CN101292036A - 用于重组表达多肽的方法 - Google Patents
用于重组表达多肽的方法 Download PDFInfo
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Abstract
本发明描述了用于在真核宿主细胞中重组产生异源多肽的方法。该宿主细胞包含表达质粒，其中该表达质粒在5’至3’方向包含a)启动子，b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1，c)编码第二多肽的核酸，其中该核酸包含编码异源多肽的核酸、编码接头的核酸和编码免疫球蛋白片段的核酸，以及d)包含聚腺苷酸化信号的3’非翻译区。还描述了质粒和配套元件。
Description
本发明涉及用于在真核细胞中重组表达多肽的方法。
发明背景
用于产生重组多肽的表达系统在现有技术领域中是众所周知的并且例如由Marino，M.H.，Biopharm.2(1989)18-33；Goeddel，D.V.等，MethodsEnzymol.185(1990)3-7；Wurm，F.和Bernard，A.，Curr.Opin.Biotechnol.10(1999)156-159描述。用于药物应用中的多肽优选在哺乳动物细胞如CHO细胞、NS0细胞、Sp2/0细胞、COS细胞、HEK细胞、BHK细胞等中产生。表达质粒的必需元件是原核质粒增殖单元，例如对于大肠杆菌(E.coli)而言，包含复制起点和选择标记、真核选择标记和用以表达目的结构基因的一个或多个表达盒，其中每个表达盒包含启动子、结构基因和转录终止子(包括聚腺苷酸化信号)。对于哺乳动物细胞中的瞬时表达，可以包括哺乳动物复制起点，如SV40 Ori或OriP。就启动子而言，可以选择组成型启动子或诱导型启动子。对于优化的转录，可以在5′非翻译区中包括Kozak序列。对于mRNA加工，尤其mRNA剪接及转录终止，取决于结构基因的组织形式(外显子/内含子组织形式)，可以包括mRNA剪接信号以及聚腺苷酸化信号。
基因的表达以瞬时表达或永久表达而实施。目的多肽通常是分泌性多肽并且因此含有氨基端延伸物(也称作信号序列)，此延伸物是使多肽穿过细胞运输/分泌至细胞外介质所必需的。
通常，信号序列可以衍生自编码分泌性多肽的任何基因。若使用异源信号序列，它优选是由宿主细胞识别并加工(即由信号肽酶切割)的一种信号序列。例如对于酵母中的分泌，待表达的异源基因的天然信号序列可以由衍生自分泌型基因的同源酵母信号序列置换，如酵母转化酶信号序列、α因子前导序列(包括酵母属(Saccharomyces)、克鲁维酵母属(Kluyveromyces)、毕赤酵母属(Pichia)和汉逊酵母属(Hansenula)的α因子前导序列，其中克鲁维酵母属α因子前导序列在US 5,010,182中描述)、酸性磷酸酶信号序列或白色假丝酵母(C.albicans)葡糖淀粉酶信号序列(EP 0362 179)。在哺乳动物细胞表达中，目的蛋白质的天然信号序列是令人满意的，虽然其它的哺乳动物信号序列可以是适用的，如来自相同物种或相关物种的分泌性多肽的信号序列，例如对免疫球蛋白而言，来自人或小鼠来源的分泌信号序列以及病毒的分泌信号序列，例如单纯疱疹病毒糖蛋白D信号序列。编码此种前节段(presegment)的DNA片段以符合可读框方式与编码目的多肽的DNA片段连接。
在WO 98/28427中，报道以遗传或化学方式制备的融合蛋白，其包含与OB蛋白质氨基端部分融合的Fc免疫球蛋白区、衍生物或类似物。在WO 03/035892中给出了包含羧基端蛋白质输入序列及氨基端货物区的嵌合分子，即抗体融合物或融合蛋白。
在US 2003/0049227中，报道用于通过施用免疫细胞因子而在哺乳动物中诱导抗肿瘤的杀细胞性免疫应答的方法，其中所述的免疫细胞因子是包含氨基端的免疫球蛋白部分和羧基端的细胞因子部分的融合蛋白。
WO 91/16437报道在哺乳动物循环系统中稳定的可溶性重组融合蛋白，该融合蛋白包含如此多肽，其含有对靶分子的识别位点如补体受体位点，并与免疫球蛋白链的氨基末尾端连接。在US 2003/0103984中报道由抗体和具有生物学活性的肽制成的融合蛋白。
在US 2004/0033511中报道了抗体-细胞因子融合蛋白以及在US2004/0180035中报道了抗体-细胞因子免疫缀合物。在WO 94/26910中报道了包含多花白树毒蛋白和抗体的免疫毒素。
发明概述
本发明包含用于在包含表达质粒的真核宿主细胞中重组产生异源多肽的方法，其中所述的表达质粒在5’至3’方向包含a)启动子，b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1，c)编码第二多肽的核酸，其中该核酸包含编码异源多肽的核酸、编码接头的核酸和编码免疫球蛋白片段的核酸，以及d)包含聚腺苷酸化信号的3’非翻译区。该方法还包括导入表达质粒至培养于适合表达第二多肽的条件下的真核宿主细胞中，以及将第二多肽从培养基中回收。
在本发明的一个实施方案中，编码第二多肽的核酸含有位于编码异源多肽的核酸5’位置的编码单个氨基酸或二肽或氨基酸序列QIWNN(SEQID NO：472)的肽或其片段的额外核酸。
在另一个实施方案中，免疫球蛋白片段从IgG或从IgE得到。
在又一个实施方案中，真核细胞是哺乳动物细胞，尤其是CHO细胞、NS0细胞、Sp2/0细胞、COS细胞、K562细胞、BHK细胞、PER.C6细胞或HEK细胞。
又在另一个实施方案中，接头是选自SEQ ID NO：06、07、08、09、10、139、140、554、555、556和557的肽或多肽。
在另一个实施方案中，免疫球蛋白片段包含a)天然存在的或合成的免疫球蛋白的重链或轻链的羧基端恒定结构域，即重链的CH1-、铰合区、CH2-和CH3-结构域或轻链的CL-结构域。额外地，免疫球蛋白片段包含可变结构域片段。
在另一个实施方案中，可变结构域片段是其中可变结构域的1-6个氨基酸被缺失的免疫球蛋白重链可变结构域或轻链可变结构域。
在又一个实施方案中，可变结构域的1-6个区域(FR1、FR2、FR3、CDR1、CDR2、CDR3)被缺失。
在又一个实施方案中，可变结构域被缺失。
在另一个实施方案中，免疫球蛋白片段衍生自天然存在的免疫球蛋白或其变体。
在又一个实施方案中，免疫球蛋白片段衍生自至少部分合成的免疫球蛋白。
仍在本发明的另一个实施方案中，异源多肽的氨基酸序列有5-500个氨基酸残基，更优选10-350个氨基酸残基，最优选15-150个氨基酸残基。
本发明还包含质粒，该质粒在5’至3’方向包含a)启动子，b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1，c)编码第二多肽的核酸，其中该核酸包含编码异源多肽的核酸、编码接头的核酸和编码免疫球蛋白片段的核酸，以及d)包含聚腺苷酸化信号的3’非翻译区。
本发明还包含用来制备质粒的配套元件(kit)，用于在包含所述质粒的真核细胞中表达异源多肽，其在5’至3’方向包含a)启动子，b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列选自SEQ ID NO：36、37、319、320、321、322、323、324、325、326、327、328和329，c)编码第二多肽的核酸，该核酸包含i)编码氨基酸序列QIWNN(SEQ ID NO：472)的肽或其氨基端部分的核酸，ii)包含至少一个限制性切割位点的克隆位点，适用于插入编码异源多肽的核酸，iii)编码选自SEQ ID NO：06、07、08、09、10、139、140、554、555、556和557的接头的核酸，和iv)编码免疫球蛋白片段的核酸，以及d)包含聚腺苷酸化信号的3’非翻译区。
发明详述
本发明包含用于在包含表达载体的真核宿主细胞中重组表达目的异源多肽的方法，其中所述表达载体含有合适的启动子、转录终止子、选择标记、编码多肽的核酸序列和编码信号序列的核酸序列，其中编码信号序列的核酸序列根据后续多肽的头两个氨基酸选自表1。编码异源多肽的核酸序列始于编码信号序列的核酸序列的终点后的15个核苷酸中。编码异源多肽的核酸序列可以插入免疫球蛋白FR1区中、免疫球蛋白VL区中或免疫球蛋白第一恒定结构域中或它可以替换全部或部分的免疫球蛋白FR1区、免疫球蛋白VL区或免疫球蛋白第一恒定结构域。
在本发明范围中所用的一些术语定义如下：
“核酸分子”如本文中所用，指天然存在的或者部分或完全地非天然存在的编码多肽的核酸，其中所述多肽可以重组地产生。核酸分子可以由分离的或由化学手段合成的DNA片段组建。核酸分子可以整合至另一种核酸中，例如整合于表达质粒中或真核宿主细胞的基因组/染色体中。质粒包括穿梭载体及表达载体。通常，质粒还包含原核增殖单元，该单元含有分别用于细菌中载体复制和选择的复制起点(例如ColE1复制起点)和选择标记(例如氨苄青霉素或四环素抗性基因)。
“表达盒”指核酸序列，其含有对至少所含有的结构基因在细胞中表达及分泌所必需的元件。
核酸分子同样地通过由分别的核苷酸组成的其核酸序列表征或/和由该核酸分子所编码的氨基酸序列表征。
“基因”指例如对肽、多肽或蛋白质在染色体或在质粒上的表达必需的节段。除编码区之外，基因还包含其它功能性元件，包括启动子、内含子和终止子。
“结构基因”指基因的无信号序列的编码区。
在本申请中可互换加以使用的“抗性基因”或“选择标记”是如此基因，其允许携带该基因的细胞在相应选择剂存在下受到特异性选择。有用的阳性选择标记是抗生素抗性基因。这种选择标记允许以抗生素抗性基因转化的宿主细胞在相应抗生素存在下受到阳性选择；非转化宿主细胞将不能在选择性培养条件下生长或存活。选择标记可以是阳性的、阴性的或双功能性的。阳性选择标记允许选择携带该标记的细胞，而阴性选择标记允许携带该标记的细胞受到选择性消除。通常，选择标记在宿主细胞中赋予耐药性或补偿代谢缺陷或异化缺陷。用于真核细胞的抗性基因包括例如编码氨基糖甙类磷酸转移酶(APH)如潮霉素磷酸转移酶(hyg)、新霉素和G418APH、二氢叶酸还原酶(DHFR)、胸苷激酶(tk)、谷氨酰胺合成酶(GS)、天冬酰胺合成酶、色氨酸合成酶(吲哚)、组氨醇脱氢酶(组氨醇D)的基因和编码对嘌呤霉素、博来霉素、腐草霉素、氯霉素、Zeocin和霉酚酸抗性的基因。其它标记基因在WO 92/08796和WO 94/28143中描述。
“调节元件”如本文中所用，指以顺式方式存在的核苷酸序列，其对转录和/或翻译包含编码目的多肽的核酸序列的基因为必需。转录调节元件通常包含位于待表达的结构基因序列上游的启动子、转录起始位点和终止位点以及聚腺苷酸化信号序列。术语“转录起始位点”指与基因中掺入初级转录物即mRNA前体的第一个核酸相对应的核酸碱基；转录起始位点可以与启动子序列重叠。术语“转录终止位点”指通常位于待转录目的基因3′端的引起RNA聚合酶终止转录的核苷酸序列。聚腺苷酸化信号序列或聚腺苷酸添加信号提供信号用于在真核mRNA 3′端的特定位点处切割并以转录后方式添加约100-200个腺嘌呤核苷酸的核心序列(聚A尾)至已切割的3′端。聚腺苷酸化信号序列可以包含位于切割位点上游约10-30个核苷酸的共有序列AATAAA。
为产生分泌性多肽，目的结构基因包括编码信号序列/前导肽的DNA节段。信号序列指导新合成的多肽抵达并穿过ER膜，于此处多肽可以被通向分泌途径。信号序列在蛋白质跨越ER膜期间由信号肽酶切去。就信号序列的功能而言，被宿主细胞的分泌装置识别是必需的。因此，所用的信号序列必须被宿主细胞分泌装置的蛋白质和酶识别。
翻译调节元件包括翻译起始密码子(AUG)和终止密码子(TAA、TAG或TGA)。在某些构建体中可以包括内部核糖体进入位点(IRES)。
“启动子”指控制与其有效连接的基因/结构基因或核酸序列转录的多核苷酸序列。启动子包括用于RNA聚合酶结合并启动转录的信号。所用的启动子将在宿主细胞的如此细胞类型中有功能，其中在所述细胞类型中所选择序列的表达是想要得到的。多种启动子(包括来自多种不同来源的组成型、诱导型和阻遏型启动子)是本领域众所周知(并且在数据库如GenBank中得到鉴定)并且可作为克隆的多核苷酸获得或可在此多核苷酸中获得(例如来自如ATCC的保藏物以及其它商业来源或个人来源)。“启动子”包含指导结构基因转录的核苷酸序列。通常，启动子位于基因的5′非编码区或非翻译区，接近于结构基因的转录起点。启动子中发挥转录起始功能的序列元件常常以共有核苷酸序列为特征。这些启动子元件包括RNA聚合酶结合位点、TATA序列、CAAT序列、分化特异性元件(DSE；McGehee，R.E.等，Mol.Endocrinol.7(1993)551)、环AMP应答元件(CRE)、血清应答元件(SRE；Treisman，R.，Seminars in Cancer Biol.1(1990)47)、糖皮质激素应答元件(GRE)和用于其它转录因子的结合位点，如CRE/ATF(O′Reilly、M.A.，等，J.Biol.Chem.267(1992)19938)、AP2(Ye，J.，等，J.Biol.Chem.269(1994)25728)、SP1、cAMP应答元件结合蛋白(CREB；Loeken，M.R.，Gene Expr.3(1993)253)和八聚体因子(通常见Watson等编辑，Molecular Biology of the Gene，第四版(TheBenjamin/Cummings Publishing Company，Inc.1987)以及Lemaigre，F.P.和Rousseau，G.G.，Biochem.J.303(1994)1-14)。若启动子是诱导型启动子，则对诱导剂应答而增加转录速率。相反若启动子是组成型启动子，则转录速率不受诱导剂调节。阻遏型启动子也是已知的。例如c-fos启动子在生长激素结合至细胞表面的生长激素受体时受到特异性激活。四环素(tet)调节的表达可以通过由例如后接2个Tet操纵基因位点的CMV启动子组成的人工杂合启动子实现。Tet阻遏物结合至2个Tet操纵基因位点上并阻断转录。在添加诱导物四环素后，Tet阻遏物自Tet操纵基因位点释放并且转录继续(Gossen，M.和Bujard，H.，PNAS 89(1992)5547-5551)。对于其它诱导型启动子，包括金属硫蛋白启动子和热休克启动子，见例如Sambrook等(见上文)和Gossen等，Curr.Opin.Biotech.5(1994)516-520。在因高水平表达而已鉴定为强启动子的真核生物启动子当中有SV40早期启动子、腺病毒主要晚期启动子、小鼠金属硫蛋白-I启动子、劳斯肉瘤病毒长末端重复序列、中国仓鼠(Chinese hamster)延伸因子1α(CHEF-1，见例如US 5,888,809)、人EF-1α启动子、遍在蛋白启动子和人巨细胞病毒立即早期启动子(CMV IE).
