CN106977608A - 白蛋白衍生物和变体 - Google Patents
白蛋白衍生物和变体 Download PDFInfo
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- CN106977608A CN106977608A CN201710158973.1A CN201710158973A CN106977608A CN 106977608 A CN106977608 A CN 106977608A CN 201710158973 A CN201710158973 A CN 201710158973A CN 106977608 A CN106977608 A CN 106977608A
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Abstract
本发明公开了包含或组成为域III和至少一种其它域的白蛋白衍生物,其中所述衍生物或变体并非天然存在的白蛋白衍生物或变体。所述衍生物可用于缀合物和融合物多肽。
Description
本申请是申请日为2011年4月8日、申请号为201180028537.3、发明名称为“白蛋白衍生物和变体”的专利申请的分案申请。
涉及序列表
本申请含有计算机可读形式的序列表。所述计算机可读形式通过提述并入本文。
技术领域
本发明涉及白蛋白衍生物和变体和/或包含此类白蛋白衍生物和变体的融合多肽。
本发明进一步涉及白蛋白衍生物和变体和/或包含此类白蛋白衍生物和变体的融合多肽作为供药物递送、多肽稳定性和体内半寿期延长或调节的工具中的用途。
发明背景
白蛋白是天然见于哺乳动物血浆中的蛋白,在血浆中,其为最丰富的蛋白。其在维持血液理想的渗透压方面发挥重要作用,并在血流中的多种物质的转运中具有作用。
白蛋白在体内与其受体,即新生儿Fc受体(FcRn)“Brambell”结合,且已知该相互作用对于增加白蛋白的血浆半寿期是重要的。FcRn是膜结合蛋白,在多种细胞和组织类型中表达,并已发现其降低白蛋白的胞内降解的速率(Roopenian D.C.和Akilesh,S.(2007),Nat.Rev.Immunol 7,715-725.)。FcRn有助于维持哺乳动物如人血清的高水平的IgG和白蛋白。
尽管现有技术中已表征了FcRn-免疫球蛋白G(IgG)相互作用,对FcRn-白蛋白相互作用的表征和理解尚不充分。主要白蛋白-FcRn结合位点位于域III(DIII:381-585)内(Andersen等(2010)Clinical Biochemistry 43,367-372)。然而,本领域已知IgG和白蛋白非协同性结合于FcRn上的不同位点(Andersen等(2006),Eur.J.Immunol 36,3044-3051;Chaudhury等(2006),Biochemistry 45,4983-4990)。
人类血清白蛋白(HSA)已表征为585个氨基酸的多肽,其序列可见于Peters,T.,Jr.(1996)All about Albumin:Biohemistry,Genetics and Medical,Applicationspp10,Academic Press,Inc.,Orlando(ISBN 0-12-552110-3)。白蛋白具有对FcRn的特征性pH-依赖性结合,其中它在酸性pH如pH 6.0结合,但在中性以上的pH如pH 7.4不结合。
已发现HSA的血浆半寿期为大约19日(Peters,T.,Jr.(1985)Adv.ProteinChem.37,161-245;Peters,T.,Jr.(1996)All about Albumin,Academic Press,Inc.,SanDiego,CA.(page 245-246));Benotti P,Blackburn GL:Crit Care Med(1979)7:520-525)。一个天然存在的、具有取代D494N的点突变体,具有较低的血浆半寿期(BiochimBiophys Acta.1991,1097:49-54)。该单个取代在此变体/突变体中生成N-连接糖基化位点,该位点不存在于野生型(wt)HSA中。不知道观察到的导致血浆半寿期的变化归因于在该位点的潜在糖基化还是氨基酸变化自身。
白蛋白是被视为具有长血浆半寿期的血浆蛋白,且因为该特性,已提出将其用于药物递送。已将白蛋白缀合于药学上有益的化合物(WO0069902A)。因此,已发现所得的缀合物血浆半寿期一般显著长于有益化合物本身的血浆半寿期。
此外,已将白蛋白融合于治疗上有益的肽(WO 01/79271 A和WO 03/59934 A),这通常导致融合多肽具有所述治疗上有益的肽的活性和以及长血浆半寿期,其与所述治疗上有益的肽本身的血浆半寿期相比显著较长。
Otagiri等(2009),Biol.Pharm,Bull.32(4),527-534公开了已知77个白蛋白变体,其中25个见于域III。已显示缺乏羧基端最后175个氨基酸的天然变体具有减少的半寿期(Andersen等(2010),Clinical Biohemistry 43,367-372)。Iwao等(2007)使用小鼠模型研究了天然存在的人白蛋白变体的半寿期,并发现K541E和K560E具有减少的半寿期,E501K和E570K具有增加的半寿期,而K573E对半寿期几乎无作用(Iwao等(2007)B.B.A.Proteinsand Proteomics 1774,1582-1590)。
Galliano等(1993)Biochim.Biophys.Acta 1225,27-32公开了天然变体E505K。Minchiotti等(1990)公开了天然变体K536E。Minchiotti等(1987)Biochim.Biophys.Acta916,411-418公开了天然变体K574N。Takahashi等(1987)Proc.Natl.Acad.Sci.USA 84,4413-4417公开了天然变体D550G。Carlson等(1992).Proc.Nat.Acad.Sci.USA 89,8225-8229公开了天然变体D550A。
WO 2007112940公开了包含至少一个白蛋白域III和至少一个治疗模块的构建体,和此类构建体在药物半寿期延长中的用途。
白蛋白具有允许多种配体结合的固有能力,这些配体与白蛋白相缔合(缔合物)。已利用该特性以延长此类前述配体的血浆半寿期,例如延长具有非共价结合于白蛋白的能力的药物的血浆半寿期。这亦可通过将几乎不具或不具白蛋白结合特性的药学上有益的化合物与具有白蛋白结合特性的模块相结合来实现。参见综述文献Kratz(2008).Journal ofControlled Release 132,171-183及其中的参考文献。
US7,253,259公开了通过基因重组技术产生的蛋白,其包括至少一个选自血清白蛋白的域I、II和III的域,但与天然白蛋白具有不同结构;以及公开了产生该蛋白的方法。
白蛋白用于制备药学上有益的化合物,其中此种制备物可例如但不限于白蛋白的纳米颗粒或微米颗粒。在这些实例中,药学上有益的化合物或化合物的混合物的递送可受益于白蛋白对FcRn受体亲和力的改变,其中对于递送手段而言,已显示所述有益化合物与白蛋白相缔合。
影响形成的缀合物或融合多肽的血浆半寿期的延长的准确特性或相关性质尚不清楚(例如,但不限于Kurtzhals P等Biochem.J.1995;312:725-731),但其似乎直接涉及其包含的白蛋白模块和选择的药学上有益的化合物/肽。会需要能够控制给定白蛋白域III衍生物,片段,或其变体,以及缀合物、融合物或缔合物的血浆半寿期,从而使得与所述缀合物/融合物的组分本身给出的血浆半寿期相比,可获得更长或更短的血浆半寿期。这会允许根据旨在治疗的适应症的详情定制设计特定药物。
已知白蛋白在肿瘤中蓄积并发生分解代谢,亦显示其在类风湿性关节炎患者的发炎的关节中蓄积。参见Kratz(2008)Journal of Controlled Release 132,171-183的综述文献和其中的参考文献。预计对于FcRn亲和力增加的HSA变体对于药学上有益的化合物的递送和/或靶向(如被动靶向)会是有利的。
可期望获得对FcRn几乎无或无结合的白蛋白变体,以供提供较短的半寿期或受控的血清药代动力学,如Vania Kenanova,Tove Olafsen,Felix Bergara和Anna Wu(2009)J.Nucl.Med.;50(Supplement 2):1582)所述。
发明内容
本发明的第一方面提供了白蛋白衍生物或变体,其片段,或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白衍生物或变体或其片段包含或由如下组成:白蛋白域III或衍生物或其变体,以及至少一个其它白蛋白域,片段或衍生物或其变体。优选地,第一方面并不包括野生型白蛋白自身。然而,所述第一方面可包括经修饰的野生型白蛋白,其修饰使其包含或由如下组成:野生型白蛋白和改变,如添加一个或多个(几个)来自任何白蛋白的域,一个或多个(几个)点突变,融合于有益模块,缀合于有益模块和/或与有益模块缔合。
在一个优选实施方案中,所述白蛋白衍生物或变体,其片段,或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽在对应于SEQ ID NO:31或SEQ ID NO:1(HSA)中选自下组的一个或多个(几个)位置的位置的位置中包含一个或多个(几个)取代、插入或缺失,最优选取代:417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584,或由在所述位置取代、插入或缺失(最优选取代)一个或多个(几个)氨基酸的序列组成。
在第二个方面,本发明涉及分离的多核苷酸,其编码任何本发明的衍生物或变体,例如(i)核酸,其编码白蛋白衍生物,其片段,或者包含所述白蛋白衍生物或其片段或由所述白蛋白衍生物或其片段组成的融合多肽,(ii)包含所述核酸的质粒,和(iii)包含所述质粒的宿主细胞。
根据本发明,包含白蛋白衍生物或变体,或其片段,以及至少一种治疗或诊断模块的缀合物,形成本发明的第三个方面。
本发明的第四个方面提供了融合多肽,其包含所述白蛋白衍生物或变体或其片段以及至少一种治疗性蛋白或肽或者由所述物质组成。本发明的第五个方面涉及白蛋白的衍生物或变体或其片段与另一种化合物的“缔合物”,该化合物与衍生的白蛋白、变体白蛋白或其片段通过非共价结合而结合或缀合。
本发明的第六个方面涉及组合物,优选药物组合物,其包含或由如下组成:与治疗性、药物性或其它有益多肽缀合、融合或缔合的白蛋白衍生物,片段,其变体,或者融合多肽(所述融合多肽包含所述白蛋白衍生物、片段、其变体或由所述白蛋白衍生物、片段、其变体组成)。
本发明的第七个方面涉及产生所述衍生物或变体的方法。
本发明的第八个方面涉及所述衍生物和/或变体在显影中的用途,例如缀合物、缔合物或融合多肽在动物或人类显影目的中的用途。
本发明的第九个方面涉及治疗方法和/或本发明的多肽序列或核苷酸序列在治疗方法中的用途。
第十个方面,本发明涉及组合物,其包含根据本发明的衍生的白蛋白,变体白蛋白,其缔合物或其片段,衍生的或变体白蛋白片段或其缔合物或者包含衍生的或变体白蛋白或其片段的融合多肽。
附图简述
图1:A)shFcRn-GST与野生型HSA和野生型HSA衍生物(2000-0.9nM)在(A)pH 6.0和(B)pH 7.4的结合。ELISA值代表重复测量的平均值。
图2:代表性感应谱(sensorgram),显示1μM的野生型HSA和野生型HSA衍生物对固定化的shFcRn-GST(~1400RU)在pH 6.0和pH 7.4的结合。(A)DI-DII(B)DI-DIII,(C)DII-DIII,(D)DIII,(E)DIII-DIII和(F)野生型HSA。
图3:将分别给出在55nM,166nM和500nM,和500nM和1500nM的最终样品浓度的野生型HSA和野生型HSA域构建体的系列稀释与shFcRn(50nM)预温育,并针对固定化的HSA(~2600RU)进行注射。注射在25℃以50μl/min的流速在pH 6.0进行。
图4:下述氨基酸序列的多重比对:(i)全长成熟HSA(Hu_1_2_3),(ii)白蛋白变体,其包含HSA的域I和域III(Hu_1_3),(iii)白蛋白变体,其包含HSA的域II和域III(Hu_2_3),(iv)全长恒河猴/猕猴(Macaca mulatta)白蛋白(Mac_mul),(v)全长大鼠(Rattusnorvegicus)白蛋白(大鼠)和(vi)全长小鼠(Mus musculus)白蛋白(小鼠)。位置500、550和573(相对于全长HSA)由箭头指示。在图4中,域I、II和III称作1、2和3(分别)。
图5:来自人、绵羊、小鼠、兔和山羊的成熟血清白蛋白和来自黑猩猩(“Chimp”)、恒河猴/猕猴、仓鼠、豚鼠、大鼠、牛、马、驴、犬、鸡和猪的不成熟白蛋白的氨基酸序列的多重比对。域1、2和3的起始和终止氨基酸(如Dockal等,(The Journal of BiologicalChemistry,1999,Vol.274(41):29303–29310))所定义)针对成熟人血清白蛋白标出。
图6:质粒pDB2305的概略图。
图7:总结体内生成表达质粒的概略图。A.使用PCR生成两个PCR片段。片段1和2与Acc65I/BamHI消化的pDB3936在其5’和3’端分别分享247个碱基对(bp)和217bp的同源性。片段1和2分别在其3’和5’端彼此分享27-30bp的同源性。B.将纯化的PCR片段与Acc65I/BamHI消化的pDB3936一同用于共转化酿酒酵母(S.cerevisiae)BXP10cir0。X=前导序列。Y=白蛋白DI+DII。Z=白蛋白DIII。十字代表体内重组。
图8:代表性感应谱,其显示10μM的HSA域III及其变体对固定化的shFcRn-HIS(~2100RU)在pH 5.5的结合。图8a:DIII野生型和DIII K573D,图8b:DIII野生型和DIIIK573H,图8c:DIII野生型和DIII K573N,图8d:DIII野生型和DIII K573W,图8e:DIII和DIIIQ580K。
图9:白蛋白和衍生物及其变体(一些缀合于HRP)的非还原性SDS-PAGE分析:(1)标记(SeeBlueTM),(2)HRP标样,(3)DI+DIII+DIII:HRP(1μg),(4)白蛋白标样(1μg),(5)DI+DIII-HRP(1μg),(6)DI+DIII K500A-HRP(1μg),(7)DI+DIII K573P-HRP(1μg),(8)DI+DIIIK573Y-HRP(1μg),(9)DI+DIII D550N-HRP(1μg),(10)DIII+DI-HRP(1μg),(11)HRP和白蛋白标样的混合物(各1μg),(12)HRP+和白蛋白标样的混合物(各2μg)。
图10,代表性感应谱,其显示10μM缀合于HRP的HSA DI+III(及其变体)对固定化的shFcRn-HIS(~1500RU)在pH 5.5的结合。(1)DI+DIII K573P-HRP,(2)野生型HSA,(3)DI+DIII野生型-HRP和(4)DI+DIII K500A-HRP。
图11:代表性感应谱,显示10μM融合于HSA DII+III和DII+III K573P的N端的IL-1ra对固定化的shFcRn-HIS(~2100RU)在pH 5.5的结合。
图12:代表性感应谱,显示10μM DIII、融合的DIII和融合的DIII K573P的HSA串联重复对scFv(~1500RU)在pH 5.5的结合。
图13:代表性感应谱,显示10μM DIII、融合的DIII和融合的DIII D550N的HSA串联重复对scFv(~1500RU)在pH 5.5的结合。
图14:代表性感应谱,显示10μM DIII、融合的DIII和融合的DIII K573P的HSA串联重复对IL-1ra(~1500RU)在pH 5.5的结合。
图15:代表性感应谱,显示10μM DIII、融合的DIII和融合的DIII D550N的HSA串联重复对IL-1ra(~1500RU)在pH 5.5的结合。
图16:用UV光(A)和商业性蛋白质染料(B)显现融合于荧光素的DI+DIII变体蛋白。白蛋白和衍生物及其变体(一些缀合于F5M)的非还原性SDS-PAGE分析:(1)标记(SeeBlueTM)(10μL),(2)HSA-F5M对照(1μg),(3)标记(See BlueTM)(10μL),(4)DI+DIII+DIII-F5M(1μg),(5)DI+DIII野生型-F5M(1μg),(6)DI+DIII K500A-F5M(1μg),(7)DI+DIII K573P-F5M(1μg),(8)DI+DIII K573Y-F5M(1μg),(9)DI+DIII D550N-F5M(1μg),(10)DIII+DI-F5M(1μg),(11)标记(SeeBlueTM)(10μL)。
图17:代表性感应谱,显示10μM野生型HSA,HSA DI+DIII K573P-F5M,HSA DI+DIIIK500A-F5M对固定化的shFcRn-HIS(~1500RU)在pH5.5的结合。
图18:代表性感应谱,显示10μM野生型HSA,HSA DI+DIII+DIII-F5M,HSA DI+DIII-F5M对固定化的shFcRn-HIS(~1500RU)在pH5.5的结合。
发明详述
本发明的第一方面涉及白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白衍生物或变体或其片段包含或由如下组成:第一白蛋白域III,片段或衍生物或其变体,以及至少一个第二白蛋白域,片段或衍生物或其变体。优选地,所述衍生物或变体并非天然存在的衍生物或变体如来自如下之一的野生型白蛋白:人;灵长类如黑猩猩、大猩猩或恒河猴/猕猴;兔;啮齿类如小鼠、大鼠和仓鼠;牛;马类如马或驴;山羊;绵羊;犬;豚鼠;鸡和猪。所述第一方面可以或可以不包括白蛋白衍生物或变体,其包含或由如下组成:野生型白蛋白的域I、II和III(或其片段),以及来自任何白蛋白如来自人或本文中公开的其它物种的白蛋白的一个或多个(几个)其它域(或其片段)。
根据本发明第一方面的一些白蛋白衍生物或变体,其片段或融合多肽并不包含白蛋白的域I(或其片段)。根据本发明第一方面的一些白蛋白衍生物或变体,其片段或融合多肽并不包含白蛋白的域II(或其片段)。根据本发明第一方面的其它白蛋白衍生物或变体,其片段或融合多肽包含白蛋白的域III以及白蛋白的域I(或其片段)或域II(或其片段)之一或两者。
本发明基于下述发现:包含第一白蛋白域III和至少一种第二白蛋白域的多肽,片段或衍生物或其变体,与对应的域III自身相比具有对FcRn更强的结合。这根据现有技术特别是WO 2007112940是令人意想不到的,在该文中似乎域III的氨基酸残基涉及白蛋白与FcRn受体的相互作用,其涉及延长循环中例如血浆中的白蛋白的半寿期。已知域III负责白蛋白与FcRn的结合。根据本发明,术语“白蛋白”意指与HSA具有相同和/或非常相似三维结构,并具有长血浆半寿期的蛋白质。如SEQ ID NO:31或SEQ ID NO:1中公开的HSA或其任何天然存在的等位基因,是根据本发明的优选白蛋白。本领域技术人员亦会了解HSA域III衍生物,片段,其变体的所述的特征对于其它依照所述的本发明的非人白蛋白亦会是可能的。
因此根据本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽与白蛋白类似,具有长血浆半寿期的益处。
本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽的大小可根据片段的大小,域的数量,融合多肽的非白蛋白部分的大小等而变化。原则上,其大小可在略微大于域III的大小及其之上变动,但实践中优选其大小大约为天然白蛋白的大小。不愿拘于任何理论,认为大于肾阈值的大小,如天然白蛋白的大小,对于高血浆半寿期是理想的。因此,优选本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,和/或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的缀合物具有40-80kDa范围,优选50-70kDa的范围,更优选55-65kDa的范围,和最优选大约60kDa的大小。
HSA是根据本发明优选的白蛋白,并为组成为585个氨基酸残基并具有67kDa的分子量的蛋白质。在其天然形式其不受糖基化。HSA的氨基酸序列示于SEQ ID NO:31或SEQ IDNO:1。本领域技术人员会了解可存在天然等位基因,其基本上具有与HSA相同的性质,但与SEQ ID NO:31或SEQ ID NO:1相比具有一个或多个(几个)氨基酸改变,且本发明人亦涵盖了使用此类天然等位基因作为根据本发明的亲本白蛋白。
白蛋白一般具有大约20日或更长的长血浆半寿期,例如HSA具有19日的血浆半寿期。已知HSA的长血浆半寿期是通过与其受体FcRn的相互作用介导的,然而,对HSA的长血浆半寿期之后的准确机理的理解或认识对于本发明不是必需的。
根据本发明,术语“白蛋白”意指与HSA具有相同或非常类似的三维结构,并具有长血浆半寿期的蛋白质。根据本发明的白蛋白蛋白质的实例可提出人血清白蛋白(例如AAA98797或P02768-1,SEQ ID NO:31或SEQ ID NO:1(成熟),SEQ ID NO:4(不成熟)),灵长类血清白蛋白(如黑猩猩血清白蛋白(例如预测的序列XP_517233.2SEQ ID NO:5),大猩猩血清白蛋白或恒河猴/猕猴血清白蛋白(例如NP_001182578,SEQ ID NO:6),啮齿类血清白蛋白(如仓鼠血清白蛋白(例如A6YF56,SEQ ID NO:7),豚鼠血清白蛋白(例如Q6WDN9-1,SEQID NO:8),小鼠血清白蛋白(例如AAH49971或P07724-1Version 3,SEQ ID NO:9)和大鼠血清白蛋白(例如AAH85359或P02770-1Version 2,SEQ ID NO:10))),牛血清白蛋白(例如奶牛(cow)血清白蛋白P02769-1,SEQ ID NO:11),马类血清白蛋白如马血清白蛋白(例如P35747-1,SEQ ID NO:12)或驴血清白蛋白(例如Q5XLE4-1,SEQ ID NO:13),兔血清白蛋白(例如P49065-1Version 2,SEQ ID NO:14),山羊血清白蛋白(例如ACF10391,SEQ ID NO:15),绵羊血清白蛋白(例如P14639-1,SEQ ID NO:16),狗血清白蛋白(例如P49822-1,SEQID NO:17),鸡血清白蛋白(例如P19121-1Version 2,SEQ ID NO:18)和猪血清白蛋白(例如P08835-1 Version 2,SEQ ID NO:19)。HSA,如SEQ ID NO:31或SEQ ID NO:1中所公开的,或其任何天然存在的等位基因,是根据本发明的优选的白蛋白。
根据本发明,亲本白蛋白,其片段,或包含白蛋白或其片段或由白蛋白或其片段组成的融合多肽的白蛋白部分,一般与SEQ ID NO:31或SEQ ID NO:1所示的HSA序列具有至少60%,优选至少70%,优选至少80%,优选至少85%,优选至少86%,优选至少87%,优选至少88%,优选至少89%,优选至少90%,优选至少91%,优选至少92%,优选至少93%,优选至少94%,优选至少95%,更优选至少96%,更优选至少97%,更优选至少98%和最优选至少99%的序列同一性。
所述亲本优选包含SEQ ID NO:31或SEQ ID NO:1的氨基酸序列的至少一部分或由其组成。在另一个实施方案中,所述亲本包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的至少一部分或由其组成。
在另一个实施方案中,所述亲本是SEQ ID NO:31或SEQ ID NO:1的成熟多肽的至少一部分的等位衍生物或变体。
术语“分离的衍生物”或“分离的变体”意指经人力修饰的衍生物或变体。在一个实施方案中,如通过SDS-PAGE或GP-HPLC确定的,该衍生物或变体为至少1%纯的,例如至少5%纯的,至少10%纯的,至少20%纯的,至少40%纯的,至少60%纯的,至少80%纯的,和至少90%纯的。
术语“基本上纯的衍生物”或“基本上纯的变体”意指一种制备物,其包含以重量计至多10%,至多8%,至多6%,至多5%,至多4%,至多3%,至多2%,至多1%,和至多0.5%的与其天然或重组结合的其他多肽物质。优选地,所述衍生物或变体以存在于该制备物中的总多肽物质重量计是至少92%纯的,例如至少94%纯的,至少95%纯的,至少96%纯的,至少97%纯的,至少98%纯的,至少99%纯的,至少99.5%纯的,和100%纯的。本发明的衍生物或变体优选为基本上纯的形式。其可通过,例如,以公知的重组方法或经典的纯化方法制备该变体而达成。
术语“成熟多肽”意指经翻译和任何翻译后修饰,如N末端加工、C末端截短、糖基化、磷酸化等之后的最终形式的多肽。在一个实施方案中,所述成熟多肽是氨基酸1至585。
术语“成熟多肽编码序列”意指编码成熟多肽的多核苷酸。在一个方面,所述成熟多肽编码序列是SEQ ID NO:2的核苷酸1至1758。
术语“FcRn”意指人新生儿Fc受体(FcRn)。‘shFcRn’是FcRn的可溶性重组形式。术语smFcRn是小鼠新生Fc受体的可溶性重组形式。
根据本发明,术语“白蛋白衍生物,其片段或包含所述白蛋白衍生物或其片段或由所述白蛋白衍生物或其片段组成的融合多肽”意指非天然的,经工程改造的分子,其包含指定的白蛋白域或由指定的白蛋白域组成。因此,该术语并不包括天然的全长白蛋白或包含全长白蛋白的融合多肽。术语“衍生物”包括在一个或多个(几个)位置包含一个或多个改变,例如取代、插入和/或缺失的白蛋白多肽。取代意指用不同氨基酸替代占据某位置的氨基酸;缺失意指去除占据某位置的氨基酸;而插入意指紧接着占据某位置的氨基酸添加1,2或3个,或更多个氨基酸,插入可为在氨基酸的C侧或N侧,但通常是在氨基酸的C侧。
术语“变体”包括白蛋白或白蛋白衍生物或其融合蛋白,其中所述白蛋白衍生物或融合物通过化学手段而改变,所述手段如多肽的翻译后衍生化或修饰,例如PEG化和/或将所需的模块(如治疗性模块)缀合于巯基基团,如由未配对的半胱氨酸提供的巯基基团。术语“变体”亦包括根据本发明的白蛋白衍生物的融合蛋白,其中所述衍生物并未通过化学手段改变。
术语“衍生物”和“变体”可以或可以不互换使用。
白蛋白为蛋白质,并构成哺乳动物血浆中最丰富的蛋白质,且来自大量和多样哺乳动物的白蛋白已经通过生化方法和/或序列信息表征。几种白蛋白,例如HSA,亦已通过晶体学方法表征,并确定了其结构,且已显示白蛋白组成为三个不同的域,称为域I、域II和域III。
本发明的域可原则上来源于任何白蛋白,然而优选所述域来源于人血清白蛋白,灵长类血清白蛋白如黑猩猩血清白蛋白、大猩猩血清白蛋白或恒河猴/猕猴血清白蛋白,啮齿类血清白蛋白如兔血清白蛋白、小鼠白蛋白和大鼠血清白蛋白,牛血清白蛋白,马血清白蛋白,驴血清白蛋白,仓鼠血清白蛋白,山羊血清白蛋白,绵羊血清白蛋白,犬血清白蛋白,豚鼠血清白蛋白,鸡血清白蛋白和猪血清白蛋白。
根据本发明特别优选的白蛋白是具有SEQ ID NO:31或SEQ ID NO:1中所示序列的HSA,且本发明优选的白蛋白域是HSA域I,其组成为SEQ ID NO:31或SEQ ID NO:1的氨基酸残基1至194±1至15个氨基酸;HSA域II,其组成为SEQ ID NO:31或SEQ ID NO:1的氨基酸残基192至387±1至15个氨基酸;和HSA域III,其组成为SEQ ID NO:31或SEQ ID NO:1的氨基酸残基381至585±1至15个氨基酸,或这些域的一个或多个(几个)的组合,例如域1和2,域2和3,或域1和3融合在一起。对于白蛋白域的准确边界并无广泛接受的惯例,且对于每个域,上述提及的范围的重叠以及在域的N端和/或C端允许加减1,2,3,4,5,6,7,8,9,10,11,12,13,14或15个氨基酸,优选1至15个氨基酸,更优选1至10个氨基酸,最优选1至5个氨基酸的变化长度,允许长度上的总变化高至30个氨基酸,优选高至20个氨基酸,更优选高至10个氨基酸,反映了这个事实,且对于在域之间边界上的氨基酸残基属于一个或另一个域可能有一些歧异的观点。出于相同理由,可能可以发现与上述数值不同的对白蛋白域的氨基酸残基的提及,然而,本领域技术人员会了解如何基于文献中的教导和上述教导鉴定白蛋白域。非人白蛋白的对应域可通过与HSA使用Needleman-Wunsch算法(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453)的比对来鉴定,所述算法如EMBOSS软件包(EMBOSS:欧洲分子生物学开放软件组(The European Molecular Biology Open Software Suite),Rice等,2000,Trends Genet.16:276-277)的Needle程序,优选为3.0.0版或之后的版本中执行的。所用的可选参数为缺口开放罚分(gap open penalty)10,缺口延伸罚分(gap extensionpenalty)0.5,和EBLOSUM62(BLOSUM62的EMBOSS版)取代矩阵。亦可使用其它的比对工具,例如本文中所述的MUSCLE。
所述域亦可根据Dockal或Kjeldsen来定义:Dockal等(The Journal ofBiological Chemistry,1999,Vol.274(41):29303–29310)将HSA的域定义为:域I:氨基酸1至197,域II:氨基酸189至385,域III:氨基酸381至585。Kjeldsen等(Protein Expressionand Purification,1998,Vol 13:163–169)将域定义为:域I:氨基酸1至192,域II:氨基酸193至382,域III:氨基酸383至585。
因此,在本发明中,优选下述域定义:氨基酸数对应于SEQ ID NO:31或SEQ ID NO:1(HSA)中的那些。然而,使用这些数,本领域技术人员可鉴定出其它白蛋白序列中的对应域。
域I可以或可以不从氨基酸1起始,且可以或可以不在任何氨基酸192,193,194,195,196或197,优选任何氨基酸192,194或197终止。
域II可以或可以不从氨基酸189,190,191,192或193,优选任何氨基酸189,192或193起始,且可以或可以不在任何氨基酸382,383,384,385,386或387,优选任何氨基酸382,285(385)或387终止。
域III可以或可以不从氨基酸381,382或383,优选氨基酸381或383起始,且可以或可以不在氨基酸585终止。
非人白蛋白中的域可具有与HSA相同或不同的氨基酸长度和/或残基数量。举例而言,可使用HSA和一个或多个(几个)其它白蛋白,片段,衍生物,变体和/或融合物准备多重比对或逐对比对以供鉴定对应于HSA的域1、2和/或3的域。合适的比对的实例在图5中给出。图5使用MUSCLE和Boxshade以对图4所述相同的方式构建。为清楚起见,提供了HSA、绵羊、小鼠、兔和山羊白蛋白的成熟序列(即在前导序列和原(肽)序列之后的第一个氨基酸开始编号),而任何其它提供的白蛋白序列是不成熟序列(即包括前导序列,原肽序列(若存在)和成熟白蛋白序列)。对于人,绵羊,兔,和小鼠白蛋白的域坐标的实例在实施例中给出。可将这些坐标应用于本发明的任何方面。对于所有白蛋白的域坐标可从合适的比对,如图5,通过鉴定对应于一个或多个(几个)HSA的域坐标(如本文中所公开)的氨基酸而鉴定或外推出。通常域坐标使用成熟白蛋白的第一个氨基酸作为位置1来命名,因此前导序列和/或原肽的氨基酸序列通常在此情况下忽略。
第一白蛋白域III,片段或衍生物或其变体,可原则上为任何白蛋白域III,然而优选HSA域III(例如SEQ ID NO:23),片段或衍生物或其变体。
在整个说明书中,包含域I和域II的分子可称作‘DI-DII’或称作‘DI+DII’或称作‘D1+D2’或称作D1-D2’。类似地,包含域I和域III的分子可称作任何的‘DI-DIII’或称作‘DI+DIII’或称作‘D1+D3’或称作D1-D3’。因此,包含域II和域III的分子可称作‘DII-DIII’或称作‘DII+DIII’或称作‘D2+D3’或称作D2-D3’。此外,如“HSA 1/2-RSA 3”的命名意指该分子包含HSA域1,HSA域2和RSA域3,其与HSA域I,HSA域II和RSA域III相同。
对于白蛋白域,术语“衍生物”意指多肽与所述白蛋白域在其天然形式(下文中称作亲本域)具有类似的一级和/或三级结构,但与所述亲本域在一个或多个(几个)位置相差一个或多个(几个)氨基酸残基的一个或多个(几个)取代、插入和/或缺失。所述衍生物可通过人为介入修饰编码亲本域的核酸序列并在合适的宿主生物中使用本领域已知技术表达经修饰的核酸序列来获得。
术语“片段”意指从白蛋白的氨基和/或羧基端和/或白蛋白的内部区缺失一个或多个(几个)氨基酸、保留结合于FcRn的活性的多肽。片段可包含或组成为一个不中断的来源于HSA的序列,或其可包含或组成为两个或更多个来源于HSA的序列。根据本发明的片段具有至少或多于大约20个氨基酸残基,优选至少或多于30个氨基酸残基,更优选至少或多于40个氨基酸残基,更优选至少或多于50个氨基酸残基,更优选至少或多于75个氨基酸残基,更优选至少或多于100个氨基酸残基,更优选至少或多于200个氨基酸残基,更优选至少或多于300个氨基酸残基,甚至更优选至少或多于400个氨基酸残基且最优选至少或多于500个氨基酸残基的大小。
对于本发明的第一白蛋白域III,术语“片段”意指具体相关白蛋白域的保留了结合FcRn的能力的部分。片段可组成为一个不中断的来源于亲本域的序列,或可包含或组成为两个或更多个来源于亲本域的序列。根据本发明的片段具有至少或多于大约20个氨基酸残基,优选至少或多于30个氨基酸残基,更优选至少或多于40个氨基酸残基,更优选至少或多于50个氨基酸残基,更优选至少或多于75个氨基酸残基,且最优选至少或多于100个氨基酸残基的大小。
所述至少一种第二白蛋白域,片段或衍生物或其变体可原则上为任何白蛋白域,片段或衍生物或其变体。
对于本发明的第二白蛋白域,术语“变体”意指具体相关白蛋白域的一部分。片段可组成为一个不中断的来源于亲本域的序列,或可包含或组成为两个或更多个来源于亲本域的序列。根据本发明的片段具有至少或多于大约20个氨基酸残基,优选至少或多于30个氨基酸残基,更优选至少或多于40个氨基酸残基,更优选至少或多于50个氨基酸残基,更优选至少或多于75个氨基酸残基,且最优选至少或多于100个氨基酸残基的大小。
所述第一白蛋白域III,片段或衍生物或其变体,以及所述至少一个第二白蛋白域,片段或衍生物或其变体,可来源于相同物种,或其可来源于不同物种。举例而言,所述第一白蛋白域III,片段或衍生物或其变体可为HSA域III,而所述至少一个第二白蛋白域,片段或衍生物或其变体为小鼠血清白蛋白域II,或所述第一白蛋白域III,片段或衍生物或其变体可为兔血清白蛋白域III而所述至少一个第二白蛋白域,片段或衍生物或其变体为人血清白蛋白域I。
所述白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽包含或组成为至少两个白蛋白域或其片段,且其可包含或组成为多于两个域。原则上对于可组合于根据本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽的白蛋白域或其片段的数量并无上限,然而,优选根据本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽包含或组成为2或3个白蛋白域,最优选2个域。
作为根据本发明优选的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽的实例可提出白蛋白域I+白蛋白域III(例如SEQ ID NO:22),白蛋白域II+白蛋白域III(例如SEQ ID NO:21),白蛋白域III+白蛋白域III(例如SEQ ID NO:24),白蛋白域III+白蛋白域I以及白蛋白域III+白蛋白域II。
优选的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,包含或组成为来源于一个物种的白蛋白域III以及来源于不同物种的白蛋白域I和II。实例包括白蛋白衍生物,其组成为来源于人血清白蛋白的域I和II以及来源于兔血清白蛋白的域III(例如SEQ ID NO:25),衍生物,其组成为来源于兔血清白蛋白的域I和II以及来源于人血清白蛋白的域III(例如SEQID NO:26),衍生物,其组成为来源于绵羊血清白蛋白的域I和II以及来源于人血清白蛋白的域III(例如SEQ ID NO:27),以及衍生物,其组成为来源于人血清白蛋白的域I和域II以及来源于小鼠血清白蛋白的域III(例如SEQ ID NO:29)。这些组合物与衍生物的域III衍生自的完整白蛋白相比,具有令人惊讶地不同的对FcRn的结合性质。
组成为来源于人血清白蛋白的域I和II以及来源于兔血清白蛋白的域III(例如SEQ ID NO:25)的衍生物,组成为来源于绵羊血清白蛋白的域I和II以及来源于人血清白蛋白的域III(例如SEQ ID NO:27)的衍生物,以及组成为来源于人血清白蛋白的域I和II以及来源于小鼠血清白蛋白的域III(例如SEQ ID NO:29)的衍生物与人血清白蛋白相比具有更强的对FcRn的结合。组成为来自兔血清白蛋白的域I和II以及来自人血清白蛋白的域III(例如SEQ ID NO:26)的衍生物与HSA相比具有更弱的对FcRn的结合。亦考虑了衍生物的变体并包含于本发明。
在一个实施方案中白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽中的一个或多个(几个)白蛋白域III在对应于HSA中选自下组一个或多个(几个)的位置的一个或多个位置中包含一个或多个(几个)改变如取代,缺失或插入:417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584,或由在所述位置改变如取代、缺失或插入一个或多个(几个)氨基酸的序列组成。本发明人发现这些氨基酸残基对于血清白蛋白与FcRn受体的相互作用是重要的,且在这些位置的一个或多个的改变会改变根据本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽对于FcRn受体的结合,并由此改变其血浆半寿期。在一个或多个(几个)位置的改变可独立地选自取代、插入和缺失。优选取代。
根据本发明,所述衍生的或变体白蛋白,其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽的白蛋白部分通常具有域III,其与HSA域III的序列(如本文中关于SEQ ID NO:31或SEQ ID NO:1定义的)具有至少60%,优选至少70%,优选至少80%,优选至少81%,82%,83%,84%,85%,86%,87%,88%或89%,优选至少90%,更优选至少95%,更优选至少96%,更优选至少97%,更优选至少98%和最优选至少99%的氨基酸序列同一性。甚至更优选地,根据本发明,所述衍生的或变体白蛋白,其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽的白蛋白部分通常具有域III,其与白蛋白如任何SEQ IDNO:31或SEQ ID NO:1的氨基酸381至585,或SEQ ID NO:4,5,6,7,8,9,10,11,12,13,14,15,16,17,18或19,SEQ ID NO:31或SEQ ID NO:1(人血清白蛋白)的一个或多个(几个)中的等同位置,具有至少60%,优选至少70%,优选至少80%,优选至少81%,82%,83%,84%,85%,86%,87%,88%或89%,优选至少90%,更优选至少95%,更优选至少96%,更优选至少97%,更优选至少98%和最优选至少99%的氨基酸序列同一性。
在一个进一步的实施方案中,根据本发明,所述白蛋白的衍生物或变体,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽具有的血浆半寿期与亲本白蛋白其片段或包含所述亲本白蛋白或其片段或由所述亲本白蛋白或其片段组成的融合多肽的血浆半寿期相比更长。根据该实施方案的实例包括白蛋白的衍生物或变体,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽,它们包含或由如下组成:在对应于HSA中下组的一个或多个(几个)位置中的一个或多个(几个)取代:E492,N503,D550和K573。优选对应于HSA中E492的位置的氨基酸在用G残基取代,在对应于在HSA中的N503的位置的氨基酸用H或K残基取代,在对应于的位置的氨基酸D550在HSA中用取代E残基,而在对应于在HSA中的K573的位置的氨基酸用A或P残基取代。同样优选的是衍生物或变体,其中对应于在HSA中的E492的氨基酸用G残基取代,而对应于在HSA中的K573的氨基酸用A或P残基取代。其它优选的衍生物或变体具有多个取代,分别对应于在HSA中的E492用H残基,在HSA中的E501用P,在HSA中的N503用H,在HSA中的E505用D,在HSA中的T506用S,在HSA中的T540用S,在HSA中的K541用E取代。
在一个进一步的实施方案中,根据本发明,白蛋白的衍生物或变体,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽具有的血浆半寿期与亲本白蛋白其片段或包含所述亲本白蛋白或其片段或由所述亲本白蛋白或其片段组成的融合多肽的血浆半寿期相比更短。根据该实施方案的实例包括白蛋白的衍生物或变体,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽,它们在对应于HSA中下组的一个或多个(几个)位置中包含取代:Q417,H440,H464,D494,E495,T496,P499,K500,E501,H510,H535,K536,P537,K538,K541,D550N,D494+T496或E492+V493。优选的取代包括对应于在HSA中Q417A,H440A,H464Q,D494E+Q417H,D494N,Q,A,E495Q,A,T496A,D494N+T496A或,P499A,K500A E501A,E501Q,H510Q,H535Q,K536A,P537A,K538A,K541G,K541A K541D或D550N的取代。
除了在对应于下组位置的一个或多个(几个)位置中的一个或多个(几个)取代、插入或缺失(其中优选取代)之外:SEQ ID NO:31或SEQ ID NO:1的417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584,根据本发明的衍生的或变体白蛋白,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽可在分子的其它位置包含其它取代、缺失或插入。此类其它的取代、缺失或插入可用于改变分子的其它性质,如但不限于改变的糖基化;导入表面的反应性基团如巯基基团,去除/生成氨甲酰化位点等等。
可加以改变以在表面上提供反应性残基并可有利地应用于本发明的残基已在未公开的专利申请EP 2009 152 625(通过提述并入本文)中披露。特别优选的残基包括对应于HSA中在与FcRn相互作用的区之外的位置的位置。
作为可在SEQ ID NO:31或SEQ ID NO:1中或在其它白蛋白中的相应位置(如SEQID NO:4至19中)进行以在表面上提供反应性巯基基团的改变的实例包括:L585C,D1C,A2C,D562C,A364C,A504C,E505C,T79C,E86C,D129C,D549C,A581C,D121C,E82C,S270C,A578C,L595LC,D1DC,A2AC,D562DC,A364AC,A504AC,E505EC,T79TC,E86EC,D129DC,D549DC,A581AC,A581AC,D121DC,E82EC,S270SC,A579AC,C360*,C316*,C75*,C168*,C558*,C361*,C91*,C124*,C169*和C567*。或者,可将半胱氨酸残基添加至白蛋白的N端或C端区。
在一个实施方案中,在本发明的衍生物或变体中的改变的数量为1至20个氨基酸,例如1至10和1至5,如1,2,3,4,5,6,7,8,9或10个改变。
所述衍生的或变体白蛋白,其片段或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽与亲本白蛋白域,其片段,或包含所述衍生的或变体白蛋白域或其片段或由所述衍生的或变体白蛋白域或其片段组成的融合多肽相比具有改变的血浆半寿期。
在一个特别优选的实施方案中,亲本白蛋白域来自HSA,而衍生的或变体白蛋白,其片段或包含所述衍生的或变体白蛋白域或其片段或由所述衍生的或变体白蛋白域或其片段组成的融合多肽与HSA域,对应片段或包含HSA域或其片段或由HSA域或其片段组成的融合多肽相比具有改变的血浆半寿期。
一种确定衍生的或变体白蛋白对FcRn的亲和力与亲本白蛋白相比是更高或是更低的方法是使用如下文中所述的表面等离子共振测定法(Surface Plasmon Resonance,SPR)。本领域技术人员会理解其它方法可用于确定衍生的或变体白蛋白对FcRn的亲和力与亲本白蛋白对FcRn的亲和力相比是更高或是更低,例如,确定并比较结合常数KD。因此,根据本发明,具有与天然HSA的KD相比较低KD的衍生的或变体白蛋白视为与HSA相比具有更高血浆半寿期,而具有与天然HSA的KD相比较高KD的变体白蛋白视为与HSA相比具有更低血浆半寿期。
所述白蛋白的衍生物或变体或其片段或包含白蛋白或其片段或由白蛋白或其片段组成的融合多肽包含或由如下组成:在对应于HSA(SEQ ID NO:31或SEQ ID NO:1)中选自下组的位置的一个或多个(几个)位置的一个或多个(几个)改变,如取代,缺失或插入:417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584。所述取代可为任何取代,其中在天然白蛋白序列中的氨基酸用选自剩余19中天然存在的氨基酸的不同氨基酸取代。为了避免疑问,本领域技术人员可使用本文中使用的命名法鉴定在HSA的域中或在另一个白蛋白的白蛋白、域或片段中的位置。
在一个实施方案中,衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584的一个或多个(几个)位置包含改变。在另一个实施方案中,衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中下述任何的两个位置包含改变:417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584。在另一个实施方案中,衍生物或变体在对应于SEQ IDNO:31或SEQ ID NO:1中下述任何位置的三个位置包含改变:417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584。在另一个实施方案中,衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中位置417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584的各个位置包含改变。
