CN108570109B - 包含免疫球蛋白Fc部分的双靶点融合蛋白 - Google Patents
包含免疫球蛋白Fc部分的双靶点融合蛋白 Download PDFInfo
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Abstract
本发明涉及一种融合蛋白,包含免疫球蛋白Fc部分的双靶点融合蛋白,包含第一多肽、第二多肽和第三多肽,其中第一多肽包含GLP‑1或其类似物,第二多肽包含IgG4Fc部分,第三多肽包含FGF21或其变体,第一多肽的通过第一接头与第二多肽相连,第三多肽的通过第二接头与第二多肽相连;该融合蛋白与现有已公开的融合蛋白具有不同的突变位点,具有更好地稳定性和显著延长的半衰期,且在降糖、降脂、降体重等方面发挥了协同效应。
Description
技术领域
本发明涉及一种包含成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)和胰高血糖样素肽-1(Glucagon like peptide-1,GLP-1)的融合蛋白,其包含免疫球蛋白Fc部分,该融合蛋白可用于治疗代谢性疾病。
技术背景
目前治疗糖尿病的药物有三大类,口服小分子药物、胰岛素和GLP-1受体激动剂类药物。小分子药物长期服用副作用明显,且对糖尿病后期的血糖控制不理想。胰岛素需要每天多次(至少一次)注射,且由于个体剂量差异易引发低血糖。单一的GLP-1受体激动剂不属于一线用药,对糖尿病代谢异常导致的心血管等并发症疗效有限。
胰高血糖素样肽-1(Glucagon like peptide-1,GLP-1)是一种由小肠L细胞分泌的肠促胰素,其可以刺激胰岛β细胞分泌胰岛素,从而维持病患体内胰岛素的平衡。天然GLP-1仅能在体外存活2分钟,并不适合作为药物。在过去的几年中,礼来,诺和诺德,GSK等竞相改造该蛋白,以期获得长效GLP-1类降糖药物。目前最为长效的GLP-1类药物,如杜拉鲁肽(dulaglutide)通过使用抗体片段融合至GLP-1蛋白上,可以实现每周一次的用药时长,尽管如此,通过研究发现,杜拉鲁肽的降糖曲线并不平稳,用药后第二天开始血糖便开始不断上升,这种情况对于糖尿病人控制病情并不理想,可能会引发多种并发症。
二型糖尿病有外周胰岛素抵抗、胰岛β细胞的血糖依赖性胰岛素分泌受损两个主要特征。代谢紊乱往往由多种复杂因素导致,因此针对多重代谢通路的治疗将更具潜力。
成纤维细胞生长因子21(FGF21)是近年新发现的一种细胞因子,其本身也能刺激GLUT1受体,促进葡萄糖向细胞内的转运,因此其本身也有希望成为治疗一类糖尿病的药物。然而,FGF21在成药性方面也面临着巨大的问题。这主要是由于FGF21的半衰期很短,在小鼠模型中其半衰期为一小时左右(但最大生物活性可保持六小时以上)。其原因是FGF21在体内会被蛋白酶迅速降解,同时其在体外形成聚集物的倾向也会导致免疫原性,不利于半衰期的延长。
近年来,为了开发FGF21在制药方面的用途,人们在增加FGF21在体内的稳定性方面做出了多种尝试,如在FGF21天然序列的基础上进行不同位点的突变或插入氨基酸或脂肪链或删除部分氨基酸,如,WO 2003011213、WO 2005072769、WO 2005061712、WO2006065582、WO 2010065439、WO2013052311、WO 2013188182、WO 2013033452、WO2005091944、WO 2012066075、WO 2013188181。
发明内容
本发明提供了一种GLP-1与FGF21双靶点融合蛋白,与现有已公开的融合蛋白具有不同的突变位点,发明人惊讶的发现,本发明双靶点融合蛋白具有更好地稳定性和显著延长的半衰期,且在降糖、降脂、降体重等方面发挥了协同效应。
在本发明的一个方面,提供了一种融合蛋白,包含或由以下组成:第一多肽-GLP-1或其类似物、第二多肽-IgG4Fc部分和第三多肽-FGF21或其变体,第一多肽通过第一接头与第二多肽的相连,第三多肽的通过第二接头与第二多肽相连。其中,所述IgG4Fc部分第228位的丝氨酸被脯氨酸替换,且409位的精氨酸被赖氨酸替换。由此增加了该融合蛋白的安全性、稳定性,使该融合蛋白具有显著延长的半衰期。
第一多肽,所述的GLP-1类似物包含在天然GLP-1序列(SEQ ID NO:14)上的1-10个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸替换、缺失或插入,从而延长GLP-1的体内半衰期,并且同时保留或加强GLP-1的生物活性。
在一些实施例中,所述GLP-1类似物包含或由氨基酸序列SEQ ID NO:7(HX1EGTFTSDV SSYLEX2QAAK EFIAWLX3X4GX5X6)组成,其中,X1选自G或V;X2选自E或G;X3选自V或K;X4选自K或N;X5选自G或E;X6选自G或P或缺失。
在另一些实施例中,所述GLP-1类似物包含或由SEQ ID NO:1的氨基酸序列组成。
第二多肽,在一些实施例中,所述IgG4Fc部分还包含选自以下任意一个或多个突变:E233P,F234V或F234A,L235E或L235A,N297A,K447。
在另一些实施例中,所述IgG4Fc部分包含以下任意一个突变组合:
1)S228P及R409K;
2)S228P、E233P以及R409K;
3)S228P、N297A以及R409K;
4)S228P、F234A、L235A以及R409K;
5)S228P、F234V、L235E以及R409K;和
6)S228P、F234A、L235A、R409K以及K447。
又有一些实施例中,所述IgG4Fc部分包含或由SEQ ID NO:2所示的氨基酸序列组成。
第三多肽,所述FGF21变体,包含在天然FGF21序列上的1个或多个氨基酸替换、缺失或插入,从而延长FGF21的体内半衰期,并且同时保留或加强FGF21的生物活性。
在一些实施例中,所述FGF21变体,包含至少一个在170位或171位或172位的氨基酸突变,170位的氨基酸突变选自如下任意一个:G170E,G170A,G170C,G170D,G170N,G170S;171位的氨基酸突变选自如下任意一个:P171A,P171E,P171H,P171Q,P171T,P171Y,P171W,P171C,P171G,P171S,P171T;172位的氨基酸突变选自如下任意一个:S172L,S172I,S172V,S172A,S172M。在一些实施例中,170位的氨基酸突变选自如下任意一个:G170E,G170A,G170D,G170S;171位的氨基酸突变选自如下任意一个:P171A,P171E,P171Q,P171W,P171C,P171G,P171T;172位的氨基酸突变选自如下任意一个:S172L,S172V,S172M。在一些实施例中,170位的氨基酸突变选自如下任意一个:G170E,G170A;171位的氨基酸突变选自如下任意一个:P171A,P171C,P171G;172位的氨基酸突变选自:S172L。
在一些实施例中,所述FGF21变体,还包含一个或多个选自以下位点的突变:45位,98位,100位,118位,134位,150位,151位,152位,167位,175位,179位,180位;在一些实施例中,45位的氨基酸突变选自如下任意一个:A45K,A45R,A45E,A45Q;98位的氨基酸突变选自如下任意一个:L98D,L98R,L98E,L98Q,L98K,L98T;100位的氨基酸突变选自:L100K;118位的氨基酸突变选自:L118C;134位的氨基酸突变选自:A134C;150位的氨基酸突变选自:P150A;151位的氨基酸突变选自:G151A;152位的氨基酸突变选自:I152V;167位的氨基酸突变选自:S167H,S167C,S167R;175位的氨基酸突变选自:R175L,R175H,R175P;179位的氨基酸突变选自如下任意一个:Y179S,Y179A,Y179F;180位的氨基酸突变选自如下任意一个:A180S,A180E,A180G。
在另一些实施例中,所述FGF21变体,还包含一个或多个选自以下位点的突变:45位,98位,100位,167位,175位,179位,180位;在一些实施例中,45位的氨基酸突变选自如下任意一个:A45K,A45R,A45E,A45Q;98位的氨基酸突变选自如下任意一个:L98D,L98R,L98E,L98Q,L98K,L98T;100位的氨基酸突变选自:L100K;167位的氨基酸突变选自:S167H,S167C;175位的氨基酸突变选自:R175L,R175H;179位的氨基酸突变选自如下任意一个:Y179S,Y179A,Y179F;180位的氨基酸突变选自如下任意一个:A180S,A180E,A180G。
在另一些实施例中,所述FGF21变体,还包含一个或多个选自以下位点的突变:45位,98位,167位,175位,179位,180位;在一些实施例中,45位的氨基酸突变选自如下任意一个:A45K,A45R,A45E,A45Q;98位的氨基酸突变选自如下任意一个:L98D,L98R,L98E,L98Q,L98K,L98T;167位的氨基酸突变选自:S167H,S167C;175位的氨基酸突变选自:R175L,R175H;179位的氨基酸突变选自如下任意一个:Y179S,Y179A,Y179F;180位的氨基酸突变选自如下任意一个:A180S,A180E,A180G。
在另一些实施例中,所述FGF21变体,还包含一个或多个选自以下位点的突变:98位,167位,175位,179位;在一些实施例中,98位的氨基酸突变选自如下任意一个:L98D,L98R,L98E,L98K;167位的氨基酸突变选自:S167H,S167C;175位的氨基酸突变选自:R175L,R175H;179位的氨基酸突变选自如下任意一个:Y179S,Y179F。
在另一些实施例中,所述FGF21变体,还包含一个或多个选自以下位点的突变:98位,167位,175位,179位;在一些实施例中,98位的氨基酸突变选自如下任意一个:L98D,L98R;167位的氨基酸突变选自:S167H;175位的氨基酸突变选自:R175L;179位的氨基酸突变选自:Y179F。
在一些实施例中,所述FGF21变体,包含至少第98位和第171位氨基氨位点的突变,其中,98位的氨基酸突变选自如下任意一个:L98D,L98R;170位的氨基酸突变选自如下任意一个P171A,P171G;在一些实施例中,还包含一个或多个选自以下位点的突变:第167位、175位或179位;其中,167位的氨基酸突变选自如下任意一个:S167H,S167C;175位的氨基酸突变选自:R175L,R175H,R175P;179位的氨基酸突变选自如下任意一个:Y179S,Y179F。
在一些实施例中,所述FGF21变体,包含至少第98位和第171位氨基氨位点的突变,其中,98位的氨基酸突变为L98R;170位的氨基酸突变选自如下任意一个P171A,P171G;在一些实施例中还包含一个或多个选自以下位点的突变:第167位、175位或179位;其中,167位的氨基酸突变为S167H;175位的氨基酸突变为R175L;179位的氨基酸突变为Y179F。
在另一些实施例中,所述FGF21变体,包含以下任意一个突变组合:
1)L98R及P171G;
2)L98R及P171A;
3)L98R、P171G以及Y179F;
4)L98R、P171G以及A180E;
5)L98R、G170E、P171A以及S172L;
6)L98R、S167H以及P171A;和
7)L98R、S167H、P171A以及R175L。
在又一些实施例中,所述FGF21变体,还包含:
a)不超过8个氨基酸残基的氨基末端截短;
b)不超过12个氨基酸残基的羧基末端截短;
c)不超过8个氨基酸残基的氨基末端截短和不超过12个氨基酸残基的羧基末端截短;或
d)不超过6个氨基酸残基的羧基末端延长。
本发明中所述第一多肽通过第一接头,第三多肽通过第二接头分别与IgG4Fc部分进行融合,所述第一接头和/或第二接头包含5至50个氨基酸残基的多肽,且所述多肽至少包含50%的G。在一些实施例中,所述第一接头和第二接头分别独立地包含1、2或3个富含G的多肽;在另一些实施例中,所述第一接头和第二接头分别独立地选自GGGGSGGGGS或GGGGSGGGGSGGGGS(SEQ ID NO:13)或GGGGSGGGGSGGGGSA。
在一些实施例中,所述融合蛋白为同源二聚体融合蛋白。
在一些实施例中,所述融合蛋白为非同源二聚体融合蛋白。
在本发明的另一个方面,提供多核苷酸,其编码本发明的融合蛋白。
在本发明的另一个方面,还提供了载体,其包含本发明的多核苷酸。
在本发明的另一个方面,还提供了宿主细胞,其包含本发明的载体。
在本发明的另一个方面,还提供了一种生产根据本发明的融合蛋白的方法,所述方法包括在宿主细胞中表达本发明的载体。
在本发明的另一个方面,还提供了一种组合物(如药物组合物),其包含本发明所述的融合蛋白,以及任选地一种或多种药学上可接受的辅料。所述药学上可接受的辅料包括但不限于药学上可接受的载体、赋形剂、稀释剂、媒介物、以及其他药物制剂需要辅料,或他们任意的组合。
本发明所述的融合蛋白或组合物(如药物组合物)可用于治疗代谢性疾病。所述代谢性疾病可选自糖尿病、肥胖和肝脂肪变性。
在本发明的另一个方面,还提供了本发明的融合蛋白在制备药物中的应用,在一些实施例中,所述药物用于治疗代谢性疾病。例如,所述代谢性疾病可选自糖尿病、肥胖和肝脂肪变性。
在本发明的另一个方面,还提供了一种治疗代谢性疾病的方法,所述方法包括向有需要的受试者施用治疗有效量的本发明所述的融合蛋白或本发明所述的药物组合物。例如,所述代谢性疾病可选自糖尿病、肥胖和肝脂肪变性。
在本发明的另一方面,提供了一种用于治疗代谢性疾病的融合蛋白或药物组合物。所述代谢性疾病可选自糖尿病、肥胖和肝脂肪变性。