“启动子”可以是组成型的或诱导型的。增强子(即作用于启动子以增加转录的顺式作用DNA元件)可能对与启动子联合发挥作用以增加仅用启动子所得到的表达水平是必需的，并且可以作为转录调节元件而包括。含有启动子的多核苷酸节段往往也包括增强子序列(例如CMV或SV40)。
“增强子”如本文中所用，指增强与其有效连接的基因或编码序列转录的多核苷酸序列。与启动子不同，增强子对方向和位置是相对不依赖的并且发现它位于转录单位的5′或3′(Lusky，M.，等，Mol.Cell Bio.3(1983)1108)、在内含子(Banerji，J.，等，Cell 33(1983)729)中以及在编码序列中(Osborne，T.F.等，Mol.Cell Bio.4(1984)1293)。因此，增强子可以置于转录起点的上游或下游，或距离启动子非常远，当然在实践中增强子可以与启动子物理性或功能性地重叠。包括来自多种不同来源的多种增强子是本领域众所周知(并且在数据库如GenBank中得到鉴定)并且可作为克隆的多核苷酸获得或可在此多核苷酸中获得(例如来自如ATCC的保藏物以及其它商业来源或个人来源)。很多含有启动子序列的多核苷酸(如常用的CMV启动子)也包含增强子序列。例如，以上所列的全部强启动子也可以含有强增强子(见例如Bendig，M.M.，Genetic Engineering 7(1988)91-127)。
“内部核糖体进入位点”或“IRES”描述在动物细胞中不依赖于IRES的基因5′而功能性促进翻译起始并允许从一个转录物中翻译两个顺反子(可读框)的序列。IRES为紧邻其下游(下游在本文中与3′可互换地使用)的可读框翻译提供独立的核糖体进入位点。与可以为多顺反子(即编码从mRNA上依次受到翻译的数种不同多肽)的细菌mRNA不同，大多数的动物细胞mRNA是单顺反子的并且编码合成仅一种蛋白质。借助真核细胞中的多顺反子转录物，翻译将从最5′端翻译起点起始，终止于第一终止密码子，并且转录物将从核糖体释放，导致仅翻译mRNA中编码的首个多肽。在真核细胞中，具有与转录物中第二可读框或后续可读框有效连接的IRES的多顺反子转录物允许依次翻译下游的可读框以产生由相同转录物编码的一种或多种多肽。先前已经描述IRES元件在载体构建中的用途，见例如Pelletier，J.，等，Nature 334(1988)320-325；Jang，S.K.，等，J.Virol.63(1989)1651-1660；Davies，M.V.，等，J.Virol.66(1992)1924-1932；Adam，M.A.，等，J.Virol.65(1991)4985-4990；Morgan，R.A.，等，Nucl.Acids Res.20(1992)1293-1299；Sugimoto，Y.，等，Biotechnology 12(1994)694-698；Ramesh，N.，等，Nucl.Acids Res.24(1996)2697-2700；以及Mosser，D.D.，等，Biotechniques 22(1997)150-152)。
“有效连接”指两种或多种成分的毗连，其中所述的成分处于允许它们以独立方式发挥作用的关系中。例如若启动子和/或增强子以顺式方式发挥作用以控制或调节所连接的序列转录，则它与编码序列有效连接。通常，但非必需，呈“有效连接”的DNA序列是连续的，并且当需要连接两个蛋白质编码区如分泌前导/信号序列和多肽时，呈“有效连接”的DNA序列是连续的并且符合可读框的。然而尽管有效连接的启动子通常位于编码序列上游，启动子实际上与编码序列并非必须是连续的。
增强子并非必须是连续的。若增强子增强编码序列转录，则它与编码序列有效连接。有效连接的增强子可以位于编码序列的上游、其内部或下游并且距离启动子序列相当远。若聚腺苷酸化作用位点位于编码序列的下游末端以至于转录前进通过编码序列至聚腺苷酸化序列，则聚腺苷酸化作用位点与编码序列有效连接。连接通过本领域已知的重组方法实现，例如使用PCR方法和/或通过在便利的限制性位点处的连接。若便利的限制性位点不存在时，则根据常规习惯使用合成的寡核苷酸衔接子或接头。
术语“表达”如本文中所用指转录和/或翻译发生在宿主细胞中。宿主细胞中所需产物的转录水平可以基于细胞中存在的相应mRNA的量加以测定。例如，从所选择的序列中转录出的mRNA可以通过PCR或通过Northern杂交(见Sambrook等，Molecular Cloning：A LaboratoryManual，Cold Spring Harbor Laboratory Press(1989))定量。由所选择的序列编码的蛋白质可以通过多种方法定量，例如通过ELISA、通过分析蛋白质的生物学活性或通过使用识别并与该蛋白质结合的抗体，采用不依赖于所述活性的验定法，如蛋白质印迹法或放射免疫测定法(见Sambrook等，1989，见上文)。
“宿主细胞”指向其中导入编码本发明多肽的基因的细胞。宿主细胞包括用于增殖质粒/载体的原核细胞和用于表达结构基因的真核细胞。通常，真核细胞是哺乳动物细胞。
“多肽”是通过肽键连接的氨基酸残基的聚合物，无论它是天然产生的或是合成产生的。少于约20个氨基酸残基的多肽可以称作“肽”。包含一个或多个多肽链或包含100个或更多个氨基酸长度的氨基酸链的多肽可以称作“蛋白质”。
“蛋白质”是包含一个或多个多肽链的其中至少一条链具有氨基酸长度100个或更多个氨基酸的大分子。蛋白质也可以包含非肽成分，如糖基。
糖类和其它非肽取代基可以由细胞添加至蛋白质，其中该蛋白质在所述细胞中产生，并且可以随细胞类型而不同。蛋白质在本文中就其氨基酸主链结构进行定义；添加物如糖基通常不予以说明，然而却可以存在。
“异源DNA”或“异源多肽”指给定宿主细胞中不天然存在的DNA分子或多肽，或者DNA分子群或多肽群。对特定宿主细胞为异源的DNA分子可以含有衍生自宿主细胞物种的DNA(即内源DNA)，只要宿主DNA与非宿主DNA(即外源DNA)连接。例如将含有与包含启动子的宿主DNA节段有效连接的编码多肽的非宿主DNA节段的DNA分子认为是异源DNA分子。相反，异源DNA分子可以包含与外源启动子有效连接的内源结构基因。
由非宿主DNA分子编码的肽或多肽是“异源的”肽或多肽。
“克隆载体”是具有在宿主细胞中自主复制能力的核酸分子，如质粒、粘粒、噬菌粒或细菌人工染色体(BAC)。克隆载体通常含有允许以可确定方式插入核酸分子而无损载体基本生物学功能的一个或少量的限制性核酸内切酶识别位点，以及编码抗性基因的核苷酸序列，其中抗性基因适用于鉴定并选择以克隆载体所转化的细胞。抗性基因通常包括提供四环素抗性或氨苄青霉素抗性的基因。
“表达质粒”是宿主细胞中编码待表达蛋白质的核酸分子。通常，表达质粒包含原核质粒增殖单元，例如对于大肠杆菌而言，包含复制起点和选择标记、真核选择标记和用以表达目的结构基因的一个或多个表达盒。其中所述的表达盒包含启动子、结构基因和转录终止子(包括聚腺苷酸化信号)。基因表达通常处于启动子控制下并且称该结构基因与启动子是“有效连接”的。类似地，若调节元件调节核心启动子的活性，则调节元件和核心启动子是有效连接的。
“多顺反子转录单位”是其中超过一个结构基因处于相同启动子控制下的转录单位。
“分离的多肽”是基本上不含与多肽天然结合的污染性细胞成分如糖类、脂类或其它蛋白质杂质的多肽。通常，分离多肽的制备物含有高度纯化形式的即至少约80％纯度、至少约90％纯度、至少约95％纯度、大于95％纯度或大于99％纯度的多肽。一种显示特定蛋白质制备物含有分离多肽的方法是对蛋白质制备物进行十二烷基硫酸钠(SDS)-聚丙烯酰胺凝胶电泳并对凝胶进行考马斯亮蓝染色后显示出单一条带。然而，术语“分离的”不排除存在处于备选物理形式(如二聚体或备选地糖基化形式或其衍生形式)的相同多肽。
术语“免疫球蛋白”指由基本上由通过免疫球蛋白基因所编码的一种或多种多肽组成的蛋白质。已识别的免疫球蛋白基因包括不同的恒定结构域(区)基因以及复杂的免疫球蛋白可变区基因。免疫球蛋白可以多种形式存在，包括例如Fv、Fab和F(ab)2以及单链(scFv)(例如Huston，J.S.，等，PNAS USA 85(1988)5879-5883；Bird，R.E.，等，Science 242(1988)423-426；通常Hood等，Immunology，Benjamin N.Y.，第二版(1984)；以及Hunkapiller，T.和Hood，L，Nature 323(1986)15-16)。
免疫球蛋白通常包含至少两条轻链多肽和两条重链多肽。每条重链多肽和每条轻链多肽可以含有可变结构域(区)(通常是多肽链的氨基端部分)，可变结构域含有能够与抗原相互作用的结合区(结构域)。每条重链多肽链和每条轻链多肽链包含恒定区(通常是羧基端部分)。重链恒定区介导抗体与i)携带Fcγ受体(FcγR)的细胞如吞噬细胞结合或与ii)携带新生Fc受体(FcRn)(也称作Brambell受体)的细胞结合。重链恒定区还介导与一些因子包括经典补体系统的因子如成分(C1q)的结合。
免疫球蛋白的轻链或重链的可变结构域分别包含不同节段，即4个构架区(FR)和3个超变区(CDR)。
“免疫球蛋白片段”指这样的多肽，其至少包含免疫球蛋白的链的恒定结构域，即免疫球蛋白重链的CH1、铰合区、CH2和CH3和任选地CH4或免疫球蛋白轻链的CL。还包含其衍生物和变体。此外，可以存在其中一个或多个氨基酸或氨基酸区域被缺失的可变结构域。在优选的实施方案中，在免疫球蛋白片段中可变结构域被缺失。
“转录终止子”如本申请中所指，是向RNA聚合酶发出信号以终止mRNA合成的长度50-750个碱基对的DNA序列。建议在表达盒3’末端使用极高效(强)的终止子以防止RNA聚合酶通读，尤其防止当使用强启动子时的RNA聚合酶通读。无效的转录终止子可以导致形成操纵子样mRNA，这可能是不想要的基因表达(如质粒编码的基因表达)的原因。
术语“接头”如本申请中所用指天然来源或合成来源的肽接头。它们构成线形氨基酸链。该链的长度是1-50个氨基酸，优选在3-25个氨基酸间。接头可以含有重复的氨基酸序列或天然存在的多肽的部分，如具有铰合功能的多肽。
“合成的接头”设计为富含甘氨酸残基、谷氨酰胺残基和丝氨酸残基。这些残基以不超过5个氨基酸的小肽单位如GGGGS、QQQQG或SSSSG排列。小肽单位重复2-5次以形成多聚体单位。在多聚体单位的每一氨基末尾端和/或羧基末尾端均可以添加多达6个额外氨基酸。
术语“生物活性分子”如本文中所用指当施用于或施用至人工生物系统(如使用细胞系和病毒的生物分析法)中或体内施用至动物(包括但不限于鸟和哺乳动物，包括人)时，引起生物学效应的有机分子，例如生物大分子如肽、蛋白质、糖蛋白、核蛋白、黏蛋白、脂蛋白、合成多肽或蛋白质。这种生物学效应可以是但不限于酶抑制或激活、在结合位点处或在周边与受体或配体结合、信号触发或信号调节。
生物活性分子不限于例如激素、细胞因子、生长因子、受体配体、激动剂或拮抗剂、细胞毒性剂、抗病毒剂、成像剂、酶抑制物、酶激活物或酶活性调节物如别构物质。
术语“氨基酸”如本申请中所用，包含丙氨酸(三字母代码：ala，单字母代码：A)、精氨酸(arg，R)、天冬酰胺(asn，N)、天冬氨酸(asp，D)、半胱氨酸(cys，C)、谷氨酰胺(gln，Q)、谷氨酸(glu，E)、甘氨酸(gly，G)、组氨酸(his，H)、异亮氨酸(ile，I)、亮氨酸(leu，L)、赖氨酸(lys，K)、甲硫氨酸(met，M)、苯丙氨酸(phe，F)、脯氨酸(pro，P)、丝氨酸(ser，S)、苏氨酸(thr，T)、色氨酸(trp，W)、酪氨酸(tyr，Y)和缬氨酸(val，V)。
本领域技术人员已知的用于实施本发明的方法和技术例如在Ausubel，F.M.编辑，Current Protocols in Molecular Biology，第I至III卷(1997)，Wiley and Sons；Sambrook等，Molecular Cloning：A LaboratoryManual，第二版，Cold Spring Harbor Laboratory Press，Cold SpringHarbor，N.Y.(1989)中描述。
本发明包含用于在真核宿主细胞中重组地产生异源多肽的方法。宿主细胞包含表达质粒，该表达质粒在5’至3’方向包含a)启动子，b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1，c)编码第二多肽的核酸，其中该核酸包含编码具有生物学活性的异源多肽的核酸、编码选自SEQ ID NO：06-10、139、140及554-557的肽或多肽的核酸，和编码免疫球蛋白片段的核酸，以及d)3’非翻译区。该表达质粒被导入在适合表达第二多肽的条件下培养的真核宿主细胞中。将分泌的第二多肽从培养基中回收。
第一多肽是所谓的信号序列。信号序列负责所连接/续接/有效连接的多肽的分泌。为产生有效结果，信号序列必需由表达多肽的细胞中的蛋白质和酶识别。在真核宿主细胞的情况时，信号序列优选地是真核信号序列。为确保正确分泌本发明的第二多肽，信号序列选自人和鼠的免疫球蛋白信号序列。信号序列的汇集示于表1。
选择哪种信号序列取决于后续的氨基酸。必需确保在分泌过程后切割信号序列的信号肽酶识别并将分泌性多肽的信号序列除去。为提供从信号序列至异源多肽的“自然”转移，应当以如此方式选择信号序列，即异源多肽的头两个氨基酸与自然续接的免疫球蛋白FR1区的氨基酸序列的头两个氨基酸相同。
表1：分配给信号肽(以单字母代码显示的第一多肽)的第二多肽的头两个氨基酸组(以单字母代码显示)。
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| AC | MEFQTQVLMSLLLCMSMESQTQVLMFLLLWVSMVSTPQFLVFLLFWIP | 163164165 |
| AD | MESQTLVFISILLWLY | 166 |
| AG | MSVPTQLLGLLLLWLT | 167 |
| AH | MKSQTQVFIFLLLCVSMKSQTQVFVFLLLCVS | 168169 |
| AI | MDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLQLWLSGARCMDMRVPAQLLGLLLLWLSGARCMDMRVPAQLLGLLLLWLPDTRCMDMRVPAQLLGLLLLWFPGARCMDMRVPAQLLGLLLLWFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWLPGARC | 6869707172737475767778798081 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| AI(续上页) | MDMRVPAQRLGLLLLWFPGARCMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGAKCMAWISLILSLLALSSMAWTSLILSLLALCSMRCLAEFLGLLVLWIP | 8283848586170171172 |
| AL | MGWNWIFILILSVTT | 173 |
| AQ | MRFQVQVLGLLLLWISMRPSIQFLGLLLFWLH | 174175 |
| AR | MDIRAPAQFLGILLLWFPMDMMVLAQFLAFLLLWFPMDMRAPAQFLGILLLWFPMDMRAPAQFLGILLLWFPMDMRAPAQVFGFLLLWFPMDMRASAQFHGILLLWFPMDMRASAQFHGILLLWFPMDMWTSAQFLGILLLWFLMNTRAPAEFLGFLLLWFLMRAPAPFLGLLLFCFLMRTPAPFLGLLLFCFSMSISTQLLGLLLLWLTMSLPTQLQGLLLLWLTMSVLTQVLALLLLWLTMSVPTQLLALLLLWLTMSVPTQVLGLLLLWLTTDFHMQIFSFMLISFT | 176177178179180181182183184185186187188189190191192 |
| AS | MAWTSLILSLLALCS | 193 |
| AT | MRCLAEFLRLLVLWIP | 194 |
| CQ | MPWALLLLTLLTHSAVSVV | 138 |
| DA | MKLPVRLLVLMFWIPSSS | 195 |
| DI | MDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLQLWLSGARCMDMRVPAQLLGLLLLWLSGARCMDMRVPAQLLGLLLLWLPDTRCMDMRVPAQLLGLLLLWFPGARCMDMRVPAQLLGLLLLWFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQRLGLLLLWFPGARCMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARC | 6869707172737475767778798081828384 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| DI(续上页) | MDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGAKCMRLPAQLLGLLMLWVPGSSEM RLPAQLLGLLMLWVPGSSEMRLPA QLLGLLMLWVPGSSGMRLPAQLLGLLMLWVPGSSGMRLPAQLLGLLMLWIPGSSAMRLPAQLLGLLMLWIPGSSAMRLPAQLLGLLMLWVSGSSGMRLPAQLLGLLMLWVSGSSGMRLLAQLLGLLMLWVPGSSGMVLQTQVFISLLLWISGAYGMDIRAPAQFLGILLLWFPARCMDMMVLAQFLAFLLLWFPARCMDMRAPAQFFGILLLWFPIRCMDMRAPAQFLGILLLWFPARCMDMRAPAQIFGFLLLLFQTRCMDMRAPAQVFGFLLLWFPARCMDMRASAQFLGFLLLWFPMDMRDPPQFLAFLLLWIPMDMRTPAQFLGILLLWFPIKCMDMRVPAHVFGFLLLWFPTRCMDSQAQVLILLLLWVSTCGMDSQAQVLMLLLLSVSTCGMDSQAQVLMLLLLWVSTCGMDSQARVLMLLLLWVSTCGMEFQTQVFVFVLLWLSVDGMEFQTQVLMSLLLCMSACAMEKDTLLLWVLLLWVPSTGMESDTLLLWVLLLWVPSTGMESQIQAFVFVFLWLSVDGMESQIQVFVFVFLWLSVDGMESQNHVLMFLLLWVSTCGMESQTHVLMFLLLWVSTCGMESQTQVFVYMLLWLSVDGMESQTQVLISLLFWVSTCGMESQTQVLMFLLLWVSACAMESQTQVLMSLLFWVSTCGMETDPLLLWVLLLWVPSTGMETDTILLWVLLLWVPSTGMETDTLLLWVLLLWVPSTGMETDTLLLWVLLLWVPSTGMETHSQVFVYMLLWLSVEGMGFKMESHTQAFVFAFLWLSVDGMGVPTQLLLLWLTVRCMIASAQFLGLLLLCFQTRCMKFPSQLLLFLLFRITIICMKFPSQLLLLLLFGIPMICMMSSAQFLGLLLLCFQTRC | 8586878889909192939495103196197198199200201202203204205206207208209210211212213214215473474475476477478479480481482483484485486487488489 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| DI(续上页) | MMSSAQFLGLLLLCFQTRYMNMLTQLLGLLLLWFAGKCMRCLAEFLGLLVLWIPAIGMRCLAEFLRLLVLWIPATGMRCSLQFLGVLMFWISVSGMRFSAQLLGLLVLWIPSTAMRPSIQFLGLLLFWLHAQCMRVLAELLGLLLFCFLVRCMRVLPEFLGLLLLWISVRCMSISTQLLGLLLLWLTARCMSVLTQVLALLLLWLTARCMSVPTQLLALLLLWLTARCMSVPTQLLGLLLLWLTAGCMSVPTQVLGLLLLWLTARCMVFTPQILGLMLFWISSTGMVFTPQILGLMLFWISSRGMVLGLKWVFFVVFYQSRGMVSTSQLLGLLLFWTSSRGPAQFLFLLVLWIQSRC | 490491492493494495496497498499500501502503504505506507508 |
| DR | MSLLTQLQGLLLLWLT | 216 |