在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代Q417A,H。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:1的成熟多肽的取代H440Q。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ IDNO:1的成熟多肽的取代H464Q。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A490D。在另一个实施方案中,所述衍生物或变体包含SEQID NO:31或SEQ ID NO:1的成熟多肽的取代E492G,T,P,H。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代V493P,L。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的D494N,Q,A,E,P。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代E495Q,A。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代T496A。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代P499A。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的K500E,G,D,A,S,C,P,H,F,N,W,T,M,Y,V,Q,L,I,R。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代E501A,P,Q。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ IDNO:1的成熟多肽的取代N503K,D,H。在另一个实施方案中,所述衍生物或变体包含SEQ IDNO:31或SEQ ID NO:1的成熟多肽的取代A504E。在另一个实施方案中,所述衍生物或变体SEQ ID NO:31或SEQ ID NO:1的成熟多肽的包含取代E505K,D。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代T506F,S。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H510Q。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H535Q。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K536A。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ IDNO:1的成熟多肽的取代P537A。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K538A,H。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代T540S。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K541A,D,G,N,E。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代E542P,D。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代D550N。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K573Y,W,P,H,F,V,I,T,N,S,G,M,C,A,E,Q,R,L,D。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K574N。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代Q580K。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代L575F。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A577T,E。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQID NO:1的成熟多肽的取代A578R,S。在另一个实施方案中,所述衍生物或变体包含SEQ IDNO:31或SEQ ID NO:1的成熟多肽的取代S579C,T。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代Q580K。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A581D。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A582T。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代G584A。
在一个实施方案中,所述衍生物或变体在对应于位置417的位置包含改变。在另一个实施方案中,在对应于位置417的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala或His取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代Q417A,H。
在另一个实施方案中,所述衍生物或变体在对应于位置440的位置包含改变。在另一个实施方案中,在对应于位置440的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H440Q。
在另一个实施方案中,所述衍生物或变体在对应于位置464的位置包含改变。在另一个实施方案中,在对应于位置464的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H464Q。
在另一个实施方案中,所述衍生物或变体在对应于位置490的位置包含改变。在另一个实施方案中,在对应于位置490的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A490G。
在另一个实施方案中,所述衍生物或变体在对应于位置492的位置包含改变。在另一个实施方案中,在对应于位置492的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Gly取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的E492G。
在另一个实施方案中,所述衍生物或变体在对应于位置493的位置包含改变。在另一个方面,在对应于位置493的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Pro取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的V493P。
在另一个实施方案中,所述衍生物或变体在对应于位置494的位置包含改变。在另一个实施方案中,在对应于位置494的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Asn,Gln或Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代D494N,Q,A。
在另一个实施方案中,所述衍生物或变体在对应于位置495的位置包含改变。在另一个实施方案中,在对应于位置495的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Gln或Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代E495Q或A。
在另一个实施方案中,所述衍生物或变体在对应于位置496的位置包含改变。在另一个实施方案中,在对应于位置496的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的T496A。
在另一个实施方案中,所述衍生物或变体在对应于位置499的位置包含改变。在另一个实施方案中,在对应于位置499的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的P499A。
在另一个实施方案中,所述衍生物或变体在对应于位置500的位置包含改变。在另一个实施方案中,在对应于位置500的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K500E,G,D,A,S,C,P,H,F,N,W,T,M,Y,V,Q,L,I,R。
在另一个实施方案中,所述衍生物或变体在对应于位置501的位置包含改变。在另一个实施方案中,在对应于位置501的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代,优选用Ala或Gln取代以减少亲和力而用Pro取代以增加亲和力。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代E501A,Q,P。
在另一个实施方案中,所述衍生物或变体在对应于位置503的位置包含改变。在另一个实施方案中,在对应于位置503的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Asp或Lys或His取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代N503D,K,H。
在另一个实施方案中,所述衍生物或变体在对应于位置504的位置包含改变。在另一个实施方案中,在对应于位置504的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A504。
在另一个实施方案中,所述衍生物或变体在对应于位置505的位置包含改变。在另一个实施方案中,在对应于位置505的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的E505D。
在另一个实施方案中,所述衍生物或变体在对应于位置506的位置包含改变。在另一个实施方案中,在对应于位置506的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的T506S,F。
在另一个实施方案中,所述衍生物或变体在对应于位置510的位置包含改变。在另一个实施方案中,在对应于位置510的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Gln取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H510Q。
在另一个实施方案中,所述衍生物或变体在对应于位置535的位置包含改变。在另一个实施方案中,在对应于位置535的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Gln取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代H535Q。
在另一个实施方案中,所述衍生物或变体在对应于位置536的位置包含改变。在另一个实施方案中,在对应于位置536的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含取SEQ ID NO:31或SEQ ID NO:1的成熟多肽的代K536A。
在另一个实施方案中,所述衍生物或变体在对应于位置537的位置包含改变。在另一个实施方案中,在对应于位置537的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代P537A。
在另一个实施方案中,所述衍生物或变体在对应于位置538的位置包含改变。在另一个实施方案中,在对应于位置538的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K538H,A。
在另一个实施方案中,所述衍生物或变体在对应于位置540的位置包含改变。在另一个实施方案中,在对应于位置540的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代T540S。
在另一个实施方案中,所述衍生物或变体在对应于位置541的位置包含改变。在另一个实施方案中,在对应于位置541的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Gly,Asp或Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K541G,D,A,N。
在另一个实施方案中,所述衍生物或变体在对应于位置542的位置包含改变。在另一个实施方案中,在对应于位置542的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Asp或Pro取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的E542D,P。
在另一个实施方案中,所述衍生物或变体在对应于位置550的位置包含改变。在另一个实施方案中,在对应于位置550的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val取代,优选用Asn取代以减少亲和力,优选用Glu取代以增加亲和力。
在另一个实施方案中,所述衍生物或变体在对应于位置573的位置包含改变。在另一个实施方案中,在对应于位置573的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Tyr,Trp,Pro,His,Phe,Val,Ile,Thr,Asn,Ser,Gly,Met,Cys,Ala,Glu,Gln,Arg,Leu,Asp取代。在另一个实施方案中,所述衍生物或变体包含取代SEQ ID NO:31或SEQ ID NO:1的成熟多肽的K573Y,W,P,H,F,V,I,T,N,S,G,M,C,A,E,Q,R,L,D。
在另一个实施方案中,所述衍生物或变体在对应于位置574的位置包含改变。在另一个实施方案中,在对应于位置574的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Asn取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代K574N。
在另一个实施方案中,所述衍生物或变体在对应于位置575的位置包含改变。在另一个实施方案中,在对应于位置575的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Phe取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代L575F。
在另一个实施方案中,所述衍生物或变体在对应于位置577的位置包含改变。在另一个实施方案中,在对应于位置577的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Thr或Glu取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A577TE。
在另一个实施方案中,所述衍生物或变体在对应于位置578的位置包含改变。在另一个实施方案中,在对应于位置578的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Arg或Ser取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A578R,S。
在另一个实施方案中,所述衍生物或变体在对应于位置579的位置包含改变。在另一个实施方案中,在对应于位置579的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Cys或Thr取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代S579C,T。
在另一个实施方案中,所述衍生物或变体在对应于位置580的位置包含改变。在另一个实施方案中,在对应于位置580的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Lys取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代Q580K。
在另一个实施方案中,所述衍生物或变体在对应于位置581的位置包含改变。在另一个实施方案中,在对应于位置581的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Asp取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A581D。
在另一个实施方案中,所述衍生物或变体在对应于位置582的位置包含改变。在另一个实施方案中,在对应于位置582的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Thr取代。在另一个实施方案中,所述衍生物或变体包含TSEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代A582T。
在另一个实施方案中,所述衍生物或变体在对应于位置584的位置包含改变。在另一个实施方案中,在对应于位置584的位置的氨基酸用Ala,Arg,Asn,Asp,Cys,Gln,Glu,Gly,His,Ile,Leu,Lys,Met,Phe,Pro,Ser,Thr,Trp,Tyr,或Val,优选用Ala取代。在另一个实施方案中,所述衍生物或变体包含SEQ ID NO:31或SEQ ID NO:1的成熟多肽的取代G584A。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置494和496的位置包含改变,如上述那些。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492和493的位置包含改变,如上述那些。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置494和417的位置包含改变,如上述那些。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492和503的位置包含改变,如上述那些。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492和573的位置包含改变,如上述那些。
在另一个实施方案中,所述衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492,503,和573的位置包含改变,如上述那些。
在一个实施方案中,根据本发明,所述衍生的或变体白蛋白或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽在对应于HSA中选自下组的位置的位置含有一个取代:SEQ ID NO:31或SEQ ID NO:1中的417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584,条件是所述衍生的或变体白蛋白并非由具有取代D494N,E501K,K541E,D550G,A,K573E或K574N的SEQ ID NO:31或SEQ ID NO:1组成的衍生物或变体。根据本发明,所述衍生的或变体白蛋白,其片段或包含衍生的或变体白蛋白或其片段的融合多肽在对应于在HSA中的其它位置的一个或多个(几个)位置可包含其它取代、插入或缺失。
在另一个实施方案中,根据本发明,所述衍生的或变体白蛋白或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽在对应于HSA中选自下组的位置的位置含有两个,三个,四个,五个,六个,七个,八个,九个,十个,十一个,十二个,十三个,十四个,十五个,十六个,十七个,十八个,十九个,二十个或甚至更多取代:SEQ ID NO:31或SEQ ID NO:1的417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584。根据本发明,所述衍生的或变体白蛋白或其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽可在对应于HSA中其它位置的位置包含其它取代、插入或缺失。
在一个进一步的实施方案中,根据本发明,所述白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽具有的血浆半寿期与亲本白蛋白,其片段或包含亲本白蛋白或其片段或由亲本白蛋白或其片段组成的融合多肽的血浆半寿期相比更长。根据该实施方案的实例包括白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽,它们在对应于SEQ ID NO:31或SEQ ID NO:1中的492,503,542,550,573,574,580,581,582或584的位置包含取代。根据本发明的该实施方案,优选的取代包括对应于SEQ ID NO:31或SEQ ID NO:1中492的位置的氨基酸用G残基取代,对应于SEQ ID NO:31或SEQ ID NO:1中503的位置的氨基酸用H或K残基取代,对应于SEQ IDNO:31或SEQ ID NO:1中的位置550的氨基酸用E残基取代,在对应于SEQ ID NO:31或SEQ IDNO:1中的位置573的氨基酸用Y,W,P,H,F,V,I,T,N,S,G,M,C,A,E,Q,R,L或D残基取代,在对应于SEQ ID NO:31或SEQ ID NO:1中的位置574的氨基酸残基用N残基取代,或对应于SEQID NO:31或SEQ ID NO:1中的位置580的氨基酸用K残基取代。其它优选的衍生物或变体在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492具有用G残基的取代和在对应于SEQ IDNO:31或SEQ ID NO:1中的位置573具有用用A或P残基的取代。其它优选的衍生物或变体具有多个取代,其对应于SEQ ID NO:31或SEQ ID NO:1中的位置492及在SEQ ID NO:31或SEQID NO:1中位置503用H残基的取代。
其它优选的衍生物或变体具有在对应于SEQ ID NO:31或SEQ ID NO:1中的位置492用G残基的取代和在对应于SEQ ID NO:31或SEQ ID NO:1中的位置503用H或K的取代和在对应于SEQ ID NO:31或SEQ ID NO:1中的位置573用A或P残基的取代。
在一个进一步的实施方案中,根据本发明,所述白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段或由所述衍生的或变体白蛋白或其片段组成的融合多肽具有的血浆半寿期与亲本白蛋白,其片段或包含亲本白蛋白或其片段的融合多肽的血浆半寿期相比更短。根据该实施方案的实例包括白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽,它们在对应于SEQ ID NO:31或SEQ IDNO:1中的417,440,494,495,496,499,500,501,536,537,538,541,494+496或492+493的位置包含取代。优选的取代包括对应于SEQ ID NO:31或SEQ ID NO:1中的Q417A,H440Q,D494E+Q417H,D494N,Q,A,E495Q,A,T496A,D494N+T496A或,P499A,K500A,E501A,E501Q,K536A,P537A,K538A,K541G,K541A K541D或D550N的取代。
在本发明的另一个实施方案中,根据本发明,所述白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽丧失了结合FcRn的能力。与此相关,所述白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽视为丧失结合FcRn的能力,若在下文中所述的SPR测定中对所述衍生物或变体测得的共振单位低于对于相应的亲本白蛋白或其片段测得的共振单位的10%。根据该实施方案的实例包括白蛋白的衍生物或变体或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽,它们在对应于SEQ ID NO:31或SEQ ID NO:1中的464,500,510或535的位置包含取代。优选的取代包括对应于SEQ ID NO:31或SEQ ID NO:1中的H464Q,K500A,P,C,S,A,D,GH510Q或H535Q的取代。
除了在对应于SEQ ID NO:31或SEQ ID NO:1中的位置417,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,580 581,582和584的一个或多个(几个)位置的一个或多个(几个)取代之外,根据本发明的所述衍生的或变体白蛋白或其片段,或包含所述衍生的或变体白蛋白或其片段的融合多肽在分子的其它位置可含有其它取代、缺失或插入。此类其它的取代、缺失或插入可用于改变分子的其它性质,如但不限于改变的糖基化;导入表面的反应性基团如巯基基团,去除/生成氨甲酰化位点等等。
可加以改变以在表面上提供反应性残基并可有利地应用于本发明的残基已在未公开的专利申请WO 2010/092135(通过提述并入本文)中披露。特别优选的残基包括对应于SEQ ID NO:31或SEQ ID NO:1中的位置的位置。
作为可在SEQ ID NO:31或SEQ ID NO:1中或其它白蛋白的相应位置加以改变以提供表面上的活性巯基基团的改变包括对应于SEQ ID NO:31或SEQ ID NO:1中下述改变的改变:L585C,D1C,A2C,D562C,A364C,A504C,E505C,T79C,E86C,D129C,D549C,A581C,D121C,E82C,S270C,A578C,L595LC,D1DC,A2AC,D562DC,A364AC,A504AC,E505EC,T79TC,E86EC,D129DC,D549DC,A581AC,A581AC,D121DC,E82EC,S270SC,A579AC,C360*,C316*,C75*,C168*,C558*,C361*,C91*,C124*,C169*和C567*。或者,可将半胱氨酸残基添加至白蛋白的N或C端。
在第二个方面,本发明涉及分离的多核苷酸,其编码本发明的任何多肽,例如,(1)核酸,其编码白蛋白衍生物或变体,其片段,或包含所述白蛋白衍生物或变体或其片段的融合多肽,(ii)包含所述核酸的质粒,和(iii)包含所述质粒的宿主细胞。本发明亦涉及核酸构建体,其包含编码本发明的衍生物或变体的多核苷酸,所述多核苷酸可操作地连接于一个或多个(几个)调控序列,所述调控序列指导所述编码序列在合适的宿主细胞中在与所述调控序列相容的条件下表达。在本发明的该第二个方面,所述亲本优选由多核苷酸编码,所述多核苷酸在非常低严格条件,低严格条件,中等严格条件,中-高严格条件,高严格条件或非常高严格条件下与以下杂交:(i)SEQ ID NO:2的成熟多肽编码序列(SEQ ID NO:3:NCBIReference Sequence:NM_000477.5,SEQ ID NO:3为基因组DNA);(ii)编码成熟多肽的cDNA序列(cDNA是SEQ ID NO:2);或(iii)(i)或(ii)的全长互补链(J.Sambrook,E.F.Fritsch和T.Maniatis,1989,Molecular Cloning,A Laboratory Manual,第2版,Cold SpringHarbor,New York)。
SEQ ID NO:2的多核苷酸或其亚序列,以及SEQ ID NO:2的氨基酸序列或其片段,可用于设计核酸探针,以根据本领域内公知的方法从不同属和种的菌株鉴定和克隆编码亲本的DNA。具体而言,根据标准的Southern印迹方法,可将这些探针用于与感兴趣的属或种的基因组或cDNA杂交,以鉴定和从其中分离相应的基因。这些探针可明显短于完整序列,但长度上应为至少14,例如至少25,至少35,或至少70个核苷酸。优选地,所述核酸探针是至少100个核苷酸长度,例如,至少200个核苷酸,至少300个核苷酸,至少400个核苷酸,至少500个核苷酸,至少600个核苷酸,至少700个核苷酸,至少800个核苷酸,或至少900个核苷酸的长度。DNA和RNA探针二者均可使用。通常将探针标记以检测相应的基因(例如,用32P、3H、35S、生物素或抗生物素蛋白(avidin)标记)。本发明涵盖此类探针。
可从由这些其它生物体制备的基因组DNA或cDNA文库中筛选与上述探针杂交并编码亲本的DNA。可以通过琼脂糖或聚丙烯酰胺凝胶电泳,或通过其它分离技术分离来自这些其它生物体的基因组或其它DNA。可以将来自文库的DNA或分离的DNA转移至硝化纤维素(nitrocellulose)或其它合适的载体材料并且固定于其上。为了鉴定与SEQ ID NO:2或其亚序列同源的克隆或DNA,将所述载体材料用在Sounthern印迹中。
就本发明而言,杂交表示多核苷酸在非常低至非常高的严格条件下与标记的核苷酸探针杂交,所述核苷酸探针对应于SEQ ID NO:2中所示的多核苷酸,其互补链,或其亚序列。可使用例如X射线片(X-ray film)或任何其他本领域中已知的检测手段来检测与所述探针杂交的分子。
在一个实施方案中,所述核酸探针是SEQ ID NO:2的成熟多肽编码序列。在另一个实施方案中,所述核酸探针是SEQ ID NO:2的核苷酸1至1758。在另一个方面,所述核酸探针是编码SEQ ID NO:1的多肽或其片段的多核苷酸。在另一个方面,所述核酸探针是SEQ IDNO:2。
对于长度至少100个核苷酸的长探针,将非常低至非常高的严格条件定义为在42℃,在5X SSPE、0.3%SDS、200μg/ml已剪切并且变性的鲑精DNA中,并且对于非常低和低严格性为25%的甲酰胺、对于中和中-高严格性为35%的甲酰胺、或对于高和非常高严格性为50%的甲酰胺,根据标准的Southern印迹法进行预杂交和杂交最佳12至24小时。使用2XSSC、0.2%SDS在45℃(非常低严格性),在50℃(低严格性),在55℃(中严格性),在60℃(中-高严格性),在65℃(高严格性),或70℃(非常高严格性)将载体材料最终洗涤三次,每次15分钟。
对于长度大约15个核苷酸至大约70个核苷酸的短探针,将严格条件定义为在比使用根据Bolton和McCarthy的计算法(1962,Proc.Natl.Acad.Sci.USA 48:1390)计算出的Tm低大约5℃至大约10℃,在0.9M NaCl,0.09M Tris-HCl pH 7.6,6mM EDTA,0.5%NP-40,1×Denhardt溶液,1mM焦磷酸钠(sodium pyrophosphate),1mM磷酸二氢钠(sodium monobasicphosphate),0.1mM ATP和0.2mg每ml的酵母RNA中,根据标准的Southern印迹步骤进行预杂交和杂交最佳12至24小时。将所述载体材料在6×SSC加0.1%SDS中最终洗涤一次15分钟,并用6×SSC在比计算的Tm低5℃至10℃的温度洗涤两次,每次15分钟。
所述亲本可由多核苷酸编码,所述多核苷酸与SEQ ID NO:2的成熟多肽编码序列具有至少60%,例如至少65%,至少70%,至少75%,至少80%,至少85%,至少90%,至少95%,至少96%,至少97%,至少98%,至少99%,或100%序列同一性,并编码能够作为白蛋白起作用的多肽。在一个实施方案中,所述亲本由包含SEQ ID NO:2或由SEQ ID NO:2组成的多核苷酸编码。
根据本发明的第三个方面,根据本发明的白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段的融合蛋白可使用本领域中公知的技术缀合于第二分子。所述第二分子可包含诊断模块或由诊断模块组成,且在该实施方案中所述缀合可用作如在显影中的诊断工具,或所述第二分子可为治疗化合物,且在该实施方案中所述缀合物可用于治疗目的,其中所述缀合物具有所述治疗化合物的治疗特性以及白蛋白的改变的血浆半寿期,这来源于其与白蛋白衍生物,片段,其变体的缀合。白蛋白和治疗分子的缀合物在本领域中是已知的,且已验证此类缀合物与未缀合的游离的治疗分子本身相比具有较长的血浆半寿期。所述缀合物可方便地通过白蛋白衍生物,片段,衍生物或其变体的表面上存在的游离巯基基团连接。该巯基基团的存在可为天然存在的(例如,所述游离巯基基团可等同于成熟HSA的氨基酸残基34),或使用遗传工程和缀合物化学领域公知的技术工程改造入该多肽。或者,所述缀合物可通过HSA域III衍生物,片段,或其变体的表面上提供的其它游离巯基基团连接,例如如于共同未决的专利申请(EP 2009 152 625.1,通过提述并入本文)公开的。
根据本发明的白蛋白缀合物的半寿期与缀合伴侣分子自身的半寿期相比可更长或更短。根据本发明的白蛋白缀合物的半寿期与包含天然HSA(而非根据本发明的白蛋白变体或衍生物)和该缀合分子的类似/等同的白蛋白缀合物的半寿期相比可为更长或更短。
在一个特别优选的实施方案中,将所述衍生的或变体白蛋白及其片段缀合于有益的治疗化合物,并将该缀合物用于治疗有此需要的患者中的病状,其中所述病状响应该特别选定的治疗化合物。用于将此种治疗化合物缀合于衍生的或变体白蛋白或其片段的技术在本领域中是已知的。WO 2009/019314公开了适于将治疗化合物缀合于多肽的技术的实例,且该技术亦可适用于本发明。此外,WO 2009/019314公开了可缀合于取代的转铁蛋白的化合物和模块的实例,且这些实例亦可应用于本发明。WO 2009/019314的教导通过提述并入本文。
HSA以其天然形式含有一个游离巯基基团,其可方便地用于缀合。作为该实施方案中的具体实施方案,所述衍生的或变体白蛋白或其片段可包含提供用于在其表面生成其他游离巯基基团的进一步修饰。这具有下述益处:使得所述衍生的或变体白蛋白或其片段的有效负载增加,从而可将超过一个分子的治疗化合物缀合于每分子的衍生的或变体白蛋白或其片段,或可将两个或更多个不同的治疗化合物缀合于每分子的衍生的或变体白蛋白或其片段,例如,将具有靶向特性的化合物如对例如肿瘤具特异性的抗体;以及细胞毒性药物缀合于衍生的或变体白蛋白或其片段,由此构建针对肿瘤的高度特异性药物。对可修饰以在表面提供更多游离巯基基团的特定残基的教导亦可见于共同未决的专利申请WO 2010/092135,其通过提述并入本文。
根据本发明的第四个方面,根据本发明的白蛋白衍生物,片段,及其变体亦可与非白蛋白多肽融合伴侣相融合。所述融合伴侣原则上可为任何多肽,但一般优选所述融合伴侣是具有治疗或诊断特性的多肽。包含白蛋白的融合多肽在本领域中是已知的。已发现此种包含白蛋白以及融合伴侣多肽或由白蛋白以及融合伴侣多肽组成的融合多肽与未融合的融合伴侣多肽自身相比具有较长的血浆半寿期。根据本发明,可改变本发明的融合多肽相对于现有技术的相应融合多肽的血浆半寿期。关于白蛋白与融合伴侣多肽的融合的进一步教导,以及合适的融合伴侣多肽的实例可见于WO 01/79271A和WO 03/59934A。根据本发明的白蛋白融合物的半寿期与融合伴侣多肽自身的半寿期相比可更长或更短。根据本发明的白蛋白融合物的半寿期与包含天然HSA(而非根据本发明的白蛋白变体或衍生物)和该融合伴侣或由天然HSA和该融合伴侣组成的类似/等同的白蛋白融合物的半寿期相比可为更长或更短。
对于本发明的所有方面,融合伴侣多肽和/或缀合物可包含下述一种或多种(几种):4-1BB配体,5-螺旋,人C-C趋化因子,人L105趋化因子,命名为huL105_3.的人L105趋化因子,由γ-干扰素诱导的单核因子(MIG),部分CXCR4B蛋白,血小板碱性蛋白(PBP),α1-抗胰蛋白酶,ACRP-30类似物;补体成分C1q C,腺样-表达的趋化因子(ADEC),aFGF;FGF-1,AGF,AGF蛋白,白蛋白,依托泊苷(etoposide),血管他丁(angiostatin),炭疽疫苗,对脑衰蛋白有特异性的抗体,antistasin,抗TGFβ家族抗体,抗凝血酶III(antithrombin III),APM-1;ACRP-30;Famoxin,载脂蛋白物种(apo-lipoprotein species),芳基硫酸酯酶B(Arylsulfatase B),b57蛋白,BCMA,Β-血小板球蛋白(β-TG),bFGF;FGF2,凝血因子,BMP加工酶Furin,BMP-10,BMP-12,BMP-15,BMP-17,BMP-18,BMP-2B,BMP-4,BMP-5,BMP-6,BMP-9,骨形态形成蛋白-2,降钙素(calcitonin),钙激活中性蛋白酶-10a,钙激活中性蛋白酶-10b,钙激活中性蛋白酶-10c,癌症疫苗,羧肽酶,C-C趋化因子,MCP2,CCR5变体,CCR7,CCR7,CD11a Mab,CD137;4-1BB受体蛋白,CD20Mab,CD27,CD27L,CD30,CD30配体,CD33免疫毒素,CD40,CD40L,CD52Mab,Cerebus蛋白,嗜酸细胞活化趋化因子(Chemokine Eotaxin),趋化因子hIL-8,趋化因子hMCP1,趋化因子hMCP1a,趋化因子hMCP1b,趋化因子hMCP2,趋化因子hMCP3,趋化因子hSDF1b,趋化因子MCP-4,趋化因子TECK和TECK变体,趋化因子样蛋白IL-8M1全长和成熟,趋化因子样蛋白IL-8M10全长和成熟,趋化因子样蛋白IL-8M3,趋化因子样蛋白IL-8M8全长和成熟,趋化因子样蛋白IL-8M9全长和成熟,趋化因子样蛋白PF4-414全长和成熟,趋化因子样蛋白PF4-426全长和成熟,趋化因子样蛋白PF4-M2全长和成熟,霍乱疫苗,Chondromodulin样蛋白,c-kit配体;SCF;肥大细胞生长因子;MGF;纤维肉瘤来源的干细胞因子,CNTF及其片段(如CNTFAx15`(AxokineTM)),前体或活性形式的凝血因子,胶原,补体C5Mab,结缔组织活化蛋白-III,CTAA16.88Mab,CTAP-III,CTLA4-Ig,CTLA-8,CXC3,CXC3,CXCR3;CXC趋化因子受体3,cyanovirin-N,Darbepoetin,命名为exodus,命名为huL105_7.,DIL-40,DNA酶,EDAR,EGF受体Mab,ENA-78,内皮他丁(Endostatin),嗜酸细胞活化趋化因子(Eotaxin),上皮嗜中性粒细胞活化蛋白-78,EPO受体;EPOR,红细胞生成素(erythropoietin)(EPO)和EPO模拟物,优托品(Eutropin),Exodus蛋白,因子IX,因子VII,因子VIII,因子X和因子XIII,FAS配体抑制蛋白(DcR3),FasL,FasL,FasL,FGF,FGF-12;成纤维细胞生长因子同源因子-1,FGF-15,FGF-16,FGF-18,FGF-3;INT-2,FGF-4;白树霉素(gelonin),HST-1;HBGF-4,FGF-5,FGF-6;肝素结合分泌的转化因子-2(Heparin bindingsecreted transforming factor-2),FGF-8,FGF-9;神经胶质活化因子,纤维蛋白原(fibrinogen),flt-1,flt-3配体,促卵泡激素α亚基,促卵泡激素β亚基,促卵泡素(Follitropin),Fractalkine,片段,肌纤维蛋白肌钙蛋白I(Troponin I),FSH,半乳糖苷酶(Galactosidase),半乳凝素-4(Galectin-4),G-CSF,GDF-1,基因疗法,神经胶质瘤-衍生的生长因子,胰高血糖素,胰高血糖素样肽,葡糖脑苷酯酶(Glucocerebrosidase),葡糖氧化酶(glucose oxidase),葡糖苷酶(Glucosidase),Glycodelin-A;黄体酮相关子宫内膜蛋白,GM-CSF,促性腺素(gonadotropin),粒细胞趋化蛋白-2(GCP-2),粒细胞-巨噬细胞集落刺激因子,生长激素,生长相关癌基因-α(GRO-α),生长相关癌基因β(GRO-β),生长相关癌基因γ(GRO-γ),hAPO-4;TROY,hCG,乙型肝炎表面抗原,乙型肝炎疫苗,HER2受体Mab,水蛭素(hirudin),HIV gp120,HIV gp41,HIV抑制肽,HIV抑制肽,HIV抑制肽,HIV蛋白酶抑制肽,HIV-1蛋白酶抑制剂,HPV疫苗,人6CKine蛋白,人Act-2蛋白,人脂肪形成抑制因子,人B细胞刺激因子-2受体,人β-趋化因子H1305(MCP-2),人C-C趋化因子DGWCC,人CC趋化因子ELC蛋白,人CC型趋化因子白细胞介素C,人CCC3蛋白,人CCF18趋化因子,命名为SLC(二级淋巴趋化因子)的人CC-型趋化因子蛋白,人趋化因子β-8短形式(short form),人趋化因子C10,人趋化因子CC-2,人趋化因子CC-3,人趋化因子CCR-2,人趋化因子Ckβ-7,人趋化因子ENA-78,人趋化因子嗜酸细胞活化趋化因子,人趋化因子GROα,人趋化因子GROα,人趋化因子GROβ,人趋化因子HCC-1,人趋化因子HCC-1,人趋化因子I-309,人趋化因子IP-10,人趋化因子L105_3,人趋化因子L105_7,人趋化因子MIG,人趋化因子MIG-β蛋白,人趋化因子MIP-1α,人趋化因子MIP1β,人趋化因子MIP-3α,人趋化因子MIP-3β,人趋化因子PF4,人趋化因子蛋白331D5,人趋化因子蛋白61164,人趋化因子受体CXCR3,人趋化因子SDF1α,人趋化因子SDF1β,人趋化因子ZSIG-35,人Chr19Kine蛋白,人CKβ-9,人CKβ-9,人CX3C 111氨基酸趋化因子,人DNAX白细胞介素-40,人DVic-1C-C趋化因子,人EDIRF I蛋白序列,人EDIRF II蛋白序列,人嗜曙红细胞CC型趋化因子嗜酸细胞活化趋化因子,人嗜曙红细胞-表达的趋化因子(EEC),人快速颤搐骨骼肌肌钙蛋白C(Human fast twitch skeletal muscle troponinC),人快速颤搐骨骼肌肌钙蛋白I,人快速颤搐骨骼肌肌钙蛋白亚基C,人快速颤搐骨骼肌肌钙蛋白亚基I蛋白,人快速颤搐骨骼肌肌钙蛋白亚基T,人快速颤搐骨骼肌肌钙蛋白T,人胎儿脾脏表达的趋化因子,FSEC,人GM-CSF受体,人gro-α趋化因子,人gro-β趋化因子,人gro-γ趋化因子,人IL-16蛋白,人IL-1RD10蛋白序列,人IL-1RD9,人IL-5受体α链,人IL-6受体,人IL-8受体蛋白hIL8RA,人IL-8受体蛋白hIL8RB,人IL-9受体蛋白,人IL-9受体蛋白变体#3,人IL-9受体蛋白变体片段,人IL-9受体蛋白变体片段#3,人白细胞介素1δ,人白细胞介素10,人白细胞介素10,人白细胞介素18,人白细胞介素18衍生物,人白细胞介素-1β前体,人白细胞介素-1β前体,人白细胞介素-1受体辅助蛋白,人白细胞介素-1受体拮抗剂β,人白细胞介素-1型-3受体,人白细胞介素-10(前体),人白细胞介素-10(前体),人白细胞介素-11受体,人白细胞介素-12 40 kD亚基,人白细胞介素-12β-1受体,人白细胞介素-12β-2受体,人白细胞介素-12p35蛋白,人白细胞介素-12p40蛋白,人白细胞介素-12受体,人白细胞介素-13α受体,人白细胞介素-13β受体,人白细胞介素-15,来自克隆P1的人白细胞介素-15受体,人白细胞介素-17受体,人白细胞介素-18蛋白(IL-18),人白细胞介素-3,人白细胞介素-3受体,人白细胞介素-3变体,人白细胞介素-4受体,人白细胞介素-5,人白细胞介素-6,人白细胞介素-7,人白细胞介素-7,人白细胞介素-8(IL-8),人胞内IL-1受体拮抗剂,人IP-10和HIV-1gp120超变区融合蛋白,人IP-10和人Muc-1核心表位(VNT)融合多肽,人肝和活化调节趋化因子(LARC),人Lkn-1全长和成熟蛋白,人乳腺相关趋化因子(MACK)蛋白全长和成熟,人成熟趋化因子Ckβ-7,人成熟gro-α,用于治疗败血病的人成熟gro-γ多肽,人MCP-3和人Muc-1核心表位(VNT)融合蛋白,人MI10蛋白,人MI1A蛋白,人单核细胞化学引诱物因子hMCP-1,人单核细胞化学引诱物因子hMCP-3,人单核细胞趋化前蛋白(MCPP)序列,人神经趋化因子(neurotactin)趋化因子样域,人非-ELR CXC趋化因子H174,人非-ELR CXC趋化因子IP10,人非-ELR CXC趋化因子Mig,人PAI-1突变体,具有IL-16活性的人蛋白,具有IL-16活性的人蛋白,人二级淋巴样趋化因子(SLC),人SISD蛋白,人STCP-1,人基质细胞衍生的趋化因子,SDF-1,人T细胞混合淋巴细胞反应表达的趋化因子(TMEC),人胸腺和活化调节细胞因子(TARC),人胸腺表达的,人TNF-α,人TNF-α,人TNF-β(LT-α),人类型CC趋化因子嗜酸细胞活化趋化因子3蛋白序列,人类型II白细胞介素-1受体,人野生型白细胞介素-4(hIL-4)蛋白,人ZCHEMO-8蛋白,人源化抗VEGF抗体,及其片段,人源化抗VEGF抗体,及其片段,透明质酸酶(Hyaluronidase),ICE 10 kD亚基,ICE 20 kD亚基,ICE 22 kD亚基,艾杜糖醛酸2-硫酸酯酶(Iduronate-2-sulfatase),艾杜糖苷酸酶(Iduronidase),IL-1α,IL-1β,IL-1抑制剂(IL-1i),IL-1成熟,IL-10受体,IL-11,IL-11,IL-12p40亚基,IL-13,IL-14,IL-15,IL-15受体,IL-17,IL-17受体,Il-17受体,Il-17受体,IL-19,IL-1i片段,IL1-受体拮抗剂,IL-21(TIF),含IL-3的融合多肽,IL-3突变体蛋白,IL-3变体,IL-3变体,IL-4,IL-4突变蛋白,IL-4突变蛋白Y124G,IL-4突变蛋白Y124X,IL-4突变蛋白,Il-5受体,IL-6,Il-6受体,IL-7受体克隆,IL-8受体,IL-9成熟蛋白变体(Met117型),免疫球蛋白或基于免疫球蛋白的分子,或任一者的片段(例如Small Modular ImmunoPharmaceuticalTM(“SMIP”)或dAb,Fab’片段,F(ab’)2,scAb,scFv或scFv片段),包括但不限于纤溶酶原,流感疫苗,抑制素(Inhibin)α,抑制素β,胰岛素,胰岛素样生长因子,整联蛋白Mab,间-α胰蛋白酶抑制剂,间-α胰蛋白酶抑制剂,干扰素γ-诱导蛋白(IP-10),干扰素(如干扰素α种和亚种,干扰素β种和亚种,干扰素γ种和亚种),干扰素(如干扰素α种和亚种,干扰素β种和亚种,干扰素γ种和亚种),白细胞介素6,白细胞介素8(IL-8)受体,白细胞介素8受体B,白细胞介素-1α,白细胞介素-2受体相关蛋白p43,白细胞介素-3,白细胞介素-4突变蛋白,白细胞介素-8(IL-8)蛋白,白细胞介素-9,白细胞介素-9(IL-9)成熟蛋白(Thr117型),白细胞介素(如IL10,IL11和IL2),白细胞介素(如IL10,IL11和IL2),日本脑炎疫苗,Kalikrein抑制剂,角质细胞生长因子,Kunitz域蛋白(如抑肽酶(aprotinin),淀粉状前体蛋白和WO 03/066824中所述那些,具有或不具有白蛋白融合),Kunitz域蛋白(如抑肽酶(aprotinin),淀粉状蛋白前体蛋白和WO 03/066824中所述那些,具有或不具有白蛋白融合),LACI,乳铁蛋白(lactoferrin),潜在的TGF-β结合蛋白II,来普汀/瘦素(leptin),肝表达的趋化因子-1(LVEC-1),肝表达的趋化因子-2(LVEC-2),LT-α,LT-β,黄体化激素,莱姆病疫苗,淋巴细胞趋化因子(Lymphotactin),巨噬细胞衍生的趋化因子类似物MDC(n+1),巨噬细胞衍生的趋化因子类似物MDC-eyfy,巨噬细胞衍生的趋化因子类似物MDC-yl,巨噬细胞衍生的趋化因子,MDC,巨噬细胞衍生的趋化因子(MDC),Maspin;蛋白酶抑制剂5,MCP-1受体,MCP-1a,MCP-1b,MCP-3,MCP-4受体,M-CSF,黑素瘤抑制蛋白,膜结合蛋白,Met117人白细胞介素9,MIP-3α,MIP-3β,MIP-Γ,MIRAP,修饰的Rantes,单克隆抗体,MP52,突变白细胞介素6S176R,肌纤维收缩蛋白肌钙蛋白I,利钠肽(Natriuretic Peptide),神经生长因子-β,神经生长因子-β2,神经菌毛素(Neuropilin)-1,神经菌毛素-2,神经趋化因子,神经营养因子-3,神经营养因子-4,神经营养因子-4a,神经营养因子-4b,神经营养因子-4c,神经营养因子-4d,嗜中性粒细胞活化肽-2(NAP-2),NOGO-66受体,NOGO-A,NOGO-B,NOGO-C,命名为PTEC的新β-趋化因子,N-端修饰趋化因子GroHEK/hSDF-1α,N-端修饰趋化因子GroHEK/hSDF-1β,N-端修饰趋化因子met-hSDF-1α,N-端修饰趋化因子met-hSDF-1β,OPGL,成骨蛋白-1;OP-1;BMP-7,成骨蛋白-2,OX40;ACT-4,OX40L,催产素(神经垂体素运载蛋白I),甲状旁腺素,Patched,Patched-2,PDGF-D,百日咳类毒素(Pertussis toxoid),垂体表达的趋化因子(PGEC),胎盘生长因子,胎盘生长因子-2,纤溶酶原活化物抑制剂-1;PAI-1,纤溶酶原活化物抑制剂-2;PAI-2,纤溶酶原活化物抑制剂-2;PAI-2,血小板衍生的生长因子,血小板衍生的生长因子Bv-sis,血小板衍生的生长因子前体A,血小板衍生的生长因子前体B,血小板Mab,血小板衍生的内皮细胞生长因子(PD-ECGF),血小板衍生的生长因子A链,血小板衍生的生长因子B链,用于治疗败血病的多肽,前原载脂蛋白“米兰”变体(Preproapolipoprotein“milano”variant),前原载脂蛋白“巴黎”变体,前凝血酶(pre-thrombin),灵长类CC趋化因子"ILINCK",灵长类CXC趋化因子"IBICK",胰岛素原,促乳素(Prolactin),促乳素2,prosaptide,蛋白酶抑制肽,蛋白C,蛋白S,凝血酶原,尿激酶原,RANTES,RANTES 8-68,RANTES 9-68,RANTES肽,RANTES受体,重组白细胞介素-16,抵抗素(Resistin),局限曲菌素(restrictocin),逆转录病毒蛋白酶抑制剂,蓖麻毒蛋白(ricin),轮状病毒疫苗,RSV Mab,皂草素(saporin),八叠球菌(sarcin),分泌和跨膜多肽,分泌和跨膜多肽,血清胆碱酯酶,血清蛋白(如凝血因子),可溶性BMP受体激酶蛋白-3,可溶性VEGF受体,干细胞抑制因子,葡萄球菌疫苗,基质衍生的因子-1α,基质衍生的因子-1β,物质P(速激肽),T1249肽,T20肽,T4内切核酸酶,TACI,Tarc,TGF-β1,TGF-β2,Thr117人白细胞介素9,凝血酶,促血小板生成素(thrombopoietin),促血小板生成素衍生物1,促血小板生成素衍生物2,促血小板生成素衍生物3,促血小板生成素衍生物4,促血小板生成素衍生物5,促血小板生成素衍生物6,促血小板生成素衍生物7,胸腺表达的趋化因子(TECK),促甲状腺激素(Thyroid stimulating Hormone),蜱抗凝肽,Tim-1蛋白,TNF-α前体,TNF-R,TNF-RII;TNF p75受体;死亡受体,tPA,转铁蛋白(transferrin),转化生长因子β,肌钙蛋白肽,截短的单核细胞趋化蛋白2(6-76),截短的单核细胞趋化蛋白2(6-76),截短的RANTES蛋白(3-68),肿瘤坏死因子,尿酸氧化酶,尿激酶,加压素(Vasopressin)(神经垂体素运载蛋白(Neurophysin II)),VEGF R-3;flt-4,VEGF受体;KDR;flk-1,VEGF-110,VEGF-121,VEGF-138,VEGF-145,VEGF-162,VEGF-165,VEGF-182,VEGF-189,VEGF-206,VEGF-D,VEGF-E;VEGF-X,von Willebrand因子,野生型单核细胞趋化蛋白2,野生型单核细胞趋化蛋白2,ZTGF-β9;