本发明提供的上述融合蛋白包含以下优点:能增强融合蛋白的稳定性,避免因二聚体的解离而造成与体内的抗体随意组合的情况,更加安全;具有较长的半衰期,给药周期大于一周,增加药物的顺应性;不会引发ADCC效应或CDC效应。另一方面,本发明提供的包含第一多肽、第二多肽和第三多肽同源二聚体融合蛋白,具有独特的优点:在代谢性疾病方面具有良好的生物活性,第一多肽及第三多肽发挥独特的协同效应,能够实现平稳的降糖效果,同时具备良好的降血脂、降体重等生物活性。
附图说明
图1一个实施例中同源二聚体融合蛋白结构示意图;
图2应用GLP-1R细胞模型检测杜拉鲁肽及D3F1刺激产生cAMP情况。
图3融合蛋白D1F1、D1F2、D6F1以及D7F1微量热差示扫描量热结果。
图4杜拉鲁肽、S1F1以及D1F1在db/db小鼠模型中的降糖药效果。
图5融合蛋白D1F1、D2F1以及D7F1在db/db小鼠模型中的降糖药效果。
图6融合蛋白D3F1、D4F1以及D5F1在db/db小鼠模型中的降糖药效果。
图7杜拉鲁肽、S1F1以及D1F1在db/db小鼠模型中的降总胆固醇效果。
图8杜拉鲁肽、S1F1以及D1F1在db/db小鼠模型中的降甘油三酯效果。
图9融合蛋白D1F2、D2F1以及D7F1在db/db小鼠模型中的降甘油三酯效果。
图10融合蛋白D1F2、D2F1以及D7F1在db/db小鼠模型中的降总胆固醇效果。
图11融合蛋白D1F2、D2F1以及D7F1在db/db小鼠模型中的降高密度脂蛋白效果。
图12融合蛋白D1F2、D2F1以及D7F1在db/db小鼠模型中的降低密度脂蛋白效果。
图13融合蛋白D3F1、D4F1以及D5F1在db/db小鼠模型中的降甘油三酯效果。
图14融合蛋白D3F1、D4F1以及D5F1在db/db小鼠模型中的降总胆固醇效果。
图15融合蛋白D3F1、D4F1以及D5F1在db/db小鼠模型中的降低密度脂蛋白效果。
图16杜拉鲁肽、S1F1以及D1F1在db/db小鼠模型中的降体重效果。
图17杜拉鲁肽以及D5F1在ob/ob小鼠模型中的降糖效果。
图18杜拉鲁肽以及D5F1在ob/ob小鼠模型中禁食16小时后的血糖浓度。
图19杜拉鲁肽以及D5F1在ob/ob小鼠模型中改善肝脂肪病变的效果。
具体实施方式
本发明的其他特点和优越性可通过以下详细的描述体现。但是,应该理解的是,仅以示例性的方式给出详细描述和具体实施例以表明本发明的实施方案,这是因为对于本领域熟练技术人员从所述的详细描述中,在本发明的实质和范围内多种改变和改良是显而易见的。
术语定义
本文所述“天然GLP-1序列”是指通过切除自然存在的GLP-1序列的N端6肽,得到的具有生物活性的天然GLP-1(7-37)序列,所述天然GLP-1序列,即天然的GLP-1(7-37)序列为:HAEGTFTSDVSSYLEGQAAK EFIAWLVKGR G(SEQ ID NO:14)。
本文所述“GLP-1的生物活性”是指GLP-1诱导的多种生物学效应,例如刺激胰岛素分泌、抑制胰高血糖素分泌、抑制胃排空、抑制胃运动或肠运动及诱导重量减轻。GLP-1的显著特征是其刺激胰岛素分泌而不伴有低血糖相关危险的能力。
本文所述“Fc部分”由抗体的铰链区、CH2和CH3恒定区结构组成。抗体包含两个在功能上独立的部分,称为“Fab”的与抗原结合的可变结构域和称为“Fc”的参与效应物功能(例如补体活化和被吞噬细胞攻击)的恒定结构域。Fc具有长的血清半寿期,而Fab是短寿的(Capon等,1989,Nature 337:525-31)。当与治疗蛋白质连接在一起时,Fc结构域可提供较长的半寿期,或者掺入如Fc受体结合、蛋白A结合、补体结合或许甚至胎盘转移的这类功能(Capon等,1989)。这里所使用的术语“Fc”指的是野生型Fc序列来自天然抗体(例如,人类IgG1,IgG2,IgG3或IgG4),还包括他们的变体。变体可能包括已经披露的一个或多个氨基酸替换、添加和/或删除。在一些实施例中,所述Fc变体具备野生型Fc的活性,如与Fc受体的结合。
本文所述IgG4Fc部分的氨基酸编号为根据EU编号系统编号,例如,所述“S228P”是指按EU编号系统编号第228位的丝氨酸被脯氨酸替代;“K447”是指按EU编号系统编号第447位的赖氨酸缺失或不存在。
FGF21野生型序列含有209个氨基酸,具有NCBI参考序列号NP_061986.1,成熟的FGF21序列较FGF21野生型缺少前导序列,其含有181个氨基酸;本文中所述“天然FGF21序列”是指成熟的FGF21序列,具有如下氨基酸序列(SEQ ID NO:15);本文中所述“FGF21变体”是指具有以下FGF21氨基酸序列(SEQ ID NO:15)的突变体多肽,其氨基酸突变位点编号按以下列序列(SEQ ID NO:15)编号顺序编号,所述FGF21变体的氨基酸序列因一个或多个氨基酸而不同于天然FGF21序列氨基酸序列。FGF21变体可通过利用天然或非天然存在的氨基酸在天然FGF21多肽的特定位置进行修饰,所述修饰包含在特定位置插入、替换或删除保守或非保守的一个或多个氨基酸来产生,也包含在特定位置引入非氨基酸结构。
SEQ ID NO:15为:HPIPDSSPLL QFGGQVRQRY LYTDDAQQTE AHLEIREDGT VGGAADQSPESLLQLKALKP GVIQILGVKT SRFLCQRPDG ALYGSLHFDP EACSFRELLL EDGYNVYQSE AHGLPLHLPGNKSPHRDPAP RGPARFLPLP GLPPALPEPP GILAPQPPDV GSSDPLSMVG PSQGRSPSYA S
FGF-21变体可以额外地或备选地包含氨基酸的缺失,其可以是N-端截短、C-端截短或内部缺失或这些的任意组合。包含N-端截短、C-端截短和/或内部缺失的这些变体在本发明的上下文中称作“缺失变体”或“片段”。术语“缺失变体”或“片段”在本文可互换使用。片段可以是天然存在的(例如剪接变体)或其可以人工构建,例如通过基因技术手段。
“保守氨基酸取代”可包括天然氨基酸残基(即存在于野生型FGF21多肽序列给定位置上的残基)被非天然残基(即不存在于野生型FGF21多肽序列给定位置上的残基)取代,使得对该位置上的氨基酸残基的极性或电荷几乎没有或没有影响。保守氨基酸取代还包括通常通过化学上的肽合成而不是通过在生物系统中的合成而掺入的非天然存在的氨基酸残基。这些包括肽模拟物(peptidomimetics)和氨基酸部分的其它反转形式或反向形式。
可根据共同的侧链性质将天然存在的残基分为以下几类:
(1)疏水性:正亮氨酸、M、A、V、L、I;
(2)中性亲水性:C、S、T;
(3)酸性:D、E;
(4)碱性:N、Q、H、K、R;
(5)影响链方向的残基:G、P;和
(6)芳族的:W、Y、F。
保守取代可包括这些类别之一的成员被同一类别的另一个成员交换。
某些保守氨基酸取代的示例见下表:
可供选择的,下表列出保守氨基酸取代示例,0以上代表两个氨基酸为保守氨基酸取代:
C | G | P | S | A | T | D | E | N | Q | H | K | R | V | M | I | L | F | Y | W | |
W | -8 | -7 | -6 | -2 | -6 | -5 | -7 | -7 | -4 | -5 | -3 | -3 | 2 | -6 | -4 | -5 | -2 | 0 | 0 | 17 |
Y | 0 | -5 | -5 | -3 | -3 | -3 | -4 | -4 | -2 | -4 | 0 | -4 | -5 | -2 | -2 | -1 | -1 | 7 | 10 | |
F | -4 | -5 | -5 | -3 | -4 | -3 | -6 | -5 | -4 | -5 | -2 | -5 | -4 | -1 | 0 | 1 | 2 | 9 | ||
L | -6 | -4 | -3 | -3 | -2 | -2 | -4 | -3 | -3 | -2 | -2 | -3 | -3 | 2 | 4 | 2 | 6 | |||
I | -2 | -3 | -2 | -1 | -1 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | 2 | 5 | ||||
M | -5 | -3 | -2 | -2 | -1 | -1 | -3 | -2 | 0 | -1 | -2 | 0 | 0 | 2 | 6 | |||||
V | -2 | -1 | -1 | -1 | 0 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | ||||||
R | -4 | -3 | 0 | 0 | -2 | -1 | -1 | -1 | 0 | 1 | 2 | 3 | 6 | |||||||
K | -5 | -2 | -1 | 0 | -1 | 0 | 0 | 0 | 1 | 1 | 0 | 5 | ||||||||
H | -3 | -2 | 0 | -1 | -1 | -1 | 1 | 1 | 2 | 3 | 6 | |||||||||
Q | -5 | -1 | 0 | -1 | 0 | -1 | 2 | 2 | 1 | 4 | ||||||||||
N | -4 | 0 | -1 | 1 | 0 | 0 | 2 | 1 | 2 | |||||||||||
E | -5 | 0 | -1 | 0 | 0 | 0 | 3 | 4 | ||||||||||||
D | -5 | 1 | -1 | 0 | 0 | 0 | 4 | |||||||||||||
T | -2 | 0 | 0 | 1 | 1 | 3 | ||||||||||||||
A | -2 | 1 | 1 | 1 | 2 | |||||||||||||||
S | 0 | 1 | 1 | 1 | ||||||||||||||||
P | -3 | -1 | 6 | |||||||||||||||||
G | -3 | 5 | ||||||||||||||||||
C | 12 |
当形成本发明的融合蛋白时,可以、但并非必须使用接头或连接子。当接头存在时,接头的化学结构可能不是决定性的,因为它主要起间隔基的作用。接头可由通过肽键连接在一起的氨基酸构成。在本发明的一些实施方案中,接头由通过肽键连接的1-20个氨基酸构成;在另一些实施例中,所述1-20个氨基酸选自20种天然存在的氨基酸。在多个实施方案中,1-20个氨基酸选自氨基酸甘氨酸、丝氨酸、丙氨酸、脯氨酸、天冬酰胺、谷氨酰胺和赖氨酸。在一些实施方案中,接头由空间上不受阻碍的多个氨基酸构成;在另一些实施例中空间不受阻碍的氨基酸为甘氨酸和丙氨酸构成。本发明所述富含G的多肽,可以选自(G)3-S(即“GGGS”)、(G)4-S(即“GGGGS”)和(G)5-S(即“GGGGGS”)。在一些实施方案中,接头包含GGGGSGGGGS、GGGGSGGGGSGGGGS或GGGGSGGGGSGGGGSA。其它合适的接头包括:GGGGGSGGGSGGGGS、GGGKGGGG、GGGNGSGG、GGGCGGGG和GPNGG等。虽然发现对于双靶点融合蛋白,15个氨基酸残基的接头发挥特别好的作用,但是本发明考虑任何长度或组成的接头。
本文所述接头是示例性的,本发明接头可以为长得多的接头以及包含其它残基的接头。本发明接头还可为非肽接头。例如可以使用烷基接头,例如-NH-(CH2)S-C(O)-,其中s=2-20。这些烷基接头可被任何无空间位阻的基团进一步取代,所述无空间位阻的基团包括但不限于低级烷基(例如C1-C6)、低级酰基、卤素(例如Cl、Br)、CN、NH2或苯基。示例性的非肽接头还可以为聚乙二醇接头,其中接头的分子量为100-5000kD,例如100-500kD。
本文所述“一个或多个”氨基酸替换,其中“多个”是指大于1个,例如1~30个、1~20个、1~10个,1~5个,例如,1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个、26个、27个、28个、29个、30个。
本文所述“第一”、“第二”只是为了在描述上进行区分,并没有特殊的含义。
本文所述“ADCC效应”即抗体依赖细胞的细胞毒作用(Antibody-dependentcellular cytotoxicity,ADCC);人IgG各亚类(G1、G2、G3、G4)具有不同的生物活性(称作效应子功能)。这些效应子功能通常由与Fcγ受体(FcγR)的相互作用或通过结合补体1(C1q)亚成分来介导,其中所述的补体1亚成分识别并结合免疫球蛋白G或免疫球蛋白M的重链,启动经典补体途径。与FcγR的结合可以导致抗体依赖细胞介导的细胞裂解,而与补体因子的结合可以导致补体介导的细胞裂解,即补体依赖的细胞毒作用(Complement-dependentcytotoxicity,CDC)。
如本文所用,术语“包含”通常是指包括所述要素,但不排除其他要素。
术语“蛋白质”和“多肽”可互换使用,并且在其最广泛的意义下,是指两个或更多个亚单位氨基酸、氨基酸类似物或肽模拟物的化合物。亚单位可通过肽键连接。在另一实施方案中,亚单位可通过其他键连接,如酯、醚、氨基,等等。蛋白质或多肽必须含有至少两个氨基酸并且对于可构成蛋白质或肽序列的氨基酸的最大数目没有设限。如本文所用的术语“氨基酸”是指天然和/或非天然或合成的氨基酸,包括氨基酸的D和L光学异构体,例如甘氨酸及D和L光学异构体、氨基酸类似物和肽模拟物。
“同源性”或“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。同源性可通过比较各序列中可为比较目的来比对的位置而确定。当所比较序列中的位置被相同的碱基或氨基酸占据时,那么这些分子在那个位置上是同源的。序列之间的同源性程度随着序列共有的匹配或同源位置的数目而变化。“无关”或“非同源的”序列与本公开的序列中之一共有小于40%的同一性,或替代地小于25%的同一性。