| DV | MRLPAQLLGLLMLWVPGSSEMRLPAQLLGLLMLWVPGSSEMRLPAQLLGLLMLWVPGSSGMRLPAQLLGLLMLWVPGSSGMRLPAQLLGLLMLWIPGSSAMRLPAQLLGLLMLWIPGSSAMRLPAQLLGLLMLWVSGSSGMRLPAQLLGLLMLWVSGSSGMRLLAQLLGLLMLWVPGSSGMLPSQLIGFLLLWVPASRGMLPSQLIGFLLLWVPASRGMVSPLQFLRLLLLWVPASRGLILKVQCLVLKVLCMDMRASAQFHGILLLWFPARCMKLPVLLVVLLLFTSPSSSMKLPVRLLVLMFWIPSSSMMSPAQFLFLLVLWIQTNGMMSPAQFLFLLVLWIRTNGMMSPVHSIFILLLWIVISGMMSPVQFLFLLMLWIQTNGMNFGLRLIFLVLTLKVQCMNLPVHLLVLLLFWIPSRGMNTRAPAEFLGFLLLWFLARCMRFQVQVLGLLLLWISAQCMRVLSLLYLLTAIPGILS | 878889909192939495105106107217218219220221222223224225226227228229230 |
| EI | METPAQLLFLLLLWLPDTTGMETPAQLLFLLLLWLPDTTGMEAPAQLLFLLLLWLPDTTG | 969798 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| EI(续上页) | MEAPAQLLFLLLLWLPDTTGMEAPAQLLFLLLLWLPDTTGMEAPAQLLFLLLLWLTDTTGMEPWKPQHSFFFLLLLWLPDTTGMLPSQLIGFLLLWVPASRGMLPSQLIGFLLLWVPASRGMVSPLQFLRLLLLWVPASRGMDFHVQIFSFMLISVTISSGMDFQMQIISLLLISVTIVSNGMDFQVQIFSFLLISVTILTNGMDMRAPAQFLGILLLWFPARCMNFHVQIFSFMLISVTIGSSGMTMLSLVLLLSFLLLCSRAMVSTPQFLVFLLFWIPACGTELICVFLFLLSVTAILSSG | 99100101102105106107231232233234235236237238 |
| EI | MDCGISLVFLVLILKVC | 239 |
| EM | MDMWVQIFSLLLICVTSKG | 240 |
| EN | LLISVTIMSRGMDFQVQIFSFLLISASIMSRGMDFQVQIFSFLLISISVMSRGMDFQVQIFSFLLISVSIMSRGMDLQVQIISFLLIIVTIMSRG | 241242243244245 |
| ET | MGSQVHLLSFLLLWISDTRAMGEQRIRSCHATSGAESARMGSQVHLLSFLLLWISDTRAMTMFSLALLLSLLLLCVSSRAMTMLSLAPLLSLLLLSRAMXTMDEHESGAVTPHQVLKSRA | 104246247248249250 |
| EV | MDWTWRILFLVAAATGAHSMDWTWRILFLVAAATGAHSMDWTWRILFLVAAATSAHSMDWTWSILFLVAAPTGAHSMDCTWRILFLVAAATGTHAMDWTWRILFLVAAATDAYSMDWTWRVFCLLAVAPGAHSMDWIWRILFLVGAATGAHSMELGLSWVFLVAILEGVQCMELGLSWIFLLAILKGVQCMEFGLSWVFLVAIIKGVQCMELGLSWVFLVAILEGVQCMEFGLSWIFLAAILKGVQCMEFGLSWVFLVAILKGVQCMELGLRWVFLVAILEGVQCMEFGLSWLFLVAILKGVQCMEFGLSWVFLVALLRGVQCMEFGLSWVFLVALLRGVQCMEFGLSWVFLVAILKGVQCMELGLCWVFLVAILEGVQCMEFGLSWVFLVAILKGVQC | 282930313233343538394041424344454647484950 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| EV(续上页) | MEFWLSWVFLVAILKGVQCMTEFGLSWVFLVAIFKGVQCMEFGLSWVFLVAILKGVQCMEFGLSWVFLVVILQGVQCMEFGLSWVFLVAILKGVQCMGSTAILALLLAVLQGVCSMGSTAILGLLLAVLQGVCAIKWSWIFLFLLSGTAVHSIKWSWISLFLLSGTAVHSLILKVQCLVLKVQCMAVVTGKGLPSPKLEVNSMDFGLIFFIVALLKVQCMDFGLSLVFLVLILKVQCMDMRASAQFHGILLLWFPARCMEWELSLIFIFALLKDVQCMEWSCIFLFLLSVTAVHSMEWSCIFLFLLSVTAIHSMEWSWIFLFLLSGTAVLSMGWNWIFILILSVTTALSMGWSCIILFLVATATVHSMGWNWIFILILSVTTVHSMGWSCIMLFLAATATVHSMGWSWIFFFLLSGTAVLSMGWSWIFLFFLSGTAVLSMGWSWIFLFLLSGSAVLSMGWSWIFLFLLSGSAVHSMGWSWIFLFLLSGTAVHSMGWSWIFLFLLSGTAVLSMGWSWIFLFLLSGTAVLSMGWSWIFLLFLSGTAVLSMGWSWIFLLFLSGTAVHSMGWSWIFLLFLSGTAVLSMGWSWVFLSFLSGTAVLSMKCSWVIFFLMAVVIINSMKLWLNWILLVALLNIQCMLLGLKWVFFVVFYQVHCMLLGLKWVFFVVFYQGVHCMMVLSLLYLLTALPGILSMNFGLSLIFLVLILKVQCMQLGHLLPDGSVNSMVSETHVLIFLLLWVSVHCRSVPTQLLGLLLLWLTVNS | 51525354556465251252253254255256257258259260261262263264265266267268269270271509510511512513514515516517518519520521522523 |
| GH | MGWSYIILFLVATAT | 272 |
| GI | IDINVQIFRFLLISVTSSG | 273 |
| GK | MNMLTQLLGLLLLWFA | 274 |
| GR | MRTPAHFLGLLLLCFL | 275 |
| HV | MRWSCIILFLVATATVHS | 276 |
| IG | MNFHVQIFSFMLISVT | 277 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| IH | MEWSCIFLFLLSVTA | 278 |
| II | MDFQVQIFQIPVKQCLMDFQVQIFSFLLISASMKFPSQLLLFLLFRIT | 279280281 |
| IK | MDMRTPAQFLGILLLWFP | 282 |
| IL | MAVLALLFCLVTFPSMDFHVQIFSFMLISVTMDFQVQIFSFLLISASMDFQVQIFSFLLISRMDFQVQIFSFLLISVTTELICVFLFLLSVTA | 283284285286287288 |
| IM | LLISVTMDFQVQIFSFLLISASMDFQVQIFSFLLISVSMDFQVQIFSFLLISVSMDFQVQIFSFLLMSASMDLQVQIISFLLIIVTMHFQVQIFSFLLISAS | 289290291292293294295 |
| IN | MKCSWVIFFLMAVVI | 296 |
| IQ | MKLWLNWILLVALLN | 297 |
| IR | MDMRAPAQFFGILLLWFP | 298 |
| IS | MIYSLQLLRMLVLWIPMMSPVHSIFILLLWIVMSYSLQLLRMLVLWIP | 299300301 |
| IT | MSYSLQLLRMLVLWIP | 302 |
| IV | MDFQMQIISLLLISVT | 303 |
| KN | MDFQVQIFQIPVKQCLIISRG | 304 |
| LM | MDFQVQIFSFLLISAS | 305 |
| LP | MAWVSFYLLPFIFSTGLCAMAWTQLLLLFPLLLHWTGSLSMAWTPLLFLTLLLHCTGSLS | 127128129 |
| LR | MRPTLSFLGSCCSSLI | 306 |
| MI | MKFPSQLLLLLLFGIP | 307 |
| NF | MAWAPLLLTLLAHCTGSWA | 133 |
| NI | MDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLLLWLRGARCMD MRVPAQLLGLLQLWLSGARCMDMRVPAQLLGLLLLWLSGARCMDMRVPAQLLGLLLLWLPDTRCMDMRVPAQLLGLLLLWFPGARCMDMRVPAQLLGLLLLWFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWLPGARC | 6869707172737475767778798081 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| NI(续上页) | MDMRVPAQRLGLLLLWFPGARCMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGAKCMESDTLLLWVLLLWVPSTSMESQTLVFISILLWLYADGMESQTQVFLSLLLWVSTCGMETDTLLLWVLLLWVPSTG | 8283848586308309310311 |
| PV | MGWSCIMLFLAATATVHSMGWSCIMLFLAATATGVHS | 312313 |
| QA | MD M RVP AQ LLGLLLLWLRGARCMD M RVP AQ LLGLLLLWLRGARCMD M RVP AQ LLGLLQLWLSGARCMD M RVP AQ LLGLLLLWLSGARCMD M RVP AQ LLGLLLLWLPDTRCMD M RVP AQ LLGLLLLWFPGARCMD M RVP AQ LLGLLLLWFPGARCMD M RVL AQ LLGLLLLCFPGARCMD M RVL AQ LLGLLLLCFPGARCMD M RVP AQ LLGLLLLWLPGARCMD M RVP AQ LLGLLLLWLPGARCMD M RVP AQ LLGLLLLWFPGSRCMD M RVP AQ LLGLLLLWFPGSRCMD M RVP AQ LLGLLLLWLPGARCMD M RVP AQ RLGLLLLWFPGARCM RVP AQ LLGLLLLWLPGARCMD M RVP AQ LLGLLLLWLPGARCMD M RVP AQ LLGLLLLWLPGARCMD M RVP AQ LLGLLLLWLPGAKCMAW TP LLLLLLSHCTGSLSMAW TP LLLLFLSHCTGSLSMAW TL LLLVLLSHCTGSLSMAW TP LFLFLLTCCPGSNSMAW TP LFLFLLTCCPGSNSMAWISLILSLLALSSAISIGWSYIILLLVATATVHSMAWTSLILSLLALCSASSMAWTSLILSLLALCSAISMGWSCVLLFLVSGTAVLC | 68697071727374757677787980818283848586130131132134135314315316317318 |
| QI | MDTLCSTLLLLTIPSWVLSMDTLCYTLLLLTTPSWVLSMDFQVQIFSFLLISASIISRGMDFQVQIFSFLLISASILFRGMDFQVQIFSFLLISASILSRGMDFQVQIFSFLLISASIMSRGMDFQVQIFSFLLISASLMSRGMDFQVQIFSFLLISRILSRGMDFQVQIFSFLLISVSIMSRG | 3637319320321322323324325 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| QI(续上页) | MDFQVQIFSFLLMSASIMSRGMDTLCSTLLLLTIPSWVLSMGWSWIFLFLLSGTAVHCMHFQVQIFSFLLISASIMSRG | 326327328329 |
| QL | MKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLPMKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLSMKH LW FFLLLVAAPRWVLSMAW VS FYLLPFIFSTGLCAM A WTQ LL LLFPLLLHWTGSLSM AWT PL LFLTLLLHCTGSLSMAWTPLFFFFVLHCSSFS | 5657585960616263127128129330 |
| QM | MDWTWRILFLVAAATGAHSMDWTWRILFLVAAATGAHSMDWTWRILFLVAAATSAHSMDWTWSILFLVAAPTGAHSMDCTWRILFLVAAATGTHAMDWTWRILFLVAAATDAYSMDWTWRVFCLLAVAPGAHSMDWIWRILFLVGAATGAHSMRVLGFLCLVTVLPGSLS | 2829303132333435331 |
| QP | MAWVSFYLLPFIFSTGLCAMAWTQLLLLFPLLLHWTGSLSMAWTPLLFLTLLLHCTGSLSMAWTPLLLLLLSHCTGSLSMAWTPLLLLFLSHCTGSLSMAWTLLLLVLLSHCTGSLSMAWAPLLLTLLSLLTGSLSMAWTPLFFFFLLHCSSFS | 127128129130131132137332 |
| QS | MAWSPLFLTLITHCAGSWAMAWSPLLLTLLAHCTGSWAMASFPLLLTLLTHCAGSWAMAGFPLLLTLLTHCAGSWAMTCSPLLLTLLIHCTGSWAMAWALLLLTLLTQGTGSWAMAWALLLLSLLTQGTGSWAMAWALLLLTLLTQGTGSWAMAWALLLLTLLTQGTGSWAMAWALLLLTLLTQDTGSWA | 108109110111112113114115116117 |
| QT | MAWTPLFLFLLTCCPGSNSMAWTPLFLFLLTCCPGSNSMAWMMLLLGLLAYGSGVDS | 134135136 |
| QV | MDWTWRILFLVAAATGAHSMDWTWRILFLVAAATGAHSMDWTWRILFLVAAATSAHS | 282930 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| QV(续上页) | MDWTWSILFLVAAPTGAHSMDCTWRILFLVAAATGTHAMDWTWRILFLVAAATDAYSMDWTWRVFCLLAVAPGAHSMDWIWRILFLVGAATGAHSMDTLCSTLLLLTIPSWVLSMDTLCYTLLLLTTPSWVLSMELGLSWVFLVAILEGVQCMELGLSWIFLLAILKGVQCMEFGLSWVFLVAIIKGVQCMELGLSWVFLVAILEGVQCMEFGLSWIFLAAILKGVQCMEFGLSWVFLVAILKGVQCMELGLRWVFLVAILEGVQCMEFGLSWLFLVAILKGVQCMEFGLSWVFLVALLRGVQCMEFGLSWVFLVALLRGVQCMEFGLSWVFLVAILKGVQCMELGLCWVFLVAILEGVQCMEFGLSWVFLVAILKGVQCMEFWLSWVFLVAILKGVQCMTEFGLSWVFLVAIFKGVQCMEFGLSWVFLVAILKGVQCMEFGLSWVFLVVILQGVQCMEFGLSWVFLVAILKGVQCMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLPMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLSMKHLWFFLLLVAAPRWVLSMSVSFLIFLPVLGLPWGVLSMDWTWRILFLVAAATGAHSIFLFLLSITAVHCKGGSCVSLFLVATANVHFMAVLALLFCLVTFPSILSMAVLGLLFCLVTFPSVLSMAVLGLLLCLVTFPSVLSMAWSWVFLFFLSVTTVHSMDWIWIMLHLLAATGIQSMECSWVFLFLLSLTAVHCMEFGLSWVFLVALLRGVQCMEWLXXFLLFLSLTAVHCMEWSGVFIFLLSVTAVHSMEWSGVFIFLLSVTAVYSMEWSRVFIFLLSVTAVHSMEWSWVFLFFLSVTTVHS | 3132333435363738394041424344454647484950515253545556575859606162636667333334335336337338339340341342343524525526 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| QV(续上页) | MEWSWVFLFLLSLTSVHSMGRLTFSFLLLLPVPAVLSMGWSCIIFFLVATATVHFMGWSCIILFLVAAANVHSMGWSCIILFLVAAATVHSMGWSCIILFLVATATVHSMGWSCIILFLVATATVHSMGWSCIILFLVSTATVHSMGWSCIILILVAAATVHSMGWSCIILILVAAATVHSMGWSCIILILVAAATVQFMGWSCIMLFLAARATVHSMGWSCIMLFLAATATVHFMGWSCIMLFLAATATVHFMGWSCIMLFLAATATVHSMGWSCIMLFLAATATVHSMGWSCIMLFLAATATVHSMGWSFLPLFLAATATGVHSMGWSRIFLFLLSITAVHCMGWSSIILFLVATATVHSMGWSWIFPFLLSGTAVHCMGWSYIIFFLVATATVHFMGWSYIIFFLVATATVHSMGWSYIILFLVATATGHSMGWSYIILFLVATATVHSMGWSYIILFLVATATVNSMRWSCIILFLVATATVHS | 527528529530531532533534535536537538539540541542543544545546547548549550551552553 |
| SA | METPASFLCLLLLWTT | 344 |
| SF | MAWTPLFFFFLLHCSMAWTPLFFFFVLHCS | 345346 |
| SI | MKSQTQVFIFLLLCVSAHGMKSQTQVFVFLLLCVSAHG | 347348 |
| SK | MDMWVQIFSLLLICVT | 349 |
| SR | MXTMDEHESGAVTPHQVLKMGEQRIRSCHATSGAEMNLPVHLLVLLLFWIPMTMFSLALLLSLLLLCVSMTMLSLAPLLSLLLLMTMLSLVLLLLSFLLLCMVFTPQILGLMLFWISMVLGLKWVFFVVFYQMVSTSQLLGLLLFWTSPAQFLFLLVLWIQ | 350351352353354355356357358359 |
| SS | MAWIPLFLGVLAYCTGSVAMAWTALLLSLLAHFTGSVAMAWTPLLLPLLTFCTVSEAMAWI PLLLPLLTLCTGSEAMAWTPLWLTLLTLCIGSVVMAWTVLLLGLLSHCTGSVT | 118119120121122123 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| SS(续上页) | MAWATLLLPLLNLYTGSIAMAWIPLLLPLLTLCTGSEAMAWIPLLLPLLILCTVSVAIDINVQIFRFLLISVTMKLPVLLVVLLLFTSPMKLPVRLLVLMFWIPMKLPVRLLVLMFWIP | 124125126360361362363 |
| ST | MEKDTLLLWVLLLWVPMESDTLLLWVLLLWVPMESDTLLLWVLLLWVPMETDPLLLWVLLLWVPMETDTILLWVLLLWVPMETDTLLLWVLLLWVPMETDTLLLWVLLLWVPMETDTLLLWVLLLWVPMRFSAQLLGLLVLWIPMVFTPQILGLMLFWIS | 364365366367368369370371372373 |
