190
Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro
195 200 205
Pro
<210> 70
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 70
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Ala Pro Ala
50 55 60
Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala
65 70 75 80
Pro Gly Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
85 90 95
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
100 105 110
Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys
115 120 125
Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr
130 135 140
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
145 150 155 160
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
165 170 175
Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser
180 185 190
Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr
195 200 205
Val Ser Ser Pro Pro
210
<210> 71
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 71
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Glu Pro Glu
50 55 60
Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu
65 70 75 80
Pro Gly Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
85 90 95
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
100 105 110
Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys
115 120 125
Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr
130 135 140
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
145 150 155 160
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
165 170 175
Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser
180 185 190
Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr
195 200 205
Val Ser Ser Pro Pro
210
<210> 72
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 72
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Lys Pro Lys
50 55 60
Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys
65 70 75 80
Pro Gly Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
85 90 95
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
100 105 110
Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys
115 120 125
Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr
130 135 140
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
145 150 155 160
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
165 170 175
Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser
180 185 190
Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr
195 200 205
Val Ser Ser Pro Pro
210
<210> 73
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 73
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Glu Pro Gly Pro
50 55 60
Glu Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro Glu Pro Gly Pro
65 70 75 80
Glu Pro Gly Pro Glu Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 74
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 74
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Pro Gly Pro Lys Pro Gly Pro
50 55 60
Lys Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro Lys Pro Gly Pro
65 70 75 80
Lys Pro Gly Pro Lys Pro Gly Pro Gln Glu Val Gln Leu Leu Glu Ser
85 90 95
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
100 105 110
Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala Trp Phe Arg Gln
115 120 125
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly Ile Gly Gly Gly Val
130 135 140
Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
145 150 155 160