本说明书通篇使用关于多肽序列比较的术语“至少80%序列同一性”。该表述通常指与各参考序列至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列同一性。
术语“约”当与数值关联使用时意在包括如下范围内的数值,该范围具有比所示数值小5%的下限并具有比所示数值大5%的上限。
术语“融合蛋白”通常指由两个或更多个蛋白或多肽融合得到的蛋白。编码所述两个或更多个蛋白或多肽的基因或核酸分子可彼此连接而形成融合基因或融合的核酸分子,该融合基因或融合的核酸分子可编码所述融合蛋白。所述融合基因的翻译产生单一多肽,其具有融合前的所述两个或更多个蛋白或多肽中至少一个、甚至每一个的性质。重组融合蛋白通过用于生物学研究或治疗的重组DNA技术人工创造。重组融合蛋白是通过融合基因的遗传工程创造的蛋白质。本发明涉及重组融合蛋白,并且术语融合蛋白和重组融合蛋白在本文以相同含义使用。本文描述的融合蛋白通常包含至少两个结构域(A和C),并且任选地包含第三组分,介于所述两个结构域之间的接头。重组融合蛋白的生成是本领域已知的,并且通常涉及自编码第一蛋白或多肽的cDNA序列去除终止密码子,然后通过连接或重叠延伸PCR以符合读框的方式附接第二蛋白的cDNA序列。该DNA序列然后会由细胞表达成为单一蛋白质。该蛋白质可以经工程化以包括两种原始蛋白质或多肽的完整序列,或仅仅任一的一部分。
除非上下文另外明确规定,否则如在本说明书和权利要求书中所用,单数形式“一”和“所述”包括复数个提及物。例如,术语“药学上可接受的载体”包括多个药学上可接受的载体,包括其混合物。
“组合物”通常是两种或更多种物质的组合,例如,活性剂与其它惰性或活性化合物的组合。
“药物组合物”通常包括活性剂与惰性或活性载体的组合,从而使该组合物适于体内或体外或离体的诊断或治疗用途。
在本发明中,术语“治疗有效量”通常指对受试者产生治疗益处所需的活性成分的最小剂量。例如,对于表现出患有或易感2型糖尿病、肥胖症或代谢综合征的患者或为预防其发病的患者而言,“治疗有效量”是指能够诱导、改进或者造成与上述紊乱相关或因与之对抗所致的病理症状、疾病进展、生理情况改善的剂量。本申请中,术语“受试者”或“患者”可为人,但也可为非人动物,更具体而言可为同伴动物(如狗、猫等)、农场动物(如牛、羊、猪、马等)或者实验室动物(如大鼠、小鼠、豚鼠等)等。
在本发明中,当描述序列中氨基酸残基的取代时,表述“XnY”表示序列中第n位的残基X被残基Y取代。例如,氨基酸取代“R175L”表示,序列中第175位的残基R被残基L取代。
融合蛋白、制备方法及应用
本发明发明人发现目前的双靶点融合蛋白无法完全克服二聚体解离的问题,可能是由于双靶点融合蛋白在Fc的另一端增加了一段约200个氨基酸的长链,在立体结构上发生的相互作用,因此需要IgG4Fc部分结构更加稳定才能防止二聚体的解离。
在发明人大量的创造性劳动的基础上,惊讶的发现当在IgG4的Fc中引入S228P和R409K两个突变时,能使IgG4Fc部分结构的稳定性大大增强。并且,突变后的Fc比起常用的Fc有更低的(或者完全没有)ADCC或者CDC效应。因此,本发明提供了一个稳定性高ADCC/CDC效应低的融合蛋白结构。
在本发明的一方面,本发明提供了一种融合蛋白,包含或由以下组成:
A-L1-B-L2-C或C-L1-B-L2-A,
其中,A为GLP-1受体激动剂,包含SEQ ID NO:1(HGEGTFTSDV SSYLEEQAAKEFIAWLVKGGG)所示氨基酸序列或者与SEQ ID NO:1所示氨基酸序列至少具有约80%同一性,或者与SEQ ID NO:1所示氨基酸序列至少具有约90%同一性,或者与SEQ ID NO:1所示氨基酸序列至少具有约95%同一性,或者与SEQ ID NO:1所示氨基酸序列至少具有约98%同一性,或者与SEQ ID NO:1所示氨基酸序列至少具有约99%同一性;
B为IgG4-Fc突变体,包含SEQ ID NO:2 所示氨基酸序列或者或者与SEQ ID NO:2所示氨基酸序列至少具有约95%同一性,或者与SEQ ID NO:2所示氨基酸序列至少具有约98%同一性,或者与SEQ ID NO:2所示氨基酸序列至少具有约99%同一性,其中,B包含第10个氨基酸残基为P(EU编号对应228)且第191个氨基酸残基为K(EU编号对应409);
C为FGF21,包含SEQ ID NO:6 所示氨基酸序列或者与SEQ ID NO:6所示氨基酸序列至少具有约90%同一性,或者与SEQ ID NO:6所示氨基酸序列至少具有约95%同一性,或者与SEQID NO:6所示氨基酸序列至少具有约98%同一性,或者与SEQ ID NO:6所示氨基酸序列至少具有约99%同一性,且具有FGF21活性的多肽;和
L1和/或L2为包含5至50个氨基酸残基的多肽,且所述多肽至少包含50%的G。
在一些实施例中,A包含或由氨基酸序列SEQ ID NO:7组成,(HX1EGTFTSDVSSYLEX2QAAKEFIAWLX3X4GX5X6)(SEQ ID NO:7),
其中,X1选自G或V;
X2选自E或G;
X3选自V或K;
X4选自K或N;
X5选自G或E;和
X6选自G或P或缺失。
在另一些实施例中,所述A,包含或由SEQ ID NO:1的氨基酸序列组成。
在一些实施例中,所述B,包含或由氨基酸序列SEQ ID NO:8组成,
ESKYGPPCPP CPAPX7X8X9GGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWYVDGVEVHNAK TKPREEQFX10S TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQVYTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQEGNVFSCSVM HEALHNHYTQ KSLSLSLGX11(SEQ ID NO:8)
其中,X7选自P或E;
X8选自F、V或A;
X9选自L、E或A;
X10选自N或A;和
X11选自K或不存在。
在另一些实施例中,所述B,包含或由SEQ ID NO:2所示的氨基酸序列组成。
在一些实施例中,所述C,包含或由氨基酸序列SEQ ID NO:9组成,
其中,
X12选自A、K、R、E或Q;
X13选自L、D、R、E、Q、K或T;
X14选自L或K;
X15选自L或C;
X16选自A或C;
X17选自P或A;
X18选自G或A;
X19选自I或V;
X20选自S、H、C或R;
X21选自G、E、A、D或S;
X22选自P、A、E、Q、W、C、G或T;
X23选自S、L、V或M;
X24选自R、L、H或P;
X25选自Y、S、A或F;和
X26选自A、S、E或G。
在另一些实施例中,所述C,还包含:
a)不超过8个氨基酸残基的氨基末端截短;
b)不超过12个氨基酸残基的羧基末端截短;
c)不超过8个氨基酸残基的氨基末端截短和不超过12个氨基酸残基的羧基末端截短;或
d)不超过6个氨基酸残基的氨基酸羧基末端延长。
在一些实施例中,所述L1和/或L2包含1、2或3个富含G的多肽,在一些实施例中,L1和/或L2选自GGGGSGGGGS或GGGGSGGGGSGGGGS(SEQ ID NO:13)或GGGGSGGGGSGGGGSA。
在一些实施例中,所述融合蛋白为同源二聚体。
在另一些实施例中,所述融合蛋白为非同源二聚体。
由于FGF21天然分子存在易被蛋白酶水解的位点,其在体内的半衰期非常短,由于FGF21的立体结构尚未破解,科研工作者们通过各种尝试对其结构进行改造,以期待获得更长的半衰期。这些尝试包括在天然氨基酸序列的基础上进行氨基酸序列的截短、延长、替换、插入或删除某些氨基酸,一些科研工作者甚至对各个位点进行逐一突变,以期待找到影响活性和半衰期的关键核心的位点。
本发明提供了一种GLP-1与FGF21的双靶点融合蛋白,具有与现有已公开的融合蛋白不同的突变位点,发明人意外地发现,本发明提供的融合蛋白具有较长的半衰期,给药频率可以达一周以上,更为可喜的是,该融合蛋白能够发挥协同作用,具有显著的平稳的降糖作用,同时具有良好的降脂、降体重等生物活性。
在本发明的另一个方面,提供了一种同源二聚体融合蛋白,其包含或由以下组成:
A-L1-B-L2-C,
其中,A为GLP-1受体激动剂,包含SEQ ID NO:10(HX1EGTFTSDV SSYLEX2QAAKEFIAWLVKGX5G)所示氨基酸序列,其中,X1选自G或V;X2选自E或G;和X5选自G或E。
其中,X13选自L、D、R、E;
X20选自S、H或C;
X22选自A或G;
X24选自R、L或P;和
X25位的氨基酸突变选自如下任意一个:Y、S、F。
L1和/或L2为包含5至50个氨基酸残基的多肽,且所述多肽至少包含50%的G。
在一些实施例中,所述A,包含或由SEQ ID NO:1所示的氨基酸序列组成。
在一些实施例中,所述B,包含或由SEQ ID NO:2所示的氨基酸序列组成。
在一些实施例中,所述同源二聚体融合蛋白包含或由SEQ ID NO:5、17、18、19、20、21所示的氨基酸序列组成。
在本发明的另一个方面,提供多核苷酸,其编码本发明的融合蛋白。编码上述蛋白质的多核苷酸可以是RNA的形式,或者DNA的形式,所述DNA包括cDNA和合成的DNA。DNA可以是双链或单链的。编码本发明的蛋白质的编码序列可以由于遗传密码的冗余或简并性的结果而不同。编码本发明蛋白的多核苷酸可以包含如下:仅仅蛋白的编码序列,蛋白的编码序列和其他的编码序列,如引导序列或分泌序列或前蛋白序列;蛋白的编码序列和非编码序列,如内含子或蛋白的编码序列的5’和/或3’非编码序列。因此,术语“编码蛋白的多核苷酸”涵盖这样的多核苷酸,所述多核苷酸可不仅仅包括蛋白的编码序列,还包括包括其他的编码序列和/或非编码序列的多核苷酸。
在本发明的另一个方面,还提供了载体,其包含根据本发明的多核苷酸。表达载体通常作为附加体或作为宿主染色体DNA的整体部分在宿主生物体中复制。一般地,表达载体含有选择标记物,例如,四环素、新霉素和二氢叶酸还原酶,以允许检测被期望的DNA序列转化的那些细胞。
在本发明的另一个方面,还提供了宿主细胞,其包含根据本发明的载体。本发明的双靶点蛋白可以容易地在如下细胞中生产:在哺乳动物细胞中如CHO、NS0、HEK293或COS细胞;在细菌细胞中如大肠杆菌、枯草芽孢杆菌(Bacillus subtilis)、荧光假单胞菌(Pseudomonas fluorescence);或在真菌或酵母细胞中。使用本领域已知的技术培养宿主细胞。例如HEK293。
在本发明的另一个方面,还提供了一种生产根据本发明的融合蛋白的方法,所述方法包括在宿主细胞中表达根据本发明的载体。可以通过熟知的方法将含有目的多核苷酸序列(例如双靶点融合蛋白和表达调控序列)的载体转移至宿主细胞中,这样的方法取决于宿主细胞的类型而不同。例如,氯化钙转化通常用于原核细胞,而磷酸钙处理或电穿孔可用于其他宿主细胞。
在本发明的另一个方面,还提供了本发明的融合蛋白在制备药物组合物中的应用,所述药物组合物其包含本发明融合蛋白、和至少一种可药用的载体、稀释级或赋形剂。在一些实施例中,所述药物用于治疗代谢性疾病。在一些实施例中,所述代谢性疾病是糖尿病,例如2型糖尿病。在另一些实施例中,所述代谢性疾病是肥胖症。其他实施方案包括代谢病况或代谢紊乱,例如血脂异常、高血压、肝脂肪变性,例如非酒精性脂肪肝(NASH)、心血管疾病,例如动脉粥样硬化、以及老化。
实施例
通过下列实施例进一步理解本公开,这些实施例仅为本公开的示例。本公开在范围上不受限于所例示的实施方案,所述实施方案仅旨在说明本发明的单一方面。任何在作用上等价的方法都包括在本发明范围之内。根据上文的描述和附图,除本文所述之外的对本发明的各种修改对于本领域的技术人员是显而易见的。这些修改也在附属权利要求范围之内。
实施例1:载体的构建
采用分子克隆的方法,构建了融合蛋白的载体,所述融合蛋白见表1。
表1
编码杜拉鲁肽以及S1F1融合蛋白的核苷酸序列是委托金斯瑞生物科技有限公司通过化学合成获得的,编码D1F1融合蛋白的载体则通过设计引物PCR模板杜拉鲁肽及S1F1融合蛋白合成的序列,得到片段GLP-1及Fc-FGF21,通过SOE-PCR技术进行片段连接得GLP-1-Fc-FGF21,为编码D1F1突变体融合蛋白的核苷酸序列。
编码D1F2、D2F1、D3F1、D4F1、D5F1、D6F1以及D7F1融合蛋白的核苷酸序列是委托苏州金唯智生物科技有限公司通过化学合成获得。
在37℃条件下,利用内切酶HindⅢ和EcoRⅠ(TAKARA,Japan)消化处理核苷酸序列和载体质粒pcDNA3.4,采用Gel Extraction Kit试剂盒(OMEGA,America)按厂商说明纯化回收消化产物。利用DNALigation Kit Ver.2.1(TAKARA,Japan)按厂商说明将纯化回收的目的基因和载体连接,16℃恒温处理1小时,得到重组表达质粒。
将上述重组表达质粒转化到感受态细胞DH5a中,取菌体涂布氨苄平板。挑取平板上的单克隆于1ml LB培养基(蛋白胨10g/L,酵母膏5g/L,氯化钠10g/L和琼脂2%,抗生素含量100μg/mL)中培养后提取质粒,经测序验证正确后,采用Invitrogen质粒大提试剂盒提取一系列经验证正确的表达载体,用限制性内切酶PvuⅠ(TAKARA,Japan)酶切,进行线性化后利用乙醇沉淀方法纯化回收,-20℃保藏备用。
实施例2:编码杜拉鲁肽载体转染及在细胞中表达
将CHOK1SV GS-KO(Lonza)宿主细胞用CD CHO培养基(gibco)复苏培养后,当细胞密度约8x 105cell/mL时收集细胞进行转染。转染细胞约1x107cell,载体约40μg,通过电击方法转染(Bio-Rad,Gene pulSXcell)。电击后细胞于20mL CD CHO培养基中培养。培养第二天,在200g下离心10min收集细胞,并在加入MSX(sigma)至终浓度50μM的20mL CD CHO培养基中重悬培养。当细胞密度约0.6x106cell/mL时,对获得的混合克隆株用CD CHO培养基进行传代,传代细胞密度约0.2x106cell/mL。当细胞存活率约90%时,收集细胞培养液。