| SY | MAWIPLFLGVLAYCTGSVAMAWTALLLSLLAHFTGSVAMAWTPLLLPLLTFCTVSEAMAWIPLLLPLLTLCTGSEAMAWTPLWLTLLTLCIGSVVMAWTVLLLGLLSHCTGSVTMAWATLLLPLLNLYTGSIAMAWIPLLLPLLTLCTGSEAMAWIPLLLPLLILCTVSVA | 118119120121122123124125126 |
| TC | MDSQAQVLILLLLWVSMDSQAQVLMLLLLSVSMDSQAQVLMLLLLWVSMDSQARVLMLLLLWVSMESQNHVLMFLLLWVSMESQTHVLMFLLLWVSMESQTQVFLSLLLWVSMESQTQVLISLLFWVSMESQTQVLMSLLFWVS | 374375376377378379380381382 |
| TG | METPASFLCLLLLWTTSAV | 383 |
| TN | QHGHEGLCSVSWVPVAMMSPAQFLFLLVLWIQMMSPAQFLFLLVLWIRMMSPVQFLFLLMLWIQ | 384385386387 |
| TR | MIASAQFLGLLLLCFQMMSSAQFLGLLLLCFQMMSSAQFLGLLLLCFQMDMRAPAQIFGFLLLLFQMDMRVPAHVFGFLLLWFP | 388389390391392 |
| VC | MDCGISLVFLVLILK | 393 |
| VD | MEFQTQVFVFVLLWLSMESQIQAFVFVFLWLSMESQIQVFVFVFLWLS | 394395396 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| VD(续上页) | MESQTQVFVYMLLWLSMGFKMESHTQAFVFAFLWLS | 397398 |
| VE | METHSQVFVYMLLWLS | 399 |
| VH | MEWLXXFLLFLSLTAMEWSCIFLFLLSVTAMEWSGVFIFLLSVTAMEWSRVFIFLLSVTAMEWSWVFLFFLSVTTMEWSWVFLFLLSLTSMGWNWIFILILSVTTMGWSCIIFFLVATATMGWSCIILFLVAAANMGWSCIILFLVAAATMGWSCIILFLVATATMGWSCIILFLVATATMGWSCIILFLVATATMGWSCIILFLVSTATMGWSCIILILVAAATMGWSCIILILVAAATMGWSCIMLFLAARATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSCIMLFLAATATMGWSRIFLFLLSITAMGWSSIILFLVATATMGWSWIFLFLLSGSAMGWSWIFLFLLSGTAMGWSWIFLFLLSGTAMGWSWIFLLFLSGTAMGWSWIFPFLLSGTAMGWSYIIFFLVATATMGWSYIIFFLVATATMGWSYIILFLVATATMGWSYIILFLVATATMGWSYIILFLVATATMLLGLKWVFFVVFYQMRWSCIILFLVATATMRWSCIILFLVATATMVSETHVLIFLLLWVSIFLFLLSITAIGWSYIILLLVATATIKWSWIFLFLLSGTAIKWSWISLFLLSGTAKGGSCVSLFLVATANMAWSWVFLFFLSVTT | 400401402403404405406407408409410411412413414415416417418419420421422423424425426427428429430431432433434435436437438439440441442443444445 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| VH(续上页) | MECSWVFLFLLSLTA | 446 |
| VI | MDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLLLWLRGARCMDMRVPAQLLGLLQLWLSGARCMDMRVPAQLLGLLLLWLSGARCMDMRVPAQLLGLLLLWLPDTRCMDMRVPAQLLGLLLLWFPGARCMDMRVPAQLLGLLLLWFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVLAQLLGLLLLCFPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWFPGSRCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQRLGLLLLWFPGARCMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGARCMDMRVPAQLLGLLLLWLPGAKCMIYSLQLLRMLVLWIPISKMSYSLQLLRMLVLWIPISKMSYSLQLLRMLVLWIPITK | 68697071727374757677787980818283848586447448449 |
| VL | LVLKMAVLGLLFCLVTFPSMAVLGLLLCLVTFPSMDRLTSSFLLLIVPAMEWSWIFLFLLSGTAMGRLTFSFLLLLPVPAMGWSCVLLFLVSGTAMGWSWIFFFLLSGTAMGWSWIFLFFLSGTAMGWSWIFLFLLSGSAMGWSWIFLFLLSGTAMGWSWIFLFLLSGTAMGWSWIFLLFLSGTAMGWSWIFLLFLSGTAMGWSWVFLSFLSGTA | 450451452453454455456457458459460461462463464 |
| VM | MDFQVQIFSFLLISIS | 465 |
| VN | MAVVTGKGLPSPKLEMGWSYIILFLVATATMQLGHLLPDGSRSVPTQLLGLLLLWLT | 466467468469 |
| VQ | LILKLVLKMDFGLIFFIVALLKMDFGLSLVFLVLILKMGWSCIILILVAAATMNFGLRLIFLVLTLK | 470471141020520 |
| 第二多肽始于氨基酸 | 第一肽(信号序列)氨基酸序列 | SEQ ID NO： |
| VQ(续上页) | MNFGLSLIFLVLILK | 21 |
| VR | MGVPTQLLLLWLTMRVLAELLGLLLFCFLMRVLPEFLGLLLLWIS | 222324 |
| VS | MRCSLQFLGVLMFWISREWSWNFLFLLSGTT | 2526 |
| VY | MEWSGVFIFLLSVTA | 27 |
| 如果第二多肽的头两个氨基酸的组合没在此表中列出，可以使用这些第一多肽 | ELWVLMVWVPELWVLMVWVPSTSHDHALTSSSPQPSSPLCLLAVITSNIWFPMVCMSMDMWTSAQFLGILLLWFLARCMDRLTSSFLLLIVPAVLSMLRAIKAAPFSRFGCSMRAPAPFLGLLLFCFLARCMRCSPHFLELLVFWILMRPTLSFLGSCCSSLILRCMRTPAHFLGLLLLCFLGRCMRTPAPFLGLLLFCFSARCMSLLTQLQGLLLLWLTDRCMSLPTQLQGLLLLWLTARCMTMLSLAPLLSLLLLCVSMTSLSQLLGMLMLQSLMVFAPQILGFLLLWISMVFTPHILGLLLFWISQHGHEGLCSVSWVPVATNSREWSWNFLFLLSGTTVSSTDFHMQIFSFMLISFTARC | 142143144145146147148149150151152153154155156157158159160161162 |
若第二多肽的头两个氨基酸的二肽未在表1中明确地列出，并且不想使用在表1最后一行中列出的序列，则不使第一多肽与第二多肽直接连接是有益的。在这种情况下，有益的是插入多达5个氨基酸的短序列以便模仿免疫球蛋白FR1区域序列的开始部分，其中所述的开始部分天然地连接在第一多肽之后。这种序列可以是单个氨基酸或二肽、肽QIWNN(SEQ IDNO：472)或其片段，以便模仿天然续接的免疫球蛋白FR1区域的头两个氨基酸。在一个实施方案中，这种序列是肽QIWNN(SEQ ID NO：472)或其包含至少二肽QI的氨基端部分。
在第一多肽后或任选地在插入的短序列后，第二多肽包含异源多肽。此异源多肽具有5-500个氨基酸残基的氨基酸序列。在本发明的优选实施方案中，氨基酸序列是10-350个氨基酸残基并且在更优选的实施方案中是15-150个氨基酸残基。与免疫球蛋白缀合的异源多肽选自生物活性分子。这些分子在施用至人工生物系统或活细胞(如在分析法)中或施用至活生物(如鸟和哺乳动物，包括人)时，表现生物学效应。这些生物活性化合物包含但不限于受体的激动剂以及拮抗剂、酶抑制物及激活物等，并且还包含显示细胞毒活性、抗病毒活性、抗细菌活性或抗癌活性的肽、多肽和蛋白质，以及抗原。生物学效应可以是但不限于酶抑制、在结合位点处或在周边与受体结合和信号触发。这些生物活性化合物例如用于药物、治疗或诊断用途。
第二多肽还包含在异源多肽之后的接头。可以与本发明优选使用的接头列于表2。
表2：可能的接头
| 接头编号 | 接头氨基酸序列 | SEQ NO： |
| 1 | [Ser(Gly)4]3 | 06 |
| 2 | [Ser(Gly)4]5 | 07 |
| 3 | [Gly(Gln)4]3 | 08 |
| 4 | Gly(Ser)15Gly | 09 |
| 5 | GST | 10 |
| 6 | [(Gly)4Ser]3-Gly-Ala-Ser | 139 |
| 7 | Gly(Ser)15-Gly-Ala-Ser | 140 |
| 8 | [(Gly)4Ser]3-Gly | 554 |
| 9 | [(Gly)4Ser]5-Gly | 555 |
| 10 | [(Gly)4Ser]3-Gly2 | 556 |
| 11 | [(Gly)4Ser]5-Gly2 | 557 |
在接头后面是作为第二多肽羧基端部分的免疫球蛋白片段。
第二多肽包含在接头前面的异源多肽和在接头后面作为羧基端部分的免疫球蛋白片段，即编码第二多肽的核酸在5’至3’方向包含编码异源多肽、接头和免疫球蛋白片段的核酸。
免疫球蛋白分子分成5个不同的类：IgA(免疫球蛋白A)、IgD、IgE、IgG和IgM。这些类中IgG和IgE更常在药物应用和诊断应用中使用。在这些类中，免疫球蛋白在其整体结构方面不同，但是结构单元是相似的。所有的免疫球蛋白均由两种不同的多肽链即轻链和重链构成。
免疫球蛋白片段包含免疫球蛋白轻链或重链的羧基端恒定结构域，例如它包含免疫球蛋白重链的至少CH1-、CH2-、CH3-结构域和铰合区以及任选地包含CH4-结构域，或免疫球蛋白轻链的CL-结构域。从中衍生该片段的免疫球蛋白可以是天然存在的或合成的免疫球蛋白。在本发明的一个实施方案中，免疫球蛋白片段额外地含有重链可变结构域或轻链可变结构域或其变体的片段。在可变结构域片段中，氨基酸或氨基酸区域被缺失。在一个实施方案中，可变结构域的1-6个氨基酸被缺失。在另一个实施方案中，可变结构域的1-6个区域被缺失。在又一个实施方案中，可变结构域被缺失。免疫球蛋白片段中的功能性(即抗原识别性)可变结构域对本发明不是必需的。本发明的无功能性免疫球蛋白是没有抗原识别性可变结构域的免疫球蛋白。在一个实施方案中，免疫球蛋白片段是无功能的免疫球蛋白。在一个实施方案中，免疫球蛋白片段中包含的可变结构域和恒定结构域衍生自相同的抗体，即属于相同抗体。
在表达质粒中有效连接有不同的核酸序列。为了表达，将质粒导入宿主细胞。蛋白质优选地在哺乳动物细胞如CHO细胞、NS0细胞、Sp2/0细胞、COS细胞、HEK细胞、K562细胞、BHK细胞、PER.C6细胞等中产生。
提供下列实施例、序列表和图以辅助理解本发明，本发明的真实范围在后附权利要求书中描述。应当理解可以对所述的方法进行修改而不脱离本发明的精神。
附图简述
图1IgG类免疫球蛋白的共同结构。
图2抗IGF-1Rγ1-重链表达载体4818的质粒图。
图3抗IGF-1Rκ-轻链表达载体4802的质粒图。
图4γ1-重链恒定区基因载体4962的质粒图。
图5修饰的抗IGF-1Rκ-轻链表达载体4964的质粒图。
图6修饰的抗IGF-1R轻链表达载体4963的质粒图。
图7亲和纯化的免疫球蛋白缀合物的考马斯兰染色的SDS-PAGE-凝胶；根据表6的样品排列。
图8在HEK293 EBNA细胞中瞬时表达后，对细胞培养上清液中轻链的免疫检测；根据表6的样品排列。
图9在HEK293EBNA细胞中瞬时表达后，对细胞培养上清液中重链的免疫检测；根据表6的样品排列。
实施例
材料与方法
关于人免疫球蛋白轻链和重链的核苷酸序列一般信息在Kabat，E.A.等，(1991)具有免疫学意义的蛋白质的序列，第五版，NIH出版编号91-3242中给出。
抗体链的氨基酸根据EU编号法(Edelman，G.M.，等，PNAS 63(1969)78-85；Kabat，E.A.等，(1991)具有免疫学意义的蛋白质的序列，第五版，NIH出版编号91-3242)编号。
重组DNA技术
使用标准方法以如Sambrook，J.等，分子克隆：实验手册(Molecularcloning：A laboratory manual)；Cold Spring Harbor Laboratory Press，Cold Spring Harbor，纽约，1989中所述操作DNA。分子生物学试剂根据制造商说明书使用。
蛋白质测定
蛋白质浓度使用基于氨基酸序列计算的摩尔消光系数，通过确定在280nm处的光密度(OD)而测定。
DNA序列测定
DNA序列通过在MediGenomix GmbH(Martinsried，德国)开展的双链测序法测定。
DNA和蛋白质的序列分析和序列数据管理
GCG(Genetics Computer Group，Madison，Wisconsin)软件包10.2版本和Infomax′s Vector NTI高级套装8.0版本用于序列生成、作图、分析、注释和阐述。
基因合成
所需的基因节段由Medigenomix GmbH(Martinsried，德国)从通过化学合成制造的寡核苷酸中制备。两侧具有单一限制性核酸内切酶切割位点的100-600 bp长的基因节段通过寡核苷酸的复性和连接而组装，包括PCR扩增，并随后通过A突出端克隆至pCR2.1-TOPO-TA克隆载体(InvitrogenCorp.，美国)。亚克隆的基因片段的DNA序列通过DNA测序证实。
免疫球蛋白缀合物的亲和纯化
根据已知方法，使用蛋白A-SepharoseTM CL-4B(GE Healthcare创造者Amersham Bioscience，瑞典)，通过亲和层析法纯化已表达和分泌的免疫球蛋白缀合物。简而言之，在离心(10,000g持续10分钟)和通过0.45μm滤器过滤后，将含有免疫球蛋白缀合物的澄清的培养上清液施加至用PBS缓冲液(10mM Na2HPO4，1mM KH2PO4，137mM NaCl和2.7mM KCl，pH 7.4)平衡的蛋白A-SepharoseTM CL-4B柱上。未结合的蛋白质用PBS平衡缓冲液和0.1M柠檬酸盐缓冲液，pH 5.5洗去。免疫球蛋白缀合物用0.1M柠檬酸盐缓冲液，pH 3.0洗脱并且含有免疫球蛋白缀合物的级分用1M Tris碱中和。随后，免疫球蛋白缀合物在4℃用PBS缓冲液作充分透析，用配有Biomax-SK膜(Millipore Corp.，美国)的离心超滤装置进行浓缩并贮存在0℃的冰水浴中。
实施例1
表达质粒的制备
连接编码抗胰岛素样生长因子I受体(IGF-1R)抗体轻链可变结构域(区)(VL)和人κ-轻链恒定结构域(区)(CL)的基因节段，连接编码抗IGF-1R重链可变结构域(区)(VH)和人γ1-重链恒定区(CH1-铰合区-CH2-CH3)的基因节段。
a)载体4818
载体4818是用于HEK293 EBNA细胞中瞬时表达抗IGF-1R抗体(在下文中也称作抗IGF-1R)重链(基因组方式组织的表达盒；外显子-内含子组织方式)(序列见US 2005/0008642)的表达质粒。该载体包含下列功能性元件：
除了抗IGF-1Rγ1-重链表达盒之外，该载体还含有：
-作为选择标记的潮霉素抗性基因，
-EB病毒(EBV)的复制起点oriP，
-来自载体pUC18的允许该质粒在大肠杆菌中复制的复制起点，和
-在大肠杆菌中赋予氨苄青霉素抗性的β-内酰胺酶基因。
抗IGF-1Rγ1-重链基因的转录单位包含下列元件：
-来自人巨细胞病毒(HCMV)的立即早期增强子和启动子，
-合成的5′-非翻译区(UT)，
-鼠免疫球蛋白重链信号序列，包括信号序列内含子(信号序列1、内含子、信号序列2[L1-内含子-L2])，
-克隆的编码抗IGF-1R可变重链的节段，在5′端具有单一Bsml限制性位点(L2信号序列)并在3′端具有剪接供体位点和单一Notl限制性位点，
-小鼠/人重链杂合内含子2，包括小鼠重链增强子元件(部分JH3、JH4)(Neuberger，M.S.，EMBO J.2(1983)1373-1378)，
-基因组的人γ1-重链基因恒定区，
-人γ1-免疫球蛋白聚腺苷酸化作用(“聚A”)信号序列，和
-分别在5′-和3′端的单一限制性位点Ascl和SgrAI。
抗IGF-1Rγ1-重链表达载体4818的质粒图示于图2。
b)载体4802
载体4802是用于HEK293 EBNA细胞中瞬时表达抗IGF-1R抗体轻链(cDNA)的表达质粒。该载体包含下列功能性元件：
除了抗IGF-1Rκ-轻链表达盒之外，该载体还含有：
-作为选择标记的潮霉素抗性基因，
-EB病毒(EBV)的复制起点oriP，
-来自载体pUC18的允许该质粒在大肠杆菌中复制的复制起点，和
-在大肠杆菌中赋予氨苄青霉素抗性的β-内酰胺酶基因。
抗IGF-1Rκ-轻链基因的转录单位包含下列元件：
-来自人巨细胞病毒(HCMV)的立即早期增强子和启动子，
-克隆的抗IGF-1R可变轻链cDNA，包括
-人免疫球蛋白胚系基因的天然5′-UT和
-天然轻链信号序列，在5′端具有单一BglII限制性位点，
-人κ-轻链基因恒定区，
-人免疫球蛋白κ-聚腺苷酸化作用(“聚A”)信号序列，和
-分别在5′-和3′端的单一限制性位点Ascl和Fsel。
抗IGF-1Rκ-轻链表达载体4802的质粒图示于图3。
c)质粒4962
载体4962作为装配表达质粒4965、4966和4967的基础结构。这些质粒使得能够在HEK293 EBNA细胞中瞬时表达经修饰的抗体重链(无可变结构域的氨基端缀合，cDNA组织方式)。质粒4962包含下列功能性元件。
除了γ1-重链恒定区的表达盒之外，该载体还含有：
-作为选择标记的潮霉素抗性基因，
-EB病毒(EBV)的复制起点oriP，
-来自载体pUC18的允许该质粒在大肠杆菌中复制的复制起点，和
-在大肠杆菌中赋予氨苄青霉素抗性的β-内酰胺酶基因。
γ1-重链恒定区基因(CH1-铰合部-CH2-CH3)的转录单位由下列元件组成：
-来自人巨细胞病毒(HCMV)的立即早期增强子和启动子，
-合成的接头(SEQ ID NO：01)，包含在5′端的单一BglII限制性位点和在3′端的单一NheI限制性位点(Nhel位点位于CH1氨基端中)
HCMV-启动子 AlaSer(CH1)
...agatcttttgccaccgctagc...
BglII NheI
-人γ1-重链基因恒定结构域(区)(CH1-铰合部-CH2-CH3，cDNA组织方式)，
-人γ1-免疫球蛋白聚腺苷酸化作用(“聚A”)信号序列，和
-分别在5′-和3′端的单一限制性位点Ascl和Fsel。
γ1-重链恒定结构域/区域基因载体4962的质粒图示于图4。
d)质粒4964
载体4964作为装配表达质粒4976和4977的基础结构。这些质粒使得能够在HEK293 EBNA细胞中瞬时表达经修饰的抗IGF-1R抗体轻链(氨基端缀合)。
质粒4964是表达质粒4802的变体。
抗IGF-1Rκ-轻链基因的转录单位受到如下所示的修饰：
天然轻链信号序列由在5′-端配置单一BglII限制性位点和在3′-端配置单一NheI限制性位点的合成的接头(SEQ ID NO：03)替换，此合成的接头与VL-IGF-1R可变结构域(区)直接连接。
I-VL-1R18
...agatctatatatatatatgctagcgaaattgtgttgaca...
AlaSerGluIleValLeuThr...
BglII NheI
经修饰的抗IGF-1Rκ-轻链表达载体4964的质粒图示于图5。
e)质粒4969
表达质粒4969衍生自作为抗IGF-1R抗体轻链表达质粒的质粒4802。表达质粒4969编码经修饰的抗体轻链片段(无可变结构域的氨基端缀合；多肽-接头-κ链恒定区)。
为构建质粒4969，将单一BglII限制性位点引入CMV-启动子的3′端并将单一BbsI限制性位点引入抗IGF-1R抗体轻链恒定区内部(SEQ IDNO：04)。
I--C-κ Bbsl
cgaactgtggctgcaccatctgtcttcatcttc...