此外,缀合物可包含一种或多种(几种)化疗药如:13-顺-视黄酸(13-cis-Retinoic Acid),2-CdA,2-氯脱氧腺苷(2-Chlorodeoxyadenosine),5-阿扎胞苷(5-Azacitidine),5-氟尿嘧啶(5-Fluorouracil),5-FU,6-巯基嘌呤(6-Mercaptopurine),6-MP,6-TG,6-硫代鸟嘌呤(6-Thioguanine),A,Abraxane,放线菌素-D(Actinomycin-D),阿霉素 Ala-阿地白介素(Aldesleukin),阿仑单抗(Alemtuzumab),ALIMTA,阿利维A酸(Alitretinoin),Alkaban-爱克兰全反视黄酸(All-transretinoic Acid),α干扰素,六甲蜜胺(Altretamine),甲氨蝶呤(Amethopterin),氨磷汀(Amifostine),氨鲁米特(Aminoglutethimide),阿那格雷(Anagrelide),阿那曲唑(Anastrozole),阿糖胞苷(Arabinosylcytosine),Ara-C, 三氧化二砷(Arsenic Trioxide),天冬酰胺酶(Asparaginase),ATRA,阿扎胞苷(Azacitidine),BCG,BCNU,贝伐单抗(Bevacizumab),贝沙罗汀(Bexarotene),比卡鲁胺(Bicalutamide),BiCNU,博来霉素(Bleomycin),Bortezomib,白消安(Busulfan),C225,亚叶酸钙(CalciumLeucovorin),喜树碱-11(Camptothecin-11),卡培他滨(Capecitabine),CaracTM,卡铂(Carboplatin),卡莫司汀(Carmustine),CarmustineWafer,康士德CC-5013,CCNU,CDDP,CeeNU,西妥昔单抗(Cetuximab),苯丁酸氮芥(Chlorambucil),顺铂(Cisplatin),亚叶酸因子(CitrovorumFactor),克拉屈滨(Cladribine),可的松(Cortisone),CPT-11,环磷酰胺(Cyclophosphamide),阿糖胞苷(Cytarabine),阿糖胞苷脂质体(CytarabineLiposomal),赛德萨(Cytosar)-达卡巴嗪(Dacarbazine),Dacogen,更生霉素(Dactinomycin),Darbepoetin Alfa,Dasatinib,柔红霉素(Daunomycin),柔红霉素(Daunorubicin),盐酸柔红霉素(Daunorubicin Hydrochloride),柔红霉素脂质体(Daunorubicin Liposomal),地卡特隆(Decadron),地西他滨(Decitabine),Delta-地尼白介素-毒素连接物(Denileukindiftitox),DepoCytTM,地塞米松(Dexamethasone),醋酸地塞米松(Dexamethasoneacetate),地塞米松磷酸钠(Dexamethasone Sodium Phosphate),地塞米松(Dexasone),右雷佐生(Dexrazoxane),DHAD,DIC,Diodex,多西紫杉醇(Docetaxel),多柔比星(Doxorubicin),多柔比星脂质体(Doxorubicin liposomal),DroxiaTM,DTIC,DTIC-EligardTM,EllenceTM,乐沙定(Eloxatin)TM,表柔比星(Epirubicin),阿法依伯汀(Epoetin alfa),ErbituxTM,Erlotinib,欧文氏菌属L-天冬酰胺酶(Erwinia L-asparaginase),雌莫司汀(Estramustine),氨磷汀(Ethyol),依托泊苷(Etoposide),磷酸依托泊苷(Etoposide Phosphate),依西美坦(Exemestane),法乐通 非格司亭(Filgrastim),氟尿苷(Floxuridine),氟达拉滨(Fludarabine),氟尿嘧啶(Fluorouracil),氟尿嘧啶(Fluorouracil)(乳膏),氟甲睾酮(Fluoxymesterone),氟他胺(Flutamide),亚叶酸(Folinic Acid),氟维司群(Fulvestrant),G-CSF,Gefitinib,吉西他滨(Gemcitabine),吉姆单抗(Gemtuzumab)奥佐米星(ozogamicin),健择GleevecTM,Wafer,GM-CSF,戈舍瑞林(Goserelin),粒细胞集落刺激因子,粒细胞巨噬细胞集落刺激因子,地塞米松(Hexadrol),克瘤灵六甲蜜胺(Hexamethylmelamine),HMM,和美新羟基脲醋酸氢化可的松氢化可的松(Hydrocortisone),氢化可的松磷酸钠(Hydrocortisone Sodium Phosphate),氢化可的松琥珀酸钠(Hydrocortisone Sodium Succinate),氢化可的松磷酸(Hydrocortone Phosphate),羟脲(Hydroxyurea),替伊莫单抗(Ibritumomab),替伊莫单抗(Ibritumomab Tiuxetan),伊达比星(Idarubicin),IFN-α,异环磷酰胺(Ifosfamide),IL-11,IL-2,甲磺酸伊马替尼(Imatinib mesylate),咪唑羧酰胺(Imidazole Carboxamide),干扰素alfa,干扰素Alfa-2b(PEG缀合物),白细胞介素-2,白细胞介素-11,Intron(干扰素alfa-2b),伊立替康(Irinotecan),异维A酸(Isotretinoin),Lapatinib,L-天冬酰胺酶,LCR,Lenalidomide,来曲唑(Letrozole),亚叶酸钙(Leucovorin),苯丁酸氮芥(Leukeran),LeukineTM,亮丙瑞林(Leuprolide),长春新碱(Leurocristine),LeustatinTM,脂质体Ara-C,Liquid洛莫司汀(Lomustine),L-PAM,L-沙可来新(L-Sarcolysin),LupronM,Maxidex,氮芥(Mechlorethamine),盐酸氮芥(MechlorethamineHydrochloride),美卓乐梅格施甲地孕酮(Megestrol),醋酸甲地孕酮(Megestrol Acetate),美法仑(Melphalan),巯嘌呤(Mercaptopurine),美司钠(Mesna),MesnexTM,甲氨蝶呤(Methotrexate),甲氨蝶呤钠(Methotrexate Sodium),甲泼尼龙(Methylprednisolone),丝裂霉素(Mitomycin),丝裂霉素-C(Mitomycin-C),米托蒽醌(Mitoxantrone),M-MTC,MTX,氮芥(Mustine),马利兰MylocelTM,诺维本萘拉滨(Nelarabine),NeulastaTM,优保津尼鲁米特(Nilutamide),氮芥(Nitrogen Mustard),能灭瘤奥曲肽(Octreotide),醋酸奥曲肽(Octreotide acetate),安可平 OnxalTM,Oprevelkin,奥沙利铂(Oxaliplatin),紫杉醇(Paclitaxel),蛋白结合紫杉醇,帕米磷酸(Pamidronate),Panitumumab,伯尔定PEG干扰素,培门冬酶(Pegaspargase),PEG菲格司亭(Pegfilgrastim),PEG-INTRONTM,PEG-L-天冬酰胺酶,培美曲塞(PEMETREXED),喷司他丁(Pentostatin),苯丙氨酸氮芥(Phenylalanine Mustard),Platinol-泼尼松龙(Prednisolone),泼尼松(Prednisone),丙卡巴肼(Procarbazine),具有卡莫司汀(Carmustine)植入物的Prolifeprospan 20,R,雷洛昔芬(Raloxifene),利妥昔单抗(Rituximab),Roferon-(干扰素Alfa-2a),柔红霉素盐酸盐(Rubidomycin hydrochloride),善得定Sandostatin沙格司亭(Sargramostim),Solu-Solu-Sorafenib,SPRYCELTM,STI-571,链佐星(Streptozocin),SU11248,Sunitinib,他莫昔芬(Tamoxifen),泰素泰索帝 替莫唑胺(Temozolomide),替尼泊苷(Teniposide),TESPA,沙利度胺(Thalidomide),硫鸟嘌呤(Thioguanine),ThioguanineThiophosphoamide,塞替派(Thiotepa),托泊替康(Topotecan),托瑞米芬(Toremifene),托西莫单抗(Tositumomab),曲妥单抗(Trastuzumab),维A酸(Tretinoin),TrexallTM,TSPA,VCR,VectibixTM,凡毕士ViadurTM,长春碱(Vinblastine),硫酸长春碱(Vinblastine Sulfate),Vincasar长春新碱(Vincristine),长春瑞滨(Vinorelbine),酒石酸长春瑞滨(Vinorelbine tartrate),VLB,VM-26,Vorinostat,VP-16,威猛希罗达 ZevalinTM,诺雷德唑来膦酸(Zoledronic acid),Zolinza,放射性药品如:碳-11,碳-14,铬-51,钴-57,钴-58,铒-169,氟-18,镓-67,金-198,铟-111,铟-113m,碘-123,碘-125,碘-131,铁-59,氪-81m,氮-13,氧-15,磷-32,铼-186,铷-82,钐-153,硒-75,锶-89,锝-99m,铊-201,氚,氙-127,氙-133,钇-90;显像剂如钆,磁铁矿/磁石(magnetite),锰,锝,I125,I131,P32,Tl201,碘帕醇(Iopamidol),PET-FDG。
此类多肽和化学化合物可称作诊断模块,治疗模块或有益模块。
可将一种或多种治疗多肽融合于白蛋白的N端,C端,插入白蛋白结构中的环(loop),或其任意组合。其可包含或其可不包含将融合多肽多种组分分开的接头序列。
涉及白蛋白或其片段的融合的教导在本领域是已知的,且本领域技术人员会知道此类教导亦可适用于本发明。WO 2001/79271 A和WO 2003/59934 A亦包含可融合于白蛋白或其片段的治疗多肽的实例,且这些实例亦适用于本发明。
根据本发明的融合或缀合多肽的白蛋白衍生物,片段,或其变体部分一般而言与其亲本白蛋白的对应部分的序列具有至少60%,优选至少70%,优选至少80%,优选至少81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,或94%,更优选至少95%,更优选至少96%,更优选至少97%,更优选至少98%和最优选至少99%的序列同一性。
在一个优选实施方案中,根据本发明的融合或缀合多肽的白蛋白衍生物,片段,或其变体部分一般而言与SEQ ID NO:31或SEQ ID NO:1中所示的HSA的对应部分的序列具有至少60%,优选至少70%,优选至少80%,优选至少85%,优选至少90%,更优选至少95%,更优选至少96%,更优选至少97%,更优选至少98%和最优选至少99%的序列同一性。
两个氨基酸序列间或两个核苷酸序列间的相关性由参数“序列同一性”描述。
就本发明而言,两个氨基酸序列之间的同一性程度使用如EMBOSS软件包(EMBOSS:The European Molecular Biology Open Software Suite,Rice等,2000,Trends inGenetics 16:276-277)的Needle程序,优选为3.0.0版或之后的版本中执行的Needleman-Wunsch算法(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453)确定。所用的可选参数为缺口开放罚分(gap open penalty)10,缺口延伸罚分(gap extension penalty)0.5,和EBLOSUM62(BLOSUM62的EMBOSS版)取代矩阵。使用标记为“最长同一性”的Needle输出(使用-nobrief选项获得)作为百分比同一性并如下计算:
(相同的残基×100)/(比对长度-比对中缺口总数)。
在描述本发明的多种衍生物或变体中,为了方便参照,采用下文所述的命名法。在所有情况下,使用通用的IUPAC单字母或三字母氨基酸缩写。
就本发明而言,两个脱氧核糖核苷酸序列之间的序列同一性程度使用如EMBOSS软件包(EMBOSS:The European Molecular Biology Open Software Suite,Rice等,2000,见上)的Needle程序,优选为3.0.0版或之后的版本中执行的Needleman-Wunsch算法(Needleman和Wunsch,1970,见上)确定。所用的可选参数为缺口开放罚分10,缺口延伸罚分0.5,和EDNAFULL(NCBI NUC4.4的EMBOSS版)取代矩阵。使用标记为”最长同一性”的Needle输出(使用-nobrief选项获得)作为百分比同一性并如下计算:
(相同的脱氧核糖核苷酸×100)/(比对长度–比对中缺口总数)
就本发明而言,将公开于SEQ ID NO:31或SEQ ID NO:1中的成熟多肽用于确定在其他白蛋白中对应的氨基酸残基。将其他白蛋白的氨基酸序列与公开于SEQ ID NO:31或SEQ ID NO:1中的成熟多肽进行比对,并基于该比对,使用如EMBOSS包(EMBOSS:TheEuropean Molecular Biology Open Software Suite,Rice等,2000,Trends Genet.16:276-277)的Needle程序(优选版本3.0.0或更新)中执行的Needleman-Wunsch算法(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453)确定了对应于SEQ ID NO:31或SEQID NO:1所公开的成熟多肽中任何氨基酸残基的氨基酸位置编号。
在其他白蛋白中鉴定对应的氨基酸残基可通过使用“ClustalW”(Larkin等,2007,Bioinformatics 23:2947-2948)比对多个多肽序列来确认。
当其他多肽(或蛋白)从SEQ ID NO:31或SEQ ID NO:1的成熟多肽分歧到传统的基于序列的比较无法检测出其关系的程度时(Lindahl和Elofsson,2000,J.Mol.Biol.295:613-615),可使用其他逐对序列比较算法。在基于序列的搜索中较高的敏感度可使用采用多肽家族的概率表现(probabilistic representation)(序型)来搜索数据库的搜索程序获得。举例而言,PSI-BLAST程序通过迭代的(iterative)数据库搜索过程来产生序型,并能够检测出较远的同源物(Atschul等,1997,Nucleic Acids Res.25:3389-3402)。当多肽的家族或超家族在蛋白质结构数据库中具有一个或多个代表时,甚至可达成更高的敏感度。程序如GenTHREADER(Jones 1999,J.Mol.Biol.287:797-815;McGuffin和Jones,2003,Bioinformatics 19:874-881)使用来自多个来源(PSI-BLAST、二级结构预测(secondarystructure prediction)、结构比对序型(structural alignment profile)以及溶解势(solvation potential))的信息作为向预测查询序列(query sequence)的结构折叠(structural fold)的神经网络的输入。类似地,Gough等,2000,J.Mol.Biol.313:903-919的方法可用于将未知结构的序列在存在于SCOP数据库中的超家族模型内进行比对。这些比对继而能够用于生成多肽的同源性模型,且上述模型可就准确度使用多种为此目的开发的工具加以评价。
对于已知结构的蛋白质,可用数种工具和资源以供找回(retrieve)和生成结构比对。举例而言,已将SCOP超家族的蛋白质进行了结构比对,且这些比对是可获取并可下载的。两个或更多蛋白质结构可使用多种算法,如距离比对矩阵(distance alignmentmatrix)(Holm和Sander,1998,Proteins 33:88-96)或组合延伸(combinatorialextension)(Shindyalov和Bourne,1998,Protein Engineering 11:739-747)进行比对,且这些算法的执行可另外用于查询具有目标结构的结构数据库,以发现可能的结构同源物(例如Holm和Park,2000,Bioinformatics 16:566-567)。另一种比对程序是MUSCLE(通过log-期待的多重序列比较(Multiple sequence comparison by log-expectation,RobertC.Edgar,版本3.6,http://www.drive5.com/muscle;Edgar(2004)Nucleic AcidsResearch 32(5),1792-97和Edgar(2004)BMC Bioinformatics,5(1):113)),其可以以用户说明(版本3.6,2005年7月)中所述的缺省设定使用。比3.6更迟的MUSCLE版本亦可用于本发明的任何方面。
在描述本发明的白蛋白衍生物或变体时,为了参照方便起见,采用了下述的命名法。使用通用的IUPAC单字母缩写或三字母氨基酸缩写。
取代。对于氨基酸取代,使用下述命名法:初始氨基酸,位置,取代氨基酸。相应地,在226位用丙氨酸取代苏氨酸命名为“Thr226Ala”或“T226A”。多重突变用加号(“+”)分开,例如,“Gly205Arg+Ser411Phe”或“G205R+S411F”,代表在205和411位分别用精氨酸(R)取代甘氨酸(G),以及用苯丙氨酸(F)取代丝氨酸(S)的突变。附图亦使用(“/”),例如“E492T/N503D”,这应视作可与(“+”)互换。
缺失。对于氨基酸缺失,使用了如下命名法:初始氨基酸,位置*。相应地,在位置195缺失甘氨酸命名为“Gly195*”或“G195*”。多个缺失由加号(“+”)分开,例如“Gly195*+Ser411*”或“G195*+S411*”。
插入。对于氨基酸插入,使用了如下的命名法:初始氨基酸,位置,初始氨基酸,新插入的氨基酸。因此,在位置195的甘氨酸之后插入赖氨酸命名为“Gly195GlyLys”或“G195GK”。多个氨基酸的插入命名为[初始氨基酸,位置,初始氨基酸,新插入的氨基酸#1,新插入的氨基酸#2;等等]。例如,在位置195的甘氨酸之后插入赖氨酸和丙氨酸记为“Gly195GlyLysAla”或“G195GKA”。
在此情况下,通过在插入的氨基酸残基前的氨基酸残基的位置号添加小写字母而对插入的氨基酸残基进行编号。因此,在上一例子中序列为:
亲本: | 变体: |
195 | 195 195a 195b |
G | G-K-A |
多重改变。包含多重改变的变体或衍生物由加号(“+”)分开,例如“Arg170Tyr+Gly195Glu”或“R170Y+G195E”代表在位置170和195分别用酪氨酸和谷氨酸取代精氨酸和甘氨酸。
不同的取代。当可在一个位置导入不同取代时,不同的取代由逗号分开,例如“Arg170Tyr,Glu”代表在位置170用酪氨酸或谷氨酸取代精氨酸。因此,“Tyr167Gly,Ala+Arg170Gly,Ala”指下述变体或衍生物:“Tyr167Gly+Arg170Gly”,“Tyr167Gly+Arg170Ala”,“Tyr167Ala+Arg170Gly”和“Tyr167Ala+Arg170Ala”。亦可使用单字母编码,例如:“Y167G+R170G”,“Y167G+R170A”,“R167A+R170G”,和“R167A+R170A”。
表述“对应于”参照序列中的位置的“氨基酸位置”和类似的表述旨在鉴定在一级或空间结构中对应于参照序列中特定位置的氨基酸残基。本领域技术人员会知道这可通过将给定序列与参照序列进行比对,并鉴定出与参照序列中特定位置对齐的氨基酸残基来完成。举例而言,为了在给定白蛋白序列中寻找对应于HSA中位置492的氨基酸残基,将给定白蛋白序列与HSA进行比对,并将与HSA(SEQ ID NO:31或SEQ ID NO:1)中位置492对齐的氨基酸鉴定为给定白蛋白序列中对应于HSA中位置492的氨基酸。
表述Xnnn意指氨基酸残基X位于对应于HSA中位置nnn的位置,而表述XnnnY意指在用氨基酸残基Y取代任何对应于HSA中位置nnn的位置的氨基酸X。
在整个本说明书中,氨基酸位置相对于全长成熟人血清白蛋白(即无前导序列)定义。然而,可在人血清白蛋白的片段中,在动物白蛋白中和在片段,融合物和其它衍生物或其变体中,通过使用逐对(例如ClustalW)或多重(例如MUSCLE)比对比较氨基酸序列来鉴定出等同位置。举例而言,图4显示等同于全长人血清白蛋白中的500,550和573的位置可容易地在人血清白蛋白的片段和其它物种的白蛋白中鉴定出。位置500,550和573由箭头标出。进一步的细节提供于下表1。
表1:来自不同动物的白蛋白,显示等同于HSA的500,550和573的位置。
图4是通过MUSCLE使用缺省参数生成的,包括ClustalW 1.81格式的输出。原始输出数据使用BoxShade 3.21(http://www.ch.embnet.org/software/BOX_form.html)使用输出格式(Output Format):RTF_new;Font Size:10;共有行(Consensus Line):无共有线(no consensus line);序列部分(Fraction of sequences)(必须与阴影化一致):0.5;输入序列格式(Input sequence format)ALN来阴影化。因此,在整个该说明书中,在人血清白蛋白中定义的氨基酸位置亦适用于人血清白蛋白的片段、衍生物或变体,以及融合物,来自其它物种的动物及其片段和融合物的等同位置。此类等同位置可具有(i)在其天然蛋白质中不同的残基编号和/或(ii在其天然蛋白质中不同的天然氨基酸。
血浆半寿期理想地是在合适的个体中使用体内确定法来确定的。然而,由于这耗费时间且成本不菲,而且在动物或人中进行实验不可避免地涉及伦理问题,因此期望使用体外测定以供确定血浆半寿期是否延长或减少。认为白蛋白对其受体FcRn的结合对于血浆半寿期是重要的,且受体结合和血浆半寿期之间的关联性在于白蛋白对其受体FcRn的较高亲和力导致较长的血浆半寿期。因此,对于本发明,白蛋白衍生物,片段,或其变体对FcRn的更高亲和力视作表明增加的(较长的)血浆半寿期,而白蛋白衍生物,片段,或其变体对FcRn受体的较低亲和力视作表明减少的(较短的)血浆半寿期。
在本申请中,白蛋白衍生物,片段,或其变体对受体FcRn的结合使用术语亲和力(KD)和表述“较强”或“较弱”来描述。因此,应理解的是与HSA相比对FcRn具有较高亲和力的分子视作与HSA相比对FcRn结合较强,而与HSA相比对FcRn具有较低亲和力的分子视作与HSA相比对FcRn结合较弱。
术语“较长的血浆半寿期”或“较短的血浆半寿期”和类似的表述应理解为针对相应的亲本白蛋白分子,其可为全长白蛋白,白蛋白片段或变体或衍生物或白蛋白融合蛋白。因此,对于本发明的变体白蛋白较长的血浆半寿期意指该变体与除了在对应于SEQ ID NO:31或SEQ ID NO:1中的417,440,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574,575,577,578,579,580,581,582和584的位置的改变之外具有相同序列的对应白蛋白相比,具有较长的血浆半寿期。因此,举例而言,在位置535具有突变的全长人血清白蛋白必须与在位置535不具有突变的全长人血清白蛋白进行比较。类似地,包含小鼠白蛋白域2和3并在位置582具有突变的小鼠白蛋白片段必须与包含小鼠白蛋白域2和3但在位置582不具有突变的小鼠白蛋白片段进行比较。
“长”或“短”血浆半寿期,例如在血中的,可为相对于(i)血清白蛋白(或其片段)和/或(ii)融合于感兴趣的多肽的血清白蛋白(或其片段)。举例而言,长血浆半寿期可为与血清白蛋白或融合于感兴趣的多肽的血清白蛋白相比,长至少5%,优选至少10%,20%,30%,40%,50%,60%,70%,80%,90%,100%,150%,200%,250%,300%,350%,400%,450%,500%更长。长血浆半寿期包括至少5至100日,例如至少5,6,7,8,9,10,14,15,20,21,28,30,35,40,42,50,60,70,80,90,100日。短血浆半寿期可为与血清白蛋白或融合于感兴趣的多肽的血清白蛋白相比,短至少5%,更优选至少10%,20%,30%,40%,50%,60%,70%,80%,90%,95%,96%,97%,98%或99%更短。短血浆半寿期包括最多5,4,3,2,1,0.5或0.25日。优选地,未融合的白蛋白衍生物或变体的半寿期与未融合的亲本或天然白蛋白进行比较。类似地,优选融合的白蛋白衍生物或变体(“白蛋白融合物”)的半寿期与融合的亲本或天然白蛋白进行比较。
白蛋白衍生物,片段,或其变体对FcRn的结合亦可使用动力学因子,特别是“结合速率(on-rate)”(ka)和“解离速率(off-rate)”(kd)来描述,这些描述了本发明的白蛋白衍生物,片段,或其变体分别与FcRn结合或解离的反应速率。本发明人进一步了解,白蛋白衍生物,片段,或其变体与FcRn相互作用的动力学可对血浆半寿期有影响,并了解具有较慢解离速率的白蛋白衍生物,片段或其变体与具有较快解离速率的类似分子相比具有较高的血浆半寿期。
本发明人已基于本发明所属领域的现有技术了解了白蛋白衍生物,片段,或其变体对FcRn受体的结合与血浆半寿期之间的关联。
一种确定白蛋白衍生物,片段,或其变体的亲和力是否与野生型白蛋白相比较高或较低的方式是使用如下文所述的表面等离子共振测定(SPR)。本领域技术人员会知道其它方法可用于确定白蛋白衍生物,片段,或其变体对FcRn的亲和力与对应的野生型白蛋白对FcRn的亲和力相比是否较高或较低,例如,对结合常数KD进行确定和比较。因此,根据本发明,与天然HSA的KD相比具有较低KD的白蛋白衍生物,片段,或其变体视作具有与HSA相比较高的血浆半寿期,而与天然HSA的KD相比具有较高KD的白蛋白衍生物,片段,或其变体视作具有与HSA相比较低的血浆半寿期。
衍生物和变体的制备
本发明的白蛋白衍生物,片段,或其变体可使用本领域技术人员已知的技术来制备。一种方便的方式是通过克隆编码亲本白蛋白,其片段或包含HSA域III衍生物,片段,或其变体的融合多肽的核酸。可以用许多方式操作多核苷酸以提供衍生物或变体的表达。依赖于表达载体,在将多核苷酸插入载体之前对其进行操作可能是理想的或必需的。使用重组DNA方法修饰多核苷酸的技术是本领域熟知的。
调控序列可以是启动子序列,其由用于表达多核苷酸的宿主细胞识别。启动子序列含有介导衍生物或变体的表达的转录调控序列。启动子可以是在宿主细胞中显示转录活性的任何核酸序列,包括突变的、截短的和杂合的启动子,并且可以从编码与宿主细胞同源或异源的胞外或胞内多肽的基因获得。
在酵母宿主中,有用的启动子从如下酶的基因获得:酿酒酵母烯醇化酶(ENO1)、酿酒酵母蛋白酶A(PRA1)、酿酒酵母蛋白酶B(PRB1)、酿酒酵母翻译延伸因子(TEF1)、酿酒酵母翻译延伸因子(TEF2)、酿酒酵母半乳糖激酶(GAL1)、酿酒酵母醇脱氢酶/甘油醛-3-磷酸脱氢酶(ADH1,ADH2/TDH1)、酿酒酵母丙糖磷酸异构酶(TPI1)、酿酒酵母金属硫蛋白(CUP1)和酿酒酵母3-磷酸甘油酸激酶。对于酵母宿主细胞其它有用的启动子由Romanos等,1992,Yeast8:423-488描述。
调控序列也可以是合适的转录终止子序列,其由宿主细胞识别以终止转录的序列。所述终止子序列与编码所述衍生物或变体的多核苷酸的3’末端可操作地连接。可以使用在宿主细胞中有功能的任何终止子。
对于酵母宿主细胞优选的终止子从如下酶的基因获得:酿酒酵母烯醇化酶、酿酒酵母细胞色素C(CYC1)、酿酒酵母醇脱氢酶(ADH1)和酿酒酵母甘油醛-3-磷酸脱氢酶(TDH1)。对于酵母宿主细胞其它有用的终止子由Romanos等,1992,见上文描述。
调控序列还可以是合适的前导序列,其为对于宿主细胞的翻译重要的mRNA非翻译区。前导序列可操作地连接于编码衍生物或变体的多核苷酸的5’-末端。可以使用在宿主细胞中有功能的任何前导序列。
本发明的白蛋白衍生物,片段,或其变体亦可连接于信号序列(亦称作‘信号肽’或‘前导序列’)以供将所述多肽在培养转化的宿主生物过程中分泌入生长培养基。一般而言,为了方便回收和纯化,使得衍生物或变体分泌入生长培养基是有利的。对于酵母宿主细胞合适的前导序列从如下酶的基因获得:酿酒酵母烯醇化酶(ENO1)、酿酒酵母3-磷酸甘油酸激酶、酿酒酵母α因子和酿酒酵母醇脱氢酶/甘油醛-3-磷酸脱氢酶(ADH2/TDH1)。
调控序列也可以是聚腺苷酸化序列,其是与衍生物-或变体-编码序列的3’末端可操作地连接的序列,并且在转录时,宿主细胞将其识别为将聚腺苷残基添加至转录的mRNA的信号。可以使用在宿主细胞中有功能的任何聚腺苷酸化序列。
对于酵母宿主细胞有用的聚腺苷酸化序列由Guo和Sherman,1995,Mol.CellularBiol.15:5983-5990描述。
调控序列还可以是信号肽编码区,其编码与衍生物或变体的N端相连的信号肽,并且指导所述衍生物或变体进入细胞分泌途径。所述多核苷酸的编码序列5’端可固有地包含信号肽编码区,其与编码分泌衍生物或变体的编码区片段一起天然地连接在翻译阅读框中。可供选择的是,编码序列5’端可含有对于所述编码序列异源的信号肽编码区。异源信号肽编码区在编码序列不天然地含有信号肽编码区时可为必需的。或者,外源信号肽编码区可以简单地取代天然信号肽编码区以增强衍生物或变体的分泌。然而,可使用任何指导表达的衍生物或变体进入宿主细胞的分泌途径的信号肽编码区。
对于酵母宿主细胞有用的信号肽从酿酒酵母α因子(MATΑLPHA)和酿酒酵母转化酶(SUC2)的基因获得。其它有用的信号肽编码序列由Romanos等,1992,见上文描述。
当信号肽和前肽区二者均出现在衍生物或变体的N端时,将前肽区置于紧接着(next to)所述衍生物或变体的N端,并且将信号肽区置于紧接着前肽区的N端。
用于制备衍生物或变体多肽的技术亦公开于WO 2009019314和PCT/EP2010/066572(通过提述并入),且这些技术亦可适用于本发明。
白蛋白已成功地作为重组蛋白在多种宿主包括真菌(包括但不限于曲霉属(Aspergillus)(WO06066595)、克鲁维酵母属(Kluyveromyces)(Fleer 1991,Bio/technology 9,968-975),毕赤酵母属(Pichia)(Kobayashi 1998Therapeutic Apheresis2,257-262)和酵母属(Saccharomyces)(Sleep 1990,Bio/technology 8,42-46)),细菌(Pandjaitab 2000,J.Allergy Clin.Immunol.105,279-285)),动物(Barash 1993,Transgenic Research 2,266-276)和植物(包括但不限于马铃薯和烟草(Sijmons 1990,Bio/technology 8,217and Farran 2002,Transgenic Research 11,337-346)中得到表达。本发明的HSA域III衍生物,片段,或其变体优选在合适的宿主细胞中通过重组产生。原则上,任何能够以合适量产生多肽的宿主细胞均可使用,且一般技术人员具有根据本发明选择合适宿主细胞的能力。优选的宿主生物是酵母,优选选自酵母属(Saccharomycacae),更优选为酿酒酵母。
可使用已知的分离技术如过滤、离心、层析、亲和分离技术等的组合从生长培养基回收和纯化本发明的白蛋白衍生物,片段,或其变体。一般技术人员有使用此类已知分离步骤的特定组合纯化所述白蛋白衍生物,片段,或其变体的能力。作为可应用于本发明的衍生物或变体的纯化技术的实例,可提及WO0044772的教导。
本发明的白蛋白衍生物,片段,或其变体可用于将治疗上有益的化合物递送至有此需要的动物或人类个体。此类治疗上有益的化合物包括但不限于用于诊断如多种显影技术的标记和容易检测的化合物;药学活性化合物如药物,或特异性结合模块如抗体。本发明的白蛋白衍生物,片段,或其变体甚至可连接至两种或更多种不同的治疗上有益的化合物,例如一种抗体和一种药物,这赋予组合分子以特异性结合于所需的靶的能力,并由此对于该特定靶提供高浓度的所连接的药物。
在一个特别优选的实施方案中,将所述白蛋白衍生物,片段,或其变体缀合于有益的治疗化合物,并将该缀合物用于治疗有此需要的患者中的病状,其中所述病状响应该特别选定的治疗化合物。用于将此种治疗化合物缀合于白蛋白衍生物,片段,或其变体的技术在本领域中是已知的。WO 2009/019314公开了适于将治疗化合物缀合于多肽的技术的实例,且该技术亦可适用于本发明。此外,WO 2009/019314公开了可缀合于取代的转铁蛋白的化合物和模块的实例,且这些实例亦可应用于本发明。WO2009019314和PCT/EP2010/066572的教导通过提述并入本文。
HSA以其天然形式在域1中含有一个游离硫醇基团,其可方便地用于缀合,只要所述白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体,其片段的融合多肽包含域1。
作为其中的具体实施方案,所述白蛋白衍生物,片段,或其变体可包含提供用于在其表面生成其他游离硫醇基团的进一步修饰。这具有下述益处:使得所述白蛋白衍生物,片段,或其变体的有效负载(pay load)增加,从而可将超过一个分子的治疗化合物缀合于每个白蛋白衍生物,片段,或其变体的分子,或可将两个或更多个不同的治疗化合物缀合于每个白蛋白衍生物,片段,或其变体的分子,例如,其可为具有靶向特性的化合物如对例如肿瘤具特异性的抗体;以及细胞毒性药物缀合于白蛋白衍生物,片段,或其变体,由此构建针对肿瘤的高度特异性药物。对可修饰以在表面提供更多游离硫醇基团的特定残基的教导亦可见于共同未决的专利申请(EP 2009 152 625.1,其通过提述并入本文),其通过提述并入本文。
在另一个优选的方面,包含所述白蛋白衍生物,片段,或其变体的融合多肽包含一个或多个(几个)治疗多肽。其中,HSA域III衍生物,片段,或其变体以及所述一个或多个(几个)治疗多肽作为单个多肽产生。
可将一个或多个(几个)治疗多肽融合于所述白蛋白衍生物,片段,或其变体的N端,C端,插入所述白蛋白衍生物,片段,或其变体结构中的环(loop),或其任意组合。其可包含或可不包含将融合多肽多种组分分开的接头序列。
涉及白蛋白或其片段的融合的教导在本领域是已知的,且本领域技术人员会知道此类教导亦可适用于本发明。WO 01/79271 A和WO 03/59934 A亦包含可融合于HSA域III衍生物,片段,或其变体的治疗多肽的实例,且这些实例亦适用于本发明。
根据本发明的白蛋白衍生物,片段,或其变体或包含所述白蛋白衍生物,片段,或其变体的融合多肽与亲本白蛋白或其片段,或者包含亲本白蛋白或其片段的融合多肽相比,具有其血浆半寿期改变的益处。其优势在于根据本发明的包含白蛋白衍生物,片段,或其变体的缀合物或包含所述白蛋白衍生物,片段,或其变体的融合多肽的血浆半寿期可依照具体治疗目的而加以选择。
举例而言,对于用于在动物或人类中显影目的的缀合物或融合多肽,当显影模块具有非常短的半寿期,以及包含所述白蛋白衍生物,片段,或其变体的缀合物或融合多肽具有远较该显影目的所需的更长的血浆半寿期时,使用与亲本白蛋白或其片段相比具有较短血浆半寿期的本发明的所述白蛋白衍生物,片段,或其变体,以提供具有长至对于显影目的足够,但短至足够从其施用的特定患者体内清除的血浆半寿期的融合多肽的缀合物是有利的。
在关于包含有效治疗或缓解需要此种治疗的患者中的特定病状的治疗化合物的缀合物或融合多肽的另一个实例中,使用与亲本白蛋白或其片段相比具有较长血浆半寿期的所述白蛋白衍生物,片段,或其变体以提供具有较长血浆半寿期的缔合物或融合多肽会是有利的,这会具有下述益处:本发明的缔合物或融合多肽的施用与使用亲本白蛋白或其片段的情况相比不需要频繁施用。
本发明的第五个方面提供了白蛋白的衍生物或变体或其片段的“缔合物”。在此方面术语“缔合物”意指包含白蛋白的衍生物或变体或其片段和通过非共价键结合而结合或缔合于所述白蛋白的衍生物或变体或其片段的另一种化合物或由这些物质组成。作为此种缔合物的实例可提及由衍生的或变体白蛋白和通过疏水相互作用缔合于白蛋白的脂质组成的缔合物。作为根据本发明的优选的缔合物的实例,可提及包含衍生的或变体白蛋白和结合的紫杉醇或紫杉醇蛋白的缔合物。根据本发明的白蛋白缔合物的半寿期与“其它化合物”自身的半寿期相比,可较长或较短。根据本发明的白蛋白缔合物的半寿期与包含HSA(而非根据本发明的白蛋白变体或衍生物)和所述“其它化合物”或由它们组成的类似/等同的白蛋白缔合物的半寿期相比可较长或较短。用于制备缔合物的方法对于本领域技术人员是公知的,例如,将HSA与脂质化合物(Lipo-compound)进行配制(通过缔合)在Hussain,R.和Siligardi,G.(2006)International Journal of Peptide Research and Therapeutics,Vol.12,No.3,pp.311-315中描述。
在第六个方面,本发明涉及组合物,该组合物包含或由如下组成:缀合、融合或缔合于治疗性、药物性或其它有益多肽的根据本发明的白蛋白衍生物,片段,或其变体或包含所述白蛋白衍生物,片段,或其变体的融合多肽。所述组合物优选为药物组合物。所述组合物可使用本领域已知的技术,如公开于医药领域内公认的手册中的技术来制备。
在一个具体实施方案中,所述组合物包含或由如下组成:根据本发明的白蛋白衍生物,片段或其变体以及包含药学上有益的模块和白蛋白结合域(ABD)的化合物。根据本发明,ABD意指能够在体内结合于循环的白蛋白,并由此使得所述ABD和任何结合于所述ABD的化合物或模块在循环中转运的位点、模块或域。ABD在本领域中是已知的,并已显示ABD非常紧密地结合于白蛋白,因此包含结合于白蛋白的ABD的化合物会在一定程度上表现得像单个分子。本发明人已意识到通过将根据本发明的白蛋白衍生物,片段或其变体与包含药学上有益的模块和ABD的化合物一同使用,可以与其中所述化合物按原样注入有此需要的患者,或在包含天然白蛋白或其片段的制剂中施用的情况相比,改变该包含药学上有益的模块和ABD的化合物的血浆半寿期。
因此,本发明涉及白蛋白的衍生物或变体或其片段,或包含白蛋白的衍生物或变体或其片段的融合多肽,或包含白蛋白的衍生物或变体或其片段的缀合物,或包含白蛋白的衍生物或变体或其片段的缔合物,在制备药物组合物中的用途,其中所述白蛋白的衍生物或变体或其片段,或包含白蛋白的衍生物或变体或其片段的融合多肽,或包含白蛋白的衍生物或变体或其片段的缀合物,或包含白蛋白的衍生物或变体或其片段的缔合物,与HSA或其相应片段,或包含HSA或其片段的融合多肽,或包含HSA的缀合物相比,具有改变的血浆半寿期。
在此方面,HSA的相应片段意指与同其进行比较的衍生的或变体白蛋白的片段对齐并具有相同数量的氨基酸的HSA的片段。类似地,相应的包含HSA的融合多肽或包含HSA的缀合物意指与同其进行比较的包含衍生的或变体白蛋白的融合多肽或缀合物具有相同大小和氨基酸序列的分子。
优选地,所述白蛋白的衍生物或变体或其片段,或包含白蛋白的衍生物或变体或其片段或由白蛋白的衍生物或变体或其片段组成的融合多肽,或包含白蛋白的衍生物或变体或其片段的缀合物具有的血浆半寿期,与HSA或其相应片段或包含HSA或其片段的融合多肽的血浆半寿期相比较高。
或者,这可表示为所述白蛋白的衍生物或变体或其片段,或包含衍生的或变体白蛋白或其片段的融合多肽,其片段,或包含白蛋白的衍生物或变体或其片段的缀合物具有的对FcRn的KD,与HSA或其相应片段或包含HSA或其片段的融合多肽的相应的KD相比较低。优选对于所述白蛋白的衍生物或变体或其片段,或包含衍生的或变体白蛋白或其片段的融合多肽,其片段,或包含白蛋白的衍生物或变体或其片段的缀合物,其KD小于0.9X HSA的KD,更优选小于0.5X HSA的KD,更优选小于0.1X HSA的KD,甚至更优选小于0.05X HSA的KD,甚至更优选小于0.02X HSA的KD,并且最优选小于0.01X HSA的KD。
所述白蛋白的衍生物或变体或其片段,或包含衍生的或变体白蛋白或其片段的融合多肽,其片段,或包含白蛋白的衍生物或变体或其片段的缀合物,优选为根据本发明的白蛋白的衍生物或变体或其片段,或包含衍生的或变体白蛋白或其片段的融合多肽,其片段,或包含白蛋白的衍生物或变体或其片段的缀合物。
本发明的第七个方面涉及产生所述衍生物或变体或缔合物的方法。本发明的衍生物或变体可使用本领域技术人员公知的技术来制备。一种方便的方式是通过克隆编码亲本白蛋白或其变体,或包含白蛋白或其变体的融合蛋白的核酸,修饰所述核酸以在对应于SEQID NO:31或SEQ ID NO:1中的位置417,464,490,492,493,494,495,496,499,500,501,503,504,505,506,510,535,536,537,538,540,541,542,550,573,574和580的一个或多个(几个)位置导入所需的取代,其中所述衍生物或变体并非由具有取代D494N,E501K,K541E,D550G,A,K573E或K574N的SEQ ID NO:31或SEQ ID NO:1组成的衍生物或变体,制备合适的基因构建体,其中所述修饰的核酸置于与合适的调节基因元件如启动子、终止子、活化位点、核糖体结合位点等可操作地连接,将所述基因构建体导入合适的宿主生物,在导致所述衍生物或变体表达的条件下培养经转化的宿主生物,和回收所述衍生物或变体。任选地,所述衍生物或变体或缔合物,例如,与药学上可接受的赋形剂一同配制。任选地,所述衍生物或变体或缔合物以单位剂量形式呈现。所有这些技术在本领域是已知的,且设计合适的方法以供制备根据本发明的特定衍生物或变体属于一般技术人员的技术范围。
亦可将本发明的衍生物或变体多肽与信号序列相连接以使得所述衍生物或变体多肽在经转化的宿主细胞的培养过程中分泌入生长培养基。一般而言,为了方便回收和纯化,使得所述衍生物或变体多肽分泌入生长培养基是有利的。
用于制备衍生物或变体多肽的技术亦公开于WO 2009019314和PCT/EP2010/066572(通过提述并入本文),且这些技术亦可适用于本发明。
白蛋白已成功地作为重组蛋白在多种宿主包括真菌(包括但不限于曲霉属(Aspergillus)(WO06066595)、克鲁维酵母属(Kluyveromyces)(Fleer 1991,Bio/technology 9,968-975),毕赤酵母属(Pichia)(Kobayashi 1998 Therapeutic Apheresis2,257-262)和酵母属(Saccharomyces)(Sleep 1990,Bio/technology 8,42-46)),细菌(Pandjaitab 2000,J.Allergy Clin.Immunol.105,279-285)),动物(Barash 1993,Transgenic Research 2,266-276)和植物(包括但不限于马铃薯和烟草(Sijmons 1990,Bio/technology 8,217and Farran 2002,Transgenic Research 11,337-346)中得到表达。本发明的衍生物或变体优选在合适的宿主细胞中重组产生。原则上,任何能够以合适量产生多肽的宿主细胞均可使用,且一般技术人员具有根据本发明选择合适宿主细胞的能力。优选的宿主生物是酵母,优选选自酵母属(Saccharomycacae),更优选为酿酒酵母。
可使用已知的分离技术如过滤、离心、层析和亲和分离技术等的组合从生长培养基回收和纯化本发明的衍生物或变体多肽。一般技术人员有使用此类已知分离步骤的特定组合纯化本发明的衍生物或变体的能力。作为可应用于本发明的衍生物或变体的纯化技术的实例,可提及WO0044772的教导。
本发明的衍生物或变体多肽可用于将治疗上有益的化合物递送至有此需要的动物或人类个体。此类治疗上有益的化合物包括但不限于用于诊断如多种显影技术的标记和容易检测的化合物;药学活性化合物如药物,或特异性结合模块如抗体。本发明的衍生物或片段甚至可连接至两种或更多种不同的治疗上有益的化合物,例如一种抗体和一种药物,这赋予组合分子特异性结合于所需的靶的能力,并由此对于该特定靶提供高浓度的所连接的药物。
根据本发明的衍生的或变体白蛋白,其片段,或包含所述衍生的或变体白蛋白,或其片段的融合多肽具有下述优点:其血浆半寿期相对于亲本白蛋白或其片段,或包含亲本白蛋白或其片段的融合多肽,或未融合、未缀合或未缔合的治疗性、诊断性或其它有益模块相比得到改变。这具有下述优点:可依照特定的治疗目的选择根据本发明包含衍生的或变体白蛋白或其片段的缀合物,或包含衍生的或变体白蛋白或其片段的融合多肽,或包含衍生的或变体白蛋白或其片段的缔合物的血浆半寿期。
本发明的第八个方面涉及显影。举例而言,对于用于在动物或人类中显影目的的缀合物、缔合物或融合多肽,当显影模块具有非常短的半寿期,以及包含HSA的缀合物或融合多肽具有远较该显影目的所需的更长的血浆半寿期时,使用与亲本白蛋白或其片段相比具有较短血浆半寿期的本发明衍生物或变体多肽,以提供具有长至对于显影目的足够,但短至足够从其施用的特定患者体内清除的血浆半寿期的融合多肽或缀合物是有利的。包含白蛋白的显影剂的实例包括WO 2004/071536的那些。
本发明的第九个方面涉及治疗方法和/或在治疗方法中的用途。所述方法可包括在需要此种治疗的患者中使用对治疗或缓解特定病状有效的治疗化合物,使用与亲本白蛋白或其片段相比具有较长血浆半寿期的衍生的或变体白蛋白或其片段以提供具有与所述治疗化合物自身或融合于、缀合于或缔合于天然HSA的治疗化合物相比具有较长血浆半寿期的缔合物或融合多肽会是有利的,这会具有下述益处:本发明的缔合物或缀合物或融合多肽的施用与使用亲本白蛋白或其缔合物或其片段的情况相比不需要频繁施用或仅需要减少的剂量,从而具有较少的副作用。本发明亦包括其中所述白蛋白变体,衍生物,融合物,缀合物或缔合物与治疗化合物自身或融合、缀合或缔合于天然HSA的治疗化合物相比具有较短的半寿期的方法。