实施例3:编码S1F1及D1F1、D1F2、D2F1、D3F1、D4F1、D5F1、D6F1、D7F1融合蛋白载体转染并在细胞中表达
将HEK293F宿主细胞(Invitrogen,Freestyle 293F)用293Expression Medium培养基(Invitrogen)复苏培养后,当细胞密度约1x106cell/mL时收集细胞进行转染。转染细胞约3x107cell,载体约37.5μg,采用FreeStyleTMMAX Reagent转染试剂盒进行。转染后细胞于30mL的293Expression Medium培养基中培养。培养第二天,开始使用遗传霉素(merck)对转化子进行筛选,根据细胞生长情况,每3~5天更换一次筛选培养基,筛选约14天后,可见有抗性的克隆出现,可进行扩大培养。细胞传代密度约0.5x106cell/mL,对获得的混合克隆株用293Expression Medium培养基进行传代培养。当细胞存活率约90%时,收集细胞培养液。
实施例4:收集细胞发酵培养液纯化融合蛋白
对实施例2、3中的8个融合蛋白进行翻译水平上的检测。采用Protein A层析柱(EzFast Protein ADiamond,博格隆)对收集的细胞培养液进行纯化,平衡液为20mM PBS,0.15M NaCl,pH7.4,关于融合蛋白杜拉鲁肽及S1F1使用洗脱液为0.1M柠檬酸缓冲液pH3.2±0.2,关于D1F1、D1F2、D2F1、D3F1、D4F1、D5F1、D6F1、D7F1融合蛋白使用洗脱液为0.1M甘氨酸Ph3.2±0.2,收集目标吸收峰下蛋白洗脱液,用PBS缓冲液透析后取部分样品进行质谱检测,质谱(Accurate-Mass Q-TOF LC/MS,型号G6530,AgilentTechnologies)检测分子量,与理论分子量一致,且为同源二聚体形式,融合蛋白经确认均为目标融合蛋白;同时对收集的样品经还原与非还原后通过10%SDS-PAGE电泳检测,电泳图谱显示单一条带,条带大小与理论一致。
实施例5:应用HEK293/GLP-1R/KLB细胞模型检测融合蛋白刺激产生cAMP情况
通过受试融合蛋白刺激表达有GLP-1R/KLB的HEK293细胞,产生cAMP,利用cAMP检测试剂盒(Cisbio 62AM6PEC)以检测融合蛋白浓度和刺激产生的cAMP量建立量效曲线,衡量受试化合物的体外活性。受试融合蛋白共2组,包括杜拉鲁肽组、D3F1组。cAMP检测结果见图2和表2。
表2
受试蛋白 | 杜拉鲁肽 | D3F1 |
EC50 | 0.2683 | 0.01984 |
氨基酸序列 | SEQ ID NO:3 | SEQ ID NO:18 |
实施例6:微量热差示扫描量热法(DSC)考察Fc409位由R突变为K对融合蛋白稳定性影响
将实施例4得到的融合蛋白D1F1、D1F2、D6F1、D7F1,用空白缓冲体系(20mM PBSpH7.4)将蛋白溶度稀释为1mg/ml,取为500μL进行DSC(Microcal vp-Capillary DSC,上海思百吉仪器系统)分析。扫描温度从20℃至100℃,升温速率为1℃/min。微量热差示扫描量热结果,如图3,用OriginTM拟合后得到的Tm值见表3。
表3
相变温度Tm越高,分子稳定性越强。由以上结果可以看出,样品D7F1、D6F1及D1F1的Tm1及Tm2值基本一致,说明3个蛋白的稳定性较一致,而D1F2其Tm1值与其他三个样品基本一致,但其Tm2明显远低于其他样品的Tm2值。由样品D1F1及D1F2蛋白结构分析看,主要不同在于IgG4Fc的CH3结构域409位氨基酸的R突变为K,409位的K突变造成D1F1的Tm2明显高于D1F2的Tm2值。表明D1F1中IgG4Fc的CH3结构域409位进行的R突变为K,提高了结构域的Tm值,从而提高了其蛋白的稳定性。
实施例7:考察Fc409位由R突变为K对融合蛋白降糖效果的影响
融合蛋白在db/db小鼠模型(南京大学模式动物研究所)中的药效研究,小鼠随机分成3组,包括空白组、D1F1组、D1F2组,按每只db/db小鼠注射24.5nM/kg的融合蛋白进行计算给药,给药体积为10ml/kg,每个融合蛋白注射7只小鼠,给药一次,测定不同时间血糖浓度,结果见表4。结果可见,IgG4Fc第409位突变为K后,降糖作用能维持的更久。
表4
实施例8:杜拉鲁肽、S1F1、D1F1在db/db小鼠模型中的降糖药效果研究
融合蛋白在db/db小鼠模型(南京大学模式动物研究所)中的药效研究,实验过程为对纯化的一系列融合蛋白用10mM的PBS稀释,小鼠随机分成4组,包括空白组、杜拉鲁肽组、S1F1组、D1F1组,按每只db/db小鼠注射40nM/kg的融合蛋白进行计算给药,给药体积为3ml/kg,每个融合蛋白注射10只小鼠,每周给药一次,给药两周。给药后取样检测血糖变化情况见图4。D1F1组较杜拉鲁肽组和S1F1组,具有明显的降糖优势,且降糖曲线更加平稳。
实施例9:D1F1、D2F1、D7F1在db/db小鼠模型中的降糖药效果研究
融合蛋白在db/db小鼠模型(南京大学模式动物研究所)中的药效研究,小鼠随机分成4组,包括空白组(10mM的PBS)、D1F1组、D2F1组、D7F1组,按每只db/db小鼠注射24.5nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为10ml/kg,每个融合蛋白注射7只小鼠,给药一次,测定不同时间血糖浓度,结果见图5。结果显示D1F1组与D2F1组较D7F1组有更好的降糖效果。
实施例10:D3F1、D4F1、D5F1在db/db小鼠模型中的降糖药效果研究
融合蛋白在db/db小鼠模型(南京大学模式动物研究所)中的药效研究,实验过程为对纯化的一系列融合蛋白用10mM的PBS稀释,小鼠随机分成4组,包括空白组(10mM的PBS)、D3F1组、D4F1组、D5F1组,按每只db/db小鼠注射30nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为10ml/kg,每个融合蛋白注射9只小鼠,每周给药一次,给药两周。给药后取样检测血糖变化情况见图6。D3F1、D4F1及D5F1均能实现较好的降糖效果。
实施例11:杜拉鲁肽、S1F1、D1F1在db/db小鼠模型中的降脂药效研究
db/db模型小鼠(南京大学模式动物研究所)随机分成4组,包括空白组(10mM的PBS)、杜拉鲁肽组、S1F1组、D1F1组,按每只db/db小鼠注射40nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为3ml/kg,每个融合蛋白注射10只小鼠,每周给药一次,给药两周。初次给药第14天后处死小鼠,检测其血液总胆固醇(TCHO)(见图7)及甘油三酯(TG)含量(见图8)。D1F1组将总胆固醇及甘油三酯的能力高于S1F1组和杜拉鲁肽组。
实施例12:D1F2、D2F1、D7F1在db/db小鼠模型中的降脂药效研究
db/db模型小鼠随(南京大学模式动物研究所)机分成4组,包括空白组(10mM的PBS)、D1F2组、D2F1组、D7F1组,按每只db/db小鼠注射24.5nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为10ml/kg,每个融合蛋白注射7只小鼠,单次给药14天后,检测血清甘油三酯(TG)结果见图9、总胆固醇(TC)结果见图10、高密度脂蛋白(HDL-C)结果见图11、低密度脂蛋白(LDL-C),结果见图12。与FGF21为天然FGF21序列的D7F1相比,D1F2组及D2F1组在降甘油三酯方面表现出更强的能力,与IgG4Fc第409位未突变为K的D1F2相比,D2F1组显示出更强的降甘油三酯、降总胆固醇的能力。
实施例13:D3F1、D4F1、D5F1在db/db小鼠模型中的降脂药效研究
db/db模型小鼠(南京大学模式动物研究所)随机分成4组,包括空白组(10mM的PBS)、D3F1组、D4F1组、D5F1组,按每只db/db小鼠注射30nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为10ml/kg,每个融合蛋白注射9只小鼠,每周给药一次,给药两周。初次给药14天后,检测血清甘油三酯(TG)结果见图13、总胆固醇(TCHO)结果见图14、低密度脂蛋白(LDL-C),结果见图15。
实施例14:杜拉鲁肽、S1F1、D1F1在db/db小鼠模型中的降体重药效研究
db/db模型小鼠(南京大学模式动物研究所)随机分成4组,包括空白组(10mM的PBS)、杜拉鲁肽组、S1F1组、D1F1组,按每只db/db小鼠注射40nM/kg的融合蛋白(用10mM的PBS稀释)进行计算给药,给药体积为3ml/kg,每个融合蛋白注射10只小鼠,每周给药一次,给药两周。给药后每天记录体重,结果见图16。
实施例15:杜拉鲁肽、D1F1药代动力学研究
雄性ICR小鼠(湖南斯莱克)分成2组,每组3只,分别皮下注射10nmol/kg杜拉鲁肽或10nmol/kgD1F1(用10mM的PBS稀释),分别于给药前、给药后1、5、7、24、48、96、144、192、240、288h通过眼眶后静脉丛采集静脉血,以抗GLP-1抗体(Bioporto,CAT.NO.ABS 033-10)作为捕获抗体,用抗人IgG Fc抗体(Southern Biotech,CAT.NO.9200-05)为检测抗体,通过ELISA方法测定药代动力学参数,结果见表5。
表5
D1F1组融合蛋白平均血浆暴露量(AUClast)及Cmax明显高于杜拉鲁肽,表明融合FGF21后,可以增加融合蛋白的吸收,MRTlast表示的是药物分子在体内的平均滞留时间,D1F1与杜拉鲁肽在小鼠体内的滞留时间相当。
实施例16:杜拉鲁肽、D5F1在ob/ob小鼠模型中的药效研究
ob/ob小鼠(南京大学模式动物研究所)随机分成4组,包括空白组(10mM的PBS)、D5F1 10nmol/kg组、D5F1 20nmol/kg组、杜拉鲁肽20nmol/kg组,给药体积为10ml/kg,每个融合蛋白注射9只小鼠,每周给药两次,连续给药3周。每次给药前取样检测血糖变化情况结果见图17,与杜拉鲁肽相比,D5F1组具有更好的降糖效果,且降糖曲线更加平稳;最后一次给药后进食16小时第二天眼眶采血,收集血清,监测血清葡萄糖(结果见图18)、并解剖称取肝重(结果见图19)。根据肝重的结果,D5F1组对于改善肝脂肪性病变具有更好的改善作用。
SEQUENCE LISTING
<110> 广东东阳光药业有限公司
<120> 包含免疫球蛋白Fc部分的双靶点融合蛋白
<130> 2017
<160> 31
<170> PatentIn version 3.5
<210> 1
<211> 31
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His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
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Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
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<210> 2
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<212> PRT
<213> 人工序列
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Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala
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Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
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Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
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Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
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Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
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Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
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Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly
225
<210> 3
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<212> PRT
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His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