ArgThrValAlaAlaProSerValPheIlePhe...
f)质粒4963
该质粒使得能够在HEK 293 EBNA细胞中瞬时表达抗IGF-1R抗体轻链。
质粒4963是表达质粒4802的变体。
抗IGF-1Rκ-轻链基因的转录单位受到如下所示的修饰：
-人κ-轻链恒定基因区域在C-κ-Ig-κpA结合区域中受到轻微修饰(插入单一HindIII限制性位点和单一Kas I限制性位点，SEQ ID NO：558)。
...C-κ Ig-κ-pA
...AaaagcttcaacaggggagagtgtTGAagggagaggcgccccca
...LysSerPheAsnArgGlyGluCys
HindIII KasI
经修饰的抗IGF-1R轻链表达载体4963的质粒图示于图6。
实施例2
制备最终的表达质粒
已经用已知的重组方法和技术通过连接相应的基因节段(核酸)组装了包含免疫球蛋白基因节段、接头基因节段和多肽基因节段的免疫球蛋白融合基因(重链和轻链)。
编码肽接头的核酸序列和编码多肽的核酸序列分别通过化学合成法合成并随后连接至大肠杆菌质粒内。亚克隆的核酸序列通过DNA测序进行验证。
所用免疫球蛋白多肽链、免疫球蛋白片段、多肽缀合(氨基端)的位置、采用的接头和采用的多肽列于表2(第29页)、表3和表3a。
表3：所用的蛋白质和多肽；氨基酸序列和位置的编号如BH8参考株那样编号(基因座HIVH3BH8；来自法国的HIV-I分离株LAI/IIIB克隆BH8；Ratner，L.等，Nature 313(1985)277-384)。
| 蛋白质和多肽 | SEQ ID NO |
| HIV-1gp41(BH8 gp 160的位置507-851) | 11 |
| T-651(见例如US 6,656,906) | 12 |
| HIV-1gp41胞外结构域变体单突变：I568P | 13 |
| HIV-1gp41胞外结构域变体四突变：I568P、L550E、I566E和L580E | 14 |
表3a：用于免疫球蛋白缀合物基因构建的化学制备的基因节段。
| 插入物 | SEQ IDNO |
| 插入物4964(导入单一限制性位点) | 15 |
| 插入物4965(具有T-651)，包含信号序列(MDTLCSTLLLLTIPSWVLS)，插入的短序列(QIWNN)，异源多肽(MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL)，接头(GGGGSGGGGSGGGGSG) | 16 |
| 插入物4966(具有T-651)，包含信号序列(MDTLCSTLLLLTIPSWVLS)，插入的短序列(QIWNN)，异源多肽(MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL)，接头(GGGGSGGGGSGGGGSGGGGSGGGGSG) | 17 |
| 插入物4967(具有T-651)，包含信号序列(MDTLCSTLLLLTIPSWVLS)，插入的短序列(QIWNN)，异源多肽 | 18 |
| (MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL)，接头(GSSSSSSSSSSSSSSSG) | |
| 插入物4969(gp41单突变)，包含信号肽(MEFGLSWVFLVALLRGVQC)，插入的短序列(Q)，异源多肽(VQARQLLSGIVQQQNNLLRAIEGQQHLLQLTVWGPKQLQARILAVERYLKDQQLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELL)，接头(GGGGSGGGGSGGGGSG) | 19 |
用于构建用来瞬时表达经修饰的免疫球蛋白多肽轻链和重链(表达盒)的最终表达质粒的组分列于表4，包括所用的基础质粒、克隆位点和插入的编码缀合的免疫球蛋白多肽的核酸序列。
表4：构建所用的表达质粒中采用的组分
在表5中列出：具有HIV-I抑制特性的所用多肽(T-651和HIV-1gp41胞外结构域变体)、使免疫球蛋白轻链或重链与该多肽连接的所用接头和如从所编码氨基酸序列中推导的经修饰抗体链的推导分子量。
表5：所用多肽和经修饰的免疫球蛋白多肽链的推导分子量的总结
实施例3 在HEK293 EBNA细胞中瞬时表达免疫球蛋白变体
重组的免疫球蛋白变体通过瞬时转染贴壁生长的HEK293-EBNA细胞(表达EB病毒核抗原的人胚肾细胞系293；美国典型培养物保藏中心保藏编号ATCC#CRL-10852)产生，其中HEK293-EBNA细胞在补充有10％超低IgG FCS(胎牛血清，Gibco，Invitrogen Corp.，美国)、2mM谷氨酰胺(Gibco，Invitrogen Corp.，美国)、1％体积比(v/v)非必需氨基酸(Gibco，Invitrogen Corp.，美国)和250μg/ml G418(Roche Molecular Biochemicals，Roche Diagnostics GmbH，德国)的DMEM(Dulbecco′s改良的Eagle ′s培养基，Gibco，Invitrogen Corp.，美国)中培养。对于转染，以试剂(μl)对DNA(μg)比率3∶1至6∶1使用FugeneTM 6转染试剂(Roche Molecular Biochemicals，Roche Diagnostics GmbH，德国)。
使用轻链编码质粒对重链编码质粒1∶2至2∶1的摩尔比，从两种不同质粒表达免疫球蛋白多肽轻链和重链。转染后第4-11日收获含有免疫球蛋白变体的细胞培养上清液。上清液在0℃贮存于冰水浴中直至纯化。
关于例如在HEK293细胞中重组表达人免疫球蛋白的一般信息在KMeissner，P.，等，Biotechnol.Bioeng.75(2001)197-203中给出。
实施例4使用SDS PAGE、蛋白质印迹转移并用免疫球蛋白特异性抗体缀合物检测的表达分析
将表达并分泌的多肽通过十二烷基硫酸钠(SDS)聚丙烯酰胺凝胶电泳(SDS-PAGE)处理，并且将分离的多肽从凝胶转移至膜上并且随后通过免疫学方法进行检测。
SDS-PAGE
LDS样品缓冲液，四倍浓缩物(4×)：4g甘油，0.682g Tris碱，0.666gTris-盐酸，0.8g LDS(十二烷基硫酸锂)，0.006g EDTA(乙二胺四乙酸)，0.75ml在水中的Serva Blue G250的1％重量(w/v)溶液，0.75ml的1％重量(w/v)酚红溶液，添加水以产生总体积10ml。
将含有分泌性多肽的培养肉汤离心以除去细胞和细胞碎片。将澄清的上清液的一等分试样与1/4体积(v/v)4×LDS样品缓冲液及1/10体积(v/v)0.5M 1，4-二硫苏糖醇(DTT)混合。样品随后在70℃温育10分钟并且将蛋白质通过SDS-PAGE分离。根据制造商说明书使用
预制凝胶系统(Invitrogen Corp.，美国)。尤其，使用10％
Bis-Tris预制凝胶(pH 6.4)和
MOPS运行缓冲液。
蛋白质印迹
转移缓冲液：39mM甘氨酸、48mM Tris-盐酸、0.04％重量(w/v)SDS和20％体积的甲醇(v/v)。
在SDS-PAGE后，将分离的免疫球蛋白缀合物多肽链根据Burnette(Burnette，W.N.，Anal.Biochem.112(1981)195-203)的“半干印迹法”以电泳方式转移至硝酸纤维素滤膜(孔径：0.45μm)。
免疫学检测
TBS-缓冲液：50mM Tris-盐酸，150mM NaCl，调整至pH 7.5。
封闭溶液：在TBS-缓冲液中的1％(w/v)Western封闭剂(RocheMolecular Biochemicals，Roche Diagnostics GmbH，德国)。
TBST-缓冲液：含0.05％体积(v/v)吐温20的1×TBS缓冲液。
为进行免疫学检测，将蛋白质印迹膜在室温在TBS-缓冲液中温育2次持续5分钟，并在封闭溶液中温育1次持续90分钟，同时振摇。
免疫球蛋白缀合物多肽链的检测
重链：为检测含有重链或含有重链片段的多肽，使用纯化的缀合过氧化物酶的兔抗人IgG抗体(产品编号P 0214，DAKO，丹麦)。
轻链：含有轻链或轻链片段的多肽用纯化的缀合过氧化物酶的兔抗人κ轻链抗体(DAKO，丹麦，产品编号P 0129)进行检测。
为使抗体轻链和重链或其片段可见，首先将已洗涤并封闭的蛋白质印迹膜与在10ml封闭溶液中的以1∶10,000稀释的缀合抗体在4℃温育过夜，同时振摇，在重链的情况下是与纯化的缀合过氧化物酶的兔抗人IgG抗体温育或在轻链的情况下与纯化的缀合过氧化物酶的兔抗人κ轻链抗体温育。将膜在室温用TBTS-缓冲液洗涤3次并用TBS缓冲液洗涤1次10分钟后，Western印迹膜用产生化学发光的鲁米诺/过氧化物溶液(Lumi-LightPLUS蛋白质印迹法底物，Roche Molecular Biochemicals，RocheDiagnostics GmbH，德国)显色。因此，将膜在10ml鲁米诺/过氧化物溶液中温育10秒至5分钟，并且发射光随后用Lumi-Imager FlAnalysator(Roche Molecular Biochemicals，Roche Diagnostics GmbH，德国)检测和/或用X射线胶片记录。
点的强度由LumiAnalyst软件(版本3.1)定量。
免疫印迹物的多重染色
可以通过将膜在70℃于含有100mM β-巯基乙醇和20％(w/v)SDS的1M Tris-盐酸-缓冲液(pH 6.7)中温育1小时而从染色的印迹物中除去检测用的过氧化物酶标记的第二抗体缀合物。在此处理后，印迹物可以用不同的第二抗体进行二次染色。在第二次检测前，印迹物在室温于TBS缓冲液中洗涤三次，每次10分钟，同时振摇。
样品排列列于表6。
表6：SDS PAGE凝胶/蛋白质印迹的样品排列。
实施例5
检测组装的免疫球蛋白多肽
通过与蛋白A SepharoseTM CL-4B的亲和结合作用纯化并浓缩免疫球蛋白多肽
将含有一种或多种质粒的HEK 293 EBNA细胞在适合瞬时表达质粒中的多肽基因的条件下培养6-10日。向1.8ml Eppendorf管中的1ml澄清培养上清液中添加0.1ml蛋白A SepharoseTM CL-4B(GE Healthcare创造者Amersham Biosciences，瑞典)混悬液(蛋白A Sepharose在PBS缓冲液(10mM Na2HPO4，1mM KH2PO4，137mM NaCl和2.7mM KCl，pH7.4)中的1∶1(v/v)混悬液)。将混悬液在室温于1小时与16小时之间温育，同时振摇。此后，通过离心(30秒，5000转/分钟)使Sepharose珠沉淀并弃去上清液。将Sepharose沉淀随后分别用1.6ml PBS缓冲液、1.6ml 0.1M柠檬酸盐缓冲液pH 5.0和1.6ml蒸馏水依次洗涤。结合蛋白A的免疫球蛋白用0.1ml1xLDS-PAGE样品缓冲液在70℃从Sepharose珠提取5-10分钟。通过SDS-PAGE并用考马斯亮蓝如实施例4中所述染色而进行分析。
结果：
在瞬时表达后对含有重链片段和/或轻链片段的多肽表达/分泌-分析：
图7a-c：亲和纯化多肽的考马斯兰染色的SDS-PAGE-凝胶；根据表6的样品排列。
对含有免疫球蛋白的多肽的免疫检测
图8a-c：在HEK293 EBNA细胞中瞬时表达后，对细胞培养上清液中含有轻链片段的多肽的免疫检测。
图9a-c：在HEK293 EBNA细胞中瞬时表达后，对细胞培养上清液中含有重链片段的多肽的免疫检测。
从图7a-c、图8a-c和图9a-c中，可以推断多肽被瞬时表达并分泌至培养基中。在含有免疫球蛋白的多肽具有一个或数个糖基化位点的情况下，最终的多肽没有明确限定的分子量，而根据糖基化程度产生分子量分布。这导致在SDS-PAGE中代表一种多肽的全部多肽种类不均匀地迁移并且条带因此变宽。
实施例6 用人IgG ELISA对表达的含有重链的多肽定量
细胞培养上清液中含有免疫球蛋白重链片段的多肽的浓度通过夹心ELISA测定，其中夹心ELISA使用了生物素化的抗人IgG F(ab′)2片段作为捕获剂并用于检测过氧化物酶缀合的抗人IgG F(ab′)2抗体片段。
链霉抗生物素包被的96孔板(Pierce Reacti-BindTM链霉抗生物素包被的聚苯乙烯条平板，产品编号15121，Pierce Chemical Company，美国)用稀释缓冲液(稀释缓冲液：含有0.5％重量比体积(w/v)的牛血清白蛋白的PBS缓冲液)中的0.5μg/ml生物素化的山羊抗人IgG F(ab′)2多克隆抗体片段((F(ab′)2<h-Fcγ>Bi；Dianova，德国，产品编号109-066-098)捕获抗体(0.1ml/孔)在室温(RT)温育1小时，同时振摇。此后，板用超过0.3ml的洗涤缓冲液(洗涤缓冲液：含有1％重量比体积(w/v)吐温20的PBS)洗涤三次。将含有IgG免疫球蛋白缀合物的细胞培养上清液(样品)在稀释缓冲液中连续(2倍)稀释直至浓度0.5-20ng/ml，添加至平板中并在室温温育1小时，同时振摇。缓冲液中纯化的抗IGF-1R标准抗体(0.5-20ng/ml)用来产生IgG蛋白质标准曲线。在用0.3ml/孔洗涤缓冲液洗涤平板3次后，与人Fcγ结合的复合物用山羊抗人F(ab′)2-特异性多克隆IgG的缀合过氧化物酶的F(ab′)2片段[F(ab′)2<h-Fcγ>POD；Dianova，产品编号109-036-098]进行检测。在用0.3ml/孔洗涤缓冲液洗涤平板3次后，平板用
(2，2′-连氮基-双(3-乙基苯并噻唑啉-6-磺酸)过氧化物酶底物溶液(Roche MolecularBiochemicals，产品编号1684302，Roche Diagnostics GmbH，德国)显色。在10-30分钟后，吸光度在Tecan Spectrafluorplus平板读数仪(TecanDeutschland GmbH，德国)上在405nm和490nm处对试剂空白(温育缓冲液+
溶液)测量。为了背景校正，将在490nm的吸光度根据式I从在405nm的吸光度中扣除。将至少作为一式两份的全部样品分析并且使来自两个或三个吸光度测量中的值平均化。样品的IgG含量从标准曲线中计算。
式I：
序列表
<110>弗·哈夫曼-拉罗切有限公司
<120>用于重组表达多肽的方法
<130>23215 FT
<150>EP 05023003
<151>2005-10-21
<150>EP 06010665
<151>2006-05-24
<160>558
<170>PatentIn版本3.2
<210>1
<211>21
<212>DNA
<213>人工的
<220>
<223>合成的接头，包含在5’端的BglII限制性位点和在3’端的NheI限制性位点(Nhel位点位于CHl氨基端中)
<400>1
agatcttttg ccaccgctag c 21
<210>2
<211>15
<212>PRT
<213>小家鼠(Mus musculus)
<400>2
Met Asp Phe Gly Leu Ser Leu Val Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210>3
<211>24
<212>DNA
<213>人工的
<220>
<223>合成的接头，5’-端配置BglII限制性位点和在3’-端配置NHEI限制性位点，直接连接至VL-IR可变区
<400>3
agatctatat atatatatgc tagc 24
<210>4
<211>27
<212>DNA
<213>人工的
<220>
<223>在CMV-启动子的3’端的BglII限制性位点和在<IGF-IR>HuMab抗体轻链恒定区内部的BbsI限制性位点
<400>4
cgaactgtgg ctgcaccatc tgtcttc 27
<210>5
<211>15
<212>PRT
<213>小家鼠
<400>5
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210>6
<211>15
<212>PRT
<213>人工的
<220>
<223>接头1
<400>6
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
<210>7
<211>25
<212>PRT
<213>人工的
<220>
<223>接头2
<400>7
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25
<210>8
<211>15
<212>PRT
<213>人工的
<220>
<223>接头3
<400>8
Gly Gln Gln Gln Gln Gly Gln Gln Gln Gln Gly Gln Gln Gln Gln
1 5 10 15
<210>9
<211>17
<212>PRT
<213>人工的
<220>
<223>接头4
<400>9
Gly Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser
1 5 10 15
Gly
<210>10
<211>3
<212>PRT
<213>人工的
<220>
<223>接头5
<400>10
Gly Ser Thr
1
<210>11
<211>345
<212>PRT
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>源自HN-1分离株LAI/IIIB克隆BH8的HIV-1gp41糖蛋白的天然氨基酸序列(基因座HIVH3BH8)(bp-位置：507-851)
<400>11
Ala Val Gly Ile Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala Ala Gly
1 5 10 15
Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg Gln
20 25 30
Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile
35 40 45
Glu Gly Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln
50 55 60
Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln
65 70 75 80
Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala
85 90 95
Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp
100 105 110
Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr
115 120 125
Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys
130 135 140
Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn
145 150 155 160
Trp Phe Asn Ile Thr Asn Trp Leu Trp Tyr Ile Lys Leu Phe Ile Met
165 170 175
Ile Val Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser
180 185 190
Ile Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr
195 200 205
His Leu Pro Asn Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu
210 215 220
Glu Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly
225 230 235 240
Ser Leu Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser
245 250 255
Tyr His Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu
260 265 270
Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu
275 280 285
Leu Gln Tyr Trp Ser Gln Glu Leu Lys Asn Ser Ala Val Asn Leu Leu
290 295 300
Asn Ala Thr Ala Ile Ala Val Ala Glu Gly Thr Asp Arg Val Ile Glu
305 310 315 320
Leu Val Gln Ala Ala Tyr Arg Ala Ile Arg His Ile Pro Arg Arg Ile
325 330 335
Arg Gln Gly Leu Glu Arg Ile Leu Leu
340 345
<210>12
<211>36
<212>PRT
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>源自HIV-1gp41胞外结构域的天然氨基酸序列(bp-位置：621-656)
<400>12
Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu
1 5 10 15
Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu
20 25 30
Gln Glu Leu Leu
35
<210>13
<211>123
<212>PRT
<213>人免疫缺陷病毒
<220>
<221>misc feature
<223>HIV-1gp41胞外结构域变体I568P(单突变)，pb-位置
534-656
<400>13
Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn
1 5 10 15
Leu Leu Arg Ala Ile Glu Gly Gln Gln His Leu Leu Gln Leu Thr Val
20 25 30
Trp Gly Pro Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr
35 40 45
Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu
50 55 60
Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser
65 70 75 80
Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
85 90 95
Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln
100 105 110
Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu
115 120
<210>14
<211>135
<212>PRT
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>HIV-1gp41胞外结构域变体I568P，L550E，L566E，I580E
(四突变)，bp-位置522-656
<400>14
Gly Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg
1 5 10 15
Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Glu Leu Arg Ala
20 25 30
Ile Glu Gly Gln Gln His Leu Glu Gln Leu Thr Val Trp Gly Pro Lys
35 40 45
Gln Leu Gln Ala Arg Glu Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln
50 55 60
Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr
65 70 75 80
Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile
85 90 95
Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr
100 105 110
Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu
115 120 125
Lys Asn Glu Gln Glu Leu Leu
130 135
<210>15
<211>133
<212>DNA
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>插入物4964
<400>15
agatctatat atatatatgc tagcgaaatt gtgttgacac agtctccagc caccctgtct 60
ttgtctccag gggaaagagc caccctctcc tgcagggcca gtcagagtgt tagtagctac 120
ttagcctggt acc 133
<210>16
<211>249
<212>DNA
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>插入物4965
<400>16
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctctctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggcgg gggtggatcc ggcggcgggg gcagcggcgg gggaggctcc 240
ggcgctagc 249
<210>17
<211>279
<212>DNA
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>插入物4966
<400>17
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctctctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggcgg gggtggctcc ggcggcgggg gcagcggcgg gggaggctcc 240
ggcgggggcg gatccggggg cggtggcagc ggcgctagc 279
<210>18
<211>252
<212>DNA
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>插入物4967
<400>18
agatcttttg ccaccatgga caccctgtgc agcaccctgc tcctgctgac catccccagc 60
tgggtgctct cccaaatctg gaacaacatg acctggatgg agtgggaccg cgagatcaat 120
aactacacaa gcttgatcca ctccctgatc gaggaaagcc agaaccagca ggagaagaac 180
gagcaggagc tcctgggatc cagctccagc tccagctcca gctccagcag tagctccagc 240
tctggcgcta gc 252
<210>19
<211>589
<212>DNA
<213>人免疫缺陷病毒
<220>
<221>misc_feature
<223>插入物4969
<400>19
agatctagct ctgggagagg agcccagcac tagaagtcgg cggtgtttcc attcggtgat 60
cagcactgaa cacagaggac tcaccatgga gtttgggctg agctgggtgt tcctcgtggc 120
actgctcagg ggtgtacagt gtcaggtgca ggcccgccag ctgctctccg gcatcgtcca 180
gcagcaaaac aatctgctgc gggcgatcga ggggcagcag cacctcctgc agctgacggt 240
gtggggtccc aagcagctgc aggcccgcat tctggccgtg gaacggtacc tgaaggacca 300
gcagctgctc ggcatctggg gatgctctgg caagcttatc tgcaccacag ccgtcccctg 360
gaacgctagc tggagtaaca aaagcctgga gcaaatttgg aacaacatga cctggatgga 420
gtgggatcgc gagatcaata attacacaag cctgatccac tccctgatcg aggaaagcca 480
gaaccagcag gagaagaacg agcaggagct cctgggcggg ggcggatccg gcggcggggg 540
cagcggtggg ggcggctccg gccgaactgt ggctgcacca tctgtcttc 589
<210>20
<211>15
<212>PRT
<213>小家鼠
<400>20
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys
1 5 10 15
<210>21
<211>15
<212>PRT
<213>小家鼠
<400>21
Met Asn Phe Gly Leu Ser Leu Ile Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210>22
<211>13
<212>PRT
<213>小家鼠
<400>22
Met Gly Val Pro Thr Gln Leu Leu Leu Leu Trp Leu Thr
1 5 10
<210>23
<211>16
<212>PRT
<213>小家鼠
<400>23
Met Arg Val Leu Ala Glu Leu Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
<210>24
<211>16
<212>PRT
<213>小家鼠
<400>24
Met Arg Val Leu Pro Glu Phe Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
<210>25
<211>16
<212>PRT
<213>小家鼠
<400>25
Met Arg Cys Ser Leu Gln Phe Leu Gly Val Leu Met Phe Trp Ile Ser
1 5 10 15
<210>26
<211>15
<212>PRT
<213>小家鼠
<400>26
Arg Glu Trp Ser Trp Asn Phe Leu Phe Leu Leu Ser Gly Thr Thr
1 5 10 15
<210>27
<211>15
<212>PRT
<213>小家鼠
<400>27
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>28
<211>19
<212>PRT
<213>人(Homo sapiens)
<400>28
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210>29
<211>19
<212>PRT
<213>人
<400>29
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210>30
<211>19
<212>PRT
<213>人
<400>30
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Ser
1 5 10 15
Ala His Ser
<210>31
<211>19
<212>PRT
<213>人
<400>31
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser
<210>32
<211>19
<212>PRT
<213>人
<400>32
Met Asp Cys Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Thr His Ala
<210>33
<211>19
<212>PRT
<213>人
<400>33
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Asp
1 5 10 15
Ala Tyr Ser
<210>34
<211>19
<212>PRT
<213>人
<400>34
Met Asp Trp Thr Trp Arg Val Phe Cys Leu Leu Ala Val Ala Pro Gly
1 5 10 15
Ala His Ser
<210>35
<211>19
<212>PRT
<213>人
<400>35
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210>36
<211>19
<212>PRT
<213>人
<400>36