在第十个方面,本发明涉及组合物,其包含根据本发明的衍生的或变体白蛋白,其缔合物或其片段,衍生的或变体白蛋白片段或其缔合物,或包含变体白蛋白或其片段的融合多肽。所述组合物优选为药物组合物。所述组合物可使用本领域已知的技术,如公开于医药领域公认的手册中的技术来制备。
在一个具体实施方案中,所述组合物包含或由如下组成:根据本发明的衍生的或变体白蛋白或其片段以及包含药学上有益的模块和白蛋白结合域(ABD)的化合物。根据本发明,ABD意指能够在体内结合于循环的白蛋白,并由此使得所述ABD和任何结合于所述ABD的化合物或模块在循环中转运的位点、模块或域。ABD在本领域中是已知的,并已显示其非常紧密地结合于白蛋白,因此包含结合于白蛋白的ABD的化合物会在一定程度上表现得像单个分子。本发明人已意识到通过将根据本发明的衍生的或变体白蛋白或其片段与包含药学上有益的模块和ABD的化合物一同使用,与其中所述化合物按原样注入有此需要的患者,或在包含天然白蛋白或其片段的制剂中施用的情况相比,能够改变该包含药学上有益的模块和ABD的化合物的血浆半寿期。
根据本发明的衍生的或变体白蛋白或其片段,包含所述衍生的或变体白蛋白或其片段的缀合物,或衍生的或变体白蛋白或其片段的融合多肽,或衍生的或变体白蛋白或其片段的缔合物亦可使用本领域公知的技术并入纳米或微米颗粒。可适用于根据本发明的衍生的或变体白蛋白或其片段的制备纳米或微米颗粒的优选的方法公开于WO 2004/071536,其通过提述并入本文。
下述定义亦适用于本文中公开的发明:
等位变体(allelic variant):术语“等位变体”意指占据相同染色体基因座的基因的任何两种以上可选形式。等位变异通过突变天然地发生,并且可导致种群内的多态性。基因突变可以是沉默的(在编码的多肽中无变化)或可以编码具有改变的氨基酸序列的多肽。多肽的等位变体是由基因的等位变体编码的多肽。
术语“编码序列”的意指直接指定其翻译的多肽产物的氨基酸序列的多核苷酸。编码序列的边界通常由开读框确定,所述开读框通常以ATG起始密码子或可供选择的起始密码子如GTG和TTG开始,并且以终止密码子如TAA、TAG和TGA结束。编码序列可以是DNA、cDNA、合成的或重组的多核苷酸。
术语“cDNA“意指可从自真核细胞获得的成熟的、经剪接的mRNA分子通过逆转录制备的DNA分子。cDNA缺乏可存在于相应的基因组DNA中的内含子序列。起始的、初级RNA转录物是mRNA的前体,其通过一系列步骤包括剪接进行加工然后作为成熟的、经剪接的mRNA出现。
术语“核酸构建体”意指单链或双链的核酸分子,所述核酸分子分离自天然存在的基因,或将所述核酸分子以本来不存在于(not otherwise exist)自然界中的方式修饰以含有核酸的区段或所述核酸分子是合成的。当所述核酸构建体含有表达本发明的编码序列所需的调控序列时,术语核酸构建体与术语“表达盒”同义。
术语“调控序列”意指包括编码本发明的衍生物或变体的多核苷酸表达所必需的所有组分。各个调控序列对于编码所述衍生物或变体的多核苷酸可以是天然的或外源的,或各个调控序列对于彼此可以是天然的或外源的。这些调控序列包括但不限于前导序列、聚腺苷酸化序列、前肽序列、启动子、信号肽序列和转录终止子。最少的情况,调控序列包括启动子和转录和翻译的终止信号。调控序列可以和用于引入特异性限制位点的接头一起提供,所述特异性限制位点促进调控序列连接于编码衍生物或多肽的多核苷酸编码区之内。
术语“可操作地连接”意指这样的构型,其中将调控序列置于相对于多核苷酸的编码序列的适当位置,使得调控序列指导编码序列的表达。
术语“表达”包括涉及衍生物或多肽产生的任何步骤,其包括但不限于转录、转录后修饰、翻译、翻译后修饰和分泌。
术语“表达载体”意指线性的或环状的DNA分子,其包含编码衍生物或变体的多核苷酸,并与供用于其表达的额外核苷酸可操作地连接。
术语“宿主细胞”意指任何细胞类型,所述细胞类型对于用包含本发明多核苷酸的核酸构建体或表达载体的转化、转染、转导等是易感的(susceptible)。术语“宿主细胞”涵盖由于在复制过程中发生的突变而不同于亲本细胞的亲本细胞的任何后代。
术语“突变体”意指编码衍生物或变体的多核苷酸。
术语“野生型白蛋白”意指由天然存在的生物,如真核生物,例如哺乳动物如人,表达的白蛋白。
术语“亲本”或“亲本白蛋白”意指对其进行改变以产生本发明的白蛋白衍生物或变体的白蛋白。所述亲本可为天然存在的(野生型)多肽或衍生物或其变体。
本发明进一步参照下述实施例来描述,其不应视作对本发明范围的限制。
实施例:
材料和方法
(a)ELISA:
将孔用在PBS中稀释、具有100-0.045μg/ml范围的浓度的HSA野生型或突变体涂覆,在4℃温育过夜,然后用4%脱脂乳(Acumedia)在室温封闭1小时。然后将孔用磷酸盐缓冲盐水(PBS)/0.005%TWEEN 20(PBS/T)pH 6.0洗涤四次,然后将与来自山羊的HRP-缀合的多克隆抗GST抗体预温育并稀释于4%脱脂乳PBS/0.005%20(PBS/T)pH 6.0的GST-融合的shFcRn(0.5μg/ml(FEBS J.2008Aug;275(16):4097-110))添加至每个孔,并在室温温育1.5h,接着用PBS/T pH 6.0洗涤四次。将100μl的底物TMB(Calbiochem)添加至每个孔,并温育45分钟,然后添加100μl的0.25M HCl。使用Sunrise TECAN分光光度计(TECAN,Maennedorf,Switzerland)在450nm测量吸光度。
用PBS/T pH 7.4重复同样的ELISA。
(b)表面等离振子共振(SPR):
SPR实验使用Biacore 3000装置(GE Healthcare)进行。将CM5传感芯片的流动室(flow cell)使用生产商提供的实验方案中描述的胺偶联化学与shFcRn-GST(~1400-5000RU)偶联。偶联通过将10μg/ml的蛋白注入10mM乙酸钠pH 5.0(GE healthcare)进行。使用pH 6.0的磷酸盐缓冲液(67mM磷酸盐缓冲液,0.15M NaCl,0.005%TWEEN 20)作为运行缓冲液和稀释缓冲液。表面再生使用注入pH 7.4的HBS-EP缓冲液(0.01M HEPES,0.15M NaCl,3mM EDTA,0.005%表面活性剂P20)(Biacore AB)完成。为了结合于固定化的shFcRn-GST,将1.0-0.5μM的每种HSA衍生物或变体在表面上在25℃以恒定流速(40μl/ml)注入。在所有实验中,将数据调零校正(zero adjust),并减去参照室数据。数据评价使用BIAevaluation4.1软件(BIAcore AB)进行。
用HBS-EP缓冲液pH 7.4重复同样的SPR测定。
SPR实验使用Biacore 3000装置(GE Healthcare)进行。将CM5传感芯片的流动室(flow cell)使用生产商提供的实验方案中描述的胺偶联化学与shFcRn-GST(~2600RU)偶联。偶联通过将10μg/ml的蛋白注入10mM乙酸钠pH 5.0(GE healthcare)进行。使用pH 6.0的磷酸盐缓冲液(67mM磷酸盐缓冲液,0.15M NaCl,0.005%TWEEN 20)作为运行缓冲液和稀释缓冲液。表面再生使用注入pH 7.4的HBS-EP缓冲液(0.01M HEPES,0.15M NaCl,3mMEDTA,0.005%表面活性剂P20)(Biacore AB)完成。竞争性结合通过将shFcRn(50nM)单独或与不同量的HSA或RSA域构建物一起注入于固定化的HSA上来测量在所有实验中,将数据调零校正(zero adjust),并减去参照室数据。数据评价使用BIAevaluation 4.1软件(BIAcore AB)进行。
HSA:对于实施例,使用在注册商标RECOMBUMIN下商业上可获得的重组人血清白蛋白。
来自其它物种的血清白蛋白:白蛋白使用从公共可获得的数据库提供的序列重组产生(数据未显示)。
FcRn:PCR和亚克隆。编码截短的可溶性hFcRn(shFcRn)HC和hβ2m的cDNA区段从U937细胞系(ATCC)cDNA文库PCR扩增,接着将片段亚克隆入pCDNA3-GST载体,所有均如前所述(Berntzen等(2005)J Immunol Methods 298:93-104)。使用小鼠肝cDNA文库(Zyagen)使用引物mFcRnForw和mFcRnRev来PCR扩增编码截短型式的mFcRn HC的cDNA(编码内源天然前导序列,α1、α2和α3域;293个氨基酸):
mFcRnForw 5-ATT ATG AAT TCA TGG GGA TGC CAC TGC CCT GG-3
mFcRnRev 5-ATA TAC TCG AGT AGG TCC ACA GTG AGA GGC TG-3
设计引物以允许编码来自Schistosoma japonicum的GST-标记的cDNA上游的片段框内连接入pcDNA3-GST-hβ2m-oriP载体,其亦含有编码hβ2m的cDNA和Epstein Barr病毒复制起点(oriP)。对最终载体进行测序并命名为pcDNA3-mFcRnwt-GST-hβ2m-oriP。
可溶性人FcRn变体(shFcRn-GST)的表达和纯化-对于瞬时转染,将hFcRn和mFcRn编码质粒遵循生产商的指示使用Lipofectamine 2000(Invitrogen)转染入HEK293E细胞(ATCC)。将HEK 293E细胞在Dulbecco改进的eagle培养基(BioWhittaker)中使用标准条件进行培养。将汇集的培养基过滤,并施于GSTrap FF柱5ml柱(GE Healthcare)上,该柱连接于半自动工作站和记录器,并且基本上如生产商的手册中推荐进行纯化。将洗脱的级分汇集、浓缩,并在使用β-巯基乙醇(Sigma-Aldrich)的还原或非还原条件下分析。将每个受体的2μg的样品施于12%SDS-PAGE(Bio-Rad)。蛋白浓度使用NanoDrop N-1000分光光度计(NanoDrop Technologies)确定。
用于生成shFcRn表达质粒,表达和纯化每种异二聚体的方法亦可见于Berntzen等(2005)J.Immunol.Methods 298:93-104)和Andersen等(2010)J.Biol.Chem.,285:4826-4836。
或者,His-标记的shFcRn FcRn异二聚体由GeneArt AG(Germany)产生。该异二聚体的两个亚基的序列可见于SEQ ID NO:32(主要组织相容性复合物类型I-样Fc受体(FCGRT)截短的重链)和SEQ ID NO:33(β-2-微球蛋白)。SEQ ID NO:32和SEQ ID NO:33一同形成FcRn。将可溶性受体表达于HEK293细胞,并使用Ni-HiTrap层析柱从培养上清纯化。His标记基因融合于β-2-微球蛋白的C端。
(c)质粒和菌株的构建
总体而言采用标准的分子生物学技术,如Sambrook,J.和D.W.Russell,2001.Molecular Cloning:a laboratory manual,第3版Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,N.Y.中描述的那些。
含有表达盒的质粒列于表2。所有表达盒包含酿酒酵母PRB1启动子和修饰的酿酒酵母ADH1终止子(mADHt),并编码前导序列[其为:融合物前导序列(FL。与质粒pDB2244中的相同,WO 0044772A),修饰的融合物前导序列(mFL。与质粒pDB2305中所述的相同,EP1788084(通过提述并入本文)),酿酒酵母转化酶前导序列(Suc2p:MLLQAFLFLLAGFAAKISA)或修饰的酿酒酵母转化酶前导序列(MLLQAFFIVSIGFAAKISA)],以及白蛋白衍生的蛋白(例如全长,域,突变体和融合物等)。表6显示质粒图的实例(pDB2305)以图示通常的表达盒的组分。除非另行说明,最终表达质粒在体内生成(即通过酿酒酵母中的同源重组;称作缺口修复或体内克隆的技术,参见Orr-Weaver&Szostak.1983.Proc.Natl.Acad.Sci.USA.80:4417-4421)。通常,对于缺口修复实验,将100ng的Acc65I/BamHI pDB3936(公开于WO 2010/092135)与等摩尔浓度的含有生成所需最终表达质粒所需要的表达盒的DNA片段混合。将这些直接用于使用下文中所述的YeastTransformation试剂盒(Sigma)来共转化酿酒酵母菌株。
表2:质粒构建体的总结
表达质粒亦使用PCR(聚合酶链式反应)片段和Acc65I/BamHI pDB3936(100ng)以等摩尔浓度使用体内克隆生成。表3列出了使用PCR片段和Acc65I/BamHI pDB3936生成的构建体。所有PCR反应使用Phusion聚合酶(New England Biolabs)遵循生产商的指示进行。通常的PCR反应混合物为:20μl Buffer HF(5X),2μl dNTP混合物(10mM),2μl引物(10μM),2μl引物(10μM),1μl Phusion聚合酶(2U/μl),1μl质粒DNA(~5ng)或总DNA(~100ng),72μl蒸馏H2O。
表3:使用PCR和Acc65I/BamHI pDB3936(100ng)以等摩尔浓度在体内生成的构建体
构建体 | 参照编号 | SEQ ID NO: |
IL1Ra+GSL+HSA DI+DIII野生型 | 9506 | - |
IL1Ra+GSL+HSA DI+DIII K573P | 9507 | - |
IL1Ra+GSL+HSA DII+DIII野生型 | 9508 | - |
IL1Ra+GSL+HSA DII+DIII K573P | 9509 | - |
IL1Ra+GSL+HSA DIII | 9504 | - |
IL1Ra+GSL+HSA DIII K573P | 9505 | - |
HSA DI+DII+MSA DIII | 9226 | 29 |
HSA DI+DII+RSA DIII | 9009 | 25 |
HSA DI+DII+SSA DIII | 9114 | 28 |
MSA DI+DII+HSA DIII | 9225 | 30 |
RSA DI+DII+HSA DIII | 9010 | 26 |
SSA DI+DII+HSA DIII | 9113 | 27 |
MSA DI+DIII | 9008 | - |
RSA DI+DIII | 9007 | - |
(i)用于表达人/动物嵌合物的质粒的构建和动物白蛋白DI+DIII构建体
除非另行指明,质粒总结于表2和表3。用于表达全长兔(SEQ ID NO:14)和小鼠白蛋白(SEQ ID NO:9)的质粒如下所述制备:将含有PRB1启动子的3’区,编码修饰的融合前导序列的DNA,兔或小鼠白蛋白,和mADHt的5’区的BfrI/SphI合成DNA片段(2.087kb)通过基因装配(GeneArt AG,Germany)来产生。将人工SphI位点添加至天然存在的BfrI位点直接上游以助于后续克隆。将合成的SphI DNA片段克隆入pCR-script(Agilent Technologies),产生pDB3248和pDB3429。将pDB2541(含有PRB1启动子,编码修饰的融合前导序列和HSA的DNA,以及mADHt的亚克隆质粒)用BfrI/SphI消化以去除编码HSA的基因,及其侧翼的PRB1和mADHt终止子的部分。将该DNA用来自pDB3248和pDB3429的类似BfrI/SphI片段替代,以分别产生pDB3256和pDB3435。将pDB3256和pDB3435用NotI消化,并将2.989kb产物各连接入NotI-消化的pSAC35(公开于EP-A-286 424并由Sleep,D.,等(1991)Bio/Technology 9,183-187描述,通过提述并入本文)以分别产生pDB3257和pDB3442。
将pDB3257和pDB3442用于直接转化酿酒酵母菌株A(描述于WO 2010/092135)。
如下所述制备用于表达绵羊白蛋白的质粒:通过基因装配(GeneArt AG,Germany)生成2.207kb PstI/SphI合成DNA片段(含有PRB1启动子的3’区,编码融合物前导序列和绵羊白蛋白的DNA(SEQ ID NO:16),和mADHt的部分)。将合成的PstI/SphI片段克隆入PstI/SphI-消化的pDB3927(描述于WO 2010/092135)以产生pDB3994。
最终表达质粒通过体内克隆/缺口修复来生成,即,将pDB3994用BstEII/BsrBI消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化,并将100ng的消化物与100ng Acc65I/BamHI-消化的pDB3936(公开于WO 2010/092135)组合,并用于转化酿酒酵母BXP10cir0(描述于WO2001/079480)。
对于多种白蛋白嵌合物的表达质粒使用PCR和体内克隆生成。表4列出了用于生成每个构建体的寡核苷酸对和模板DNA,表5提供了寡核苷酸的序列。即,使用PCR扩增两个PCR片段。片段1含有LEU2ORF和3’UTR,PRB1启动子,编码前导序列的DNA(修饰的融合物或融合物前导序列),编码白蛋白的DI+DII(例如来自人、小鼠、兔或绵羊)的DNA,和编码白蛋白的DIII(例如来自人、小鼠、兔或绵羊)的5’序列的DNA的27-30bp。片段2含有编码白蛋白的DIII(例如来自人、小鼠、兔或绵羊)的DNA,mADHt终止子和与pDB3936(公开于WO 2010/092135)中的核苷酸序列同源的217bp侧翼序列。
PCR产物使用Qiagen PCR Purification试剂盒纯化(遵循生产商的指示)。图7概述了通过体内克隆生成表达质粒。即,使用纯化的PCR产物连同Acc65I/BamHI-消化的pDB3936,以共转化酿酒酵母BXP10cir0。
供小鼠白蛋白和兔白蛋白DI+DIII的表达质粒使用PCR和体内克隆使用与上述那些用于生成人/动物嵌合物表达载体(例如HSA DI+DII+小鼠DIII,反之亦然)相同的方法制备。用于生成PCR片段的寡核苷酸对(表5)和模板DNA列于表4。
表4:用于生成PCR片段的寡核苷酸对和模板DNA。
*pDB2305示于图6,并亦描述于(公开于EP1788084,通过提述并入本文)
模板DNA示于括号中,例如(pDB2305)
表5:表4中提及的寡核苷酸的寡核苷酸序列
(ii)编码HSA DI+DIII突变体和HSA DI+DIII突变体融合物的质粒的制备
起始HSA DI+DIII表达质粒/酵母菌株通过PCR和体内克隆使用本文中所述的用于小鼠和兔DI+DIII表达构建体的方法来生成。使用寡核苷酸xAP032/xAP058(表5)和xAP059/xAP033(表5)来分别生成PCR片段1和2(使用pDB2244(描述于WO 00/44772)作为模板DNA)。所得的菌株命名为8822。
总DNA(即基因组和质粒DNA)如下所述从酵母8822提取。使用10μL灭菌环从琼脂平板刮取酵母细胞,并将细胞重悬于1.5mL微离心管中的200μL提取缓冲液[50mM Tris-HCl(pH7.5),10mM EDTA(pH8.0),100mM NaCl,2%w/v SDS]中,然后在80℃加热2分钟。将DNA提取混合物在台式微离心机中以13,000rpm离心1分钟,然后去除上清。将总DNA用3体积的乙醇和0.1体积的3M乙酸钠(pH 5.4)在-80℃沉淀10分钟。将沉淀的DNA在台式微离心机中以13,000rpm离心20分钟,去除上清,并用70%v/v乙醇洗涤DNA沉淀。将沉淀迅速风干,然后将DNA重悬于100μL TE缓冲液。
为了生成HSA DI+DIII突变体表达盒,使用寡核苷酸xAP075和xAP138(表5)从自酵母菌株8822制备的DNA来PCR扩增2.1kb DNA片段。所述PCR片段含有LEU2标志物的3’区,PRB1启动子,编码融合物前导序列和HSA DI和DIII的DNA。将PCR片段用NgoMIV/AvrII消化,并将1.395kb产物连接入NgoMIV/AvrII-消化的pDB3927(描述于WO 2010/092135),pDB4086,pDB4110和pDB4184和pDB4010(均描述于PCT/EP10/066572,通过提述并入本文)以分别产生pDB4372至pDB4375和pDB4480。将pDB4372至pDB4375和pDB4480用NsiI/PvuI消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA。最终表达质粒通过体内克隆生成,即,将酿酒酵母BXP10cir0用每个NsiI/PvuI-消化的DNA和Acc65I/BamHI-消化的pDB3936来共转化。
含有用于产生基因融合于HSA DI+DIII及其突变体的C端的IL-1ra(SEQ ID NO:34)的表达盒的质粒如下所述进行制备:将pDB2588(描述于PCT/EP10/066572,通过提述并入本文)用Bsu36I/SphI消化,且使用Qiagen PCR-纯化试剂盒遵循生产商的指示纯化编码HSA DIII的3’区,GS接头,和人IL1-RA(N84Q)和修饰的酿酒酵母mADHt的5’区的705bp DNA片段。将纯化的片段分别连接入Bsu36I/SphI-消化的pDB4372,pDB4373,pDB4374,pDB4375和pDB4480以生成pDB4382,pDB4383,pDB4385,pDB4384和pDB4481。最终表达质粒通过体内克隆生成,其涉及用NsiI/PvuI消化pDB4382至pDB4385和pDB4481,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA,然后使用该DNA,连同Acc65I/BamHI-消化的pDB3936直接转化酿酒酵母BXP10cir0。
含有用于产生基因融合于HSA DI+DIII和HSA DI+DIII K573P的N端的IL-1ra(N84Q)的表达盒的质粒使用PCR和体内克隆使用如上所述的方法制备。用于生成两个PCR片段的寡核苷酸列于表5。使用寡核苷酸xAP330/xAP337和作为模板DNA的质粒pDB2590来生成PCR片段1。质粒pDB2590与pDB2305(描述于WO2006/013859)相同,但含有编码融合物前导序列,IL-1ra(N84Q),GS接头,继以HSA的DNA。PCR片段1含有774bp的LEU2ORF上游的核苷酸序列,PRB1启动子,和编码融合物前导序列,IL1-RA(N84Q),GS接头,和HSA DI的前29bp的DNA。PCR片段2(使用寡核苷酸xAP338/xAP333使用pDB4372或pDB4374任一生成)含有编码HSA DI+DIII(野生型或K573P)的DNA,mADHt和2.031kb侧翼序列,与pDB3936中的核苷酸序列同源。使用Qiagen PCR Purification试剂盒遵循生产商的指示纯化PCR片段。最终表达质粒在体内生成,其涉及用PCR片段1和2连同Acc65I/BamHI-消化的pDB3936共转化酿酒酵母BXP10cir0。
(iii)编码HSA DII+DIII突变体及其融合物的质粒的制备
用于HSA DII+DIII及其突变体的表达质粒如下所述生成。将pDB2202,其含有HSADII+DIII表达盒(即PRB1启动子,编码融合物前导序列和HSA DII+DIII的DNA,和mADHt),用NgoMIV/AvrII消化,并使用Qiagen Gel Extraction试剂盒(遵循生产商的指示)纯化1.407kb片段。将NgoMIV/AvrII片段分别连接入NgoMIV/AvrII-消化的pDB3927(描述于WO2010/092135),pDB4010,pDB4110和pDB4184(描述于PCT/EP10/066572,通过提述并入本文)以生成pDB4386,pDB4482,pDB4387,pDB4388。将pDB4386-pDB4388和pDB4482用NsiI/PvuI消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA。最终表达质粒在体内生成,其涉及用每种NsiI/PvuI-消化的质粒DNA连同Acc65I/BamHI-消化的pDB3936共转染酿酒酵母BXP10cir0。
包含用于产生基因融合于HSA DII+DIII及其突变体的C端的IL-1ra的表达盒的质粒根据对于生成基因融合于HSA DI+DIII突变体构建体的C端的IL-1ra所述的方法来制备。生成的质粒命名为pDB4483,pDB4485,pDB4486和pDB4484。pDB4483至pDB4486NsiI/PvuI,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA。最终表达质粒在体内生成,如对于HSA DI+DIII突变体融合构建体所述的。
含有用于产生基因融合于HSA DII+DIII和HSA DII+DIII K573P的N端的IL-1ra的表达盒的质粒使用PCR和体内克隆制备,如对于生成基因融合于HSA DI+DIII和HSA DI+DIII K573P的N端的IL-1ra所述。PCR片段1使用寡核苷酸xAP330/xAP339(表5)(使用pDB2590作为模板DNA)生成,并与编码HSA DII的(即在pDB4386和pDB4387中)分享32bp的核苷酸序列同源性。PCR片段2使用寡核苷酸xAP340/xAP333(表5)(使用pDB4386或pDB4387作为模板DNA),并与pDB3936中的核苷酸序列分享2.031kb同源性侧翼序列。使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化PCR片段。最终表达质粒在体内如对于HSA DI+DIII突变体融合物构建体所述生成。
(iv)编码HSA DIII和突变体及其融合物的质粒的制备
使用PCR生成编码HSA DIII的649bp片段,在对应于成熟白蛋白蛋白序列位置573的密码子导入变化从而使得并入苯丙氨酸而非赖氨酸,并修剪片段使其可克隆入表达质粒pDB4284(描述于PCT/EP10/066572,通过提述并入本文)。具体而言,这是使用寡核苷酸xAP260和xAP253(表5)和作为模板DNA的质粒pDB3927(描述于WO 2010/092135)实现的。PCR片段使用Qiagen PCR Purification试剂盒纯化(依照生产商的指示),用BglII/Bsu36I消化,然后使用Qiagen PCR Purification试剂盒纯化消化的DNA。将纯化的BglII/Bsu36I片段连接入BglII/Bsu36I-消化的pDB4284以构建pDB4460。
制成一系列编码HSA DIII突变体的表达质粒,即将来自pDB4460的666bp AvrII/SphI片段用来自pDB3927(描述于WO 2010/092135),pDB3883,pDB4086,pDB4010,pDB4006,pDB4175,pDB4189,pDB4110,pDB4182,pDB4184,pDB4200,pDB4202和pDB4094(描述于PCT/EP10/066572,通过提述并入本文)的在编码HSA DIII的核苷酸序列内含有突变的类似序列替代以构建质粒pDB4461至pDB4473。
含有用于产生基因融合于HSA DIII和DIII变体的C端的IL-1ra或scFv(FITC8)(SEQ ID NO:35)的表达盒的质粒如下所述制备。对于IL-1ra融合物,获得1.164kb来自质粒pDB2588,pDB4288和pDB4286(描述于PCT/EP10/066572,通过提述并入本文)的AvrII/SphI片段[含有编码HSA DIII或其突变体的DNA的3’端,编码GS接头和IL-1ra(N84Q)的DNA,和mADHt的5’区),并随后连接入AvrII/SphI-消化的pDB4460。这样分别获得质粒pDB4474-pDB4476。
含有用于产生scFv融合物的表达盒的质粒通过下述方法制成:分离来自质粒pDB3008(描述于Evans等,2010.Protein Expression and Purification.73,113-124)的1.005kb Bsu36I/SphI片段(含有编码HSA DIII的C端区,GS接头和scFv的DNA和mADHt的5’区),并随后将其克隆入Bsu36I/SphI-消化的pDB4461,pDB4464和pDB4468,这样获得质粒pDB4477-pDB4479。
将质粒pDB4460-pDB4479用NsiI/PvuI消化,并使用Qiagen PCR Purification试剂盒纯化。将纯化的DNA与Acc65I/BamH-消化的pDB3936混合,并用于直接转化酿酒酵母Bcir0。
酿酒酵母菌株B cir0是酿酒酵母A cir0(描述于WO 2010/092135)的衍生物,且其构建如下所述。在进行化学诱变之后,分离酿酒酵母ura3突变体(即对于尿嘧啶为营养缺陷型),并命名为酿酒酵母菌株A-ura3。将酿酒酵母菌株A-ura3用pDB3837转化。pDB3837如下所述生成:通过PCR从酿酒酵母BY4741(描述于Brachmann,等,(1998)Yeast 14,115)基因组DNA分别使用引物B01/BO2和BO3/B04(表5)扩增HO开读框的5’和3’区。纯化PCR产物,并用酶NotI/MluI(5’区片段)和MluI/ClaI(3’区片段)限制性消化。将经消化的片段纯化,并在三元连接(three way ligation)中连接于NotI/ClaI消化的pBST+[描述于Sleep,D.(2001).Yeast 18:403-421]。将多接头(从杂交的寡核苷酸B05和BO6,表5生成)克隆在5’和3’区之间的MluI位点以构建pDB3343。将酿酒酵母URA3基因从质粒YCplac50[描述于Rose等(1987).Gene 60:237-243]使用引物B07和B08(表5)PCR扩增。将URA3产物用PacI和PmeI消化,并连接入PacI/PmeI-消化的pDB3343,构建pDB3514。含有酿酒酵母PDI1基因的2.94kbKpnI片段从pDB2389(Finnis等(2010).Microbial Cell Factories 9:87)获得,使用T4聚合酶平端化,然后连接入SfoI-消化的pDB3514。所得的质粒,pDB3837含有两个串联拷贝的PDI1片段。使用pDB3837直接转化酿酒酵母菌株A-ura3 cir0以生成菌株B cir0。酿酒酵母菌株B含有PDI1基因的天然拷贝,在HO基因座的2个拷贝的PDI1基因,和在该菌株基因组中未知位置的另一个拷贝的PDI1基因。
(v)编码HSA DIII和突变体及其融合物的质粒的制备
含有用于HSA DIII+DIII及其突变体的表达盒的质粒如下所述生成。将使用寡核苷酸xAP323/xAP324(表5)的PCR用于从pDB4282,pDB4283和pDB4284(描述于PCT/EP10/066572,通过提述并入本文)扩增636bp DNA片段。PCR片段使用Qiagen PCR Purification试剂盒遵循生产商的指示纯化,用BglII/HindIII消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化,然后连接入BglII/HindIII-消化的pDB4284(描述于PCT/EP10/066572,通过提述并入本文)。所得的质粒命名为pDB4489-pDB4491。
进行第二轮系列的PCR以扩增编码第二HSA DIII及其变体的DNA。使用寡核苷酸xAP324/xAP325(表5)以从pDB3927(描述于WO 2010/092135,通过提述并入本文),pDB4010和pDB4110(描述于PCT/EP10/066572,通过提述并入本文)PCR扩增编码HSA DIII及其变体的DNA片段。PCR片段使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化,用Bsu36I消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化,然后连接入Bsu36I-消化的pDB4489-pDB4491。所得的质粒命名为pDB4522-pDB4526。将pDB4522-pDB4526用NsiI/PvuI消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA,然后使用其连同Acc65I/BamHI-消化的pDB3936以直接转化酿酒酵母B cir0。
(vi)编码HSA DIII E492G+DIII E492G(即串联域III)的质粒的制备
含有HSA DIII E492G+DIII E492G表达盒的质粒如下所述制备。将含有PRB1启动子的3’区,编码FIVSI修饰的转化酶前导序列和HSA DIII E492G+DIII E492G的DNA和mADHt的5’区的1.488kb合成DNA片段通过基因装配(DNA2.0,USA)生成。将合成的PstI/PacI片段连接入PstI/PacI-消化的pDB4181(描述于PCT/EP10/066572,通过提述并入本文)以生成pDB4112。将pDB4112用BstEII/BsrBI消化,使用Qiagen PCR Purification试剂盒遵循生产商的指示纯化,然后将100ng与100ng Acc65I/BamHI-消化的pDB3936(公开于WO 2010/092135,通过提述并入本文)混合,并用于直接转化酿酒酵母菌株B cir0。
含有用于产生基因融合于HSA DIII+DIII及其突变体的IL-1ra或scFv(FITC8)的表达盒的质粒如下所述制备。将pDB4522,pDB4523和pDB4524用AvrII/SphI消化,并将来自每个反应的7.564kb用Qiagen Gel Extraction kit遵循生产商的指示进行纯化。将pDB4474至pDB4479用AvrII/SphI消化,并将1.164kb和1.464kb片段(分别含有编码IL-1Ra和scFv的DNA)使用Qiagen Gel Extraction kit遵循生产商的指示纯化。将来自pDB4474至pDB4479的纯化的AvrII/SphI片段连接入AvrII/SphI-消化的pDB4522至pDB4524以产生pDB4527–pDB4531和pDB4533。将pDB4527–pDB4531和pDB4533用NsiI/PvuI消化,DNA使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化,然后使用其连同Acc65I/BamHI-消化的pDB3936直接转化酿酒酵母菌株B cir0。
(vii)编码DIII+DI和DIII+DII的质粒的制备
含有用于HSA DIII+DI和DIII+DII的表达盒的质粒如下所述生成。使用pDB3927(描述于WO 2010/092135)作为模板DNA使用寡核苷酸对xAP290/xAP291和xAP292/xAP293(表5)以PCR扩增分别编码HSA DI(PCR片段=616bp)和HSA DII(PCR产物=628bp)的DNA。将两种PCR片段用Bsu36I/HindIII消化,使用Qiagen PCR-Purification试剂盒(遵循生产商的指示)纯化,然后连接入Bsu36I/HindIII-消化的pDB4478以产生pDB4487和pDB4488。将pDB4487和pDB4488用NsiI/PvuI消化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA,然后使用其连同Acc65I/BamHI-消化的pDB3936直接转化酿酒酵母B cir0。
(viii)编码DIII+DIII+DIII的质粒的制备
用于HSA DIII+DIII+DIII(即三重域III)的表达构建体如下所述制备:从pDB4527获得含有编码HSA DIII的DNA的615bp Bsu36I DNA片段,并将其连接入Bsu36I-消化的pDB4522以构建pDB4534。将pDB4534用NsiI/PvuI纯化,使用Qiagen PCR-Purification试剂盒遵循生产商的指示纯化DNA,然后使用其连同Acc65I/BamHI-消化的pDB3936直接转化酿酒酵母菌株B cir0。
(d)酿酒酵母的转化
将酿酒酵母菌株划线于YEPD平板(1%(w/v)酵母提取物,2%(w/v)细菌蛋白胨,2%(w/v)葡萄糖),1.5%琼脂)上,并在转化之前允许其在30℃生长4日。将一μg的全质粒(即环状质粒),或对于缺口修复,BstEII/BsrBI-或NsiI/PvuI-消化的含HSA变体或HSA变体融合物的质粒,和Acc65I/BamHI消化的pDB3936(100ng)用于(以等摩尔浓度)使用SigmaYeast Transformation试剂盒使用修饰的乙酸锂方法(Sigma酵母转化试剂盒,YEAST-1,方案2;Ito等(1983)J.Bacteriol.,153,16;Elble,(1992)Biotechniques,13,18)转化酿酒酵母。实验方案经细微修改,即将转化物在热激之前在室温温育长至4h。在热激之后,将细胞简单离心,然后重悬于200μl 1M山梨醇,然后铺于BMMD琼脂平板上,BMMD的组成由Sleep等,(2001),Yeast,18,403描述。将平板在30℃温育4日,然后将单个菌落缀补(patch)于新鲜BMMD平板上。
对于每个酵母菌株如下制备储液:将BMMD培养液用一重环(a heavy loop of)每个酵母补片(patch)接种,并在30℃以200rpm定轨振荡生长24h。通过在Sorval RT600离心机中以1900×g离心5分钟来收获细胞,去除15mL上清,并用海藻糖40%(w/v)替代。将细胞重悬,并转移至冷冻管(1mL)以供在-80℃储藏。
(e)酿酒酵母的摇瓶生长
将BMMD(配方:0.17%(w/v)不含氨基酸和硫酸铵的酵母氮基(Difco),37.8mM硫酸铵,29mM柠檬酸,142mM脱水正磷酸氢二钠pH 6.5,2%(w/v)葡萄糖)培养基(10mL)用每种酵母菌株接种,并在30℃以200rpm定轨振荡生长24h。将每个起子培养物的等分试样(4mL)用于接种2×200mL BMMD培养基,并在30℃以200rpm定轨振荡生长96h。通过经由包括GF-D预滤器(Whatman)的0.2μm真空过滤器膜(Stericup,Millipore)收获细胞,并保留上清以供纯化。
(f)初级浓缩
将保留的培养上清使用使用配有Omega 10KD(0.093sq.m2)过滤器、具有20psi的跨膜压力和180mL.min-1的再循环速率的Pall Filtron LV系统使用Tangential FlowFiltration(切向流过滤)浓缩。
(g)从摇瓶纯化白蛋白衍生物及其融合物
将白蛋白衍生物,变体及其融合物使用单一的层析步骤使用白蛋白亲和基质(AlbuPureTM-ProMetic BioSciences,Inc.)从烧瓶纯化(培养上清或浓缩的培养上清)。层析从头到尾以240cm/h的恒定线性速度进行。将培养上清施于用50mM乙酸钠pH5.3预平衡的6cm床高、2.0mL填充床。在加载之后,将柱用10柱体积(CV)的平衡缓冲液,然后用50mM乙酸铵pH8.0(10CV)洗涤。产物用50mM乙酸铵-10mM辛酸盐/酯pH8.0,50mM乙酸铵-30mM辛酸钠pH8.0,50mM乙酸铵-100mM辛酸钠pH8.0或200mM硫氰酸钾来洗脱。将柱用0.5M NaOH(3cv)和20mM NaOH(3.5cv)清洗。将来自每个白蛋白变体的洗脱物级分浓缩,并针对10体积的Tris缓冲盐水(25mM Tris,150mM NaCl,2mM KCl,pH7.4)使用Vivaspin20 10,000MWCO PES以任选的渗滤杯(Sartorius)进行渗滤。纯化的白蛋白变体通过GP-HPLC如下所述(部分(j))定量。
(h)2L和10L发酵
-10L发酵
将转化体作为补料分批发酵培养,在10L Sartorius Biostat C发酵器在30℃进行。监视pH并视需要通过添加氨或硫酸来调整。氨亦提供培养的氮源。监视溶解氧的水平,并将其与搅拌器速度相联系,以维持其水平为>20%饱和。将接种物在烧瓶中在缓冲的基本培养基中生长。对于分批阶段,将培养物接种入含有2%(w/v)蔗糖的发酵器缓冲液(大约50%的发酵器体积)。补料阶段由溶解氧的水平的急剧升高自动触发。通过控制补料速率至设定的正常生长速率而将蔗糖维持在生长限制浓度。给料组成为含有50%(w/v)蔗糖的发酵培养液,所有基本上如Collins所述(Collins,S.H.,(1990)Production of secretedproteins in yeast,于:T.J.R.Harris(编)Protein production by biotechnology,Elsevier,London,pp.61-77)。
-2L发酵
将转化体作为补料分批发酵培养。补料分批发酵在2L Pierre Guerin Tryton发酵器中在30℃进行。监视pH并适当地通过添加氨或硫酸来调整。氨亦提供培养的氮源。监视溶解氧的水平,并将其与搅拌器速度相联系,以维持其水平为>20%饱和。将接种物在烧瓶中在缓冲的基本培养基中生长。对于分批阶段,将培养物接种入含有2%(w/v)蔗糖的发酵器缓冲液(大约50%的发酵器体积)。补料阶段由氧消耗的水平的急剧降低自动触发。通过控制补料速率至设定的正常生长速率而将蔗糖维持在生长限制浓度。给料组成为含有50%(w/v)蔗糖的发酵培养液,所有基本上如Collins所述(Collins,S.H.,(1990)Productionof secreted proteins in yeast,于:T.J.R.Harris(编)Protein production bybiotechnology,Elsevier,London,pp.61-77)。
(i)从发酵纯化白蛋白衍生物及其融合物
在通过使用Sorvall RC 3C离心机(DuPont)的离心分离之后,从高细胞密度补料分批发酵上清纯化其中的白蛋白衍生物和融合物。将培养上清通过11cm床高柱的22mL用如上所述的定制合成的白蛋白亲和基质(AlbuPureTM-ProMetic BioSciences,Inc.)填充的填充床进行层析。使用如上所述的洗脱缓冲液以120cm/h的流速洗脱产物。将洗脱级分通过GP-HPLC(见下)和还原SDS PAGE分析纯度。将来自每个白蛋白变体的洗脱级分通过GP-HPLC(如下所述)和还原SDS-PAGE评价,且若需要,则通过使用90cm床高柱的488mL用SephacrylS200(GE Healthcare)填充的填充床并在Tris缓冲的盐水(25mM Tris,150mM NaCl,2mMKCl,pH7.4)中以4mL.min 1的制备性凝胶过滤来进一步分离。将来自AlbuPureTM或AlbuPureTM和Sephacryl S200层析的洗脱物级分使用具有可选的渗滤帽(Sartorius)的Vivaspin20 10,000MWCO PES或使用配有Omega 10KD(0.093sq.m2)过滤器(LVCentramateTM cassette,Pall Filtron)具有20psi的跨膜压力和180mL.min 1的再循环速率的Pall Filtron LV系统的切向流过滤进行浓缩。对于那些仅来源于AlbuPureTM层析的洗脱物,在浓缩之后,接着将其对10体积的Tris缓冲盐水(25mM Tris,150mM NaCl,2mM KCl,pH7.4)进行渗滤。纯化的白蛋白变体通过GP-HPLC如下所述进行定量。
将待对受体(shFcRn)结合性质和/或其它分析进行测定的所有蛋白质通过GP-HPLC如下所述进行定量,并针对其相对消光系数校正。
(j)白蛋白衍生物,变体,融合物及其缀合物通过GP-HPLC的定量分析
纯化的白蛋白衍生物,变体,融合物及其缀合物通过GP-HPLC分析,并如下所述定量。向具有6.0mm id(内径)x 40mm长TSK SW保护柱(Tosoh Bioscience)的7.8mm id(内径)x 300mm长TSK G3000SWXL柱(Tosoh Bioscience)注入25μL。将样品在25mM磷酸钠,100mM硫酸钠,0.05%(w/v)叠氮化钠,pH 7.0中进行层析。通过在280nm进行UV检测,以峰面积相对于已知浓度(10mg/mL)的重组人白蛋白标样对样品进行定量,并针对其相对消光系数校正。
(k)将辣根过氧化物酶(HRP)缀合于白蛋白及衍生物和其变体
将白蛋白和衍生物及其变体如上所述纯化(部分(g)和(i)),浓缩,并使其在TrisBuffer Saline(TBS),pH 7.2-7.3中进行缓冲液交换。
将HRP通过与2mg/mL EZ-Maleimide Activated Horseradish Peroxidase(HRP,Thermo Scientific)温育以与域I中的游离巯基反应而缀合于分子。将HRP溶解于Phosphate Buffer Saline(PBS),pH 6.5,且温育提供相对于白蛋白或变体或其衍生物的大约2倍摩尔过量的HRP。将该混合物在4℃温育至少24小时。然后使用GP-HPLC分析反应混合物以确认发生了缀合。GP-HPLC分析如上所述(部分(j))。
为了从相应的缀合物种分离未缀合的物种(DI+DIII,DI+DIII+DIII或域变体和未反应的HRP),首先将样品浓缩(Vivaspin20, 10,000 MWCO PES,Sartorius),然后分别施于Tricorn SuperdexTM200,10/300GL柱(GE Healthcare),并以45cm/hr的流速在TBS中运行。将洗脱峰分级并通过GP-HPLC分析。将含有缀合物种的级分汇集,浓缩,随后通过GP-HPLC和非还原SDS PAGE分析以显示缀合的物种。
(l)将荧光素-5-马来酰亚胺(F5M)缀合于白蛋白和衍生物及其变体
将荧光素-5-马来酰亚胺(Thermo Scientific)(F5M)溶解于二甲基甲酰胺以得到12.5mg/ml的终浓度。然后将其进一步稀释入18ml的PBS,将pH调整至大约pH 6.5。添加HSADI+DIII变体以在最终混合物中提供大约20倍最终摩尔过量的F5M。然后温育这些样品,并允许其在暗处在4℃缀合过夜,以允许F5M上的马来酰亚胺基团与白蛋白物种中存在的主要是游离的巯基反应。
在过夜温育之后,将反应混合物的等分试样充分地针对TBS渗滤以去除未缀合的F5M(Vivaspin20, 10,000 MWCO PES,Sartorius)。通过使用标准的SDS-PAGE的缀合的荧光素::DI+DIII及其中的变体的紫外显影来确认缀合。
实施例1:白蛋白衍生物或变体的构建
为了说明白蛋白衍生物或变体或片段的结合,从HSA起始制成了下述构建体。在“突变/构建体”标题下引用的位置指SEQ ID NO:31中的位置。
表6:白蛋白衍生物和变体
样品细节 | SEQ ID NO: | 浓度(mg/mL) | 突变/构建体(相对于成熟HSA的氨基酸残基) |
a)域I+II | 20 | 82.0 | 1-387 |
b)域II+III | 21 | 33.0 | 183-585 |
c)域I+III | 22 | 62.4 | 1-194+381-585 |
d)域III | 23 | 89.7 | 381-585 |
e)2x域III | 24 | 35.5 | 381-585** |
**编码N端域III的核苷酸序列经密码子优化,编码C端域III的核苷酸序列未优化。这是为了防止编码相同域III氨基酸序列的核苷酸序列的重组,并因此确保生成双重域III分子而非单域III,若核酸序列发生重组,可出现后者。
实施例2:白蛋白变体对可溶性FcRn(shFcRn)的结合
使用了三种公认的FcRn结合测定法:ELISA,SPR和Dynabead结合测定法。这些测定法之间存在重大差别:
在ELISA系统中,HSA直接涂覆于孔中,且可溶性hFcRn(shFcRn)-GST添加于溶液中,而在SPR测定法中,shFcRn-GST固定化于CM5芯片,且HSA在溶液中注入。在两种系统中pH均可变动。
FcRn Dynabead结合测定法基于捕获于抗生蛋白链菌素偶联的珠上的位点特异性生物素化的shFcRn。GST-标记的HSA在溶液中添加,而结合使用鸡HRP缀合的抗-GST Ab检测。
此外,竞争性结合通过如下测量:将shFcRn(50nM)单独或与不同浓度的HSA(55-500nM),HSA DI-DII(500+1500nM),HSA DII-DIII(500+1500nM),HSA DI-DIII(500+1500nM),HSA DIII(500+1500nM)和HSA DIII-DIII(500+1500nM)相对于(over)固定化的HSA(~2600RU)注入。注入在25℃并以50μl/min的流速进行。使用ELISA(结果示于图1)和使用SPR(结果示于图2和表7)和基于竞争性SPR的测定法(结果示于图3)对实施例2的变体分析FcRn结合。SPR和基于竞争性SPR的测定法使用shFcRn-GST进行。
计算了shFcRn与HSA域的相互作用的动力学并显示如下(表7)。
表7:shFcRn-GST与HSA域相互作用的动力学