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Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
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Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
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Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
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Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
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Ser Leu Gly
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Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala
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Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
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Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
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Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
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Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
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Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
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Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
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Leu Ser Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
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Gly Gly Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly
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Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr
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Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala
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Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly
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Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg
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Gly Arg Ser Pro Ser Tyr Ala Ser
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His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
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Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
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Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
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Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
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His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
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Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
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Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
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His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
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Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
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Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
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His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
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<213> 人工序列
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Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
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180 185 190
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Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Xaa
225
<210> 9
<211> 181
<212> PRT
<213> 人工序列
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<221> misc_feature
<222> (45)..(45)
<223> 45位的Xaa 选自Ala、Lys、Arg、Glu或Gln
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<222> (98)..(98)
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<221> misc_feature
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<221> misc_feature
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<221> misc_feature
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His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Xaa Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Xaa Leu Xaa Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Xaa Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Xaa Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Xaa Xaa Xaa Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Xaa Met Val Xaa Xaa Xaa Gln Gly Xaa Ser
165 170 175
Pro Ser Xaa Xaa Ser
180
<210> 10
<211> 31
<212> PRT
<213> 人工序列
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<221> misc_feature
<222> (2)..(2)
<223> 2位的Xaa 为Gly或Val
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<221> misc_feature
<222> (16)..(16)
<223> 16位的Xaa 为Glu或Gly
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<221> misc_feature
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His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Xaa
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Xaa Gly
20 25 30
<210> 11
<211> 229
<212> PRT
<213> 人工序列
<220>
<221> misc_feature
<222> (16)..(17)
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<220>
<221> misc_feature
<222> (229)..(229)
<223> 229位的Xaa 为Lys或不存在
<400> 11
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Xaa
1 5 10 15
Xaa Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Xaa
225
<210> 12
<211> 181
<212> PRT
<213> 人工序列
<220>
<221> misc_feature
<222> (98)..(98)
<223> 98位的Xaa 选自Leu、Asp、Arg或Glu
<220>
<221> misc_feature
<222> (167)..(167)
<223> 167位的Xaa 选自Ser、His、Cys或Arg
<220>
<221> misc_feature
<222> (171)..(171)
<223> 171位的Xaa 选自Ala或Gly
<220>
<221> misc_feature
<222> (175)..(175)
<223> 175位的Xaa 选自Arg、Leu或Pro
<220>
<221> misc_feature
<222> (179)..(179)
<223> 179位的Xaa 选自Tyr、Ser或Phe
<400> 12
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Val Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Xaa Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Xaa Met Val Gly Xaa Ser Gln Gly Xaa Ser
165 170 175
Pro Ser Xaa Ala Ser
180
<210> 13