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser
<210>37
<211>19
<212>PRT
<213>人
<400>37
Met Asp Thr Leu Cys Tyr Thr Leu Leu Leu Leu Thr Thr Pro Ser Trp
1 5 10 15
Val Leu Ser
<210>38
<211>19
<212>PRT
<213>人
<400>38
Met Glu Leu Gly Leu Ser Trp Val Phe Leu Val AlaIle Leu Glu Gly
1 5 10 15
Val Gln Cys
<210>39
<211>19
<212>PRT
<213>人
<400>39
Met Glu Leu Gly Leu Ser Trp Ile Phe Leu Leu Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>40
<211>19
<212>PRT
<213>人
<400>40
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly
1 5 10 15
Val Gln Cys
<210>41
<211>19
<212>PRT
<213>人
<400>41
Met Glu Leu Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210>42
<211>19
<212>PRT
<213>人
<400>42
Met Glu Phe Gly Leu Ser Trp Ile Phe Leu Ala Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>43
<211>19
<212>PRT
<213>人
<400>43
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>44
<211>19
<212>PRT
<213>人
<400>44
Met Glu Leu Gly Leu Arg Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210>45
<211>19
<212>PRT
<213>人
<400>45
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>46
<211>19
<212>PRT
<213>人
<400>46
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210>47
<211>19
<212>PRT
<213>人
<400>47
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210>48
<211>19
<212>PRT
<213>人
<400>48
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>49
<211>19
<212>PRT
<213>人
<400>49
Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys
<210>50
<211>19
<212>PRT
<213>人
<400>50
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>51
<211>19
<212>PRT
<213>人
<400>51
Met Glu Phe Trp Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>52
<211>20
<212>PRT
<213>人胚系序列
<400>52
Met Thr Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Phe Lys
1 5 10 15
Gly Val Gln Cys
20
<210>53
<211>19
<212>PRT
<213>人
<400>53
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>54
<211>19
<212>PRT
<213>人
<400>54
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Val Ile Leu Gln Gly
1 5 10 15
Val Gln Cys
<210>55
<211>19
<212>PRT
<213>人
<400>55
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210>56
<211>19
<212>PRT
<213>人
<400>56
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>57
<211>19
<212>PRT
<213>人
<400>57
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>58
<211>19
<212>PRT
<213>人
<400>58
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Pro
<210>59
<211>19
<212>PRT
<213>人
<400>59
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>60
<211>19
<212>PRT
<213>人
<400>60
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>61
<211>19
<212>PRT
<213>人
<400>61
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>62
<211>19
<212>PRT
<213>人
<400>62
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>63
<211>19
<212>PRT
<213>人
<400>63
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser
<210>64
<211>19
<212>PRT
<213>人
<400>64
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ser
<210>65
<211>19
<212>PRT
<213>人胚系序列
<400>65
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala
<210>66
<211>20
<212>PRT
<213>人
<400>66
Met Ser Val Ser Phe Leu Ile Phe Leu Pro Val Leu Gly Leu Pro Trp
1 5 10 15
Gly Val Leu Ser
20
<210>67
<211>19
<212>PRT
<213>人
<400>67
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210>68
<211>22
<212>PRT
<213>人
<400>68
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210>69
<211>22
<212>PRT
<213>人胚系序列
<400>69
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210>70
<211>22
<212>PRT
<213>人
<400>70
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Gln Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys
20
<210>71
<211>22
<212>PRT
<213>人
<400>71
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys
20
<210>72
<211>22
<212>PRT
<213>人
<400>72
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Asp Thr Arg Cys
20
<210>73
<211>22
<212>PRT
<213>人
<400>73
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210>74
<211>22
<212>PRT
<213>人
<400>74
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210>75
<211>22
<212>PRT
<213>人
<400>75
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210>76
<211>22
<212>PRT
<213>人
<400>76
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210>77
<211>22
<212>PRT
<213>人
<400>77
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210>78
<211>22
<212>PRT
<213>人
<400>78
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210>79
<211>22
<212>PRT
<213>人
<400>79
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys
20
<210>80
<211>22
<212>PRT
<213>人
<400>80
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys
20
<210>81
<211>22
<212>PRT
<213>人
<400>81
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210>82
<211>22
<212>PRT
<213>人
<400>82
Met Asp Met Arg Val Pro Ala Gln Arg Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
<210>83
<211>20
<212>PRT
<213>人
<400>83
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Gly Ala Arg Cys
20
<210>84
<211>22
<212>PRT
<213>人
<400>84
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210>85
<211>22
<212>PRT
<213>人胚系序列
<400>85
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys
20
<210>86
<211>22
<212>PRT
<213>人
<400>86
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Lys Cys
20
<210>87
<211>20
<212>PRT
<213>人
<400>87
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Glu
20
<210>88
<211>20
<212>PRT
<213>人
<400>88
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Glu
20
<210>89
<211>20
<212>PRT
<213>人
<400>89
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210>90
<211>20
<212>PRT
<213>人
<400>90
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210>91
<211>20
<212>PRT
<213>人
<400>91
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala
20
<210>92
<211>20
<212>PRT
<213>人
<400>92
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala
20
<210>93
<211>20
<212>PRT
<213>人
<400>93
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Ser
1 5 10 15
Gly Ser Ser Gly
20
<210>94
<211>20
<212>PRT
<213>人
<400>94
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Ser
1 5 10 15
Gly Ser Ser Gly
20
<210>95
<211>20
<212>PRT
<213>人
<400>95
Met Arg Leu Leu Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly
20
<210>96
<211>20
<212>PRT
<213>人
<400>96
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210>97
<211>20
<212>PRT
<213>人
<400>97
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210>98
<211>20
<212>PRT
<213>人
<400>98
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210>99
<211>20
<212>PRT
<213>人
<400>99
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210>100
<211>20
<212>PRT
<213>人
<400>100
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210>101
<211>20
<212>PRT
<213>人
<400>101
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Thr Thr Gly
20
<210>102
<211>23
<212>PRT
<213>人
<400>102
Met Glu Pro Trp Lys Pro Gln His Ser Phe Phe Phe Leu Leu Leu Leu
1 5 10 15
Trp Leu Pro Asp Thr Thr Gly
20
<210>103
<211>20
<212>PRT
<213>人
<400>103
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly
20
<210>104
<211>20
<212>PRT
<213>人
<400>104
Met Gly Ser Gln Val His Leu Leu Ser Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
Asp Thr Arg Ala
20
<210>105
<211>19
<212>PRT
<213>人
<400>105
Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly
<210>106
<211>19
<212>PRT
<213>人
<400>106
Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly
<210>107
<211>20
<212>PRT
<213>人
<400>107
Met Val Ser Pro Leu Gln Phe Leu Arg Leu Leu Leu Leu Trp Val Pro
1 5 10 15
Ala Ser Arg Gly
20
<210>108
<211>19
<212>PRT
<213>人
<400>108
Met Ala Trp Ser Pro Leu Phe Leu Thr Leu Ile Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210>109
<211>19
<212>PRT
<213>人
<400>109
Met Ala Trp Ser Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210>110
<211>19
<212>PRT
<213>人
<400>110
Met Ala Ser Phe Pro Leu Leu Leu Thr Leu Leu Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210>111
<211>19
<212>PRT
<213>人
<400>111
Met Ala Gly Phe Pro Leu Leu Leu Thr Leu Leu Thr His Cys Ala Gly
1 5 10 15
Ser Trp Ala
<210>112
<211>19
<212>PRT
<213>人
<400>112
Met Thr Cys Ser Pro Leu Leu Leu Thr Leu Leu Ile His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210>113
<211>19
<212>PRT
<213>人
<400>113
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210>114
<211>19
<212>PRT
<213>人
<400>114
Met Ala Trp Ala Leu Leu Leu Leu Ser Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210>115
<211>19
<212>PRT
<213>人
<400>115
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210>116
<211>19
<212>PRT
<213>人
<400>116
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Gly Thr Gly
1 5 10 15
Ser Trp Ala
<210>117
<211>19
<212>PRT
<213>人
<400>117
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Asp Thr Gly
1 5 10 15
Ser Trp Ala
<210>118
<211>19
<212>PRT
<213>人
<400>118
Met Ala Trp Ile Pro Leu Phe Leu Gly Val Leu Ala Tyr Cys Thr Gly
1 5 10 15
Ser Val Ala
<210>119
<211>19
<212>PRT
<213>人
<400>119
Met Ala Trp Thr Ala Leu Leu Leu Ser Leu Leu Ala His Phe Thr Gly
1 5 10 15
Ser Val Ala
<210>120
<211>19
<212>PRT
<213>人
<400>120
Met Ala Trp Thr Pro Leu Leu Leu Pro Leu Leu Thr Phe Cys Thr Val
1 5 10 15
Ser Glu Ala
<210>121
<211>19
<212>PRT
<213>人
<400>121
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Thr Leu Cys Thr Gly
1 5 10 15
Ser Glu Ala
<210>122
<211>19
<212>PRT
<213>人
<400>122
Met Ala Trp Thr Pro Leu Trp Leu Thr Leu Leu Thr Leu Cys Ile Gly
1 5 10 15
Ser Val Val
<210>123
<211>19
<212>PRT
<213>人
<400>123
Met Ala Trp Thr Val Leu Leu Leu Gly Leu Leu Ser Hi s Cys Thr Gly
1 5 10 15
Ser Val Thr
<210>124
<211>19
<212>PRT
<213>人
<400>124
Met Ala Trp Ala Thr Leu Leu Leu Pro Leu Leu Asn Leu Tyr Thr Gly
1 5 10 15
Ser Ile Ala
<210>125
<211>19
<212>PRT
<213>人
<400>125
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Thr Leu Cys Thr Gly
1 5 10 15
Ser Glu Ala
<210>126
<211>19
<212>PRT
<213>人
<400>126
Met Ala Trp Ile Pro Leu Leu Leu Pro Leu Leu Ile Leu Cys Thr Val
1 5 10 15
Ser Val Ala
<210>127
<211>19
<212>PRT
<213>人
<400>127
Met Ala Trp Val Ser Phe Tyr Leu Leu Pro Phe Ile Phe Ser Thr Gly
1 5 10 15
Leu Cys Ala
<210>128
<211>21
<212>PRT
<213>人
<400>128
Met Ala Trp Thr Gln Leu Leu Leu Leu Phe Pro Leu Leu Leu His Trp
1 5 10 15
Thr Gly Ser Leu Ser
20
<210>129
<211>20
<212>PRT
<213>人
<400>129
Met Ala Trp Thr Pro Leu Leu Phe Leu Thr Leu Leu Leu His Cys Thr
1 5 10 15
Gly Ser Leu Ser
20
<210>130
<211>19
<212>PRT
<213>人
<400>130
Met Ala Trp Thr Pro Leu Leu Leu Leu Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210>131
<211>19
<212>PRT
<213>人
<400>131
Met Ala Trp Thr Pro Leu Leu Leu Leu Phe Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210>132
<211>19
<212>PRT
<213>人
<400>132
Met Ala Trp Thr Leu Leu Leu Leu Val Leu Leu Ser His Cys Thr Gly
1 5 10 15
Ser Leu Ser
<210>133
<211>19
<212>PRT
<213>人
<400>133
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala
<210>134
<211>19
<212>PRT
<213>人
<400>134
Met Ala Trp Thr Pro Leu Phe Leu Phe Leu Leu Thr Cys Cys Pro Gly
1 5 10 15
Ser Asn Ser
<210>135
<211>19
<212>PRT
<213>人
<400>135
Met Ala Trp Thr Pro Leu Phe Leu Phe Leu Leu Thr Cys Cys Pro Gly
1 5 10 15
Ser Asn Ser
<210>136
<211>19
<212>PRT
<213>人
<400>136
Met Ala Trp Met Met Leu Leu Leu Gly Leu Leu Ala Tyr Gly Ser Gly
1 5 10 15
Val Asp Ser
<210>137
<211>19
<212>PRT
<213>人
<400>137
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ser Leu Leu Thr Gly
1 5 10 15
Ser Leu Ser
<210>138
<211>19
<212>PRT
<213>人
<400>138
Met Pro Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr His Ser Ala Val
1 5 10 15
Ser Val Val
<210>139
<211>18
<212>PRT
<213>人工的
<220>
<223>接头6
<400>139
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Ala Ser
<210>140
<211>19
<212>PRT
<213>人工的
<220>
<223>接头7
<400>140
Gly Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser
1 5 10 15
Gly Ala Ser
<210>141
<211>14
<212>PRT
<213>小家鼠
<400>141
Met Asp Phe Gly Leu Ile Phe Phe Ile Val Ala Leu Leu Lys
1 5 10
<210>142
<211>10
<212>PRT
<213>小家鼠
<400>142
Glu Leu Trp Val Leu Met Val Trp Val Pro
1 5 10
<210>143
<211>13
<212>PRT
<213>小家鼠
<400>143
Glu Leu Trp Val Leu Met Val Trp Val Pro Ser Thr Ser
1 5 10
<210>144
<211>18
<212>PRT
<213>小家鼠
<400>144
His Asp His Ala Leu Thr Ser Ser Ser Pro Gln Pro Ser Ser Pro Leu
1 5 10 15
Cys Leu
<210>145
<211>16
<212>PRT
<213>小家鼠
<400>145
Leu Ala Val Ile Thr Ser Asn Ile Trp Phe Pro Met Val Cys Met Ser
1 5 10 15
<210>146
<211>21
<212>PRT
<213>小家鼠
<400>146
Met Asp Met Trp Thr Ser Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Leu Ala Arg Cys
20
<210>147
<211>18
<212>PRT
<213>小家鼠
<400>147
Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Val
1 5 10 15
Leu Ser
<210>148
<211>16
<212>PRT
<213>小家鼠
<400>148
Met Leu Arg Ala Ile Lys Ala Ala Pro Phe Ser Arg Phe Gly Cys Ser
1 5 10 15
<210>149
<211>19
<212>PRT
<213>小家鼠
<400>149
Met Arg Ala Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
Ala Arg Cys
<210>150
<211>16
<212>PRT
<213>小家鼠
<400>150
Met Arg Cys Ser Pro His Phe Leu Glu Leu Leu Val Phe Trp Ile Leu
1 5 10 15
<210>151
<211>19
<212>PRT
<213>小家鼠
<400>151
Met Arg Pro Thr Leu Ser Phe Leu Gly Ser Cys Cys Ser Ser Leu Ile
1 5 10 15
Leu Arg Cys
<210>152
<211>19
<212>PRT
<213>小家鼠
<400>152
Met Arg Thr Pro Ala His Phe Leu Gly Leu Leu Leu Leu Cys Phe Leu
1 5 10 15
Gly Arg Cys
<210>153
<211>19
<212>PRT
<213>小家鼠
<400>153
Met Arg Thr Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Ser
1 5 10 15
Ala Arg Cys
<210>154
<211>19
<212>PRT
<213>小家鼠
<400>154
Met Ser Leu Leu Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Arg Cys
<210>155
<211>19
<212>PRT
<213>小家鼠
<400>155
Met Ser Leu Pro Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210>156
<211>18
<212>PRT
<213>小家鼠
<400>156
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser
<210>157
<211>16
<212>PRT
<213>小家鼠
<400>157
Met Thr Ser Leu Ser Gln Leu Leu Gly Met Leu Met Leu Gln Ser Leu
1 5 10 15
<210>158
<211>16
<212>PRT
<213>小家鼠
<400>158
Met Val Phe Ala Pro Gln Ile Leu Gly Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
<210>159
<211>16
<212>PRT
<213>小家鼠
<400>159
Met Val Phe Thr Pro His Ile Leu Gly Leu Leu Leu Phe Trp Ile Ser
1 5 10 15
<210>160
<211>19
<212>PRT
<213>小家鼠
<400>160
Gln His Gly His Glu Gly Leu Cys Ser Val Ser Trp Val Pro Val Ala
1 5 10 15
Thr Asn Ser
<210>161
<211>18
<212>PRT
<213>小家鼠
<400>161
Arg Glu Trp Ser Trp Asn Phe Leu Phe Leu Leu Ser Gly Thr Thr Val
1 5 10 15
Ser Ser
<210>162
<211>19
<212>PRT
<213>小家鼠
<400>162
Thr Asp Phe His Met Gln Ile Phe Ser Phe Met Leu Ile Ser Phe Thr
1 5 10 15
Ala Arg Cys
<210>163
<211>16
<212>PRT
<213>小家鼠
<400>163
Met Glu Phe Gln Thr Gln Val Leu Met Ser Leu Leu Leu Cys Met Ser
1 5 10 15
<210>164
<211>16
<212>PRT
<213>小家鼠
<400>164
Met Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210>165
<211>16
<212>PRT
<213>小家鼠
<400>165
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
<210>166
<211>16
<212>PRT
<213>小家鼠
<400>166
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