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
165 170 175
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg Pro Gly Arg Pro
180 185 190
Leu Ile Thr Ser Lys Val Ala Asp Leu Tyr Pro Tyr Trp Gly Gln Gly
195 200 205
Thr Leu Val Thr Val Ser Ser Pro Pro
210 215
<210> 75
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 75
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 76
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 76
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Gln Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 77
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 77
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Gln Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Gln Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 78
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 78
Phe Val Ser Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 79
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 79
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 80
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 80
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Gln Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 81
<211> 210
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 81
Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Arg
1 5 10 15
Leu Val Cys Gly Gln Arg Gly Phe His Tyr Thr Pro Lys Thr Gly Gly
20 25 30
Gly Gly Gly Gly Gly Ile Val Gln Gln Cys Cys His Ser Ile Cys Ser
35 40 45
Leu Tyr Gln Leu Glu Asn Tyr Cys Gly Gly Gly Gly Gly Gln Gly Gly
50 55 60
Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln Gly Gly Gly
65 70 75 80
Gly Gln Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
85 90 95
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Tyr Ile Asp
100 105 110
Glu Thr Ala Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu
115 120 125
Phe Val Ala Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp
130 135 140
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
145 150 155 160
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
165 170 175
Tyr Cys Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala
180 185 190
Asp Leu Tyr Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
195 200 205
Pro Pro
210
<210> 82
<211> 20
<212> PRT
<213> 小家鼠
<400> 82
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly
20
<210> 83
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 83
Thr Glu Thr Ser Gln Val Ala Pro Ala
1 5
<210> 84
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 84
Ala Ala Ser Gly Arg Thr Val Ser Ser Thr Ala Val Ala
1 5 10
<210> 85
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 85
Ala Ala Ser Gly Arg Tyr Ile Asp Ser Thr Ala Val Ala
1 5 10
<210> 86
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 86
Ala Ala Ser Gly Arg Tyr Ile Asp Glu Thr Ala Val Ala
1 5 10
<210> 87
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 87
Gly Ile Gly Gly Ser Val Asp Ile Thr Tyr Tyr Leu Asp Ser Val Lys
1 5 10 15
Gly
<210> 88
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 88
Gly Ile Gly Gly Ser Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 89
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 89
Gly Ile Gly Gly Gly Val Asp Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 90
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 90
Ala Val Arg Pro Gly Arg Pro Leu Ile Thr Ser Arg Asp Ala Asn Leu