<211> 15
<212> PRT
<213> 人工序列
<400> 13
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 14
<211> 31
<212> PRT
<213> 人工序列
<400> 14
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 15
<211> 181
<212> PRT
<213> 人工序列
<400> 15
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 16
<211> 470
<212> PRT
<213> 人工序列
<400> 16
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Gly Ser Gln Gly Arg
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 17
<211> 470
<212> PRT
<213> 人工序列
<400> 17
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Gly Ser Gln Gly Arg
450 455 460
Ser Pro Ser Phe Ala Ser
465 470
<210> 18
<211> 470
<212> PRT
<213> 人工序列
<400> 18
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Ala Ser Gln Gly Arg
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 19
<211> 470
<212> PRT
<213> 人工序列
<400> 19
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu His Met Val Gly Ala Ser Gln Gly Arg
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 20
<211> 470
<212> PRT
<213> 人工序列
<400> 20
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu His Met Val Gly Ala Ser Gln Gly Leu
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 21
<211> 470
<212> PRT
<213> 人工序列
<400> 21
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu Ser Met Val Glu Ala Leu Gln Gly Arg
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 22
<211> 470
<212> PRT
<213> 人工序列
<400> 22
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln
290 295 300
Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala
305 310 315 320
His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln
325 330 335
Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile
340 345 350
Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
355 360 365
Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe
370 375 380
Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala
385 390 395 400
His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp
405 410 415
Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
420 425 430
Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp
435 440 445
Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg
450 455 460
Ser Pro Ser Tyr Ala Ser
465 470
<210> 23
<211> 1272
<212> DNA
<213> 人工序列
<220>
<223> DNA-S1F1
<400> 23
gagtctaagt acggccctcc ctgccctcct tgtcctgctc ctgaagctgc tggcggccct 60
tccgtgttcc tgttcccccc aaagcccaag gacaccctga tgatctcccg gacccccgaa 120
gtgacctgcg tggtggtgga tgtgtcccag gaagatcccg aggtgcagtt caattggtac 180
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttcaactcc 240
acctaccggg tggtgtccgt gctgacagtg ctgcaccagg actggctgaa cggcaaagag 300
tacaagtgca aggtgtccaa caagggcctg cccagctcca tcgaaaagac catctccaag 360
gccaagggcc agccccggga accccaggtg tacacactgc ctccaagcca ggaagagatg 420
accaagaacc aggtgtccct gacctgtctc gtgaaaggct tctacccctc cgatatcgcc 480
gtggaatggg agtccaacgg ccagcctgag aacaactaca agaccacccc ccctgtgctg 540
gactccgacg gctccttctt cctgtactcc aagctgaccg tggacaagtc cagatggcag 600
gaaggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 660
aagtccctgt ccctgtctct gggaggcggc ggaggatctg gcggaggtgg aagcggaggc 720
ggtggatctc accccatccc cgacagcagc cccctgctgc agttcggcgg ccaggtgagg 780
cagaggtacc tgtacaccga cgacgcccag cagaccgagg cccacctgga gatcagggag 840
gacggcaccg tgggcggcgc cgccgaccag agccccgaga gcctgctgca gctgaaggcc 900
ctgaagcccg gcgtgatcca gatcctgggc gtgaagacca gcaggttcct gtgccagagg 960
cccgacggcg ccctgtacgg cagcctgcac ttcgaccccg aggcctgcag cttcagggag 1020
aggctgctgg aggacggcta caacgtgtac cagagcgagg cccacggcct gcccctgcac 1080
ctgcccggca acaagagccc ccacagggac cccgccccca ggggccccgc caggttcctg 1140
cccctgcccg gcctgccccc cgccctgccc gagccccccg gcatcctggc cccccagccc 1200
cccgacgtgg gcagcagcga ccccctgagc atggtgggag gatcccaggg caggagcccc 1260
agctacgcca gc 1272
<210> 24
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D1F1
<400> 24
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gtctaagtac ggccctccct gccctccttg tcctgctcct 180
gaagctgctg gcggcccttc cgtgttcctg ttccccccaa agcccaagga caccctgatg 240
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccagga agatcccgag 300
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 360
gaggaacagt tcaactccac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 420
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc cagctccatc 480
gaaaagacca tctccaaggc caagggccag ccccgggaac cccaggtgta cacactgcct 540
ccaagccagg aagagatgac caagaaccag gtgtccctga cctgtctcgt gaaaggcttc 600
tacccctccg atatcgccgt ggaatgggag tccaacggcc agcctgagaa caactacaag 660
accacccccc ctgtgctgga ctccgacggc tccttcttcc tgtactccaa gctgaccgtg 720
gacaagtcca gatggcagga aggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 780
cacaaccact acacccagaa gtccctgtcc ctgtctctgg gaggcggcgg aggatctggc 840
ggaggtggaa gcggaggcgg tggatctcac cccatccccg acagcagccc cctgctgcag 900
ttcggcggcc aggtgaggca gaggtacctg tacaccgacg acgcccagca gaccgaggcc 960
cacctggaga tcagggagga cggcaccgtg ggcggcgccg ccgaccagag ccccgagagc 1020
ctgctgcagc tgaaggccct gaagcccggc gtgatccaga tcctgggcgt gaagaccagc 1080
aggttcctgt gccagaggcc cgacggcgcc ctgtacggca gcctgcactt cgaccccgag 1140
gcctgcagct tcagggagag gctgctggag gacggctaca acgtgtacca gagcgaggcc 1200
cacggcctgc ccctgcacct gcccggcaac aagagccccc acagggaccc cgcccccagg 1260
ggccccgcca ggttcctgcc cctgcccggc ctgccccccg ccctgcccga gccccccggc 1320
atcctggccc cccagccccc cgacgtgggc agcagcgacc ccctgagcat ggtgggagga 1380
tcccagggca ggagccccag ctacgccagc 1410
<210> 25
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D1F2
<400> 25
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gtctaagtac ggccctccct gccctccttg tcctgctcct 180
gaagctgctg gcggcccttc cgtgttcctg ttccccccaa agcccaagga caccctgatg 240
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccagga agatcccgag 300
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 360
gaggaacagt tcaactccac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 420
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc cagctccatc 480
gaaaagacca tctccaaggc caagggccag ccccgggaac cccaggtgta cacactgcct 540