白蛋白变体a | SEQ ID NO: | Ka(103/Ms) | kd(10-3/s) | KDb(μM) | KD Reqc(μM) |
HSA野生型 | 31 | 3.2±0.2 | 15.5±2.5 | 4.8 | 5.4 |
HSA DII-DIII | 21 | 0.7 | 7.1 | 9.8 | ND |
HSA DI-DIII | 22 | 2.6±0.3 | 18.3±0.2 | 7.0±0.2 | ND |
HSA DIII野生型 | 23 | ND | ND | ND | 17.6±2.3 |
a:白蛋白或DIII衍生物或变体的滴定量在pH 6.0相对于固定化的shFcRn(~1500RU)注入。
b:动力学速率常数使用简单的一级(1:1)双分子相互作用模型获得。
c:稳态亲和常数使用由BIAevaluation 4.1软件提供的平衡(Req)结合模型获得。动力学值代表三次重复的平均值。
d:未确定(ND)。
SPR结果显示:DI+III,DII+III,DIII,双重DIII和全长白蛋白以pH依存性方式结合shFcRn(图2)。与之相对,ELISA数据显示DIII野生型,当固定化时,并不与shFcRn相互作用。DIII-shFcRn结合/解离速率是快速的,因此,动力学值无法直接确定,然而,稳态亲和常数的计算显示DIII与全长HSA相比结合较少的shFcRn,且在结合亲和力方面有3倍减少。该数据表明HSA的其它部分对于域III对shFcRn的最佳结合是重要的,这进一步在分析DI-DIII和DII-DIII时得到支持。DII-DIII结合shFcRn,尽管结合亲和力相对于对全长白蛋白测量的有所减少。DI-DIII亦以与DII-DIII相比较高的亲和力结合shFcRn,两者均具有与域III本身相比更高的亲和力,这再次支持了下述观察:HSA的其它部分对于对shFcRn受体的最佳结合是重要的。竞争性SPR测定显示双重域III构建体在测定中与DI+III,DII+III和DIII相比更有效地竞争野生型白蛋白,但并不如野生型白蛋白即HSA有效。
实施例3:域交换(domain swap)衍生物对shFcRn的结合
遵循方法部分(上文)生成了下述域交换衍生物:
HSA 1/2-RSA 3:HSA(人血清白蛋白)域I和II和RSA(兔血清白蛋白)域III
RSA 1/2–HSA3:RSA域I和II和HSA域III
SSA 1/2–HSA3:SSA(绵羊血清白蛋白)域I和II和HSA域III
HSA 1/2-SSA3:HSA域I和II和SSA域III
HSA 1/2–MSA3:HSA域I和II和MSA(小鼠血清白蛋白)域III
MSA 1/2–HSA3:MSA域I和II和HSA域III
在实施例中,使用的域示于表8:
表8:人、兔、绵羊和小鼠血清白蛋白的域
这些进一步显示于图5的比对中。
使用SPR对实施例3的衍生物或变体分析shFcRn结合(shFcRn-GST),且结果如下所示(表9):
表9:白蛋白衍生物和特征
a:HSA衍生物或变体的稀释物在pH 6.0相对于固定化的shFcRn(~1500RU)注入。
b:动力学速率参数使用简单的一级(1:1)双分子相互作用模型获得。
c:稳态亲和常数使用由BIAevaluation 4.1软件提供的平衡(Req)结合模型获得。动力学值代表三次重复的平均值。
d:未确定(ND)(即未获得KD)。
SSA(SEQ ID NO:16)和包含SSA域III的衍生物(SEQ ID NO:28)和MSA1/2–HSA3(SEQ ID NO:30)在该实验中不结合FcRn。
HSA DI+DII+RSA DIII和HSA DI+DII+MSA DIII与HSA、MSA和RSA相比对shFcRn具有增加的亲和力。数据亦显示多种物种的白蛋白DI+DII可调节来自不同物种的白蛋白DIII的亲和力(即增加或减少)。
实施例4:HSA衍生物DI+DIII及其融合物对shFcRn的结合
HSA衍生物DI+DIII及其融合物(表10)根据方法部分(上文)制备。
使用Biacore X和Biacore 3000装置(G E Healthcare)进行SPR测定。将CM5芯片通过胺偶联化学根据生产商的指示偶联于shFcRn-HIS(GeneArt)(1600–2500RU)。偶联通过将shFcRn稀释于10mM乙酸钠pH4.5(G E Healthcare)进行。使用磷酸盐缓冲液(67mM磷酸盐缓冲盐水,0.15M NaCl,0.005%Tween 20,在pH5.5±0.25)作为运行缓冲液和稀释缓冲液。使用HBS-EP缓冲液pH7.4进行再生。对于对固定化的shFcRn的结合,将HSA衍生物或变体在活性细胞表面上以恒定流速(30μl/min)在25℃注入90s。对于在pH 7.4的结合测定,使用HBS-EP(GE Healthcare)作为稀释和运行缓冲液。在所有实验中,将数据调零校正,并减去参照室。对于数据解释和动力学值确定,使用Biaevaluation软件进行动力学结合建模。
shFcRn结合分子的动力学值提供于表10。
表10:shFcRn结合HSA域I+III(未融合的和融合的)的动力学值
分子 | KD(μM) |
野生型DI+DIII | 3.0 |
DI+DIII K500A | ND |
DI+DIII K573P | 0.86 |
DI+DIII K573Y | 0.45 |
DI+DIII D550N | 8.4 |
野生型DI+DIII::GSL::IL-1ra | 5.5 |
DI+DIII K500A::GSL::IL-1ra | ND |
DI+DIII K573P::GSL::IL-1ra | 0.42 |
DI+DIII K573Y::GSL::IL-1ra | 0.26 |
DI+DIII D550N::GSL::IL-1ra | 11 |
ND:由于弱结合而未确定
野生型DI+DIII及其衍生物以pH依存性方式结合于shFcRn(数据未显示),即在pH5.5检测到结合但在pH 7.4未检测到。结果显示DI+DIII衍生物及其融合物对shFcRn的结合的等级(hierarchy)是K573Y>K573P>野生型>D550N(亲和力最高至最低)。对DI+DIII K500A(融合或未融合于IL1Ra)和shFcRn之间在pH 5.5或pH 7.4均检测出弱结合。
实施例5:HSA衍生物DII+DIII及其融合物对shFcRn的结合
根据方法部分(上文)制备HSA DII+DIII及其融合物(表11)。根据实施例4进行SPR分析和解释。
表11:shFcRn-HIS结合HSA DII+DIII(未融合和融合的)的动力学值
分子 | KD(μM) |
野生型DII+DIII | 6.8 |
DII+DIII K573P | 0.48 |
DII+DIII K573Y | 0.47 |
DII+DIII D550N | 7.3 |
野生型DII+DIII::GSL::IL-1ra | 5.1 |
DII+DIII K573Y::GSL::IL-1ra | 0.5 |
DII+DIII D550N::GSL::IL-1ra | 6.0 |
DII+DIII K573P::GSL::IL-1ra | 0.98 |
所有HSA DII+DIII衍生物及其融合物与shFcRn以pH依存性方式相互作用(数据未显示),即在pH 5.5检测到结合但在pH 7.4未检测到。HSA DI+DIII衍生物(无论融合和未融合的)的结合的等级与对于HSA DI+DIII衍生物及其融合物(实施例4)所描述的相同,即K573Y>K573P>野生型>D550N(对shFcRn的亲和力最高至最低)。
实施例6:HSA衍生物DIII及其衍生物对shFcRn的结合
未融合的DIII衍生物(表12a)根据方法部分(上文)制备。根据实施例4进行了SPR分析和解释。
表12a:shFcRn-HIS结合HSA DIII的动力学值
所有的HSA DIII衍生物与shFcRn以pH依存性方式相互作用(数据未显示),即在pH5.5检测到结合但在pH 7.4未检测到。对shFcRn的结合等级为DIII K573Y,DIII K573P,DIII K573F,DIII K573A,DIII E492G,DIII D550N,野生型DIII,DIII E492/N503K,DIIIK500A(对shFcRn的亲和力最高至最低)。
对无法确定动力学值的DIII衍生物分析相对于野生型DIII的结合响应(RU)。在pH7.4未检测到结合,仅在pH 5.5检测到。结果示于表12b。更高的RU值表明更紧密的结合。因此,相对于野生型HSA,所有在表12b中测试的突变体对shFcRn显示较弱的结合。野生型HSADIII及其衍生物以pH依存性方式结合于shFcRn。对于HSA DIII K573D,DIII K573H,DIIIK573N,DIII K573W和DIII Q580K代表性的感应谱示于图8。
表12b:shFcRn与HSA DIII相互作用的结合响应值
分子 | 结合响应(RU) |
野生型HSA | 34.2 |
野生型DIII | 7.0 |
DIII K573D | 7.2 |
DIII K573H | 13.3 |
DIII K573W | 16.5 |
DIII K573N | 12.2 |
DIII Q580K | 11.5 |
表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
实施例7:基因融合于IL-1ra或scFv的HSA衍生物对shFcRn的结合
根据方法部分(上文)制备了分子(表13)。SPR分析和解释根据实施例4进行。
表13:shFcRn-HIS结合基因融合于IL-1ra或scFv的HSA DIII衍生物的动力学值
结果显示基因融合于IL-1ra的HSA DIII衍生物对shFcRn的结合等级是D550N>K573P>野生型。与之相对,基因融合于scFv的HSA DIII衍生物对shFcRn的结合等级是K573P>D550N>野生型。
实施例8:辣根过氧化物酶对白蛋白和对白蛋白衍生物的缀合
根据方法(上文)将HRP缀合于白蛋白衍生物以形成白蛋白变体(表14)。分子通过GP-HPLC(数据未显示)和非还原性SDS-PAGE(图9)分析以确认该分子具有预期分子量,并因此发生缀合产生所需的分子。SPR分析和解释根据实施例4进行。
表14:与缀合于HRP的HSA DI+DIII及其衍生物相互作用的shFcRn-HIS的结合分析。
分子 | 响应(RUs) |
野生型HSA(未缀合) | 178 |
野生型DI+DIII-HRP | 58 |
DI+DIII K573P-HRP | 213 |
DI+DIII K500A-HRP | ND |
ND–由于弱结合未确定。表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
图10确认对于HSA DI+DIII K573P-HRP变体和shFcRn相互作用的结合响应相对于野生型HSA DI+DIII和野生型HSA的结合响应增加。此外,图10显示DI+DIII K500A-HRP和shFcRn的结合相互作用相对于野生型HSA DI+DIII和野生型HSA减少。
DI+DIII野生型及其变体以pH依存性方式结合于shFcRn,即在pH 5.5检测到结合但在pH 7.4未检测到。缀合的DI+DIII变体显示未缀合的DI+DIII(实施例4)中所见的相同的亲和力调节。
实施例9:shFcRn与基因融合于HSA DII+DIII的N端的IL-1ra的相互作用的结合分析
基因融合于HSA DII+DIII和HSA DII+DIII K573P的IL-1ra(表15)根据方法部分(上文)制备。SPR分析和解释根据实施例4进行。
表15:shFcRn-HIS与N端融合于HSA DII+DIII的IL-1ra的结合分析
分析 | 响应(RUs) |
野生型HSA | 162 |
IL-1ra::GSL::DII DIII | 145 |
IL-1ra::GSL::K573P DII DIII | 246 |
表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
N端融合于HSA DII+DIII的IL-1ra和N端融合于K573P DII DIII的IL-1ra以pH依存性方式结合于shFcRn,即在pH 5.5检测到结合但在pH 7.4未检测到。图11显示与DII+DIII的N端融合延长了解离时间而不干扰分子对shFcRn的结合。结果显示shFcRn和K573P变体之间的结合响应相对于野生型HSA DII+DIII和HSA增加。
实施例10:shFcRn与作为DIII及其衍生物的串联重复的融合物的分子相互作用的结合分析
HSA衍生物及其融合物(表16)根据方法部分(上文)制备。SPR分析和解释根据实施例4进行。
表16:shFcRn-HIS与DIII的串联重复的融合物相互作用的结合分析
分子 | 结合响应(RUs) |
DIII野生型+DIII野生型::GSL::IL-1ra | 30.1 |
DIII D550N+DIII D550N::GSL::IL-1ra | 82.3 |
DIII K573P+DIII K573P::GSL::IL-1ra | 48.0 |
DIII野生型+DIII野生型::GSL::scFv | 151.4 |
DIII D550N+DIII D550N::GSL::scFv | 167.5 |
DIII K573P+DIII K573P::GSL::scFv | 181.6 |
表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
串联DIII融合物以pH依存性方式结合于shFcRn(即在pH 5.5结合但在pH 7.4未结合)。对于串联DIII融合物结合响应(表16)显示下述顺序:
(i)IL-1ra融合物:DIII D550N+DIII D550N-IL-1ra,DIII K573P+DIII K573P-IL-1ra,野生型DIII-IL-1ra(最高至最低亲和力);
(ii)scFv融合物:DIII K573P+DIII K573P-scFv,D550N+DIII D550N-scFv野生型DIII-scFv(最高至最低亲和力)。
实施例11:荧光素-5-马来酰亚胺(F5M)对DI+DIII野生型及其衍生物的缀合
缀合的HSA衍生物及其变体(表17)根据方法部分(上文)制备。分子通过GP-HPLC(结果未显示)和非还原性SDS-PAGE(图16)分析。通过缀合的DI+DIII野生型和变体的UV显影确认缀合。SPR分析和解释根据实施例4进行。
表17:与缀合于F5M的HSA DI+DIII及其变体相互作用的shFcRn-HIS的结合分析
分子 | 响应(RU) |
野生型HSA | 63.8 |
DI+DIII野生型-F5M | 6.5 |
DI+DIII-K573P F5M | 53.5 |
DI+DIII-K500A F5M | ND |
ND–由于弱结合未确定。表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
图17确认HSA DI+DIII K573P-F5M变体和shFcRn相互作用的结合响应相对于HSADI+DIII-F5M但非野生型HSA的结合响应增加。此外,图17显示DI+DIII K500A-F5M和shFcRn的结合相互作用相对于HSA DI+DIII K573P-F5M和野生型HSA显著减少。
DI+DIII野生型及其变体以pH依存性方式结合于shFcRn,即在pH 5.5检测到结合但在pH 7.4未检测到。缀合的DI+DIII变体显示未缀合的DI+DIII变体和全长HSA(实施例4)中所见的相同的亲和力调节。
实施例12:荧光素-5-马来酰亚胺(F5M)对DI+DIII+DIII野生型的缀合
HSA衍生物(表18)的缀合物根据方法部分(上文)制备。分子通过GP-HPLC(结果未显示)和非还原性SDS-PAGE(图16)分析。通过缀合的DI+DIII野生型+DIII野生型的UV显影确认缀合。SPR分析和解释根据实施例4进行。
表18:shFcRn-HIS与缀合于F5M的HSA DI+DIII野生型+DIII野生型相互作用的结合分析。
表示的结合响应(RU值)代表在注入过程中注入停止且形成最多复合物时点记录的相对绝对值。较高的RU值等于较高的亲和力。
图18确认HSA DI+DIII野生型+DIII野生型-F5M变体和shFcRn相互作用的结合响应相对于HSA DI+DIII-F5M但非野生型HSA的结合响应增加。
缀合的DI+DIII野生型和DI+DIII野生型+DIII野生型以pH依存性方式结合于shFcRn,即在pH 5.5检测到结合但在pH 7.4未检测到。
实施例13:shFcRn与HSA衍生物DIII+DI和DI+DIII4的相互作用的结合分析
HSA衍生物(表19)根据方法部分(上文)制备。SPR分析和解释根据实施例4进行。
表19:shFcRn-HIS与HSA DIII+DI和DI+DIII相互作用的结合分析
分子 | KD(μM) |
DIII野生型+DI | 8.4 |
DI+DIII野生型 | 3.0 |
图19显示HSA衍生物DIII+DI对于shFcRn与HSA DI+DIII相比具有减少的亲和力。
实施例14:shFcRn-GST与白蛋白衍生物DI+DIII的相互作用相对于野生型白蛋白的结合分析
物种野生型白蛋白及其DI+DIII衍生物根据方法部分(上文)制备。SPR分析和解释根据实施例4进行。
表20:shFcRn-GST与物种白蛋白及其DI+DIII衍生物的结合分析
分子a | Ka(103/Ms) | kd(10-3/s) | KDb(μM) |
HSA野生型 | 3.2±0.2 | 15.5±2.5 | 4.8 |
MSA野生型 | 3.8±0.0 | 3.1±0.1 | 0.8±0.2 |
RSA野生型 | 1.9±0.3 | 1.7±0.1 | 0.9 |
HSA DI-DIII | 2.6±0.3 | 18.3±0.2 | 7.0±0.2 |
RSA DI-DIII | 4.8±0.0 | 3.1±0.1 | 0.6±0.0 |
MSA DI-DIII | 5.6±0.1 | 2.5±0.0 | 0.4±0.0 |
a:白蛋白或其DI+DIII衍生物的滴定量相对于固定化的shFcRn(~1500RU)注入。
b:动力学速率常数使用简单的一级(1:1)双分子相互作用模型获得。
结果显示:MSA DI-DIII和RSA DI-DIII与野生型MSA、野生型HSA和HSA DI-DIII相比均具有较高的结合亲和力。所有DI-DIII变体以pH依存性方式结合于固定化的shFcRn,(即在pH6.0结合但在pH 7.4不结合)。HSA DI-DIII与HSA野生型相比以略微减少的亲和力结合shFcRn,而RSA和MSA DI-DIII白蛋白衍生物与HSA野生型相比显示较优的结合亲和力。
序列表
<110> 诺维信生物制药英国公司(Novozymes Biopharma UK Limited)
诺维信公司(Novozymes A/S)
奥斯陆大学(University of Oslo)
<120> 白蛋白衍生物
<130> 11645-WO-PCT
<150> EP10159450.5
<151> 2010-04-09
<150> EP10174164.3
<151> 2010-08-26
<150> EP11158921.4
<151> 2011-03-18
<160> 35
<170> PatentIn version 3.5
<210> 1
<211> 585
<212> PRT
<213> 人(Homo sapiens)
<400> 1
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
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Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
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Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Lys Gln Leu Gly Glu
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Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
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Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
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Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
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Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
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Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
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Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
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<210> 2
<211> 1758
<212> DNA
<213> 人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(1758)
<223> 编码HSA的cDNA
<400> 2
gatgcacaca agagtgaggt tgctcatcgg tttaaagatt tgggagaaga aaatttcaaa 60
gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120
aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180
aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240
cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300
tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360
gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420
gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480
tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540
aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600
gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660
cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720
gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780
gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840
aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900
gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960
gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020
tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080
tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140
gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200
tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260
ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320
cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380
tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440
ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500
gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560
agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620
aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680
gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc tgcaagtcaa 1740
gctgccttag gcttataa 1758
<210> 3
<211> 2264
<212> DNA
<213> 人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(2264)
<223> 编码HSA的基因组核苷酸序列
<400> 3
agtatattag tgctaatttc cctccgtttg tcctagcttt tctcttctgt caaccccaca 60
cgcctttggc acaatgaagt gggtaacctt tatttccctt ctttttctct ttagctcggc 120
ttattccagg ggtgtgtttc gtcgagatgc acacaagagt gaggttgctc atcggtttaa 180
agatttggga gaagaaaatt tcaaagcctt ggtgttgatt gcctttgctc agtatcttca 240
gcagtgtcca tttgaagatc atgtaaaatt agtgaatgaa gtaactgaat ttgcaaaaac 300
atgtgttgct gatgagtcag ctgaaaattg tgacaaatca cttcataccc tttttggaga 360
caaattatgc acagttgcaa ctcttcgtga aacctatggt gaaatggctg actgctgtgc 420
aaaacaagaa cctgagagaa atgaatgctt cttgcaacac aaagatgaca acccaaacct 480
cccccgattg gtgagaccag aggttgatgt gatgtgcact gcttttcatg acaatgaaga 540
gacatttttg aaaaaatact tatatgaaat tgccagaaga catccttact tttatgcccc 600
ggaactcctt ttctttgcta aaaggtataa agctgctttt acagaatgtt gccaagctgc 660
tgataaagct gcctgcctgt tgccaaagct cgatgaactt cgggatgaag ggaaggcttc 720
gtctgccaaa cagagactca agtgtgccag tctccaaaaa tttggagaaa gagctttcaa 780
agcatgggca gtagctcgcc tgagccagag atttcccaaa gctgagtttg cagaagtttc 840
caagttagtg acagatctta ccaaagtcca cacggaatgc tgccatggag atctgcttga 900
atgtgctgat gacagggcgg accttgccaa gtatatctgt gaaaatcaag attcgatctc 960
cagtaaactg aaggaatgct gtgaaaaacc tctgttggaa aaatcccact gcattgccga 1020
agtggaaaat gatgagatgc ctgctgactt gccttcatta gctgctgatt ttgttgaaag 1080
taaggatgtt tgcaaaaact atgctgaggc aaaggatgtc ttcctgggca tgtttttgta 1140
tgaatatgca agaaggcatc ctgattactc tgtcgtgctg ctgctgagac ttgccaagac 1200
atatgaaacc actctagaga agtgctgtgc cgctgcagat cctcatgaat gctatgccaa 1260
agtgttcgat gaatttaaac ctcttgtgga agagcctcag aatttaatca aacaaaattg 1320
tgagcttttt gagcagcttg gagagtacaa attccagaat gcgctattag ttcgttacac 1380
caagaaagta ccccaagtgt caactccaac tcttgtagag gtctcaagaa acctaggaaa 1440
agtgggcagc aaatgttgta aacatcctga agcaaaaaga atgccctgtg cagaagacta 1500
tctatccgtg gtcctgaacc agttatgtgt gttgcatgag aaaacgccag taagtgacag 1560
agtcaccaaa tgctgcacag aatccttggt gaacaggcga ccatgctttt cagctctgga 1620
agtcgatgaa acatacgttc ccaaagagtt taatgctgaa acattcacct tccatgcaga 1680
tatatgcaca ctttctgaga aggagagaca aatcaagaaa caaactgcac ttgttgagct 1740
cgtgaaacac aagcccaagg caacaaaaga gcaactgaaa gctgttatgg atgatttcgc 1800
agcttttgta gagaagtgct gcaaggctga cgataaggag acctgctttg ccgaggaggg 1860
taaaaaactt gttgctgcaa gtcaagctgc cttaggctta taacatcaca tttaaaagca 1920
tctcagccta ccatgagaat aagagaaaga aaatgaagat caaaagctta ttcatctgtt 1980
tttctttttc gttggtgtaa agccaacacc ctgtctaaaa aacataaatt tctttaatca 2040
ttttgcctct tttctctgtg cttcaattaa taaaaaatgg aaagaatcta atagagtggt 2100
acagcactgt tatttttcaa agatgtgttg ctatcctgaa aattctgtag gttctgtgga 2160
agttccagtg ttctctctta ttccacttcg gtagaggatt tctagtttct tgtgggctaa 2220
ttaaataaat cattaatact cttctaaaaa aaaaaaaaaa aaaa 2264
<210> 4
<211> 609
<212> PRT
<213> 人(Homo sapiens)
<400> 4
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 5
<211> 621
<212> PRT
<213> 黑猩猩(Pan troglodytes)
<400> 5
Met Asn Glu Ser Ser Cys Cys Ser Thr Ser Leu Pro Ala Phe Gly Val
1 5 10 15
Ser Val Leu Asp Ser Gly His Ser Ser Ser Ser Ala Tyr Ser Arg Gly
20 25 30
Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
35 40 45
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Val Ala Phe Ala
50 55 60
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
65 70 75 80
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
85 90 95
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
100 105 110
Val Ala Thr Leu Arg Glu Lys Tyr Gly Glu Met Ala Asp Cys Cys Ala
115 120 125
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
130 135 140
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
145 150 155 160
Thr Ala Phe His Asp Asn Glu Gly Thr Phe Leu Lys Lys Tyr Leu Tyr
165 170 175
Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
180 185 190
Phe Ala Glu Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
195 200 205
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
210 215 220
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
225 230 235 240
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
245 250 255
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
260 265 270
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
275 280 285
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
290 295 300
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
305 310 315 320
Glu Lys Ser His Cys Leu Ala Glu Val Glu Asn Asp Glu Met Pro Ala
325 330 335
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Glu Val Cys
340 345 350
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
355 360 365
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
370 375 380
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
385 390 395 400
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
405 410 415
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
420 425 430
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
435 440 445
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
450 455 460
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
465 470 475 480
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
485 490 495
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
500 505 510
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
515 520 525
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
530 535 540
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
545 550 555 560
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
565 570 575
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
580 585 590
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
595 600 605
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
610 615 620
<210> 6
<211> 608
<212> PRT
<213> 猕猴(Macaca mulatta)
<400> 6
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Thr His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu His Phe Lys Gly Leu Val Leu
35 40 45
Val Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Glu Glu His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Pro Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Ala Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Ala Arg Tyr Lys Ala Ala Phe Ala Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Asp Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Lys Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Met
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Asp
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Leu Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Tyr Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Met
355 360 365
Leu Leu Leu Arg Leu Ala Lys Ala Tyr Glu Ala Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Gln Pro Leu Val Glu Glu Pro Gln Asn Leu Val Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ala Lys Cys Cys Lys Leu
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Leu Asp Glu Ala Tyr Val Pro Lys Ala Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Met Cys Thr Leu Ser Glu Lys Glu
530 535 540
Lys Gln Val Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Gly Val Met Asp Asn Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Ala Cys Phe
580 585 590
Ala Glu Glu Gly Pro Lys Phe Val Ala Ala Ser Gln Ala Ala Leu Ala
595 600 605
<210> 7
<211> 608
<212> PRT
<213> 金仓鼠(Mesocricetus auratus)
<400> 7
Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Val Ser Asp Ser Ala
1 5 10 15
Phe Ser Arg Gly Leu Phe Arg Arg Asp Ala His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln Phe Leu Gln Lys Cys Pro Tyr Glu Glu His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Ala Ile Pro Thr Leu Arg Asp Ser Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Ala Lys Lys Glu Pro Glu Arg Asn Glu Cys Phe Leu Lys
115 120 125
His Lys Asp Asp His Pro Asn Leu Pro Pro Phe Val Arg Pro Asp Ala
130 135 140
Glu Ala Met Cys Thr Ser Phe Gln Glu Asn Ala Val Thr Phe Met Gly
145 150 155 160
His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Glu Lys Tyr Ser Ala Ile Met Thr Glu Cys
180 185 190
Cys Gly Glu Ala Asp Lys Ala Ala Cys Ile Thr Pro Lys Leu Asp Ala
195 200 205
Leu Lys Glu Lys Ala Leu Ala Ser Ser Val Asn Gln Arg Leu Lys Cys
210 215 220
Ser Ser Leu Gln Arg Phe Gly Gln Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Met Ser Gln Lys Phe Pro Lys Ala Asp Phe Ala Glu Ile Thr
245 250 255
Lys Leu Ala Thr Asp Leu Thr Lys Leu Thr Glu Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met
275 280 285
Cys Glu Asn Gln Ala Ser Ile Ser Ser Lys Leu Gln Ala Cys Cys Asp
290 295 300
Lys Pro Val Leu Lys Lys Ser His Cys Leu Ser Glu Val Glu Asn Asp
305 310 315 320
Asp Leu Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Asp
325 330 335
Lys Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Thr Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Ala
355 360 365
Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys
370 375 380
Cys Ala Glu Ala Asp Pro Ser Ala Cys Tyr Gly Lys Val Leu Asp Glu
385 390 395 400
Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Ala Asn Cys
405 410 415
Glu Leu Phe Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ile
420 425 430
Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Ala Ala Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Val Leu
450 455 460
Pro Glu Ala Gln Arg Leu Pro Cys Val Glu Asp Tyr Ile Ser Ala Ile
465 470 475 480
Leu Asn Arg Val Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Gln
485 490 495
Val Thr Lys Cys Cys Thr Gly Ser Val Val Glu Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Pro Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Ser Leu Pro Glu Lys Glu
530 535 540
Lys Gln Met Lys Lys Gln Ala Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Gly Pro Gln Leu Arg Thr Val Leu Gly Glu Phe Thr
565 570 575
Ala Phe Leu Asp Lys Cys Cys Lys Ala Glu Asp Lys Glu Ala Cys Phe
580 585 590
Ser Glu Asp Gly Pro Lys Leu Val Ala Ser Ser Gln Ala Ala Leu Ala
595 600 605
<210> 8
<211> 608
<212> PRT
<213> 土拨鼠(Cavia porcellus)
<400> 8
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Val