<210>167
<211>16
<212>PRT
<213>小家鼠
<400>167
Met Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>168
<211>16
<212>PRT
<213>小家鼠
<400>168
Met Lys Ser Gln Thr Gln Val Phe Ile Phe Leu Leu Leu Cys Val Ser
1 5 10 15
<210>169
<211>16
<212>PRT
<213>小家鼠
<400>169
Met Lys Ser Gln Thr Gln Val Phe Val Phe Leu Leu Leu Cys Val Ser
1 5 10 15
<210>170
<211>15
<212>PRT
<213>小家鼠
<400>170
Met Ala Trp Ile Ser Leu Ile Leu Ser Leu Leu Ala Leu Ser Ser
1 5 10 15
<210>171
<211>15
<212>PRT
<213>小家鼠
<400>171
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser
1 5 10 15
<210>172
<211>16
<212>PRT
<213>小家鼠
<400>172
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210>173
<211>15
<212>PRT
<213>小家鼠
<400>173
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr
1 5 10 15
<210>174
<211>16
<212>PRT
<213>小家鼠
<400>174
Met Arg Phe Gln Val Gln Val Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
<210>175
<211>16
<212>PRT
<213>小家鼠
<400>175
Met Arg Pro Ser Ile Gln Phe Leu Gly Leu Leu Leu Phe Trp Leu His
1 5 10 15
<210>176
<211>18
<212>PRT
<213>小家鼠
<400>176
Met Asp Ile Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>177
<211>18
<212>PRT
<213>小家鼠
<400>177
Met Asp Met Met Val Leu Ala Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>178
<211>18
<212>PRT
<213>小家鼠
<400>178
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>179
<211>18
<212>PRT
<213>小家鼠
<400>179
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>180
<211>18
<212>PRT
<213>小家鼠
<400>180
Met Asp Met Arg Ala Pro Ala Gln Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>181
<211>18
<212>PRT
<213>小家鼠
<400>181
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>182
<211>18
<212>PRT
<213>小家鼠
<400>182
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>183
<211>18
<212>PRT
<213>小家鼠
<400>183
Met Asp Met Trp Thr Ser Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Leu
<210>184
<211>18
<212>PRT
<213>小家鼠
<400>184
Met Asn Thr Arg Ala Pro Ala Glu Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Leu
<210>185
<211>16
<212>PRT
<213>小家鼠
<400>185
Met Arg Ala Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
<210>186
<211>16
<212>PRT
<213>小家鼠
<400>186
Met Arg Thr Pro Ala Pro Phe Leu Gly Leu Leu Leu Phe Cys Phe Ser
1 5 10 15
<210>187
<211>16
<212>PRT
<213>小家鼠
<400>187
Met Ser Ile Ser Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>188
<211>16
<212>PRT
<213>小家鼠
<400>188
Met Ser Leu Pro Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>189
<211>16
<212>PRT
<213>小家鼠
<400>189
Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>190
<211>16
<212>PRT
<213>小家鼠
<400>190
Met Ser Val Pro Thr Gln Leu Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>191
<211>16
<212>PRT
<213>小家鼠
<400>191
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>192
<211>16
<212>PRT
<213>小家鼠
<400>192
Thr Asp Phe His Met Gln Ile Phe Ser Phe Met Leu Ile Ser Phe Thr
1 5 10 15
<210>193
<211>15
<212>PRT
<213>小家鼠
<400>193
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser
1 5 10 15
<210>194
<211>16
<212>PRT
<213>小家鼠
<400>194
Met Arg Cys Leu Ala Glu Phe Leu Arg Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210>195
<211>18
<212>PRT
<213>小家鼠
<400>195
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ser
1 5 10 15
Ser Ser
<210>196
<211>21
<212>PRT
<213>小家鼠
<400>196
Met Asp Ile Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>197
<211>21
<212>PRT
<213>小家鼠
<400>197
Met Asp Met Met Val Leu Ala Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>198
<211>21
<212>PRT
<213>小家鼠
<400>198
Met Asp Met Arg Ala Pro Ala Gln Phe Phe Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ile Arg Cys
20
<210>199
<211>21
<212>PRT
<213>小家鼠
<400>199
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>200
<211>21
<212>PRT
<213>小家鼠
<400>200
Met Asp Met Arg Ala Pro Ala Gln Ile Phe Gly Phe Leu Leu Leu Leu
1 5 10 15
Phe Gln Thr Arg Cys
20
<210>201
<211>21
<212>PRT
<213>小家鼠
<400>201
Met Asp Met Arg Ala Pro Ala Gln Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>202
<211>18
<212>PRT
<213>小家鼠
<400>202
Met Asp Met Arg Ala Ser Ala Gln Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>203
<211>18
<212>PRT
<213>小家鼠
<400>203
Met Asp Met Arg Asp Pro Pro Gln Phe Leu Ala Phe Leu Leu Leu Trp
1 5 10 15
Ile Pro
<210>204
<211>21
<212>PRT
<213>小家鼠
<400>204
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ile Lys Cys
20
<210>205
<211>21
<212>PRT
<213>小家鼠
<400>205
Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Thr Arg Cys
20
<210>206
<211>19
<212>PRT
<213>小家鼠
<400>206
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>207
<211>19
<212>PRT
<213>小家鼠
<400>207
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser
1 5 10 15
Thr Cys Gly
<210>208
<211>19
<212>PRT
<213>小家鼠
<400>208
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>209
<211>19
<212>PRT
<213>小家鼠
<400>209
Met Asp Ser Gln Ala Arg Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>210
<211>19
<212>PRT
<213>小家鼠
<400>210
Met Glu Phe Gln Thr Gln Val Phe Val Phe Val Leu Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210>211
<211>19
<212>PRT
<213>小家鼠
<400>211
Met Glu Phe Gln Thr Gln Val Leu Met Ser Leu Leu Leu Cys Met Ser
1 5 10 15
Ala Cys Ala
<210>212
<211>19
<212>PRT
<213>小家鼠
<400>212
Met Glu Lys Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>213
<211>19
<212>PRT
<213>小家鼠
<400>213
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>214
<211>19
<212>PRT
<213>小家鼠
<400>214
Met Glu Ser Gln Ile Gln Ala Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210>215
<211>19
<212>PRT
<213>小家鼠
<400>215
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210>216
<211>16
<212>PRT
<213>小家鼠
<400>216
Met Ser Leu Leu Thr Gln Leu Gln Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>217
<211>7
<212>PRT
<213>小家鼠
<400>217
Leu Ile Leu Lys Val Gln Cys
1 5
<210>218
<211>7
<212>PRT
<213>小家鼠
<400>218
Leu Val Leu Lys Val Leu Cys
1 5
<210>219
<211>21
<212>PRT
<213>小家鼠
<400>219
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>220
<211>19
<212>PRT
<213>小家鼠
<400>220
Met Lys Leu Pro Val Leu Leu Val Val Leu Leu Leu Phe Thr Ser Pro
1 5 10 15
Ser Ser Ser
<210>221
<211>18
<212>PRT
<213>小家鼠
<400>221
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ser
1 5 10 15
Ser Ser
<210>222
<211>19
<212>PRT
<213>小家鼠
<400>222
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10 15
Thr Asn Gly
<210>223
<211>19
<212>PRT
<213>小家鼠
<400>223
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg
1 5 10 15
Thr Asn Gly
<210>224
<211>19
<212>PRT
<213>小家鼠
<400>224
Met Met Ser Pro Val His Ser Ile Phe Ile Leu Leu Leu Trp Ile Val
1 5 10 15
Ile Ser Gly
<210>225
<211>19
<212>PRT
<213>小家鼠
<400>225
Met Met Ser Pro Val Gln Phe Leu Phe Leu Leu Met Leu Trp Ile Gln
1 5 10 15
Thr Asn Gly
<210>226
<211>18
<212>PRT
<213>小家鼠
<400>226
Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Val
1 5 10 15
Gln Cys
<210>227
<211>19
<212>PRT
<213>小家鼠
<400>227
Met Asn Leu Pro Val His Leu Leu Val Leu Leu Leu Phe Trp Ile Pro
1 5 10 15
Ser Arg Gly
<210>228
<211>21
<212>PRT
<213>小家鼠
<400>228
Met Asn Thr Arg Ala Pro Ala Glu Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Leu Ala Arg Cys
20
<210>229
<211>19
<212>PRT
<213>小家鼠
<400>229
Met Arg Phe Gln Val Gln Val Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
Ala Gln Cys
<210>230
<211>18
<212>PRT
<213>小家鼠
<400>230
Met Arg Val Leu Ser Leu Leu Tyr Leu Leu Thr Ala Ile Pro Gly Ile
1 5 10 15
Leu Ser
<210>231
<211>21
<212>PRT
<213>小家鼠
<400>231
Met Asp Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Ile Leu Ser Ser Gly
20
<210>232
<211>21
<212>PRT
<213>小家鼠
<400>232
Met Asp Phe Gln Met Gln Ile Ile Ser Leu Leu Leu Ile Ser Val Thr
1 5 10 15
Ile Val Ser Asn Gly
20
<210>233
<211>21
<212>PRT
<213>小家鼠
<400>233
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Thr
1 5 10 15
Ile Leu Thr Asn Gly
20
<210>234
<211>21
<212>PRT
<213>小家鼠
<400>234
Met Asp Met Arg Ala Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>235
<211>21
<212>PRT
<213>小家鼠
<400>235
Met Asn Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Ile Gly Ser Ser Gly
20
<210>236
<211>19
<212>PRT
<213>小家鼠
<400>236
Met Thr Met Leu Ser Leu Val Leu Leu Leu Ser Phe Leu Leu Leu Cys
1 5 10 15
Ser Arg Ala
<210>237
<211>19
<212>PRT
<213>小家鼠
<400>237
Met Val Ser Thr Pro Gln Phe Leu Val Phe Leu Leu Phe Trp Ile Pro
1 5 10 15
Ala Cys Gly
<210>238
<211>20
<212>PRT
<213>小家鼠
<400>238
Thr Glu Leu Ile Cys Val Phe Leu Phe Leu Leu Ser Val Thr Ala Ile
1 5 10 15
Leu Ser Ser Gly
20
<210>239
<211>17
<212>PRT
<213>小家鼠
<400>239
Met Asp Cys Gly Ile Ser Leu Val Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Cys
<210>240
<211>19
<212>PRT
<213>小家鼠
<400>240
Met Asp Met Trp Val Gln Ile Phe Ser Leu Leu Leu Ile Cys Val Thr
1 5 10 15
Ser Lys Gly
<210>241
<211>11
<212>PRT
<213>小家鼠
<400>241
Leu Leu Ile Ser Val Thr Ile Met Ser Arg Gly
1 5 10
<210>242
<211>21
<212>PRT
<213>小家鼠
<400>242
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>243
<211>21
<212>PRT
<213>小家鼠
<400>243
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ile Ser
1 5 10 15
Val Met Ser Arg Gly
20
<210>244
<211>21
<212>PRT
<213>小家鼠
<400>244
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>245
<211>21
<212>PRT
<213>小家鼠
<400>245
Met Asp Leu Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ile Val Thr
1 5 10 15
Ile Met Ser Arg Gly
20
<210>246
<211>19
<212>PRT
<213>小家鼠
<400>246
Met Gly Glu Gln Arg Ile Arg Ser Cys His Ala Thr Ser Gly Ala Glu
1 5 10 15
Ser Ala Arg
<210>247
<211>20
<212>PRT
<213>小家鼠
<400>247
Met Gly Ser Gln Val His Leu Leu Ser Phe Leu Leu Leu Trp Ile Ser
1 5 10 15
Asp Thr Arg Ala
20
<210>248
<211>21
<212>PRT
<213>小家鼠
<400>248
Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser Ser Arg Ala
20
<210>249
<211>18
<212>PRT
<213>小家鼠
<400>249
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu Ser
1 5 10 15
Arg Ala
<210>250
<211>22
<212>PRT
<213>小家鼠
<220>
<221>misc_feature
<222>(2)..(2)
<223>Xaa可为任一天然存在的氨基酸
<400>250
Met Xaa Thr Met Asp Glu His Glu Ser Gly Ala Val Thr Pro His Gln
1 5 10 15
Val Leu Lys Ser Arg Ala
20
<210>251
<211>18
<212>PRT
<213>小家鼠
<400>251
Ile Lys Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210>252
<211>18
<212>PRT
<213>小家鼠
<400>252
Ile Lys Trp Ser Trp Ile Ser Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210>253
<211>7
<212>PRT
<213>小家鼠
<400>253
Leu Ile Leu Lys Val Gln Cys
1 5
<210>254
<211>7
<212>PRT
<213>小家鼠
<400>254
Leu Val Leu Lys Val Gln Cys
1 5
<210>255
<211>18
<212>PRT
<213>小家鼠
<400>255
Met Ala Val Val Thr Gly Lys Gly Leu Pro Ser Pro Lys Leu Glu Val
1 5 10 15
Asn Ser
<210>256
<211>17
<212>PRT
<213>小家鼠
<400>256
Met Asp Phe Gly Leu Ile Phe Phe Ile Val Ala Leu Leu Lys Val Gln
1 5 10 15
Cys
<210>257
<211>18
<212>PRT
<213>小家鼠
<400>257
Met Asp Phe Gly Leu Ser Leu Val Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Gln Cys
<210>258
<211>21
<212>PRT
<213>小家鼠
<400>258
Met Asp Met Arg Ala Ser Ala Gln Phe His Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Ala Arg Cys
20
<210>259
<211>19
<212>PRT
<213>小家鼠
<400>259
Met Glu Trp Glu Leu Ser Leu Ile Phe Ile Phe Ala Leu Leu Lys Asp
1 5 10 15
Val Gln Cys
<210>260
<211>18
<212>PRT
<213>小家鼠
<400>260
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210>261
<211>18
<212>PRT
<213>小家鼠
<400>261
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala Ile
1 5 10 15
His Ser
<210>262
<211>18
<212>PRT
<213>小家鼠
<400>262
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>263
<211>18
<212>PRT
<213>小家鼠
<400>263
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr Ala
1 5 10 15
Leu Ser
<210>264
<211>18
<212>PRT
<213>小家鼠
<400>264
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>265
<211>18
<212>PRT
<213>小家鼠
<400>265
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210>266
<211>18
<212>PRT
<213>小家鼠
<400>266
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>267
<211>18
<212>PRT
<213>小家鼠
<400>267
Met Gly Trp Ser Trp Ile Phe Phe Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>268
<211>18
<212>PRT
<213>小家鼠
<400>268
Met Gly Trp Ser Trp Ile Phe Leu Phe Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>269
<211>18
<212>PRT
<213>小家鼠
<400>269
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala Val
1 5 10 15
Leu Ser
<210>270
<211>18
<212>PRT
<213>小家鼠
<400>270
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala Val
1 5 10 15
His Ser
<210>271
<211>18
<212>PRT
<213>小家鼠
<400>271
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210>272
<211>15
<212>PRT
<213>小家鼠
<400>272
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>273
<211>19
<212>PRT
<213>小家鼠
<400>273
Ile Asp Ile Asn Val Gln Ile Phe Arg Phe Leu Leu Ile Ser Val Thr
1 5 10 15
Ser Ser Gly
<210>274
<211>16
<212>PRT
<213>小家鼠
<400>274
Met Asn Met Leu Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Ala
1 5 10 15
<210>275
<211>16
<212>PRT
<213>小家鼠
<400>275
Met Arg Thr Pro Ala His Phe Leu Gly Leu Leu Leu Leu Cys Phe Leu
1 5 10 15
<210>276
<211>18
<212>PRT
<213>小家鼠
<400>276
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>277
<211>16
<212>PRT
<213>小家鼠
<400>277
Met Asn Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
<210>278
<211>15
<212>PRT
<213>小家鼠
<400>278
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>279
<211>16
<212>PRT
<213>小家鼠
<400>279
Met Asp Phe Gln Val Gln Ile Phe Gln Ile Pro Val Lys Gln Cys Leu
1 5 10 15
<210>280
<211>16
<212>PRT
<213>小家鼠
<400>280
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210>281
<211>16
<212>PRT
<213>小家鼠
<400>281
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
<210>282
<211>18
<212>PRT
<213>小家鼠
<400>282
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>283
<211>15
<212>PRT
<213>小家鼠
<400>283
Met Ala Val Leu Ala Leu Leu Phe Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210>284
<211>16
<212>PRT
<213>小家鼠
<400>284
Met Asp Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
<210>285
<211>16
<212>PRT
<213>小家鼠
<400>285
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210>286
<211>15
<212>PRT
<213>小家鼠
<400>286
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Arg
1 5 10 15
<210>287
<211>16
<212>PRT
<213>小家鼠
<400>287
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Thr
1 5 10 15
<210>288
<211>15
<212>PRT
<213>小家鼠
<400>288
Thr Glu Leu Ile Cys Val Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>289
<211>6
<212>PRT
<213>小家鼠
<400>289
Leu Leu Ile Ser Val Thr
15
<210>290
<211>16
<212>PRT
<213>小家鼠
<400>290
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210>291
<211>16
<212>PRT
<213>小家鼠
<400>291
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
<210>292
<211>16
<212>PRT
<213>小家鼠
<400>292
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
<210>293
<211>16
<212>PRT
<213>小家鼠
<400>293
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
1 5 10 15
<210>294
<211>16
<212>PRT
<213>小家鼠
<400>294
Met Asp Leu Gln Val Gln Ile Ile Ser Phe Leu Leu Ile Ile Val Thr
1 5 10 15
<210>295