ccaagccagg aagagatgac caagaaccag gtgtccctga cctgtctcgt gaaaggcttc 600
tacccctccg atatcgccgt ggaatgggag tccaacggcc agcctgagaa caactacaag 660
accacccccc ctgtgctgga ctccgacggc tccttcttcc tgtactccag gctgaccgtg 720
gacaagtcca gatggcagga aggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 780
cacaaccact acacccagaa gtccctgtcc ctgtctctgg gaggcggcgg aggatctggc 840
ggaggtggaa gcggaggcgg tggatctcac cccatccccg acagcagccc cctgctgcag 900
ttcggcggcc aggtgaggca gaggtacctg tacaccgacg acgcccagca gaccgaggcc 960
cacctggaga tcagggagga cggcaccgtg ggcggcgccg ccgaccagag ccccgagagc 1020
ctgctgcagc tgaaggccct gaagcccggc gtgatccaga tcctgggcgt gaagaccagc 1080
aggttcctgt gccagaggcc cgacggcgcc ctgtacggca gcctgcactt cgaccccgag 1140
gcctgcagct tcagggagag gctgctggag gacggctaca acgtgtacca gagcgaggcc 1200
cacggcctgc ccctgcacct gcccggcaac aagagccccc acagggaccc cgcccccagg 1260
ggccccgcca ggttcctgcc cctgcccggc ctgccccccg ccctgcccga gccccccggc 1320
atcctggccc cccagccccc cgacgtgggc agcagcgacc ccctgagcat ggtgggagga 1380
tcccagggca ggagccccag ctacgccagc 1410
<210> 26
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D2F1
<400> 26
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gtctaagtac ggccctccct gccctccttg tcctgctcct 180
gaagctgctg gcggcccttc cgtgttcctg ttccccccaa agcccaagga caccctgatg 240
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccagga agatcccgag 300
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 360
gaggaacagt tcaactccac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 420
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc cagctccatc 480
gaaaagacca tctccaaggc caagggccag ccccgggaac cccaggtgta cacactgcct 540
ccaagccagg aagagatgac caagaaccag gtgtccctga cctgtctcgt gaaaggcttc 600
tacccctccg atatcgccgt ggaatgggag tccaacggcc agcctgagaa caactacaag 660
accacccccc ctgtgctgga ctccgacggc tccttcttcc tgtactccaa gctgaccgtg 720
gacaagtcca gatggcagga aggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 780
cacaaccact acacccagaa gtccctgtcc ctgtctctgg gaggcggcgg aggatctggc 840
ggaggtggaa gcggaggcgg tggatctcac cccatccccg acagcagccc cctgctgcag 900
ttcggcggcc aggtgaggca gaggtacctg tacaccgacg acgcccagca gaccgaggcc 960
cacctggaga tcagggagga cggcaccgtg ggcggcgccg ccgaccagag ccccgagagc 1020
ctgctgcagc tgaaggccct gaagcccggc gtgatccaga tcctgggcgt gaagaccagc 1080
aggttcctgt gccagaggcc cgacggcgcc ctgtacggca gcctgcactt cgaccccgag 1140
gcctgcagct tcagggagag gctgctggag gacggctaca acgtgtacca gagcgaggcc 1200
cacggcctgc ccctgcacct gcccggcaac aagagccccc acagggaccc cgcccccagg 1260
ggccccgcca ggttcctgcc cctgcccggc ctgccccccg ccctgcccga gccccccggc 1320
atcctggccc cccagccccc cgacgtgggc agcagcgacc ccctgagcat ggtgggagga 1380
tcccagggca ggagccccag cttcgccagc 1410
<210> 27
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D3F1
<400> 27
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gagcaagtac ggccccccct gtcctccttg ccccgcccct 180
gaggccgccg gcggccctag cgtgtttctg tttcccccca agcctaaaga caccctgatg 240
atctccagga cccctgaggt gacctgtgtg gtggtggacg tgagccagga ggaccccgag 300
gtgcagttca actggtacgt ggatggcgtg gaagtgcaca acgccaagac caagcccagg 360
gaggagcaat tcaacagcac ctacagggtg gtgagcgtcc tcaccgtcct gcatcaggac 420
tggctgaacg gcaaggagta caagtgcaaa gtgtccaaca agggcctgcc ttcctccatc 480
gagaagacca tctccaaggc taagggccag cccagggaac cccaagtgta caccctcccc 540
ccctcccagg aggagatgac caaaaaccaa gtctccctga cctgcctggt gaagggcttc 600
tacccctccg atattgccgt cgagtgggag agcaacggcc agcccgagaa caactataag 660
accacccccc ccgtgctgga ttccgacggt tcttttttcc tgtatagcaa gctgaccgtg 720
gacaagtcca ggtggcagga gggcaacgtg ttctcctgca gcgtgatgca cgaggccctc 780
cacaaccact acacccagaa atccctgtcc ctgtccctcg gcggcggagg cggctccggc 840
ggcggcggca gcggaggcgg aggaagccat cccattcccg actccagccc cctgctgcag 900
tttggcggcc aagtgaggca gagatacctg tacaccgacg atgcccaaca gacagaggct 960
cacctggaaa tcagggagga cggcaccgtg ggcggagctg ctgatcagag ccccgagtcc 1020
ctcctccagc tgaaggccct gaagcccgga gtgatccaga tcctgggcgt gaagacatcc 1080
aggttcctgt gccagagacc cgatggcgcc ctgtacggaa gcctgcactt cgaccccgag 1140
gcttgctcct tcagggagag gctgctggag gacggctaca acgtgtacca gtccgaggct 1200
cacggactcc ctctgcacct gcctggcaac aagagccctc acagagaccc cgcccctaga 1260
ggccctgcta ggtttctgcc cctgcctggc ctgcctcctg ctctgcccga gccccctggt 1320
attttagctc ctcagcctcc cgatgtggga agcagcgacc ccctgagcat ggtgggagct 1380
agccagggca ggagccctag ctacgccagc 1410
<210> 28
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D4F1
<400> 28
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gagcaagtac ggccccccct gtcctccttg ccccgcccct 180
gaggccgccg gcggccctag cgtgtttctg tttcccccca agcctaaaga caccctgatg 240
atctccagga cccctgaggt gacctgtgtg gtggtggacg tgagccagga ggaccccgag 300
gtgcagttca actggtacgt ggatggcgtg gaagtgcaca acgccaagac caagcccagg 360
gaggagcaat tcaacagcac ctacagggtg gtgagcgtcc tcaccgtcct gcatcaggac 420
tggctgaacg gcaaggagta caagtgcaaa gtgtccaaca agggcctgcc ttcctccatc 480
gagaagacca tctccaaggc taagggccag cccagggaac cccaagtgta caccctcccc 540
ccctcccagg aggagatgac caaaaaccaa gtctccctga cctgcctggt gaagggcttc 600
tacccctccg atattgccgt cgagtgggag agcaacggcc agcccgagaa caactataag 660
accacccccc ccgtgctgga ttccgacggt tcttttttcc tgtatagcaa gctgaccgtg 720
gacaagtcca ggtggcagga gggcaacgtg ttctcctgca gcgtgatgca cgaggccctc 780
cacaaccact acacccagaa atccctgtcc ctgtccctcg gcggcggagg cggctccggc 840
ggcggcggca gcggaggcgg aggaagccat cccattcccg actccagccc cctgctgcag 900
tttggcggcc aagtgaggca gagatacctg tacaccgacg atgcccaaca gacagaggct 960
cacctggaaa tcagggagga cggcaccgtg ggcggagctg ctgatcagag ccccgagtcc 1020
ctcctccagc tgaaggccct gaagcccgga gtgatccaga tcctgggcgt gaagacatcc 1080
aggttcctgt gccagagacc cgatggcgcc ctgtacggaa gcctgcactt cgaccccgag 1140
gcttgctcct tcagggagag gctgctggag gacggctaca acgtgtacca gtccgaggct 1200
cacggactcc ctctgcacct gcctggcaac aagagccctc acagagaccc cgcccctaga 1260
ggccctgcta ggtttctgcc cctgcctggc ctgcctcctg ctctgcccga gccccctggt 1320
attttagctc ctcagcctcc cgatgtggga agcagcgacc ccctgcacat ggtgggagct 1380
agccagggca ggagccctag ctacgccagc 1410
<210> 29
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D5F1