1 5 10 15
Tyr Asp Tyr
<210> 91
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 91
Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Arg Val Ala Asn Leu
1 5 10 15
Tyr Pro Tyr
<210> 92
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 92
Ala Ala Arg Pro Gly Arg Pro Leu Ile Thr Ser Lys Val Ala Asp Leu
1 5 10 15
Tyr Pro Tyr
Claims (39)
1.包含以下结构的化合物:
VHH-L1-A-L2-B,
VHH-L1-B-L2-A,
A-L2-B-L1-VHH, 或者
B-L2-A-L1-VHH,
其中VHH包含选自SEQ ID NO:7、8和9的氨基酸序列或与其具有至少90%序列相似性的序列,
其中A是包含SEQ ID NO:3的氨基酸序列或与其具有至少90%序列相似性的序列的胰岛素A链,
其中B是包含SEQ ID NO:4的氨基酸序列或与其具有至少90%序列相似性的序列的胰岛素B链,
其中L1是包含选自SEQ ID NO:10、11、12、13、14、15、16、17、18、19、20、21和22的氨基酸序列的第一接头,且其中n可以是1-10,且
其中L2是包含选自SEQ ID NO:34、35和36的氨基酸序列的第二接头。
2.权利要求1所述的化合物,其中A是SEQ ID NO:3。
3.权利要求1所述的化合物,其中B是SEQ ID NO:4。
4.权利要求1所述的化合物,其中A是SEQ ID NO:3且B是SEQ ID NO:4。
5.权利要求1所述的化合物,其中A是SEQ ID NO:3且包括至少一个选自E4Q突变、T8H突变、Y14E突变和N21G突变的突变。
6.权利要求1所述的化合物,其中B是SEQ ID NO:4且包括至少一个选自N3D突变、N3K突变、N3S突变、S9A突变、Y16E突变、Y16F突变、Y16H突变、Y16R突变、Y16W突变、E21Q突变或F25H突变的突变。
7.权利要求1所述的化合物,其中A是SEQ ID NO:3且包括至少一个选自E4Q突变、T8H突变、Y14E突变和N21G突变的突变,且其中B是SEQ ID NO:4且包括至少一个选自N3D突变、N3K突变、N3S突变、S9A突变、Y16E突变、Y16F突变、Y16H突变、Y16R突变、Y16W突变、E21Q突变或F25H突变的突变。
8.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:23。
9.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:24。
10.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:25。
11.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:26。
12.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:27。
13.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:28。
14.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:29。
15.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:30。
16.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:31。
17.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:32。
18.权利要求1-7中的任一项所述的化合物,其中L1是SEQ ID NO:33。
19.权利要求1-18中的任一项所述的化合物,其中L2是SEQ ID NO:34。
20.化合物,其包含选自SEQ ID NO:37至81的氨基酸序列或与其具有至少90%序列相似性的序列。
21.化合物,所述化合物基本上由选自SEQ ID NO:37至81的氨基酸序列或与其具有至少90%序列相似性的序列组成。
22.化合物,所述化合物由选自SEQ ID NO:37至81的氨基酸序列组成。
23.药物组合物,其包含权利要求1-22中的任一项所述的化合物和药学上可接受的缓冲液。
24.权利要求23所述的药物组合物,所述药物组合物进一步包含另外的治疗剂。
25.权利要求24所述的药物组合物,其中所述另外的治疗剂选自:二肽基肽酶4 (DPP-IV)抑制剂、天然胰淀素或其类似物、短效(膳食)INS类似物、天然肠降血糖素或其类似物、天然胰岛素样生长因子(IGF)或其类似物、二甲双胍、钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂、抑制素、磺酰脲(SU)、噻唑烷二酮(TZD)和其它抗血糖剂或其它抗肥胖剂。
26.治疗个体的心血管代谢病症、疾病和/或障碍的方法,所述方法包括下述步骤:
给所述个体施用有效量的权利要求1-22中的任一项所述的化合物或权利要求22所述的药物组合物。
27.权利要求26所述的方法,所述方法进一步包括给所述个体施用有效量的另外的治疗剂。
28.权利要求27所述的方法,其中所述另外的治疗剂选自:二肽基肽酶4 (DPP-IV)抑制剂、天然胰淀素或其类似物、短效(膳食)INS类似物、天然肠降血糖素或其类似物、天然胰岛素样生长因子(IGF)或其类似物、二甲双胍、钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂、抑制素、磺酰脲(SU)、噻唑烷二酮(TZD)和其它抗血糖剂或其它抗肥胖剂。
29.权利要求1-22中的任一项所述的化合物,其用于治疗。
30.权利要求1-22中的任一项所述的化合物,其用于治疗心血管代谢病症、疾病和/或障碍。
31.权利要求1-22中的任一项所述的化合物用于制备药物的用途,所述药物用于治疗心血管代谢病症、疾病和/或障碍。
32.化合物,其包含SEQ ID NO:7的氨基酸序列或与其具有至少90%序列相似性的序列。
33.化合物,其包含SEQ ID NO:8的氨基酸序列或与其具有至少90%序列相似性的序列。
34.化合物,其包含SEQ ID NO:9的氨基酸序列或与其具有至少90%序列相似性的序列。
35.可以结合血清白蛋白的VHH部分,所述VHH部分包含:
互补性决定区1 (CDR1),其包含选自SEQ ID NO:84、85和86的氨基酸序列;
互补性决定区2 (CDR2),其包含选自SEQ ID NO: 87、88和89的氨基酸序列;和
互补性决定区3 (CDR3),其包含选自SEQ ID NO:90、91和92的氨基酸序列。
36.权利要求35所述的VHH部分,其中CDR1是SEQ ID NO:84,CDR2是SEQ ID NO:87且CDR3是SEQ ID NO:90。
37.权利要求35所述的VHH部分,其中CDR1是SEQ ID NO:84,CDR2是SEQ ID NO:88且CDR3是SEQ ID NO:90。
38.权利要求35所述的VHH部分,其中CDR1是SEQ ID NO:85,CDR2是SEQ ID NO:89且CDR3是SEQ ID NO:91。
39.权利要求35所述的VHH部分,其中CDR1是SEQ ID NO:86,CDR2是SEQ ID NO:89且CDR3是SEQ ID NO:92。