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Glu Ala His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Asn Asp Leu Gly Glu Gly His Phe Lys Gly Leu Val Leu
35 40 45
Ile Thr Leu Ser Gln His Leu Gln Lys Ser Pro Phe Glu Glu His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Asp Phe Ala Lys Ala Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Gln Asn Cys Gly Lys Ala Ile Ala Thr Leu Phe Gly Asp
85 90 95
Lys Val Cys Ala Ile Pro Ser Leu Arg Glu Thr Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Ala Lys Glu Asp Pro Asp Arg Val Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Pro Phe Glu Arg Pro Glu Pro
130 135 140
Glu Ala Leu Cys Thr Ala Phe Lys Glu Asn Asn Asp Arg Phe Ile Gly
145 150 155 160
His Tyr Leu Tyr Glu Val Ser Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Glu Lys Tyr Lys Asn Ala Leu Thr Glu Cys
180 185 190
Cys Glu Ala Ala Asp Lys Ala Ala Cys Leu Thr Pro Lys Leu Asp Ala
195 200 205
Ile Lys Glu Lys Ala Leu Val Ser Ser Ala Gln Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ser Val
225 230 235 240
Ala Arg Leu Ser Gln Lys Phe Pro Lys Ala Glu Phe Ala Glu Ile Ser
245 250 255
Thr Ile Val Thr Ser Leu Thr Lys Val Thr Lys Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Gln Glu Leu Ala Lys Tyr Met
275 280 285
Cys Glu His Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Val
290 295 300
Lys Pro Thr Leu Gln Lys Ala His Cys Ile Leu Glu Ile Gln Arg Asp
305 310 315 320
Glu Leu Pro Thr Glu Leu Pro Asp Leu Ala Val Asp Phe Val Glu Asp
325 330 335
Lys Glu Val Cys Lys Asn Phe Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Glu Tyr Ser Ile Gly
355 360 365
Met Leu Leu Arg Ile Ala Lys Gly Tyr Glu Ala Lys Leu Glu Lys Cys
370 375 380
Cys Ala Glu Ala Asp Pro His Ala Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Leu Gln Pro Leu Ile Asp Glu Pro Lys Lys Leu Val Gln Gln Asn Cys
405 410 415
Glu Leu Phe Asp Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ala
420 425 430
Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Tyr Ala Arg Lys Leu Gly Ser Val Gly Thr Lys Cys Cys Ser Leu
450 455 460
Pro Glu Thr Glu Arg Leu Ser Cys Thr Glu Asn Tyr Leu Ala Leu Ile
465 470 475 480
Leu Asn Arg Leu Cys Ile Leu His Glu Lys Thr Pro Val Ser Glu Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu His Val Asp Glu Thr Tyr Val Pro Lys Pro Phe His Ala
515 520 525
Asp Ser Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Glu Lys Glu
530 535 540
Lys Gln Val Lys Lys Gln Met Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Ser Glu Glu Gln Met Lys Thr Val Met Gly Asp Phe Ala
565 570 575
Ala Phe Leu Lys Lys Cys Cys Asp Ala Asp Asn Lys Glu Ala Cys Phe
580 585 590
Thr Glu Asp Gly Pro Lys Leu Val Ala Lys Cys Gln Ala Thr Leu Ala
595 600 605
<210> 9
<211> 608
<212> PRT
<213> 小鼠(Mus musculus)
<400> 9
Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Val Ser Gly Ser Ala
1 5 10 15
Phe Ser Arg Gly Val Phe Arg Arg Glu Ala His Lys Ser Glu Ile Ala
20 25 30
His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala
50 55 60
Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala
130 135 140
Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly
145 150 155 160
His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys
180 185 190
Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly
195 200 205
Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys
210 215 220
Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr
245 250 255
Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met
275 280 285
Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp
290 295 300
Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp
305 310 315 320
Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp
325 330 335
Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser
355 360 365
Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys
370 375 380
Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu
385 390 395 400
Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys
405 410 415
Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu
420 425 430
Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu
450 455 460
Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile
465 470 475 480
Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His
485 490 495
Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala
515 520 525
Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu
530 535 540
Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala
565 570 575
Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe
580 585 590
Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
595 600 605
<210> 10
<211> 608
<212> PRT
<213> 褐鼠(Rattus norvegicus)
<400> 10
Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Ile Ser Gly Ser Ala
1 5 10 15
Phe Ser Arg Gly Val Phe Arg Arg Glu Ala His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Pro Tyr Glu Glu His Ile
50 55 60
Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Asn Ala Glu Asn Cys Asp Lys Ser Ile His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Ala Ile Pro Lys Leu Arg Asp Asn Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Pro Phe Gln Arg Pro Glu Ala
130 135 140
Glu Ala Met Cys Thr Ser Phe Gln Glu Asn Pro Thr Ser Phe Leu Gly
145 150 155 160
His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Glu Lys Tyr Asn Glu Val Leu Thr Gln Cys
180 185 190
Cys Thr Glu Ser Asp Lys Ala Ala Cys Leu Thr Pro Lys Leu Asp Ala
195 200 205
Val Lys Glu Lys Ala Leu Val Ala Ala Val Arg Gln Arg Met Lys Cys
210 215 220
Ser Ser Met Gln Arg Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Met Ser Gln Arg Phe Pro Asn Ala Glu Phe Ala Glu Ile Thr
245 250 255
Lys Leu Ala Thr Asp Val Thr Lys Ile Asn Lys Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met
275 280 285
Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Ala Cys Cys Asp
290 295 300
Lys Pro Val Leu Gln Lys Ser Gln Cys Leu Ala Glu Ile Glu His Asp
305 310 315 320
Asn Ile Pro Ala Asp Leu Pro Ser Ile Ala Ala Asp Phe Val Glu Asp
325 330 335
Lys Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser
355 360 365
Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys
370 375 380
Cys Ala Glu Gly Asp Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu
385 390 395 400
Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys
405 410 415
Glu Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Val Leu
420 425 430
Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu
450 455 460
Pro Glu Ala Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile
465 470 475 480
Leu Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys
485 490 495
Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala
515 520 525
Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Asp Lys Glu
530 535 540
Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Glu Asp Gln Leu Lys Thr Val Met Gly Asp Phe Ala
565 570 575
Gln Phe Val Asp Lys Cys Cys Lys Ala Ala Asp Lys Asp Asn Cys Phe
580 585 590
Ala Thr Glu Gly Pro Asn Leu Val Ala Arg Ser Lys Glu Ala Leu Ala
595 600 605
<210> 11
<211> 607
<212> PRT
<213> 牛(Bos taurus)
<400> 11
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Leu Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Thr His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu His Phe Lys Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Asp Glu His Val
50 55 60
Lys Leu Val Asn Glu Leu Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser His Ala Gly Cys Glu Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Glu Leu Cys Lys Val Ala Ser Leu Arg Glu Thr Tyr Gly Asp Met Ala
100 105 110
Asp Cys Cys Glu Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Ser
115 120 125
His Lys Asp Asp Ser Pro Asp Leu Pro Lys Leu Lys Pro Asp Pro Asn
130 135 140
Thr Leu Cys Asp Glu Phe Lys Ala Asp Glu Lys Lys Phe Trp Gly Lys
145 150 155 160
Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu
165 170 175
Leu Leu Tyr Tyr Ala Asn Lys Tyr Asn Gly Val Phe Gln Glu Cys Cys
180 185 190
Gln Ala Glu Asp Lys Gly Ala Cys Leu Leu Pro Lys Ile Glu Thr Met
195 200 205
Arg Glu Lys Val Leu Ala Ser Ser Ala Arg Gln Arg Leu Arg Cys Ala
210 215 220
Ser Ile Gln Lys Phe Gly Glu Arg Ala Leu Lys Ala Trp Ser Val Ala
225 230 235 240
Arg Leu Ser Gln Lys Phe Pro Lys Ala Glu Phe Val Glu Val Thr Lys
245 250 255
Leu Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly Asp
260 265 270
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys
275 280 285
Asp Asn Gln Asp Thr Ile Ser Ser Lys Leu Lys Glu Cys Cys Asp Lys
290 295 300
Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Lys Asp Ala
305 310 315 320
Ile Pro Glu Asn Leu Pro Pro Leu Thr Ala Asp Phe Ala Glu Asp Lys
325 330 335
Asp Val Cys Lys Asn Tyr Gln Glu Ala Lys Asp Ala Phe Leu Gly Ser
340 345 350
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Glu Tyr Ala Val Ser Val
355 360 365
Leu Leu Arg Leu Ala Lys Glu Tyr Glu Ala Thr Leu Glu Glu Cys Cys
370 375 380
Ala Lys Asp Asp Pro His Ala Cys Tyr Ser Thr Val Phe Asp Lys Leu
385 390 395 400
Lys His Leu Val Asp Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Asp
405 410 415
Gln Phe Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ile Val
420 425 430
Arg Tyr Thr Arg Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu
435 440 445
Val Ser Arg Ser Leu Gly Lys Val Gly Thr Arg Cys Cys Thr Lys Pro
450 455 460
Glu Ser Glu Arg Met Pro Cys Thr Glu Asp Tyr Leu Ser Leu Ile Leu
465 470 475 480
Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Val
485 490 495
Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser
500 505 510
Ala Leu Thr Pro Asp Glu Thr Tyr Val Pro Lys Ala Phe Asp Glu Lys
515 520 525
Leu Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Asp Thr Glu Lys
530 535 540
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Leu Lys His Lys Pro
545 550 555 560
Lys Ala Thr Glu Glu Gln Leu Lys Thr Val Met Glu Asn Phe Val Ala
565 570 575
Phe Val Asp Lys Cys Cys Ala Ala Asp Asp Lys Glu Ala Cys Phe Ala
580 585 590
Val Glu Gly Pro Lys Leu Val Val Ser Thr Gln Thr Ala Leu Ala
595 600 605
<210> 12
<211> 607
<212> PRT
<213> 马(Equus caballus)
<400> 12
Met Lys Trp Val Thr Phe Val Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Leu Arg Arg Asp Thr His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Asn Asp Leu Gly Glu Lys His Phe Lys Gly Leu Val Leu
35 40 45
Val Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Lys Cys Ala Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Ala Thr Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Glu Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Thr
115 120 125
His Lys Asp Asp His Pro Asn Leu Pro Lys Leu Lys Pro Glu Pro Asp
130 135 140
Ala Gln Cys Ala Ala Phe Gln Glu Asp Pro Asp Lys Phe Leu Gly Lys
145 150 155 160
Tyr Leu Tyr Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Gly Pro Glu
165 170 175
Leu Leu Phe His Ala Glu Glu Tyr Lys Ala Asp Phe Thr Glu Cys Cys
180 185 190
Pro Ala Asp Asp Lys Leu Ala Cys Leu Ile Pro Lys Leu Asp Ala Leu
195 200 205
Lys Glu Arg Ile Leu Leu Ser Ser Ala Lys Glu Arg Leu Lys Cys Ser
210 215 220
Ser Phe Gln Asn Phe Gly Glu Arg Ala Val Lys Ala Trp Ser Val Ala
225 230 235 240
Arg Leu Ser Gln Lys Phe Pro Lys Ala Asp Phe Ala Glu Val Ser Lys
245 250 255
Ile Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly Asp
260 265 270
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys
275 280 285
Glu His Gln Asp Ser Ile Ser Gly Lys Leu Lys Ala Cys Cys Asp Lys
290 295 300
Pro Leu Leu Gln Lys Ser His Cys Ile Ala Glu Val Lys Glu Asp Asp
305 310 315 320
Leu Pro Ser Asp Leu Pro Ala Leu Ala Ala Asp Phe Ala Glu Asp Lys
325 330 335
Glu Ile Cys Lys His Tyr Lys Asp Ala Lys Asp Val Phe Leu Gly Thr
340 345 350
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu
355 360 365
Leu Leu Arg Ile Ala Lys Thr Tyr Glu Ala Thr Leu Glu Lys Cys Cys
370 375 380
Ala Glu Ala Asp Pro Pro Ala Cys Tyr Arg Thr Val Phe Asp Gln Phe
385 390 395 400
Thr Pro Leu Val Glu Glu Pro Lys Ser Leu Val Lys Lys Asn Cys Asp
405 410 415
Leu Phe Glu Glu Val Gly Glu Tyr Asp Phe Gln Asn Ala Leu Ile Val
420 425 430
Arg Tyr Thr Lys Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu
435 440 445
Ile Gly Arg Thr Leu Gly Lys Val Gly Ser Arg Cys Cys Lys Leu Pro
450 455 460
Glu Ser Glu Arg Leu Pro Cys Ser Glu Asn His Leu Ala Leu Ala Leu
465 470 475 480
Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Ile
485 490 495
Thr Lys Cys Cys Thr Asp Ser Leu Ala Glu Arg Arg Pro Cys Phe Ser
500 505 510
Ala Leu Glu Leu Asp Glu Gly Tyr Val Pro Lys Glu Phe Lys Ala Glu
515 520 525
Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Glu Asp Glu Lys
530 535 540
Gln Ile Lys Lys Gln Ser Ala Leu Ala Glu Leu Val Lys His Lys Pro
545 550 555 560
Lys Ala Thr Lys Glu Gln Leu Lys Thr Val Leu Gly Asn Phe Ser Ala
565 570 575
Phe Val Ala Lys Cys Cys Gly Arg Glu Asp Lys Glu Ala Cys Phe Ala
580 585 590
Glu Glu Gly Pro Lys Leu Val Ala Ser Ser Gln Leu Ala Leu Ala
595 600 605
<210> 13
<211> 607
<212> PRT
<213> 驴(Equus asinus)
<400> 13
Met Lys Trp Val Thr Phe Val Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Phe Arg Gly Val Leu Arg Arg Asp Thr His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Asn Asp Leu Gly Glu Lys His Phe Lys Gly Leu Val Leu
35 40 45
Val Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Lys Cys Ala Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Ala Thr Tyr Gly Glu Leu Ala
100 105 110
Asp Cys Cys Glu Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Thr
115 120 125
His Lys Asp Asp His Pro Asn Leu Pro Lys Leu Lys Pro Glu Pro Asp
130 135 140
Ala Gln Cys Ala Ala Phe Gln Glu Asp Pro Asp Lys Phe Leu Gly Lys
145 150 155 160
Tyr Leu Tyr Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Gly Pro Glu
165 170 175
Leu Leu Phe His Ala Glu Glu Tyr Lys Ala Asp Phe Thr Glu Cys Cys
180 185 190
Pro Ala Asp Asp Lys Ala Gly Cys Leu Ile Pro Lys Leu Asp Ala Leu
195 200 205
Lys Glu Arg Ile Leu Leu Ser Ser Ala Lys Glu Arg Leu Lys Cys Ser
210 215 220
Ser Phe Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ser Val Ala
225 230 235 240
Arg Leu Ser Gln Lys Phe Pro Lys Ala Asp Phe Ala Glu Val Ser Lys
245 250 255
Ile Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly Asp
260 265 270
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Thr Lys Tyr Ile Cys
275 280 285
Glu His Gln Asp Ser Ile Ser Gly Lys Leu Lys Ala Cys Cys Asp Lys
290 295 300
Pro Leu Leu Gln Lys Ser His Cys Ile Ala Glu Val Lys Glu Asp Asp
305 310 315 320
Leu Pro Ser Asp Leu Pro Ala Leu Ala Ala Asp Phe Ala Glu Asp Lys
325 330 335
Glu Ile Cys Lys His Tyr Lys Asp Ala Lys Asp Val Phe Leu Gly Thr
340 345 350
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu
355 360 365
Leu Leu Arg Ile Ala Lys Thr Tyr Glu Ala Thr Leu Glu Lys Cys Cys
370 375 380
Ala Glu Ala Asp Pro Pro Ala Cys Tyr Ala Thr Val Phe Asp Gln Phe
385 390 395 400
Thr Pro Leu Val Glu Glu Pro Lys Ser Leu Val Lys Lys Asn Cys Asp
405 410 415
Leu Phe Glu Glu Val Gly Glu Tyr Asp Phe Gln Asn Ala Leu Ile Val
420 425 430
Arg Tyr Thr Lys Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu
435 440 445
Ile Gly Arg Thr Leu Gly Lys Val Gly Ser Arg Cys Cys Lys Leu Pro
450 455 460
Glu Ser Glu Arg Leu Pro Cys Ser Glu Asn His Leu Ala Leu Ala Leu
465 470 475 480
Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Ile
485 490 495
Thr Lys Cys Cys Thr Asp Ser Leu Ala Glu Arg Arg Pro Cys Phe Ser
500 505 510
Ala Leu Glu Leu Asp Glu Gly Tyr Ile Pro Lys Glu Phe Lys Ala Glu
515 520 525
Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Glu Asp Glu Lys
530 535 540
Gln Ile Lys Lys Gln Ser Ala Leu Ala Glu Leu Val Lys His Lys Pro
545 550 555 560
Lys Ala Thr Lys Glu Gln Leu Lys Thr Val Leu Gly Asn Phe Ser Ala
565 570 575
Phe Val Ala Lys Cys Cys Gly Ala Glu Asp Lys Glu Ala Cys Phe Ala
580 585 590
Glu Glu Gly Pro Lys Leu Val Ala Ser Ser Gln Leu Ala Leu Ala
595 600 605
<210> 14
<211> 608
<212> PRT
<213> 兔(Oryctolagus cuniculus)
<400> 14
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Glu Ala His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Asn Asp Val Gly Glu Glu His Phe Ile Gly Leu Val Leu
35 40 45
Ile Thr Phe Ser Gln Tyr Leu Gln Lys Cys Pro Tyr Glu Glu His Ala
50 55 60
Lys Leu Val Lys Glu Val Thr Asp Leu Ala Lys Ala Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Asp Ile Phe Gly Asp
85 90 95
Lys Ile Cys Ala Leu Pro Ser Leu Arg Asp Thr Tyr Gly Asp Val Ala
100 105 110
Asp Cys Cys Glu Lys Lys Glu Pro Glu Arg Asn Glu Cys Phe Leu His
115 120 125
His Lys Asp Asp Lys Pro Asp Leu Pro Pro Phe Ala Arg Pro Glu Ala
130 135 140
Asp Val Leu Cys Lys Ala Phe His Asp Asp Glu Lys Ala Phe Phe Gly
145 150 155 160
His Tyr Leu Tyr Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Gln Lys Tyr Lys Ala Ile Leu Thr Glu Cys
180 185 190
Cys Glu Ala Ala Asp Lys Gly Ala Cys Leu Thr Pro Lys Leu Asp Ala
195 200 205
Leu Glu Gly Lys Ser Leu Ile Ser Ala Ala Gln Glu Arg Leu Arg Cys
210 215 220
Ala Ser Ile Gln Lys Phe Gly Asp Arg Ala Tyr Lys Ala Trp Ala Leu
225 230 235 240
Val Arg Leu Ser Gln Arg Phe Pro Lys Ala Asp Phe Thr Asp Ile Ser
245 250 255
Lys Ile Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Met
275 280 285
Cys Glu His Gln Glu Thr Ile Ser Ser His Leu Lys Glu Cys Cys Asp
290 295 300
Lys Pro Ile Leu Glu Lys Ala His Cys Ile Tyr Gly Leu His Asn Asp
305 310 315 320
Glu Thr Pro Ala Gly Leu Pro Ala Val Ala Glu Glu Phe Val Glu Asp
325 330 335
Lys Asp Val Cys Lys Asn Tyr Glu Glu Ala Lys Asp Leu Phe Leu Gly
340 345 350
Lys Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Gly Lys Ala Tyr Glu Ala Thr Leu Lys Lys Cys
370 375 380
Cys Ala Thr Asp Asp Pro His Ala Cys Tyr Ala Lys Val Leu Asp Glu
385 390 395 400
Phe Gln Pro Leu Val Asp Glu Pro Lys Asn Leu Val Lys Gln Asn Cys
405 410 415
Glu Leu Tyr Glu Gln Leu Gly Asp Tyr Asn Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Ile Ser Arg Ser Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Glu Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys
485 490 495
Val Thr Lys Cys Cys Ser Glu Ser Leu Val Asp Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Gly Pro Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Glu Thr Glu
530 535 540
Arg Lys Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro His Ala Thr Asn Asp Gln Leu Lys Thr Val Val Gly Glu Phe Thr
565 570 575
Ala Leu Leu Asp Lys Cys Cys Ser Ala Glu Asp Lys Glu Ala Cys Phe
580 585 590
Ala Val Glu Gly Pro Lys Leu Val Glu Ser Ser Lys Ala Thr Leu Gly
595 600 605
<210> 15
<211> 583
<212> PRT
<213> 山羊(Capra hircus)
<400> 15
Asp Thr His Lys Ser Glu Ile Ala His Arg Phe Asn Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Gln Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Asp Glu His Val Lys Leu Val Lys Glu Leu Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser His Ala Gly Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Glu Leu Cys Lys Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Asp Met Ala Asp Cys Cys Glu Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Lys His Lys Asp Asp Ser Pro Asp Leu
100 105 110
Pro Lys Leu Lys Pro Glu Pro Asp Thr Leu Cys Ala Glu Phe Lys Ala
115 120 125
Asp Glu Lys Lys Phe Trp Gly Lys Tyr Leu Tyr Glu Val Ala Arg Arg
130 135 140
His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Asn Lys Tyr
145 150 155 160
Asn Gly Val Phe Gln Glu Cys Cys Gln Ala Glu Asp Lys Gly Ala Cys
165 170 175
Leu Leu Pro Lys Ile Glu Thr Met Arg Glu Lys Val Leu Ala Ser Ser
180 185 190
Ala Arg Gln Arg Leu Arg Cys Ala Ser Ile Gln Lys Phe Gly Glu Arg
195 200 205
Ala Leu Lys Ala Trp Ser Val Ala Arg Leu Ser Gln Lys Phe Pro Lys
210 215 220
Ala Asp Phe Thr Asp Val Thr Lys Ile Val Thr Asp Leu Thr Lys Val
225 230 235 240
His Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg
245 250 255
Ala Asp Leu Ala Lys Tyr Ile Cys Asp His Gln Asp Thr Leu Ser Ser
260 265 270
Lys Leu Lys Glu Cys Cys Asp Lys Pro Val Leu Glu Lys Ser His Cys
275 280 285
Ile Ala Glu Ile Asp Lys Asp Ala Val Pro Glu Asn Leu Pro Pro Leu
290 295 300
Thr Ala Asp Phe Ala Glu Asp Lys Glu Val Cys Lys Asn Tyr Gln Glu
305 310 315 320
Ala Lys Asp Val Phe Leu Gly Ser Phe Leu Tyr Glu Tyr Ser Arg Arg
325 330 335
His Pro Glu Tyr Ala Val Ser Val Leu Leu Arg Leu Ala Lys Glu Tyr
340 345 350
Glu Ala Thr Leu Glu Asp Cys Cys Ala Lys Glu Asp Pro His Ala Cys
355 360 365
Tyr Ala Thr Val Phe Asp Lys Leu Lys His Leu Val Asp Glu Pro Gln
370 375 380
Asn Leu Ile Lys Lys Asn Cys Glu Leu Phe Glu Lys His Gly Glu Tyr
385 390 395 400
Gly Phe Gln Asn Ala Leu Ile Val Arg Tyr Thr Arg Lys Ala Pro Gln
405 410 415
Val Ser Thr Pro Thr Leu Val Glu Ile Ser Arg Ser Leu Gly Lys Val
420 425 430
Gly Thr Lys Cys Cys Ala Lys Pro Glu Ser Glu Arg Met Pro Cys Thr
435 440 445
Glu Asp Tyr Leu Ser Leu Ile Leu Asn Arg Leu Cys Val Leu His Glu
450 455 460
Lys Thr Pro Val Ser Glu Lys Val Thr Lys Cys Cys Thr Glu Ser Leu
465 470 475 480
Val Asn Arg Arg Pro Cys Phe Ser Asp Leu Thr Leu Asp Glu Thr Tyr
485 490 495
Val Pro Lys Pro Phe Asp Gly Glu Ser Phe Thr Phe His Ala Asp Ile
500 505 510
Cys Thr Leu Pro Asp Thr Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu
515 520 525
Val Glu Leu Leu Lys His Lys Pro Lys Ala Thr Asp Glu Gln Leu Lys
530 535 540
Thr Val Met Glu Asn Phe Val Ala Phe Val Asp Lys Cys Cys Ala Ala
545 550 555 560
Asp Asp Lys Glu Gly Cys Phe Leu Leu Glu Gly Pro Lys Leu Val Ala
565 570 575
Ser Thr Gln Ala Ala Leu Ala
580
<210> 16
<211> 607
<212> PRT
<213> 绵羊(Ovis aries)
<400> 16
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Leu Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Thr His Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Asn Asp Leu Gly Glu Glu Asn Phe Gln Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Asp Glu His Val
50 55 60