<400> 29
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gagcaagtac ggccccccct gtcctccttg ccccgcccct 180
gaggccgccg gcggccctag cgtgtttctg tttcccccca agcctaaaga caccctgatg 240
atctccagga cccctgaggt gacctgtgtg gtggtggacg tgagccagga ggaccccgag 300
gtgcagttca actggtacgt ggatggcgtg gaagtgcaca acgccaagac caagcccagg 360
gaggagcaat tcaacagcac ctacagggtg gtgagcgtcc tcaccgtcct gcatcaggac 420
tggctgaacg gcaaggagta caagtgcaaa gtgtccaaca agggcctgcc ttcctccatc 480
gagaagacca tctccaaggc taagggccag cccagggaac cccaagtgta caccctcccc 540
ccctcccagg aggagatgac caaaaaccaa gtctccctga cctgcctggt gaagggcttc 600
tacccctccg atattgccgt cgagtgggag agcaacggcc agcccgagaa caactataag 660
accacccccc ccgtgctgga ttccgacggt tcttttttcc tgtatagcaa gctgaccgtg 720
gacaagtcca ggtggcagga gggcaacgtg ttctcctgca gcgtgatgca cgaggccctc 780
cacaaccact acacccagaa atccctgtcc ctgtccctcg gcggcggagg cggctccggc 840
ggcggcggca gcggaggcgg aggaagccat cccattcccg actccagccc cctgctgcag 900
tttggcggcc aagtgaggca gagatacctg tacaccgacg atgcccaaca gacagaggct 960
cacctggaaa tcagggagga cggcaccgtg ggcggagctg ctgatcagag ccccgagtcc 1020
ctcctccagc tgaaggccct gaagcccgga gtgatccaga tcctgggcgt gaagacatcc 1080
aggttcctgt gccagagacc cgatggcgcc ctgtacggaa gcctgcactt cgaccccgag 1140
gcttgctcct tcagggagag gctgctggag gacggctaca acgtgtacca gtccgaggct 1200
cacggactcc ctctgcacct gcctggcaac aagagccctc acagagaccc cgcccctaga 1260
ggccctgcta ggtttctgcc cctgcctggc ctgcctcctg ctctgcccga gccccctggt 1320
attttagctc ctcagcctcc cgatgtggga agcagcgacc ccctgcacat ggtgggagct 1380
agccagggcc tgagccctag ctacgccagc 1410
<210> 30
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D6F1
<400> 30
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gtctaagtac ggccctccct gccctccttg tcctgctcct 180
gaagctgctg gcggcccttc cgtgttcctg ttccccccaa agcccaagga caccctgatg 240
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccagga agatcccgag 300
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 360
gaggaacagt tcaactccac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 420
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc cagctccatc 480
gaaaagacca tctccaaggc caagggccag ccccgggaac cccaggtgta cacactgcct 540
ccaagccagg aagagatgac caagaaccag gtgtccctga cctgtctcgt gaaaggcttc 600
tacccctccg atatcgccgt ggaatgggag tccaacggcc agcctgagaa caactacaag 660
accacccccc ctgtgctgga ctccgacggc tccttcttcc tgtactccaa gctgaccgtg 720
gacaagtcca gatggcagga aggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 780
cacaaccact acacccagaa gtccctgtcc ctgtctctgg gaggcggcgg aggatctggc 840
ggaggtggaa gcggaggcgg tggatctcac cccatccccg acagcagccc cctgctgcag 900
ttcggcggcc aggtgaggca gaggtacctg tacaccgacg acgcccagca gaccgaggcc 960
cacctggaga tcagggagga cggcaccgtg ggcggcgccg ccgaccagag ccccgagagc 1020
ctgctgcagc tgaaggccct gaagcccggc gtgatccaga tcctgggcgt gaagaccagc 1080
aggttcctgt gccagaggcc cgacggcgcc ctgtacggca gcctgcactt cgaccccgag 1140
gcctgcagct tcagggagag gctgctggag gacggctaca acgtgtacca gagcgaggcc 1200
cacggcctgc ccctgcacct gcccggcaac aagagccccc acagggaccc cgcccccagg 1260
ggccccgcca ggttcctgcc cctgcccggc ctgccccccg ccctgcccga gccccccggc 1320
atcctggccc cccagccccc cgacgtgggc agcagcgacc ccctgagcat ggtggaggcc 1380
ctgcagggca ggagccccag ctacgccagc 1410
<210> 31
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> DNA-D7F1
<400> 31
catggcgagg gcacctttac ctccgacgtg tcctcctacc tggaagaaca ggccgccaaa 60
gagtttatcg cctggctcgt gaagggcggt ggtggcggcg gaggatctgg cggaggtgga 120
agcggaggcg gtggatctga gtctaagtac ggccctccct gccctccttg tcctgctcct 180
gaagctgctg gcggcccttc cgtgttcctg ttccccccaa agcccaagga caccctgatg 240
atctcccgga cccccgaagt gacctgcgtg gtggtggatg tgtcccagga agatcccgag 300
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 360
gaggaacagt tcaactccac ctaccgggtg gtgtccgtgc tgacagtgct gcaccaggac 420
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc cagctccatc 480
gaaaagacca tctccaaggc caagggccag ccccgggaac cccaggtgta cacactgcct 540
ccaagccagg aagagatgac caagaaccag gtgtccctga cctgtctcgt gaaaggcttc 600
tacccctccg atatcgccgt ggaatgggag tccaacggcc agcctgagaa caactacaag 660
accacccccc ctgtgctgga ctccgacggc tccttcttcc tgtactccaa gctgaccgtg 720
gacaagtcca gatggcagga aggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 780
cacaaccact acacccagaa gtccctgtcc ctgtctctgg gaggcggcgg aggatctggc 840
ggaggtggaa gcggaggcgg tggatctcac cccatccccg acagcagccc cctgctgcag 900
ttcggcggcc aggtgaggca gaggtacctg tacaccgacg acgcccagca gaccgaggcc 960
cacctggaga tcagggagga cggcaccgtg ggcggcgccg ccgaccagag ccccgagagc 1020
ctgctgcagc tgaaggccct gaagcccggc gtgatccaga tcctgggcgt gaagaccagc 1080
aggttcctgt gccagaggcc cgacggcgcc ctgtacggca gcctgcactt cgaccccgag 1140
gcctgcagct tcagggagct gctgctggag gacggctaca acgtgtacca gagcgaggcc 1200
cacggcctgc ccctgcacct gcccggcaac aagagccccc acagggaccc cgcccccagg 1260
ggccccgcca ggttcctgcc cctgcccggc ctgccccccg ccctgcccga gccccccggc 1320
atcctggccc cccagccccc cgacgtgggc agcagcgacc ccctgagcat ggtgggacct 1380
tcccagggca ggagccccag ctacgccagc 1410
Claims (12)
1.一种融合蛋白,由以下组成,第一多肽:GLP-1或其类似物、第二多肽:IgG4 Fc部分和第三多肽:FGF21或其变体,第一多肽通过第一接头与第二多肽相连,第三多肽通过第二接头与第二多肽相连;其中,所述IgG4 Fc部分由SEQ ID NO:2所示的氨基酸序列组成;所述GLP-1由SEQ ID NO:14所示的氨基酸序列组成;
所述GLP-1类似物由SEQ ID NO:1所示的氨基酸序列组成;
所述FGF21由SEQ ID NO:15所示的氨基酸序列组成;
所述FGF21变体,与SEQ ID NO:15所示的氨基酸序列相比,在第98位和第171位氨基酸位点发生突变,其中,98位的氨基酸突变为L98R;171位的氨基酸突变选自如下任意一个P171A,P171G。
2.根据权利要求1所述的融合蛋白,其特征在于,所述FGF21变体,还进一步在选自以下一个或多个氨基酸位点发生突变:第167位、175位或179位;其中,167位的氨基酸突变为S167H;175位的氨基酸突变为R175L;179位的氨基酸突变为Y179F。
3.根据权利要求1-2任一项所述的融合蛋白,其特征在于,所述第一接头和第二接头分别独立地包含5至50个氨基酸残基的多肽,且所述多肽至少包含50%的G。
4.根据权利要求3所述的融合蛋白,其特征在于,所述第一接头和/或第二接头分别独立地包含1、2或3个富含G的多肽。
5.根据权利要求3所述的融合蛋白,其特征在于,所述第一接头和第二接头分别独立地选自GGGGSGGGGS、GGGGSGGGGSGGGGS、GGGGSGGGGSGGGGSA。
6.根据权利要求1-5任一项所述的融合蛋白,其特征在于,所述融合蛋白为同源二聚体融合蛋白或非同源二聚体融合蛋白。
7.多核苷酸,其编码权利要求1-6中任一项所述的融合蛋白。
8.载体,其包含权利要求7所述的多核苷酸。
9.宿主细胞,其包含权利要求8所述的载体。
10.一种生产根据权利要求1-6中任一项所述融合蛋白的方法,所述方法包括在宿主细胞中表达权利要求8所述的载体。
11.药物组合物,其包含权利要求1-6中任一项所述的融合蛋白,以及一种或多种药学上可接受的辅料。
12.权利要求1-6中任一项所述的融合蛋白在制备药物中的应用,其中所述药物用于治疗代谢性疾病,其中所述代谢性疾病选自糖尿病、肥胖和肝脂肪变性。
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