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US11186623B2 (en) | 2019-12-24 | 2021-11-30 | Akston Bioscience Corporation | Ultra-long acting insulin-Fc fusion proteins and methods of use |
FI3972987T3 (fi) | 2020-04-10 | 2023-07-25 | Akston Biosciences Corp | Antigeenispesifinen immunoterapia COVID-19-fuusioproteiineille ja sen käyttömenetelmät |
US11192930B2 (en) | 2020-04-10 | 2021-12-07 | Askton Bioscences Corporation | Ultra-long acting insulin-Fc fusion protein and methods of use |
US11198719B2 (en) | 2020-04-29 | 2021-12-14 | Akston Biosciences Corporation | Ultra-long acting insulin-Fc fusion protein and methods of use |
EP4288452A1 (en) * | 2021-02-02 | 2023-12-13 | Eli Lilly and Company | Half-life extending moieties and methods of using the same |
WO2023004406A2 (en) | 2021-07-23 | 2023-01-26 | Akston Biosciences Corporation | Insulin-fc fusion proteins and methods of use to treat cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105037542A (zh) * | 2009-10-02 | 2015-11-11 | 贝林格尔.英格海姆国际有限公司 | 用于抗血管生成治疗的双特异性结合分子 |
US20160008483A1 (en) * | 2013-02-26 | 2016-01-14 | Hanmi Pharm. Co., Ltd | Novel insulin analog and use thereof |
WO2017041001A2 (en) * | 2015-09-04 | 2017-03-09 | The California Institute For Biomedical Research | Insulin immunoglobulin fusion proteins |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4835251A (en) | 1986-06-23 | 1989-05-30 | Genetech, Inc. | Method of chain combination |
DE3837825A1 (de) | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
US5166191A (en) | 1991-08-19 | 1992-11-24 | Genentech, Inc. | Use of relaxin in cardiovascular therapy |
WO1995007931A1 (en) | 1993-09-17 | 1995-03-23 | Novo Nordisk A/S | Acylated insulin |
IL118127A0 (en) | 1995-05-05 | 1996-09-12 | Lilly Co Eli | Single chain insulin with high bioactivity |
MXPA06001283A (es) | 2003-08-05 | 2006-04-11 | Novo Nordisk As | Derivados de insulina novedosos. |
JP5697831B2 (ja) | 2003-12-03 | 2015-04-08 | ノヴォ ノルディスク アー/エス | 単鎖インシュリン |
EP1863840A1 (en) | 2005-03-18 | 2007-12-12 | Novo Nordisk A/S | Pegylated single-chain insulin |
EP1991575A1 (en) | 2006-02-21 | 2008-11-19 | Novo Nordisk A/S | Single-chain insulin analogues and pharmaceutical formulations thereof |
JP2009530243A (ja) | 2006-03-13 | 2009-08-27 | ノボ・ノルデイスク・エー/エス | アシル化単鎖インスリン |
WO2007104734A1 (en) | 2006-03-13 | 2007-09-20 | Novo Nordisk A/S | Acylated single chain insulin |
WO2007104736A2 (en) | 2006-03-13 | 2007-09-20 | Novo Nordisk A/S | Acylated single chain insulin |
EP1996223A1 (en) | 2006-03-13 | 2008-12-03 | Novo Nordisk A/S | Acylated single chain insulin |
US7888913B1 (en) | 2009-09-08 | 2011-02-15 | Intermec Ip Corp. | Smart battery charger |
US20110250215A1 (en) | 2010-04-02 | 2011-10-13 | Athena Discovery, Inc. | Structurally-related relaxin-fusion proteins with extended in vivo half-lives |
WO2011159895A2 (en) | 2010-06-16 | 2011-12-22 | Indiana University Research And Technology Corporation | Single chain insulin agonists exhibiting high activity at the insulin receptor |
MA34521B1 (fr) | 2010-08-17 | 2013-09-02 | Ambrx Inc | Polypeptides de relaxine modifiés et leurs utilisations |
CA2813802C (en) | 2010-09-08 | 2020-06-09 | Howard Florey Institute Of Experimental Physiology And Medicine | Single chain relaxin polypeptides |