Lys Leu Val Lys Glu Leu Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser His Ala Gly Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Glu Leu Cys Lys Val Ala Thr Leu Arg Glu Thr Tyr Gly Asp Met Ala
100 105 110
Asp Cys Cys Glu Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Asn
115 120 125
His Lys Asp Asp Ser Pro Asp Leu Pro Lys Leu Lys Pro Glu Pro Asp
130 135 140
Thr Leu Cys Ala Glu Phe Lys Ala Asp Glu Lys Lys Phe Trp Gly Lys
145 150 155 160
Tyr Leu Tyr Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu
165 170 175
Leu Leu Tyr Tyr Ala Asn Lys Tyr Asn Gly Val Phe Gln Glu Cys Cys
180 185 190
Gln Ala Glu Asp Lys Gly Ala Cys Leu Leu Pro Lys Ile Asp Ala Met
195 200 205
Arg Glu Lys Val Leu Ala Ser Ser Ala Arg Gln Arg Leu Arg Cys Ala
210 215 220
Ser Ile Gln Lys Phe Gly Glu Arg Ala Leu Lys Ala Trp Ser Val Ala
225 230 235 240
Arg Leu Ser Gln Lys Phe Pro Lys Ala Asp Phe Thr Asp Val Thr Lys
245 250 255
Ile Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly Asp
260 265 270
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys
275 280 285
Asp His Gln Asp Ala Leu Ser Ser Lys Leu Lys Glu Cys Cys Asp Lys
290 295 300
Pro Val Leu Glu Lys Ser His Cys Ile Ala Glu Val Asp Lys Asp Ala
305 310 315 320
Val Pro Glu Asn Leu Pro Pro Leu Thr Ala Asp Phe Ala Glu Asp Lys
325 330 335
Glu Val Cys Lys Asn Tyr Gln Glu Ala Lys Asp Val Phe Leu Gly Ser
340 345 350
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Glu Tyr Ala Val Ser Val
355 360 365
Leu Leu Arg Leu Ala Lys Glu Tyr Glu Ala Thr Leu Glu Asp Cys Cys
370 375 380
Ala Lys Glu Asp Pro His Ala Cys Tyr Ala Thr Val Phe Asp Lys Leu
385 390 395 400
Lys His Leu Val Asp Glu Pro Gln Asn Leu Ile Lys Lys Asn Cys Glu
405 410 415
Leu Phe Glu Lys His Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ile Val
420 425 430
Arg Tyr Thr Arg Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu
435 440 445
Ile Ser Arg Ser Leu Gly Lys Val Gly Thr Lys Cys Cys Ala Lys Pro
450 455 460
Glu Ser Glu Arg Met Pro Cys Thr Glu Asp Tyr Leu Ser Leu Ile Leu
465 470 475 480
Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Val
485 490 495
Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser
500 505 510
Asp Leu Thr Leu Asp Glu Thr Tyr Val Pro Lys Pro Phe Asp Glu Lys
515 520 525
Phe Phe Thr Phe His Ala Asp Ile Cys Thr Leu Pro Asp Thr Glu Lys
530 535 540
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Leu Lys His Lys Pro
545 550 555 560
Lys Ala Thr Asp Glu Gln Leu Lys Thr Val Met Glu Asn Phe Val Ala
565 570 575
Phe Val Asp Lys Cys Cys Ala Ala Asp Asp Lys Glu Gly Cys Phe Val
580 585 590
Leu Glu Gly Pro Lys Leu Val Ala Ser Thr Gln Ala Ala Leu Ala
595 600 605
<210> 17
<211> 608
<212> PRT
<213> 犬(canis lupus familiaris)
<400> 17
Met Lys Trp Val Thr Phe Ile Ser Leu Phe Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Leu Val Arg Arg Glu Ala Tyr Lys Ser Glu Ile Ala
20 25 30
His Arg Tyr Asn Asp Leu Gly Glu Glu His Phe Arg Gly Leu Val Leu
35 40 45
Val Ala Phe Ser Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Ala Lys Glu Val Thr Glu Phe Ala Lys Ala Cys Ala Ala Glu
65 70 75 80
Glu Ser Gly Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Ser Leu Arg Asp Lys Tyr Gly Asp Met Ala
100 105 110
Asp Cys Cys Glu Lys Gln Glu Pro Asp Arg Asn Glu Cys Phe Leu Ala
115 120 125
His Lys Asp Asp Asn Pro Gly Phe Pro Pro Leu Val Ala Pro Glu Pro
130 135 140
Asp Ala Leu Cys Ala Ala Phe Gln Asp Asn Glu Gln Leu Phe Leu Gly
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Tyr Tyr Ala Gln Gln Tyr Lys Gly Val Phe Ala Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Gly Pro Lys Ile Glu Ala
195 200 205
Leu Arg Glu Lys Val Leu Leu Ser Ser Ala Lys Glu Arg Phe Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Asp Arg Ala Phe Lys Ala Trp Ser Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Asp Phe Ala Glu Ile Ser
245 250 255
Lys Val Val Thr Asp Leu Thr Lys Val His Lys Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Met
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Thr Lys Leu Lys Glu Cys Cys Asp
290 295 300
Lys Pro Val Leu Glu Lys Ser Gln Cys Leu Ala Glu Val Glu Arg Asp
305 310 315 320
Glu Leu Pro Gly Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Asp
325 330 335
Lys Glu Val Cys Lys Asn Tyr Gln Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Thr Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Glu Tyr Ser Val Ser
355 360 365
Leu Leu Leu Arg Leu Ala Lys Glu Tyr Glu Ala Thr Leu Glu Lys Cys
370 375 380
Cys Ala Thr Asp Asp Pro Pro Thr Cys Tyr Ala Lys Val Leu Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Asp Glu Pro Gln Asn Leu Val Lys Thr Asn Cys
405 410 415
Glu Leu Phe Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Lys Leu Gly Lys Val Gly Thr Lys Cys Cys Lys Lys
450 455 460
Pro Glu Ser Glu Arg Met Ser Cys Ala Glu Asp Phe Leu Ser Val Val
465 470 475 480
Leu Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Arg
485 490 495
Val Thr Lys Cys Cys Ser Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Gly Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Leu Cys Thr Leu Pro Glu Ala Glu
530 535 540
Lys Gln Val Lys Lys Gln Thr Ala Leu Val Glu Leu Leu Lys His Lys
545 550 555 560
Pro Lys Ala Thr Asp Glu Gln Leu Lys Thr Val Met Gly Asp Phe Gly
565 570 575
Ala Phe Val Glu Lys Cys Cys Ala Ala Glu Asn Lys Glu Gly Cys Phe
580 585 590
Ser Glu Glu Gly Pro Lys Leu Val Ala Ala Ala Gln Ala Ala Leu Val
595 600 605
<210> 18
<211> 615
<212> PRT
<213> 鸡(Gallus gallus)
<400> 18
Met Lys Trp Val Thr Leu Ile Ser Phe Ile Phe Leu Phe Ser Ser Ala
1 5 10 15
Thr Ser Arg Asn Leu Gln Arg Phe Ala Arg Asp Ala Glu His Lys Ser
20 25 30
Glu Ile Ala His Arg Tyr Asn Asp Leu Lys Glu Glu Thr Phe Lys Ala
35 40 45
Val Ala Met Ile Thr Phe Ala Gln Tyr Leu Gln Arg Cys Ser Tyr Glu
50 55 60
Gly Leu Ser Lys Leu Val Lys Asp Val Val Asp Leu Ala Gln Lys Cys
65 70 75 80
Val Ala Asn Glu Asp Ala Pro Glu Cys Ser Lys Pro Leu Pro Ser Ile
85 90 95
Ile Leu Asp Glu Ile Cys Gln Val Glu Lys Leu Arg Asp Ser Tyr Gly
100 105 110
Ala Met Ala Asp Cys Cys Ser Lys Ala Asp Pro Glu Arg Asn Glu Cys
115 120 125
Phe Leu Ser Phe Lys Val Ser Gln Pro Asp Phe Val Gln Pro Tyr Gln
130 135 140
Arg Pro Ala Ser Asp Val Ile Cys Gln Glu Tyr Gln Asp Asn Arg Val
145 150 155 160
Ser Phe Leu Gly His Phe Ile Tyr Ser Val Ala Arg Arg His Pro Phe
165 170 175
Leu Tyr Ala Pro Ala Ile Leu Ser Phe Ala Val Asp Phe Glu His Ala
180 185 190
Leu Gln Ser Cys Cys Lys Glu Ser Asp Val Gly Ala Cys Leu Asp Thr
195 200 205
Lys Glu Ile Val Met Arg Glu Lys Ala Lys Gly Val Ser Val Lys Gln
210 215 220
Gln Tyr Phe Cys Gly Ile Leu Lys Gln Phe Gly Asp Arg Val Phe Gln
225 230 235 240
Ala Arg Gln Leu Ile Tyr Leu Ser Gln Lys Tyr Pro Lys Ala Pro Phe
245 250 255
Ser Glu Val Ser Lys Phe Val His Asp Ser Ile Gly Val His Lys Glu
260 265 270
Cys Cys Glu Gly Asp Met Val Glu Cys Met Asp Asp Met Ala Arg Met
275 280 285
Met Ser Asn Leu Cys Ser Gln Gln Asp Val Phe Ser Gly Lys Ile Lys
290 295 300
Asp Cys Cys Glu Lys Pro Ile Val Glu Arg Ser Gln Cys Ile Met Glu
305 310 315 320
Ala Glu Phe Asp Glu Lys Pro Ala Asp Leu Pro Ser Leu Val Glu Lys
325 330 335
Tyr Ile Glu Asp Lys Glu Val Cys Lys Ser Phe Glu Ala Gly His Asp
340 345 350
Ala Phe Met Ala Glu Phe Val Tyr Glu Tyr Ser Arg Arg His Pro Glu
355 360 365
Phe Ser Ile Gln Leu Ile Met Arg Ile Ala Lys Gly Tyr Glu Ser Leu
370 375 380
Leu Glu Lys Cys Cys Lys Thr Asp Asn Pro Ala Glu Cys Tyr Ala Asn
385 390 395 400
Ala Gln Glu Gln Leu Asn Gln His Ile Lys Glu Thr Gln Asp Val Val
405 410 415
Lys Thr Asn Cys Asp Leu Leu His Asp His Gly Glu Ala Asp Phe Leu
420 425 430
Lys Ser Ile Leu Ile Arg Tyr Thr Lys Lys Met Pro Gln Val Pro Thr
435 440 445
Asp Leu Leu Leu Glu Thr Gly Lys Lys Met Thr Thr Ile Gly Thr Lys
450 455 460
Cys Cys Gln Leu Gly Glu Asp Arg Arg Met Ala Cys Ser Glu Gly Tyr
465 470 475 480
Leu Ser Ile Val Ile His Asp Thr Cys Arg Lys Gln Glu Thr Thr Pro
485 490 495
Ile Asn Asp Asn Val Ser Gln Cys Cys Ser Gln Leu Tyr Ala Asn Arg
500 505 510
Arg Pro Cys Phe Thr Ala Met Gly Val Asp Thr Lys Tyr Val Pro Pro
515 520 525
Pro Phe Asn Pro Asp Met Phe Ser Phe Asp Glu Lys Leu Cys Ser Ala
530 535 540
Pro Ala Glu Glu Arg Glu Val Gly Gln Met Lys Leu Leu Ile Asn Leu
545 550 555 560
Ile Lys Arg Lys Pro Gln Met Thr Glu Glu Gln Ile Lys Thr Ile Ala
565 570 575
Asp Gly Phe Thr Ala Met Val Asp Lys Cys Cys Lys Gln Ser Asp Ile
580 585 590
Asn Thr Cys Phe Gly Glu Glu Gly Ala Asn Leu Ile Val Gln Ser Arg
595 600 605
Ala Thr Leu Gly Ile Gly Ala
610 615
<210> 19
<211> 607
<212> PRT
<213> 野猪(Sus scrofa)
<400> 19
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Thr Tyr Lys Ser Glu Ile Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Gln Tyr Phe Lys Gly Leu Val Leu
35 40 45
Ile Ala Phe Ser Gln His Leu Gln Gln Cys Pro Tyr Glu Glu His Val
50 55 60
Lys Leu Val Arg Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Ile His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Ala Ile Pro Ser Leu Arg Glu His Tyr Gly Asp Leu Ala
100 105 110
Asp Cys Cys Glu Lys Glu Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asn Asp Asn Pro Asp Ile Pro Lys Leu Lys Pro Asp Pro Val
130 135 140
Ala Leu Cys Ala Asp Phe Gln Glu Asp Glu Gln Lys Phe Trp Gly Lys
145 150 155 160
Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu
165 170 175
Leu Leu Tyr Tyr Ala Ile Ile Tyr Lys Asp Val Phe Ser Glu Cys Cys
180 185 190
Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Ile Glu His Leu
195 200 205
Arg Glu Lys Val Leu Thr Ser Ala Ala Lys Gln Arg Leu Lys Cys Ala
210 215 220
Ser Ile Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ser Leu Ala
225 230 235 240
Arg Leu Ser Gln Arg Phe Pro Lys Ala Asp Phe Thr Glu Ile Ser Lys
245 250 255
Ile Val Thr Asp Leu Ala Lys Val His Lys Glu Cys Cys His Gly Asp
260 265 270
Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys
275 280 285
Glu Asn Gln Asp Thr Ile Ser Thr Lys Leu Lys Glu Cys Cys Asp Lys
290 295 300
Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Ala Lys Arg Asp Glu
305 310 315 320
Leu Pro Ala Asp Leu Asn Pro Leu Glu His Asp Phe Val Glu Asp Lys
325 330 335
Glu Val Cys Lys Asn Tyr Lys Glu Ala Lys His Val Phe Leu Gly Thr
340 345 350
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu
355 360 365
Leu Leu Arg Ile Ala Lys Ile Tyr Glu Ala Thr Leu Glu Asp Cys Cys
370 375 380
Ala Lys Glu Asp Pro Pro Ala Cys Tyr Ala Thr Val Phe Asp Lys Phe
385 390 395 400
Gln Pro Leu Val Asp Glu Pro Lys Asn Leu Ile Lys Gln Asn Cys Glu
405 410 415
Leu Phe Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Leu Ile Val
420 425 430
Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu
435 440 445
Val Ala Arg Lys Leu Gly Leu Val Gly Ser Arg Cys Cys Lys Arg Pro
450 455 460
Glu Glu Glu Arg Leu Ser Cys Ala Glu Asp Tyr Leu Ser Leu Val Leu
465 470 475 480
Asn Arg Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Glu Lys Val
485 490 495
Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser
500 505 510
Ala Leu Thr Pro Asp Glu Thr Tyr Lys Pro Lys Glu Phe Val Glu Gly
515 520 525
Thr Phe Thr Phe His Ala Asp Leu Cys Thr Leu Pro Glu Asp Glu Lys
530 535 540
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Leu Lys His Lys Pro
545 550 555 560
His Ala Thr Glu Glu Gln Leu Arg Thr Val Leu Gly Asn Phe Ala Ala
565 570 575
Phe Val Gln Lys Cys Cys Ala Ala Pro Asp His Glu Ala Cys Phe Ala
580 585 590
Val Glu Gly Pro Lys Phe Val Ile Glu Ile Arg Gly Ile Leu Ala
595 600 605
<210> 20
<211> 387
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域1和人血清白蛋白域2
<400> 20
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu
385
<210> 21
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域2和人血清白蛋白域3
<400> 21
Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
1 5 10 15
Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
20 25 30
Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu
35 40 45
Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
50 55 60
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys
65 70 75 80
Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys
85 90 95
Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu
100 105 110
Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
115 120 125
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
130 135 140
Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser
145 150 155 160
Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu
165 170 175
Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe
180 185 190
Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
195 200 205
Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala
210 215 220
Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr
225 230 235 240
Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys
245 250 255
Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser
260 265 270
Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser
275 280 285
Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro
290 295 300
Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
305 310 315 320
Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu
325 330 335
Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys
340 345 350
His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp
355 360 365
Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr
370 375 380
Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala
385 390 395 400
Leu Gly Leu
<210> 22
<211> 399
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域1和人血清白蛋白域3
<400> 22
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu
195 200 205
Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg
210 215 220
Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val
225 230 235 240
Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu
245 250 255
Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn
260 265 270
Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr
275 280 285
Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala
290 295 300
Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr
305 310 315 320
Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln
325 330 335
Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys
340 345 350
Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe
355 360 365
Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
370 375 380
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
385 390 395
<210> 23
<211> 205
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域3
<400> 23
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
1 5 10 15
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
20 25 30
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
35 40 45
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
50 55 60
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
65 70 75 80
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
85 90 95
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
100 105 110
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
115 120 125
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
130 135 140
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
145 150 155 160
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
165 170 175
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
180 185 190
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
195 200 205
<210> 24
<211> 410
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域3的两个连续的拷贝
<400> 24
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
1 5 10 15
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
20 25 30
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
35 40 45
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
50 55 60
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
65 70 75 80
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
85 90 95
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
100 105 110
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
115 120 125
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
130 135 140
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
145 150 155 160
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
165 170 175
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
180 185 190
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Val Glu Glu
195 200 205
Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly
210 215 220
Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val
225 230 235 240
Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly
245 250 255
Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro
260 265 270
Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu
275 280 285
His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu
290 295 300
Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu
305 310 315 320
Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala
325 330 335
Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr
340 345 350
Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln
355 360 365
Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys
370 375 380
Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu
385 390 395 400
Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
405 410
<210> 25
<211> 584
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域1, 人血清白蛋白域 2和兔血清白蛋白域3
<400> 25
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Asp Glu Pro
370 375 380
Lys Asn Leu Val Lys Gln Asn Cys Glu Leu Tyr Glu Gln Leu Gly Asp
385 390 395 400
Tyr Asn Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ile Ser Arg Ser Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Glu Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Val Val Leu Asn Arg Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu Lys Val Thr Lys Cys Cys Ser Glu Ser
465 470 475 480
Leu Val Asp Arg Arg Pro Cys Phe Ser Ala Leu Gly Pro Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Pro Glu Thr Glu Arg Lys Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro His Ala Thr Asn Asp Gln Leu
530 535 540
Lys Thr Val Val Gly Glu Phe Thr Ala Leu Leu Asp Lys Cys Cys Ser
545 550 555 560
Ala Glu Asp Lys Glu Ala Cys Phe Ala Val Glu Gly Pro Lys Leu Val
565 570 575
Glu Ser Ser Lys Ala Thr Leu Gly
580
<210> 26
<211> 585
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体: 兔血清白蛋白域1,兔血清白蛋白域2和人血清白蛋白域3
<400> 26
Glu Ala His Lys Ser Glu Ile Ala His Arg Phe Asn Asp Val Gly Glu
1 5 10 15
Glu His Phe Ile Gly Leu Val Leu Ile Thr Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Pro Tyr Glu Glu His Ala Lys Leu Val Lys Glu Val Thr Asp
35 40 45
Leu Ala Lys Ala Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Asp Ile Phe Gly Asp Lys Ile Cys Ala Leu Pro Ser Leu
65 70 75 80
Arg Asp Thr Tyr Gly Asp Val Ala Asp Cys Cys Glu Lys Lys Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu His His Lys Asp Asp Lys Pro Asp Leu
100 105 110
Pro Pro Phe Ala Arg Pro Glu Ala Asp Val Leu Cys Lys Ala Phe His
115 120 125
Asp Asp Glu Lys Ala Phe Phe Gly His Tyr Leu Tyr Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Gln Lys
145 150 155 160
Tyr Lys Ala Ile Leu Thr Glu Cys Cys Glu Ala Ala Asp Lys Gly Ala
165 170 175
Cys Leu Thr Pro Lys Leu Asp Ala Leu Glu Gly Lys Ser Leu Ile Ser
180 185 190
Ala Ala Gln Glu Arg Leu Arg Cys Ala Ser Ile Gln Lys Phe Gly Asp
195 200 205
Arg Ala Tyr Lys Ala Trp Ala Leu Val Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Asp Phe Thr Asp Ile Ser Lys Ile Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Met Cys Glu His Gln Glu Thr Ile Ser
260 265 270
Ser His Leu Lys Glu Cys Cys Asp Lys Pro Ile Leu Glu Lys Ala His
275 280 285
Cys Ile Tyr Gly Leu His Asn Asp Glu Thr Pro Ala Gly Leu Pro Ala
290 295 300
Val Ala Glu Glu Phe Val Glu Asp Lys Asp Val Cys Lys Asn Tyr Glu
305 310 315 320
Glu Ala Lys Asp Leu Phe Leu Gly Lys Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Gly Lys Ala
340 345 350
Tyr Glu Ala Thr Leu Lys Lys Cys Cys Ala Thr Asp Asp Pro His Ala
355 360 365
Cys Tyr Ala Lys Val Leu Asp Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 27
<211> 585
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:羊血清白蛋白域1,羊血清白蛋白域2和人血清白蛋白域3
<400> 27
Asp Thr His Lys Ser Glu Ile Ala His Arg Phe Asn Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Gln Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Asp Glu His Val Lys Leu Val Lys Glu Leu Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser His Ala Gly Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Glu Leu Cys Lys Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Asp Met Ala Asp Cys Cys Glu Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Asn His Lys Asp Asp Ser Pro Asp Leu
100 105 110
Pro Lys Leu Lys Pro Glu Pro Asp Thr Leu Cys Ala Glu Phe Lys Ala
115 120 125
Asp Glu Lys Lys Phe Trp Gly Lys Tyr Leu Tyr Glu Val Ala Arg Arg
130 135 140
His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Asn Lys Tyr
145 150 155 160
Asn Gly Val Phe Gln Glu Cys Cys Gln Ala Glu Asp Lys Gly Ala Cys
165 170 175
Leu Leu Pro Lys Ile Asp Ala Met Arg Glu Lys Val Leu Ala Ser Ser
180 185 190
Ala Arg Gln Arg Leu Arg Cys Ala Ser Ile Gln Lys Phe Gly Glu Arg
195 200 205
Ala Leu Lys Ala Trp Ser Val Ala Arg Leu Ser Gln Lys Phe Pro Lys
210 215 220
Ala Asp Phe Thr Asp Val Thr Lys Ile Val Thr Asp Leu Thr Lys Val
225 230 235 240
His Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg
245 250 255
Ala Asp Leu Ala Lys Tyr Ile Cys Asp His Gln Asp Ala Leu Ser Ser
260 265 270
Lys Leu Lys Glu Cys Cys Asp Lys Pro Val Leu Glu Lys Ser His Cys
275 280 285
Ile Ala Glu Val Asp Lys Asp Ala Val Pro Glu Asn Leu Pro Pro Leu
290 295 300
Thr Ala Asp Phe Ala Glu Asp Lys Glu Val Cys Lys Asn Tyr Gln Glu
305 310 315 320
Ala Lys Asp Val Phe Leu Gly Ser Phe Leu Tyr Glu Tyr Ser Arg Arg
325 330 335