JP2014522641A (ja) | 2011-07-01 | 2014-09-08 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | リラキシン融合ポリペプチドおよびその使用 |
MX2014000316A (es) | 2011-07-08 | 2014-02-19 | Bayer Ip Gmbh | Proteinas de fusion liberadoras de relaxina y usos de las mismas. |
US20160152679A1 (en) | 2012-05-24 | 2016-06-02 | Angion Biomedica Corp. | Relaxin-like compounds and uses thereof |
CN103509118B (zh) | 2012-06-15 | 2016-03-23 | 郭怀祖 | 胰岛素-Fc融合蛋白 |
AR091902A1 (es) | 2012-07-25 | 2015-03-11 | Hanmi Pharm Ind Co Ltd | Formulacion liquida de un conjugado de insulina de accion prolongada |
EP2914620B1 (en) | 2012-11-05 | 2018-08-08 | Case Western Reserve University | Long-acting single-chain insulin analogues |
AR094147A1 (es) | 2012-12-27 | 2015-07-15 | Bayer Pharma Aktiengellschaft | Polipeptidos de fusion con actividad de relaxina y sus usos |
JP2016536306A (ja) * | 2013-11-07 | 2016-11-24 | シャンハイ ヘンルイ ファーマスーティカル カンパニー リミテッドShanghai Hengrui Pharmaceutical Co., Ltd. | ヒト・リラキシン類似体、その医薬組成物及びその医薬用途 |
US20160296600A1 (en) | 2013-11-11 | 2016-10-13 | Ascendis Pharma Relaxin Division A/S | Relaxin Prodrugs |
EP3098235A4 (en) | 2014-01-20 | 2017-10-18 | Hanmi Pharm. Co., Ltd. | Long-acting insulin and use thereof |
US10264071B2 (en) | 2014-03-31 | 2019-04-16 | Amazon Technologies, Inc. | Session management in distributed storage systems |
WO2015157829A1 (en) | 2014-04-17 | 2015-10-22 | The Florey Institute Of Neuroscience And Mental Health | Modified relaxin b chain peptides |
KR102569743B1 (ko) | 2014-10-06 | 2023-08-23 | 케이스 웨스턴 리저브 유니버시티 | 이상 단일 사슬 인슐린 유사체 |
MA41794A (fr) | 2015-03-18 | 2018-01-23 | The California Institute For Biomedical Res | Agents thérapeutiques modifiés et compositions associées |
AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
KR20170036643A (ko) | 2015-09-24 | 2017-04-03 | 한미약품 주식회사 | 인슐린의 제조 방법 |
EP3387019B1 (en) * | 2015-12-09 | 2021-10-20 | The Scripps Research Institute | Relaxin immunoglobulin fusion proteins and methods of use |
KR102533456B1 (ko) | 2016-05-18 | 2023-05-17 | 모더나티엑스, 인크. | 릴랙신을 인코딩하는 폴리뉴클레오타이드 |
CN110049997B (zh) * | 2016-12-07 | 2023-09-22 | 埃博灵克斯股份有限公司 | 改进的血清白蛋白结合免疫球蛋白单可变结构域 |
WO2018138170A1 (en) * | 2017-01-25 | 2018-08-02 | Medimmune, Llc | Relaxin fusion polypeptides and uses thereof |
TW201837051A (zh) | 2017-02-08 | 2018-10-16 | 美商必治妥美雅史谷比公司 | 包含藥物動力學增強劑之經修飾之鬆弛素(relaxin)多肽及其用途 |
AR111122A1 (es) | 2017-03-07 | 2019-06-05 | Univ Case Western Reserve | Análogos de insulina de cadena única estabilizados por un cuarto puente disulfuro |
JOP20190273A1 (ar) | 2017-05-26 | 2019-11-24 | Lilly Co Eli | مركب إنسولين معالج بأسيل |
KR20190036956A (ko) | 2017-09-28 | 2019-04-05 | 한미약품 주식회사 | 지속형 단쇄 인슐린 아날로그 및 이의 결합체 |
EP3717508A1 (en) * | 2017-12-01 | 2020-10-07 | The University of Copenhagen | Peptide hormone with one or more o-glycans |
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- 2023-09-27 JP JP2023165484A patent/JP2024009827A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105037542A (zh) * | 2009-10-02 | 2015-11-11 | 贝林格尔.英格海姆国际有限公司 | 用于抗血管生成治疗的双特异性结合分子 |
US20160008483A1 (en) * | 2013-02-26 | 2016-01-14 | Hanmi Pharm. Co., Ltd | Novel insulin analog and use thereof |
WO2017041001A2 (en) * | 2015-09-04 | 2017-03-09 | The California Institute For Biomedical Research | Insulin immunoglobulin fusion proteins |
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