His Pro Glu Tyr Ala Val Ser Val Leu Leu Arg Leu Ala Lys Glu Tyr
340 345 350
Glu Ala Thr Leu Glu Asp Cys Cys Ala Lys Glu Asp Pro His Ala Cys
355 360 365
Tyr Ala Thr Val Phe Asp Lys Leu Lys His Leu Val Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 28
<211> 583
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域1,人血清白蛋白域2和羊血清白蛋白域3
<400> 28
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Asp Glu Pro Gln
370 375 380
Asn Leu Ile Lys Lys Asn Cys Glu Leu Phe Glu Lys His Gly Glu Tyr
385 390 395 400
Gly Phe Gln Asn Ala Leu Ile Val Arg Tyr Thr Arg Lys Ala Pro Gln
405 410 415
Val Ser Thr Pro Thr Leu Val Glu Ile Ser Arg Ser Leu Gly Lys Val
420 425 430
Gly Thr Lys Cys Cys Ala Lys Pro Glu Ser Glu Arg Met Pro Cys Thr
435 440 445
Glu Asp Tyr Leu Ser Leu Ile Leu Asn Arg Leu Cys Val Leu His Glu
450 455 460
Lys Thr Pro Val Ser Glu Lys Val Thr Lys Cys Cys Thr Glu Ser Leu
465 470 475 480
Val Asn Arg Arg Pro Cys Phe Ser Asp Leu Thr Leu Asp Glu Thr Tyr
485 490 495
Val Pro Lys Pro Phe Asp Glu Lys Phe Phe Thr Phe His Ala Asp Ile
500 505 510
Cys Thr Leu Pro Asp Thr Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu
515 520 525
Val Glu Leu Leu Lys His Lys Pro Lys Ala Thr Asp Glu Gln Leu Lys
530 535 540
Thr Val Met Glu Asn Phe Val Ala Phe Val Asp Lys Cys Cys Ala Ala
545 550 555 560
Asp Asp Lys Glu Gly Cys Phe Val Leu Glu Gly Pro Lys Leu Val Ala
565 570 575
Ser Thr Gln Ala Ala Leu Ala
580
<210> 29
<211> 584
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:人血清白蛋白域1,人血清白蛋白域2和小鼠血清白蛋白域3
<400> 29
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala
580
<210> 30
<211> 585
<212> PRT
<213> 人工序列
<220>
<223> 人工白蛋白变体:小鼠血清白蛋白域1,小鼠血清白蛋白域2和人血清白蛋白域3
<400> 30
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 31
<211> 585
<212> PRT
<213> 人(Homo sapiens)
<400> 31
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 32
<211> 290
<212> PRT
<213> 人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(290)
<223> 主组织相容性复合物I型-样Fc受体(FCGRT)的截短的重链(一起, SEQ ID No.32和SEQ ID No. 33形成FcRN)
<400> 32
Met Gly Val Pro Arg Pro Gln Pro Trp Ala Leu Gly Leu Leu Leu Phe
1 5 10 15
Leu Leu Pro Gly Ser Leu Gly Ala Glu Ser His Leu Ser Leu Leu Tyr
20 25 30
His Leu Thr Ala Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp
35 40 45
Val Ser Gly Trp Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu
50 55 60
Arg Gly Glu Ala Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val
65 70 75 80
Ser Trp Tyr Trp Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys
85 90 95
Leu Phe Leu Glu Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr
100 105 110
Leu Gln Gly Leu Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val
115 120 125
Pro Thr Ala Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp
130 135 140
Leu Lys Gln Gly Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile
145 150 155 160
Ser Gln Arg Trp Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr
165 170 175
Phe Leu Leu Phe Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg
180 185 190
Gly Arg Gly Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys
195 200 205
Ala Arg Pro Ser Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe
210 215 220
Ser Phe Tyr Pro Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu
225 230 235 240
Ala Ala Gly Thr Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser
245 250 255
Phe His Ala Ser Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His
260 265 270
Tyr Cys Cys Ile Val Gln His Ala Gly Leu Ala Gln Pro Leu Arg Val
275 280 285
Glu Leu
290
<210> 33
<211> 119
<212> PRT
<213> 人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(119)
<223> Beta-2-微球蛋白 (一起, SEQ ID No. 32和SEQ ID No. 33形成FcRN)
<400> 33
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg
20 25 30
His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser
35 40 45
Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu
50 55 60
Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp
65 70 75 80
Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp
85 90 95
Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile
100 105 110
Val Lys Trp Asp Arg Asp Met
115
<210> 34
<211> 152
<212> PRT
<213> 人工序列
<220>
<223> 人IL-1ra (N84Q)
<400> 34
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Gln Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 35
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> scFv (FITC8)
<400> 35
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 Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Asn Gly Gly Tyr Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Asp 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 Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp Gly Ser Gly Trp Ser Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
130 135 140
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn
145 150 155 160
Ile Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Gly Asn Asn Asn Arg Pro Ser Gly Val
180 185 190
Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
195 200 205
Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala
210 215 220
Trp Asp Asp Ser Leu Ser Gly Arg Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu Gly
Claims (25)
1.一种白蛋白衍生物或变体,其片段或包含所述白蛋白衍生物或变体或其片段的融合多肽,其中所述白蛋白衍生物或变体或其片段包含或由如下组成:白蛋白域III或衍生物或其变体,和至少一个其它白蛋白域,片段或衍生物或其变体,其中所述衍生物或变体并非天然存在的白蛋白衍生物或变体。
2.权利要求1的白蛋白衍生物或变体,其片段或融合多肽,其中所述天然存在的衍生物或变体是来自下述之一的野生型白蛋白:人;灵长类,如黑猩猩,大猩猩或恒河猴/猕猴;兔;啮齿类如小鼠,大鼠和仓鼠;牛;马类如马或驴;山羊;绵羊;犬;豚鼠;鸡和猪。
3.权利要求1或2的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白域III或衍生物或其变体来源于人血清白蛋白;灵长类血清白蛋白,如黑猩猩血清白蛋白,大猩猩血清白蛋白或猕猴血清白蛋白;兔血清白蛋白;啮齿类血清白蛋白如小鼠白蛋白,大鼠血清白蛋白和仓鼠血清白蛋白;牛血清白蛋白;马类血清白蛋白如马血清白蛋白或驴血清白蛋白;山羊血清白蛋白;绵羊血清白蛋白;犬血清白蛋白;豚鼠血清白蛋白;鸡血清白蛋白和猪血清白蛋白。
4.权利要求1至3任一项的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白域III或衍生物或其变体与SEQ ID NO:31或SEQ ID NO:1的域III具有至少80%序列同一性,优选至少85%序列同一性,更优选至少90%序列同一性,甚至更优选至少90%序列同一性和最优选至少98%序列同一性。
5.权利要求4的白蛋白衍生物或变体,其中所述域III或衍生物或其变体与SEQ ID NO:31或SEQ ID NO:1的氨基酸381至585具有至少80%序列同一性,优选至少85%序列同一性,更优选至少90%序列同一性,甚至更优选至少90%序列同一性和最优选至少98%序列同一性。
6.权利要求1至5任一项的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述至少一种其它白蛋白域,片段或衍生物或其变体选自域I,域II和域III。
7.权利要求1至6任一项的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述至少一种其它白蛋白域是域III。
8.权利要求6或7的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述至少一种其它白蛋白域,片段或衍生物或其变体来源于人血清白蛋白;灵长类血清白蛋白,如黑猩猩血清白蛋白,大猩猩血清白蛋白或猕猴血清白蛋白;啮齿类血清白蛋白如兔血清白蛋白,小鼠白蛋白和大鼠血清白蛋白;牛血清白蛋白;马类血清白蛋白;驴血清白蛋白;仓鼠血清白蛋白;山羊血清白蛋白;绵羊血清白蛋白;犬血清白蛋白;豚鼠血清白蛋白;鸡血清白蛋白和猪血清白蛋白。
9.权利要求8的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白衍生物或变体由如下组成:来源于人血清白蛋白的域I和II和来源于兔血清白蛋白的域III(例如SEQID NO:25),来源于兔血清白蛋白的域I和II和来源于人血清白蛋白的域III(例如SEQ IDNO:26),来源于绵羊血清白蛋白的域I和II和来源于人血清白蛋白的域III(例如SEQ IDNO:27),来源于人血清白蛋白的域I和II和来源于小鼠血清白蛋白的域III(例如SEQ IDNO:29),来源于人血清白蛋白的域I和II和来源于绵羊血清白蛋白的域III(例如SEQ IDNO:28),或来源于小鼠血清白蛋白的域I和II和来源于人血清白蛋白的域III(例如SEQ IDNO:30)。
10.权利要求8的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述至少一种其它白蛋白域,片段或衍生物或其变体与它的亲本白蛋白的对应域具有至少80%序列同一性,优选至少85%序列同一性,更优选至少90%序列同一性,甚至更优选至少90%序列同一性和最优选至少98%序列同一性。
11.权利要求9的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述至少一种其它白蛋白域,片段或衍生物或其变体与具有SEQ ID NO:31或SEQ ID NO:1的HSA的对应域具有至少80%序列同一性,优选至少85%序列同一性,更优选至少90%序列同一性,甚至更优选至少90%序列同一性和最优选至少98%序列同一性。
12.前述任一项权利要求的白蛋白衍生物或变体,其片段或融合多肽,其中所述白蛋白衍生物或变体,其片段或融合多肽包含选自下组的氨基酸序列或由选自下组的氨基酸序列组成:
(i)由人血清白蛋白域I和人血清白蛋白域III组成的分子(例如SEQ ID NO:22)
(ii)由人血清白蛋白域I和人血清白蛋白域II组成的分子(例如SEQ ID NO:20)
(iii)由人血清白蛋白域II和人血清白蛋白域III组成的分子(例如SEQ ID NO:21),和
(iv)由人血清白蛋白域III的两个拷贝组成的分子(例如SEQ ID NO:24)。
13.权利要求1至12任一项的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述白蛋白变体的大小在40-80kDa的范围内。
14.一种白蛋白变体、或包含所述白蛋白变体的融合多肽,其中所述白蛋白变体的大小在40-80kDa的范围内且如SEQ ID NO:22所示由人血清白蛋白域I和域III组成。
15.权利要求1至14任一项的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中至少一个域III在对应于SEQ ID NO:31或SEQ ID NO:1(HSA)中选自下组的位置的位置包含一个或多个取代:573,500,550,417,440,464,490,492,493,494,495,496,499,501,503,504,505,506,510,535,536,537,538,540,541,542,574,575,577,578,579,580,581,582和584。
16.权利要求15的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其中所述在对应于SEQ IDNO:1(HSA)中的位置的位置的一个或多个取代选自:K573Y,W,P,H,F,V,I,T,N,S,G,M,C,A,E,Q,R,L,D,K500E,G,D,A,S,C,P,H,F,N,W,T,M,Y,V,Q,L,I,R,Q417A,H440A,H464Q,E492G,D494N,Q,A,E495Q,A,T496A,D494E+Q417H,D494N+T496A,E492G+V493P,P499A,E501A,Q,N503H,K,H510Q,H535Q,K536A,P537A,K538A,K541G,D,D550E,N,E492G+K573P,A,或E492G/N503H/K573P。
17.前述任一项权利要求的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其包含一个或多个其它突变,所述突变在分子表面构筑一个或多个巯基基团。
18.权利要求17的白蛋白衍生物或变体,其片段或者包含所述白蛋白衍生物或变体或其片段或由所述白蛋白衍生物或变体或其片段组成的融合多肽,其具有选自对应于如下的取代的组的取代:SEQ ID NO:31或SEQ ID NO:1中的L585C,D1C,A2C,D562C,A364C,A504C,E505C,T79C,E86C,D129C,D549C,A581C,D121C,E82C,S270C,A578C,L595LC,D1DC,A2AC,D562DC,A364AC,A504AC,E505EC,T79TC,E86EC,D129DC,D549DC,A581AC,A581AC,D121DC,E82EC,S270SC,A579AC,C360*,C316*,C75*,C168*,C558*,C361*,C91*,C124*,C169*和C567*。
19.一种缀合物,其包含根据权利要求1至18任一项的白蛋白衍生物或变体或其片段,和结合于白蛋白部分的治疗性或诊断性或其它有益模块。
20.一种核酸,其编码权利要求1至17任一项的白蛋白衍生物,其片段或包含所述白蛋白衍生物或其片段或由所述白蛋白衍生物或其片段组成的融合多肽,优选包含于质粒或表达构建体中。
21.一种宿主细胞,其包含权利要求20的核酸。
22.一种组合物,优选药物组合物,其包含权利要求1至16的白蛋白衍生物,其片段或融合多肽或包含所述白蛋白衍生物或其片段的缔合物。
23.前述任一项权利要求的白蛋白变体或衍生物或其融合物、缀合物、缔合物、组合物,编码所述变体,衍生物或融合物的核酸或宿主细胞,所述白蛋白变体,衍生物,或其衍生物、缀合物、缔合物或组合物具有(i)与天然HSA和/或包含天然HSA的融合物或缀合物,缔合物或组合物相比较长的血浆半寿期,或(ii)与天然HSA和/或包含天然HSA的融合物或缀合物,缔合物或组合物相比较短的血浆半寿期。
24.前述任一项权利要求的白蛋白变体或衍生物,其缀合物,缔合物,组合物,编码前述任一项权利要求的融合物的核酸或宿主细胞,所述融合物、缀合物、缔合物或组合物具有(i)与包含天然HSA的白蛋白融合物,缀合物,缔合物或组合物相比较长的血浆半寿期,或(ii)与包含天然HSA的融合物,缀合物,缔合物或组合物相比较短的血浆半寿期。
25.前述任一项权利要求的白蛋白变体或衍生物的融合物,或其缀合物或缔合物或组合物,其中所述融合物或缀合物或缔合物包含一个或多个选自如下的模块:
(i)4-1BB配体,5-螺旋,人C-C趋化因子,人L105趋化因子,命名为huL105_3.的人L105趋化因子,由γ-干扰素诱导的单核因子(MIG),部分CXCR4B蛋白,血小板碱性蛋白(PBP),α1-抗胰蛋白酶,ACRP-30同源物;补体成分C1q C,腺样-表达的趋化因子(ADEC),aFGF;FGF-1,AGF,AGF蛋白,白蛋白,依托泊苷(etoposide),血管他丁(angiostatin),炭疽疫苗,对脑衰蛋白有特异性的抗体,antistasin,抗TGFβ家族抗体,抗凝血酶III(antithrombin III),APM-1;ACRP-30;Famoxin,载脂蛋白物种(apo-lipoprotein species),芳基硫酸酯酶B(Arylsulfatase B),b57蛋白,BCMA,β-血小板球蛋白蛋白(β-TG),bFGF;FGF2,凝血因子,BMP加工酶Furin,BMP-10,BMP-12,BMP-15,BMP-17,BMP-18,BMP-2B,BMP-4,BMP-5,BMP-6,BMP-9,骨形态形成蛋白-2,降钙素(calcitonin),钙激活中性蛋白酶-10a,钙激活中性蛋白酶-10b,钙激活中性蛋白酶-10c,癌症疫苗,羧肽酶,C-C趋化因子,MCP2,CCR5变体,CCR7,CCR7,CD11a Mab,CD137;4-1BB受体蛋白,CD20Mab,CD27,CD27L,CD30,CD30配体,CD33免疫毒素,CD40,CD40L,CD52Mab,Cerebus蛋白,嗜酸细胞活化趋化因子(Chemokine Eotaxin),趋化因子hIL-8,趋化因子hMCP1,趋化因子hMCP1a,趋化因子hMCP1b,趋化因子hMCP2,趋化因子hMCP3,趋化因子hSDF1b,趋化因子MCP-4,趋化因子TECK和TECK变体,趋化因子样蛋白IL-8M1全长和成熟,趋化因子样蛋白IL-8M10全长和成熟,趋化因子样蛋白IL-8M3,趋化因子样蛋白IL-8M8全长和成熟,趋化因子样蛋白IL-8M9全长和成熟,趋化因子样蛋白PF4-414全长和成熟,趋化因子样蛋白PF4-426全长和成熟,趋化因子样蛋白PF4-M2全长和成熟,霍乱疫苗,Chondromodulin样蛋白,c-kit配体;SCF;肥大细胞生长因子;MGF;纤维肉瘤来源的干细胞因子,CNTF及其片段(如CNTFAx15`(AxokineTM)),前或活性形式的凝血因子,胶原蛋白,补体C5Mab,结缔组织活化蛋白-III,CTAA16.88Mab,CTAP-III,CTLA4-Ig,CTLA-8,CXC3,CXC3,CXCR3;CXC趋化因子受体3,cyanovirin-N,Darbepoetin,命名为exodus,命名为huL105_7.,DIL-40,DNA酶,EDAR,EGF受体Mab,ENA-78,内皮他丁(Endostatin),嗜酸细胞活化趋化因子(Eotaxin),上皮嗜中性粒细胞活化蛋白-78,EPO受体;EPOR,红细胞生成素(erythropoietin)(EPO)和EPO模拟物,优托品(Eutropin),Exodus蛋白,因子IX,因子VII,因子VIII,因子X和因子XIII,FAS配体抑制蛋白(DcR3),FasL,FasL,FasL,FGF,FGF-12;成纤维细胞生长因子同源因子-1,FGF-15,FGF-16,FGF-18,FGF-3;INT-2,FGF-4;白树霉素(gelonin),HST-1;HBGF-4,FGF-5,FGF-6;肝素结合分泌的转化因子-2(Heparin bindingsecreted transforming factor-2),FGF-8,FGF-9;神经胶质活化因子,纤维蛋白原(fibrinogen),flt-1,flt-3配体,促卵泡激素α亚基,促卵泡激素β亚基,促卵泡素(Follitropin),Fractalkine,片段,肌纤维蛋白肌钙蛋白I(Troponin I),FSH,半乳糖苷酶(Galactosidase),半乳凝素-4(Galectin-4),G-CSF,GDF-1,基因疗法,神经胶质瘤衍生生长因子,胰高血糖素,胰高血糖素样肽,葡糖脑苷酯酶(Glucocerebrosidase),葡糖氧化酶(glucose oxidase),葡糖苷酶(Glucosidase),Glycodelin-A;黄体酮相关子宫内膜蛋白,GM-CSF,促性腺素(gonadotropin),粒细胞趋化蛋白-2(GCP-2),粒细胞-巨噬细胞集落刺激因子,生长激素,生长相关癌基因α(Growth related oncogene-α)(GRO-α),生长相关癌基因β(Growth related oncogene-β(GRO-β)),生长相关癌基因γ(Growth relatedoncogene-γ(GRO-γ)),hAPO-4;TROY,hCG,乙型肝炎表面抗原,乙型肝炎疫苗,HER2受体Mab,水蛭素(hirudin),HIV gp120,HIV gp41,HIV抑制肽,HIV抑制肽,HIV抑制肽,HIV蛋白酶抑制肽,HIV-1蛋白酶抑制剂,HPV疫苗,人6CKine蛋白,人Act-2蛋白,人脂肪形成抑制因子,人B细胞刺激因子-2受体,人β-趋化因子H1305(MCP-2),人C-C趋化因子DGWCC,人CC趋化因子ELC蛋白,人CC型趋化因子白细胞介素C,人CCC3蛋白,人CCF18趋化因子,命名为SLC(二级淋巴样趋化因子)的人CC-型趋化因子蛋白,人趋化因子β-8短形式(short form),人趋化因子C10,人趋化因子CC-2,人趋化因子CC-3,人趋化因子CCR-2,人趋化因子Ckβ-7,人趋化因子ENA-78,人趋化因子嗜酸细胞活化趋化因子,人趋化因子GROα,人趋化因子GROα,人趋化因子GROβ,人趋化因子HCC-1,人趋化因子HCC-1,人趋化因子I-309,人趋化因子IP-10,人趋化因子L105_3,人趋化因子L105_7,人趋化因子MIG,人趋化因子MIG-β蛋白,人趋化因子MIP-1α,人趋化因子MIP1β,人趋化因子MIP-3α,人趋化因子MIP-3β,人趋化因子PF4,人趋化因子蛋白331D5,人趋化因子蛋白61164,人趋化因子受体CXCR3,人趋化因子SDF1α,人趋化因子SDF1β,人趋化因子ZSIG-35,人Chr19Kine蛋白,人CKβ-9,人CKβ-9,人CX3C 111氨基酸趋化因子,人DNAX白细胞介素-40,人DVic-1C-C趋化因子,人EDIRF I蛋白序列,人EDIRF II蛋白序列,人嗜曙红细胞CC型趋化因子嗜酸细胞活化趋化因子,人嗜曙红细胞-表达的趋化因子(EEC),人快速颤搐骨骼肌肌钙蛋白C(Human fast twitch skeletal muscletroponin C),人快速颤搐骨骼肌肌钙蛋白I,人快速颤搐骨骼肌肌钙蛋白亚基C,人快速颤搐骨骼肌肌钙蛋白亚基I蛋白,人快速颤搐骨骼肌肌钙蛋白亚基T,人快速颤搐骨骼肌肌钙蛋白T,人胎儿脾脏表达的趋化因子,FSEC,人GM-CSF受体,人gro-α趋化因子,人gro-β趋化因子,人gro-γ趋化因子,人IL-16蛋白,人IL-1RD10蛋白序列,人IL-1RD9,人IL-5受体α链,人IL-6受体,人IL-8受体蛋白hIL8RA,人IL-8受体蛋白hIL8RB,人IL-9受体蛋白,人IL-9受体蛋白变体#3,人IL-9受体蛋白变体片段,人IL-9受体蛋白变体片段#3,人白细胞介素1δ,人白细胞介素10,人白细胞介素10,人白细胞介素18,人白细胞介素18衍生物,人白细胞介素-1β前体,人白细胞介素-1β前体,人白细胞介素-1受体辅助蛋白,人白细胞介素-1受体拮抗剂β,人白细胞介素-1型-3受体,人白细胞介素-10(前体),人白细胞介素-10(前体),人白细胞介素-11受体,人白细胞介素-12 40kD亚基,人白细胞介素-12β-1受体,人白细胞介素-12β-2受体,人白细胞介素-12p35蛋白,人白细胞介素-12p40蛋白,人白细胞介素-12受体,人白细胞介素-13α受体,人白细胞介素-13β受体,人白细胞介素-15,来自克隆P1的人白细胞介素-15受体,人白细胞介素-17受体,人白细胞介素-18蛋白(IL-18),人白细胞介素-3,人白细胞介素-3受体,人白细胞介素-3变体,人白细胞介素-4受体,人白细胞介素-5,人白细胞介素-6,人白细胞介素-7,人白细胞介素-7,人白细胞介素-8(IL-8),人胞内IL-1受体拮抗剂,人IP-10和HIV-1gp120超变区融合蛋白,人IP-10和人Muc-1核心表位(VNT)融合多肽,人肝和活化调节趋化因子(LARC),人Lkn-1全长和成熟蛋白,人乳腺相关趋化因子(MACK)蛋白全长和成熟,人成熟趋化因子Ckβ-7,人成熟gro-α,用于治疗败血病的人成熟gro-γ多肽,人MCP-3和人Muc-1核心表位(VNT)融合蛋白,人MI10蛋白,人MI1A蛋白,人单核细胞化学引诱物因子hMCP-1,人单核细胞化学引诱物因子hMCP-3,人单核细胞趋化前蛋白(MCPP)序列,人神经趋化因子(neurotactin)趋化因子样域,人非ELRCXC趋化因子H174,人非ELR CXC趋化因子IP10,人非ELR CXC趋化因子Mig,人PAI-1突变体,具有IL-16活性的人蛋白,具有IL-16活性的人蛋白,人二级淋巴样趋化因子(SLC),人SISD蛋白,人STCP-1,人基质细胞衍生趋化因子,SDF-1,人T细胞混合淋巴细胞反应表达的趋化因子(TMEC),人胸腺和活化调节细胞因子(TARC),人胸腺表达的,人TNF-α,人TNF-α,人TNF-β(LT-α),人类型CC趋化因子嗜酸细胞活化趋化因子3蛋白序列,人类型II白细胞介素-1受体,人野生型白细胞介素-4(hIL-4)蛋白,人ZCHEMO-8蛋白,人源化抗VEGF抗体,及其片段,人源化抗VEGF抗体,及其片段,透明质酸酶(Hyaluronidase),ICE 10kD亚基,ICE 20kD亚基,ICE 22kD亚基,艾杜糖醛酸-2-硫酸酯酶(Iduronate-2-sulfatase),艾杜糖苷酸酶(Iduronidase),IL-1α,IL-1β,IL-1抑制剂(IL-1i),IL-1成熟,IL-10受体,IL-11,IL-11,IL-12p40亚基,IL-13,IL-14,IL-15,IL-15受体,IL-17,IL-17受体,Il-17受体,Il-17受体,IL-19,IL-1i片段,IL1-受体拮抗剂,IL-21(TIF),含IL-3的融合多肽,IL-3突变体蛋白,IL-3变体,IL-3变体,IL-4,IL-4突变蛋白,IL-4突变蛋白Y124G,IL-4突变蛋白Y124X,IL-4突变蛋白,Il-5受体,IL-6,Il-6受体,IL-7受体克隆,IL-8受体,IL-9成熟蛋白变体(Met117型),免疫球蛋白或基于免疫球蛋白的分子,或任一者的片段(例如Small Modular ImmunoPharmaceuticalTM(“SMIP”)或dAb,Fab’片段,F(ab’)2,scAb,scFv或scFv片段),包括但不限于纤溶酶原,流感疫苗,抑制素(Inhibin)α,抑制素β,胰岛素,胰岛素样生长因子,整联蛋白Mab,间-α胰蛋白酶抑制剂,间-α胰蛋白酶抑制剂,干扰素γ-诱导蛋白(IP-10),干扰素(如干扰素α种和亚种,干扰素β种和亚种,干扰素γ种和亚种),干扰素(如干扰素α种和亚种,干扰素β种和亚种,干扰素γ种和亚种),白细胞介素6,白细胞介素8(IL-8)受体,白细胞介素8受体B,白细胞介素-1α,白细胞介素-2受体相关蛋白p43,白细胞介素-3,白细胞介素-4突变蛋白,白细胞介素-8(IL-8)蛋白,白细胞介素-9,白细胞介素-9(IL-9)成熟蛋白(Thr117型),白细胞介素(如IL10,IL11和IL2),白细胞介素(如IL10,IL11和IL2),日本脑炎疫苗,Kalikrein抑制剂,角质细胞生长因子,Kunitz域蛋白(如抑肽酶(aprotinin),淀粉状前体蛋白和WO 03/066824中所述那些,具有或不具有白蛋白融合),Kunitz域蛋白(如抑肽酶(aprotinin),淀粉状蛋白前体蛋白和WO 03/066824中所述那些,具有或不具有白蛋白融合),LACI,乳铁蛋白(lactoferrin),潜在的TGF-β结合蛋白II,来普汀/瘦素(leptin),肝表达的趋化因子-1(LVEC-1),肝表达的趋化因子-2(LVEC-2),LT-α,LT-β,黄体化激素,莱姆病疫苗,淋巴细胞趋化因子(Lymphotactin),巨噬细胞衍生的趋化因子类似物MDC(n+1),巨噬细胞衍生的趋化因子类似物MDC-eyfy,巨噬细胞衍生的趋化因子类似物MDC-yl,巨噬细胞衍生的趋化因子,MDC,巨噬细胞衍生的趋化因子(MDC),Maspin;蛋白酶抑制剂5,MCP-1受体,MCP-1a,MCP-1b,MCP-3,MCP-4受体,M-CSF,黑素瘤抑制蛋白,膜结合蛋白,Met117人白细胞介素9,MIP-3α,MIP-3β,MIP-γ,MIRAP,修饰的Rantes,单克隆抗体,MP52,突变白细胞介素6S176R,肌纤维收缩蛋白肌钙蛋白I,利钠肽(Natriuretic Peptide),神经生长因子-β,神经生长因子-β2,神经菌毛素(Neuropilin)-1,神经菌毛素-2,神经趋化因子,神经营养因子-3,神经营养因子-4,神经营养因子-4a,神经营养因子-4b,神经营养因子-4c,神经营养因子-4d,嗜中性粒细胞活化肽-2(NAP-2),NOGO-66受体,NOGO-A,NOGO-B,NOGO-C,命名为PTEC的新β-趋化因子,N-端修饰趋化因子GroHEK/hSDF-1α,N-端修饰趋化因子GroHEK/hSDF-1β,N-端修饰趋化因子met-hSDF-1α,N-端修饰趋化因子met-hSDF-1β,OPGL,成骨蛋白-1;OP-1;BMP-7,成骨蛋白-2,OX40;ACT-4,OX40L,催产素(神经垂体素运载蛋白I),甲状旁腺素,Patched,Patched-2,PDGF-D,百日咳类毒素(Pertussis toxoid),垂体表达的趋化因子(PGEC),胎盘生长因子,胎盘生长因子-2,纤溶酶原活化物抑制剂-1;PAI-1,纤溶酶原活化物抑制剂-2;PAI-2,纤溶酶原活化物抑制剂-2;PAI-2,血小板衍生的生长因子,血小板衍生的生长因子Bv-sis,血小板衍生的生长因子前体A,血小板衍生的生长因子前体B,血小板Mab,血小板衍生的内皮细胞生长因子(PD-ECGF),血小板衍生的生长因子A链,血小板衍生的生长因子B链,用于治疗败血病的多肽,前原载脂蛋白“米兰”变体(Preproapolipoprotein“milano”variant),前原载脂蛋白“巴黎”变体,前凝血酶(pre-thrombin),灵长类CC趋化因子"ILINCK",灵长类CXC趋化因子"IBICK",胰岛素原,促乳素(Prolactin),促乳素2,prosaptide,蛋白酶抑制肽,蛋白C,蛋白S,凝血酶原,尿激酶原,RANTES,RANTES 8-68,RANTES 9-68,RANTES肽,RANTES受体,重组白细胞介素-16,抵抗素(Resistin),局限曲菌素(restrictocin),逆转录病毒蛋白酶抑制剂,蓖麻毒蛋白(ricin),轮状病毒疫苗,RSV Mab,皂草素(saporin),八叠球菌(sarcin),分泌和跨膜多肽,分泌和跨膜多肽,血清胆碱酯酶,血清蛋白(如凝血因子),可溶性BMP受体激酶蛋白-3,可溶性VEGF受体,干细胞抑制因子,葡萄球菌疫苗,基质衍生的因子-1α,基质衍生的因子-1β,物质P(速激肽),T1249肽,T20肽,T4内切核酸酶,TACI,Tarc,TGF-β1,TGF-β2,Thr117人白细胞介素9,凝血酶,促血小板生成素(thrombopoietin),促血小板生成素衍生物1,促血小板生成素衍生物2,促血小板生成素衍生物3,促血小板生成素衍生物4,促血小板生成素衍生物5,促血小板生成素衍生物6,促血小板生成素衍生物7,胸腺表达的趋化因子(TECK),促甲状腺激素(Thyroid stimulating Hormone),蜱抗凝肽,Tim-1蛋白,TNF-α前体,TNF-R,TNF-RII;TNF p75受体;死亡受体,tPA,转铁蛋白(transferrin),转化生长因子β,肌钙蛋白肽,截短的单核细胞趋化蛋白2(6-76),截短的单核细胞趋化蛋白2(6-76),截短的RANTES蛋白(3-68),肿瘤坏死因子,尿酸氧化酶,尿激酶,加压素(Vasopressin)(神经垂体素运载蛋白II),VEGF R-3;flt-4,VEGF受体;KDR;flk-1,VEGF-110,VEGF-121,VEGF-138,VEGF-145,VEGF-162,VEGF-165,VEGF-182,VEGF-189,VEGF-206,VEGF-D,VEGF-E;VEGF-X,von Willebrand因子,野生型单核细胞趋化蛋白2,野生型单核细胞趋化蛋白2,ZTGF-β9;
(ii)化疗药如:13-顺-视黄酸(13-cis-Retinoic Acid),2-CdA,2-氯脱氧腺苷(2-Chlorodeoxyadenosine),5-阿扎胞苷(5-Azacitidine),5-氟尿嘧啶(5-Fluorouracil),5-FU,6-巯基嘌呤(6-Mercaptopurine),6-MP,6-TG,6-硫代鸟嘌呤(6-Thioguanine),A,Abraxane,放线菌素-D(Actinomycin-D),阿霉素阿地白介素(Aldesleukin),阿仑单抗(Alemtuzumab),ALIMTA,阿利维A酸(Alitretinoin),爱克兰全反视黄酸(All-transretinoic Acid),α干扰素,六甲蜜胺(Altretamine),甲氨蝶呤(Amethopterin),氨磷汀(Amifostine),氨鲁米特(Aminoglutethimide),阿那格雷(Anagrelide),阿那曲唑(Anastrozole),阿糖胞苷(Arabinosylcytosine),Ara-C, 三氧化二砷(Arsenic Trioxide),天冬酰胺酶(Asparaginase),ATRA,阿扎胞苷(Azacitidine),BCG,BCNU,贝伐单抗(Bevacizumab),贝沙罗汀(Bexarotene),比卡鲁胺(Bicalutamide),BiCNU,博来霉素(Bleomycin),Bortezomib,白消安(Busulfan),C225,亚叶酸钙(CalciumLeucovorin),喜树碱-11(Camptothecin-11),卡培他滨(Capecitabine),CaracTM,卡铂(Carboplatin),卡莫司汀(Carmustine),CarmustineWafer,康士德CC-5013,CCNU,CDDP,CeeNU,西妥昔单抗(Cetuximab),苯丁酸氮芥(Chlorambucil),顺铂(Cisplatin),亚叶酸因子(CitrovorumFactor),克拉屈滨(Cladribine),可的松(Cortisone),CPT-11,环磷酰胺(Cyclophosphamide),阿糖胞苷(Cytarabine),阿糖胞苷脂质体(CytarabineLiposomal),赛德萨达卡巴嗪(Dacarbazine),Dacogen,更生霉素(Dactinomycin),Darbepoetin Alfa,Dasatinib,柔红霉素(Daunomycin),柔红霉素(Daunorubicin),盐酸柔红霉素(Daunorubicin Hydrochloride),柔红霉素脂质体(Daunorubicin Liposomal),地卡特隆(Decadron),地西他滨(Decitabine),地尼白介素-毒素连接物(Denileukindiftitox),DepoCytTM,地塞米松(Dexamethasone),醋酸地塞米松(Dexamethasoneacetate),地塞米松磷酸钠(Dexamethasone Sodium Phosphate),地塞米松(Dexasone),右雷佐生(Dexrazoxane),DHAD,DIC,Diodex,多西紫杉醇(Docetaxel),多柔比星(Doxorubicin),多柔比星脂质体(Doxorubicin liposomal),DroxiaTM,DTIC,EligardTM,EllenceTM,乐沙定(Eloxatin)TM,表柔比星(Epirubicin),阿法依伯汀(Epoetin alfa),ErbituxTM,Erlotinib,欧文氏菌属L-天冬酰胺酶(Erwinia L-asparaginase),雌莫司汀(Estramustine),氨磷汀(Ethyol),依托泊苷(Etoposide),磷酸依托泊苷(Etoposide Phosphate),依西美坦(Exemestane),法乐通 非格司亭(Filgrastim),氟尿苷(Floxuridine),氟达拉滨(Fludarabine),氟尿嘧啶(Fluorouracil),氟尿嘧啶(Fluorouracil)(乳膏),氟甲睾酮(Fluoxymesterone),氟他胺(Flutamide),亚叶酸(Folinic Acid),氟维司群(Fulvestrant),G-CSF,Gefitinib,吉西他滨(Gemcitabine),吉姆单抗(Gemtuzumab)奥佐米星(ozogamicin),健择GleevecTM,Wafer,GM-CSF,戈舍瑞林(Goserelin),粒细胞集落刺激因子,粒细胞巨噬细胞集落刺激因子,地塞米松(Hexadrol),克瘤灵六甲蜜胺(Hexamethylmelamine),HMM,和美新羟基脲醋酸氢化可的松氢化可的松(Hydrocortisone),氢化可的松磷酸钠(Hydrocortisone Sodium Phosphate),氢化可的松琥珀酸钠(Hydrocortisone Sodium Succinate),氢化可的松磷酸(Hydrocortone Phosphate),羟脲(Hydroxyurea),替伊莫单抗(Ibritumomab),替伊莫单抗(Ibritumomab Tiuxetan),伊达比星(Idarubicin),IFN-α,异环磷酰胺(Ifosfamide),IL-11,IL-2,甲磺酸伊马替尼(Imatinib mesylate),咪唑羧酰胺(Imidazole Carboxamide),干扰素alfa,干扰素Alfa-2b(PEG缀合物),白细胞介素-2,白细胞介素-11,Intron(干扰素alfa-2b),伊立替康(Irinotecan),异维A酸(Isotretinoin),Lapatinib,L-天冬酰胺酶,LCR,Lenalidomide,来曲唑(Letrozole),亚叶酸钙(Leucovorin),苯丁酸氮芥(Leukeran),LeukineTM,亮丙瑞林(Leuprolide),长春新碱(Leurocristine),LeustatinTM,脂质体Ara-C,Liquid洛莫司汀(Lomustine),L-PAM,L-沙可来新(L-Sarcolysin),LupronM,Maxidex,氮芥(Mechlorethamine),盐酸氮芥(MechlorethamineHydrochloride),美卓乐梅格施甲地孕酮(Megestrol),醋酸甲地孕酮(Megestrol Acetate),美法仑(Melphalan),巯嘌呤(Mercaptopurine),美司钠(Mesna),MesnexTM,甲氨蝶呤(Methotrexate),甲氨蝶呤钠(Methotrexate Sodium),甲泼尼龙(Methylprednisolone),丝裂霉素(Mitomycin),丝裂霉素-C(Mitomycin-C),米托蒽醌(Mitoxantrone),MTC,MTX,氮芥(Mustine),马利兰MylocelTM,诺维本萘拉滨(Nelarabine),NeulastaTM,优保津尼鲁米特(Nilutamide),氮芥(Nitrogen Mustard),能灭瘤奥曲肽(Octreotide),醋酸奥曲肽(Octreotide acetate),安可平 OnxalTM,Oprevelkin,奥沙利铂(Oxaliplatin),紫杉醇(Paclitaxel),蛋白结合紫杉醇,帕米磷酸(Pamidronate),Panitumumab,伯尔定PEG干扰素,培门冬酶(Pegaspargase),PEG菲格司亭(Pegfilgrastim),PEG-INTRONTM,PEG-L-天冬酰胺酶,培美曲塞(PEMETREXED),喷司他丁(Pentostatin),苯丙氨酸氮芥(Phenylalanine Mustard),泼尼松龙(Prednisolone),泼尼松(Prednisone),丙卡巴肼(Procarbazine),具有卡莫司汀(Carmustine)植入物的Prolifeprospan 20,R,雷洛昔芬(Raloxifene),利妥昔单抗(Rituximab),(干扰素Alfa-2a),柔红霉素盐酸盐(Rubidomycin hydrochloride),善得定Sandostatin沙格司亭(Sargramostim),Sorafenib,SPRYCELTM,STI-571,链佐星(Streptozocin),SU11248,Sunitinib,他莫昔芬(Tamoxifen),泰素泰索帝替莫唑胺(Temozolomide),替尼泊苷(Teniposide),TESPA,沙利度胺(Thalidomide),硫鸟嘌呤(Thioguanine),ThioguanineThiophosphoamide,塞替派(Thiotepa),托泊替康(Topotecan),托瑞米芬(Toremifene),托西莫单抗(Tositumomab),曲妥单抗(Trastuzumab),维A酸(Tretinoin),TrexallTM,TSPA,VCR,VectibixTM,凡毕士ViadurTM,长春碱(Vinblastine),硫酸长春碱(Vinblastine Sulfate),Vincasar长春新碱(Vincristine),长春瑞滨(Vinorelbine),酒石酸长春瑞滨(Vinorelbine tartrate),VLB,VM-26,Vorinostat,VP-16,威猛希罗达 ZevalinTM,诺雷德唑来膦酸(Zoledronic acid),Zolinza,放射性药品如:碳-11,碳-14,铬-51,钴-57,钴-58,铒-169,氟-18,镓-67,金-198,铟-111,铟-113m,碘-123,碘-125,碘-131,铁-59,氪-81m,氮-13,氧-15,磷-32,铼-186,铷-82,钐-153,硒-75,锶-89,锝-99m,铊-201,氚,氙-127,氙-133,钇-90;和/或
(iii)显像剂如钆,磁铁矿/磁石(magnetite),锰,锝,I125,I131,P32,Tl201,碘帕醇(Iopamidol),PET-FDG。
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US10233228B2 (en) | 2019-03-19 |
KR20130070576A (ko) | 2013-06-27 |
EP2556087A1 (en) | 2013-02-13 |
JP5969458B2 (ja) | 2016-08-17 |
US20130028930A1 (en) | 2013-01-31 |
CN102939304A (zh) | 2013-02-20 |
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CN102939304B (zh) | 2017-04-19 |
WO2011124718A1 (en) | 2011-10-13 |
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