<211>16
<212>PRT
<213>小家鼠
<400>295
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210>296
<211>15
<212>PRT
<213>小家鼠
<400>296
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Ile
1 5 10 15
<210>297
<211>15
<212>PRT
<213>小家鼠
<400>297
Met Lys Leu Trp Leu Asn Trp Ile Leu Leu Val Ala Leu Leu Asn
1 5 10 15
<210>298
<211>18
<212>PRT
<213>小家鼠
<400>298
Met Asp Met Arg Ala Pro Ala Gln Phe Phe Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>299
<211>16
<212>PRT
<213>小家鼠
<400>299
Met Ile Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210>300
<211>16
<212>PRT
<213>小家鼠
<400>300
Met Met Ser Pro Val His Ser Ile Phe Ile Leu Leu Leu Trp Ile Val
1 5 10 15
<210>301
<211>16
<212>PRT
<213>小家鼠
<400>301
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210>302
<211>16
<212>PRT
<213>小家鼠
<400>302
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
<210>303
<211>16
<212>PRT
<213>小家鼠
<400>303
Met Asp Phe Gln Met Gln Ile Ile Ser Leu Leu Leu Ile Ser Val Thr
1 5 10 15
<210>304
<211>21
<212>PRT
<213>小家鼠
<400>304
Met Asp Phe Gln Val Gln Ile Phe Gln Ile Pro Val Lys Gln Cys Leu
1 5 10 15
Ile Ile Ser Arg Gly
20
<210>305
<211>16
<212>PRT
<213>小家鼠
<400>305
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
<210>306
<211>16
<212>PRT
<213>小家鼠
<400>306
Met Arg Pro Thr Leu Ser Phe Leu Gly Ser Cys Cys Ser Ser Leu Ile
1 5 10 15
<210>307
<211>16
<212>PRT
<213>小家鼠
<400>307
Met Lys Phe Pro Ser Gln Leu Leu Leu Leu Leu Leu Phe Gly Ile Pro
1 5 10 15
<210>308
<211>19
<212>PRT
<213>小家鼠
<400>308
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Ser
<210>309
<211>19
<212>PRT
<213>小家鼠
<400>309
Met Glu Ser Gln Thr Leu Val Phe Ile Ser Ile Leu Leu Trp Leu Tyr
1 5 10 15
Ala Asp Gly
<210>310
<211>19
<212>PRT
<213>小家鼠
<400>310
Met Glu Ser Gln Thr Gln Val Phe Leu Ser Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>311
<211>19
<212>PRT
<213>小家鼠
<400>311
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>312
<211>18
<212>PRT
<213>小家鼠
<400>312
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>313
<211>19
<212>PRT
<213>小家鼠
<400>313
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210>314
<211>18
<212>PRT
<213>小家鼠
<400>314
Met Ala Trp Ile Ser Leu Ile Leu Ser Leu Leu Ala Leu Ser Ser Ala
1 5 10 15
Ile Ser
<210>315
<211>18
<212>PRT
<213>小家鼠
<400>315
Ile Gly Trp Ser Tyr Ile Ile Leu Leu Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>316
<211>18
<212>PRT
<213>小家鼠
<400>316
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser Ala
1 5 10 15
Ser Ser
<210>317
<211>18
<212>PRT
<213>小家鼠
<400>317
Met Ala Trp Thr Ser Leu Ile Leu Ser Leu Leu Ala Leu Cys Ser Ala
1 5 10 15
Ile Ser
<210>318
<211>18
<212>PRT
<213>小家鼠
<400>318
Met Gly Trp Ser Cys Val Leu Leu Phe Leu Val Ser Gly Thr Ala Val
1 5 10 15
Leu Cys
<210>319
<211>21
<212>PRT
<213>小家鼠
<400>319
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Ile Ser Arg Gly
20
<210>320
<211>21
<212>PRT
<213>小家鼠
<400>320
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Leu Phe Arg Gly
20
<210>321
<211>21
<212>PRT
<213>小家鼠
<400>321
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Leu Ser Arg Gly
20
<210>322
<211>21
<212>PRT
<213>小家鼠
<400>322
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>323
<211>21
<212>PRT
<213>小家鼠
<400>323
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Leu Met Ser Arg Gly
20
<210>324
<211>20
<212>PRT
<213>小家鼠
<400>324
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Arg Ile
1 5 10 15
Leu Ser Arg Gly
20
<210>325
<211>21
<212>PRT
<213>小家鼠
<400>325
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Val Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>326
<211>21
<212>PRT
<213>小家鼠
<400>326
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>327
<211>19
<212>PRT
<213>小家鼠
<400>327
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser
<210>328
<211>18
<212>PRT
<213>小家鼠
<400>328
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Cys
<210>329
<211>21
<212>PRT
<213>小家鼠
<400>329
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Ile Met Ser Arg Gly
20
<210>330
<211>18
<212>PRT
<213>小家鼠
<400>330
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Val Leu His Cys Ser Ser
1 5 10 15
Phe Ser
<210>331
<211>18
<212>PRT
<213>小家鼠
<400>331
Met Arg Val Leu Gly Phe Leu Cys Leu Val Thr Val Leu Pro Gly Ser
1 5 10 15
Leu Ser
<210>332
<211>18
<212>PRT
<213>小家鼠
<400>332
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Leu Leu His Cys Ser Ser
1 5 10 15
Phe Ser
<210>333
<211>13
<212>PRT
<213>小家鼠
<400>333
Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala Val His Cys
1 5 10
<210>334
<211>18
<212>PRT
<213>小家鼠
<400>334
Lys Gly Gly Ser Cys Val Ser Leu Phe Leu Val Ala Thr Ala Asn Val
1 5 10 15
His Phe
<210>335
<211>18
<212>PRT
<213>小家鼠
<400>335
Met Ala Val Leu Ala Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Ile
1 5 10 15
Leu Ser
<210>336
<211>18
<212>PRT
<213>小家鼠
<400>336
Met Ala Val Leu Gly Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Val
1 5 10 15
Leu Ser
<210>337
<211>18
<212>PRT
<213>小家鼠
<400>337
Met Ala Val Leu Gly Leu Leu Leu Cys Leu Val Thr Phe Pro Ser Val
1 5 10 15
Leu Ser
<210>338
<211>18
<212>PRT
<213>小家鼠
<400>338
Met Ala Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210>339
<211>18
<212>PRT
<213>小家鼠
<400>339
Met Asp Trp Ile Trp Ile Met Leu His Leu Leu Ala Ala Thr Gly Ile
1 5 10 15
Gln Ser
<210>340
<211>18
<212>PRT
<213>小家鼠
<400>340
Met Glu Cys Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ala Val
1 5 10 15
His Cys
<210>341
<211>19
<212>PRT
<213>小家鼠
<400>341
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys
<210>342
<211>18
<212>PRT
<213>小家鼠
<220>
<221>misc_feature
<222>(5)..(6)
<223>Xaa可为任一天然存在的氨基酸
<400>342
Met Glu Trp Leu Xaa Xaa Phe Leu Leu Phe Leu Ser Leu Thr Ala Val
1 5 10 15
His Cys
<210>343
<211>18
<212>PRT
<213>小家鼠
<400>343
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210>344
<211>16
<212>PRT
<213>小家鼠
<400>344
Met Glu Thr Pro Ala Ser Phe Leu Cys Leu Leu Leu Leu Trp Thr Thr
1 5 10 15
<210>345
<211>15
<212>PRT
<213>小家鼠
<400>345
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Leu Leu His Cys Ser
1 5 10 15
<210>346
<211>15
<212>PRT
<213>小家鼠
<400>346
Met Ala Trp Thr Pro Leu Phe Phe Phe Phe Val Leu His Cys Ser
1 5 10 15
<210>347
<211>19
<212>PRT
<213>小家鼠
<400>347
Met Lys Ser Gln Thr Gln Val Phe Ile Phe Leu Leu Leu Cys Val Ser
1 5 10 15
Ala His Gly
<210>348
<211>19
<212>PRT
<213>小家鼠
<400>348
Met Lys Ser Gln Thr Gln Val Phe Val Phe Leu Leu Leu Cys Val Ser
1 5 10 15
Ala His Gly
<210>349
<211>16
<212>PRT
<213>小家鼠
<400>349
Met Asp Met Trp Val Gln Ile Phe Ser Leu Leu Leu Ile Cys Val Thr
1 5 10 15
<210>350
<211>19
<212>PRT
<213>小家鼠
<220>
<221>misc_feature
<222>(2)..(2)
<223>Xaa可为任一天然存在的氨基酸
<400>350
Met Xaa Thr Met Asp Glu His Glu Ser Gly Ala Val Thr Pro His Gln
1 5 10 15
Val Leu Lys
<210>351
<211>16
<212>PRT
<213>小家鼠
<400>351
Met Gly Glu Gln Arg Ile Arg Ser Cys His Ala Thr Ser Gly Ala Glu
1 5 10 15
<210>352
<211>16
<212>PRT
<213>小家鼠
<400>352
Met Asn Leu Pro Val His Leu Leu Val Leu Leu Leu Phe Trp Ile Pro
1 5 10 15
<210>353
<211>18
<212>PRT
<213>小家鼠
<400>353
Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
1 5 10 15
Val Ser
<210>354
<211>15
<212>PRT
<213>小家鼠
<400>354
Met Thr Met Leu Ser Leu Ala Pro Leu Leu Ser Leu Leu Leu Leu
1 5 10 15
<210>355
<211>16
<212>PRT
<213>小家鼠
<400>355
Met Thr Met Leu Ser Leu Val Leu Leu Leu Ser Phe Leu Leu Leu Cys
1 5 10 15
<210>356
<211>16
<212>PRT
<213>小家鼠
<400>356
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
<210>357
<211>15
<212>PRT
<213>小家鼠
<400>357
Met Val Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln
1 5 10 15
<210>358
<211>16
<212>PRT
<213>小家鼠
<400>358
Met Val Ser Thr Ser Gln Leu Leu Gly Leu Leu Leu Phe Trp Thr Ser
1 5 10 15
<210>359
<211>13
<212>PRT
<213>小家鼠
<400>359
Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10
<210>360
<211>16
<212>PRT
<213>小家鼠
<400>360
Ile Asp Ile Asn Val Gln Ile Phe Arg Phe Leu Leu Ile Ser Val Thr
1 5 10 15
<210>361
<211>16
<212>PRT
<213>小家鼠
<400>361
Met Lys Leu Pro Val Leu Leu Val Val Leu Leu Leu Phe Thr Ser Pro
1 5 10 15
<210>362
<211>15
<212>PRT
<213>小家鼠
<400>362
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro
1 5 10 15
<210>363
<211>15
<212>PRT
<213>小家鼠
<400>363
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro
1 5 10 15
<210>364
<211>16
<212>PRT
<213>小家鼠
<400>364
Met Glu Lys Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>365
<211>16
<212>PRT
<213>小家鼠
<400>365
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>366
<211>16
<212>PRT
<213>小家鼠
<400>366
Met Glu Ser Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>367
<211>16
<212>PRT
<213>小家鼠
<400>367
Met Glu Thr Asp Pro Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>368
<211>16
<212>PRT
<213>小家鼠
<400>368
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>369
<211>16
<212>PRT
<213>小家鼠
<400>369
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>370
<211>16
<212>PRT
<213>小家鼠
<400>370
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>371
<211>16
<212>PRT
<213>小家鼠
<400>371
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
<210>372
<211>16
<212>PRT
<213>小家鼠
<400>372
Met Arg Phe Ser Ala Gln Leu Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
<210>373
<211>16
<212>PRT
<213>小家鼠
<400>373
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
<210>374
<211>16
<212>PRT
<213>小家鼠
<400>374
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210>375
<211>16
<212>PRT
<213>小家鼠
<400>375
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser
1 5 10 15
<210>376
<211>16
<212>PRT
<213>小家鼠
<400>376
Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210>377
<211>16
<212>PRT
<213>小家鼠
<400>377
Met Asp Ser Gln Ala Arg Val Leu Met Leu Leu Leu Leu Trp Val Ser
1 5 10 15
<210>378
<211>16
<212>PRT
<213>小家鼠
<400>378
Met Glu Ser Gln Asn His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210>379
<211>16
<212>PRT
<213>小家鼠
<400>379
Met Glu Ser Gln Thr His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210>380
<211>16
<212>PRT
<213>小家鼠
<400>380
Met Glu Ser Gln Thr Gln Val Phe Leu Ser Leu Leu Leu Trp Val Ser
1 5 10 15
<210>381
<211>16
<212>PRT
<213>小家鼠
<400>381
Met Glu Ser Gln Thr Gln Val Leu Ile Ser Leu Leu Phe Trp Val Ser
1 5 10 15
<210>382
<211>16
<212>PRT
<213>小家鼠
<400>382
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
<210>383
<211>19
<212>PRT
<213>小家鼠
<400>383
Met Glu Thr Pro Ala Ser Phe Leu Cys Leu Leu Leu Leu Trp Thr Thr
1 5 10 15
Ser Ala Val
<210>384
<211>16
<212>PRT
<213>小家鼠
<400>384
Gln His Gly His Glu Gly Leu Cys Ser Val Ser Trp Val Pro Val Ala
1 5 10 15
<210>385
<211>16
<212>PRT
<213>小家鼠
<400>385
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln
1 5 10 15
<210>386
<211>16
<212>PRT
<213>小家鼠
<400>386
Met Met Ser Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Arg
1 5 10 15
<210>387
<211>16
<212>PRT
<213>小家鼠
<400>387
Met Met Ser Pro Val Gln Phe Leu Phe Leu Leu Met Leu Trp Ile Gln
1 5 10 15
<210>388
<211>16
<212>PRT
<213>小家鼠
<400>388
Met Ile Ala Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210>389
<211>16
<212>PRT
<213>小家鼠
<400>389
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210>390
<211>16
<212>PRT
<213>小家鼠
<400>390
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
<210>391
<211>18
<212>PRT
<213>小家鼠
<400>391
Met Asp Met Arg Ala Pro Ala Gln Ile Phe Gly Phe Leu Leu Leu Leu
1 5 10 15
Phe Gln
<210>392
<211>18
<212>PRT
<213>小家鼠
<400>392
Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro
<210>393
<211>15
<212>PRT
<213>小家鼠
<400>393
Met Asp Cys Gly Ile Ser Leu Val Phe Leu Val Leu Ile Leu Lys
1 5 10 15
<210>394
<211>16
<212>PRT
<213>小家鼠
<400>394
Met Glu Phe Gln Thr Gln Val Phe Val Phe Val Leu Leu Trp Leu Ser
1 5 10 15
<210>395
<211>16
<212>PRT
<213>小家鼠
<400>395
Met Glu Ser Gln Ile Gln Ala Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
<210>396
<211>16
<212>PRT
<213>小家鼠
<400>396
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
<210>397
<211>16
<212>PRT
<213>小家鼠
<400>397
Met Glu Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
<210>398
<211>20
<212>PRT
<213>小家鼠
<400>398
Met Gly Phe Lys Met Glu Ser His Thr Gln Ala Phe Val Phe Ala Phe
1 5 10 15
Leu Trp Leu Ser
20
<210>399
<211>16
<212>PRT
<213>小家鼠
<400>399
Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
<210>400
<211>15
<212>PRT
<213>小家鼠
<220>
<221>misc_feature
<222>(5)..(6)
<223>Xaa可为任一天然存在的氨基酸
<400>400
Met Glu Trp Leu Xaa Xaa Phe Leu Leu Phe Leu Ser Leu Thr Ala
1 5 10 15
<210>401
<211>15
<212>PRT
<213>小家鼠
<400>401
Met Glu Trp Ser Cys Ile Phe Leu Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>402
<211>15
<212>PRT
<213>小家鼠
<400>402
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>403
<211>15
<212>PRT
<213>小家鼠
<400>403
Met Glu Trp Ser Arg Val Phe Ile Phe Leu Leu Ser Val Thr Ala
1 5 10 15
<210>404
<211>15
<212>PRT
<213>小家鼠
<400>404
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr
1 5 10 15
<210>405
<211>15
<212>PRT
<213>小家鼠
<400>405
Met Glu Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ser
1 5 10 15
<210>406
<211>15
<212>PRT
<213>小家鼠
<400>406
Met Gly Trp Asn Trp Ile Phe Ile Leu Ile Leu Ser Val Thr Thr
1 5 10 15
<210>407
<211>15
<212>PRT
<213>小家鼠
<400>407
Met Gly Trp Ser Cys Ile Ile Phe Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>408
<211>15
<212>PRT
<213>小家鼠
<400>408
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Asn
1 5 10 15
<210>409
<211>15
<212>PRT
<213>小家鼠
<400>409
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Thr
1 5 10 15
<210>410
<211>15
<212>PRT
<213>小家鼠
<400>410
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>411
<211>15
<212>PRT
<213>小家鼠
<400>411
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>412
<211>15
<212>PRT
<213>小家鼠
<400>412
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>413
<211>15
<212>PRT
<213>小家鼠
<400>413
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ser Thr Ala Thr
1 5 10 15
<210>414
<211>15
<212>PRT
<213>小家鼠
<400>414
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210>415
<211>15
<212>PRT
<213>小家鼠
<400>415
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr
1 5 10 15
<210>416
<211>15
<212>PRT
<213>小家鼠
<400>416
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Arg Ala Thr
1 5 10 15
<210>417
<211>15
<212>PRT
<213>小家鼠
<400>417
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>418
<211>15
<212>PRT
<213>小家鼠
<400>418
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>419
<211>15
<212>PRT
<213>小家鼠
<400>419
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>420
<211>15
<212>PRT
<213>小家鼠
<400>420
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>421
<211>15
<212>PRT
<213>小家鼠
<400>421
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>422
<211>15
<212>PRT
<213>小家鼠
<400>422
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>423
<211>15
<212>PRT
<213>小家鼠
<400>423
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr
1 5 10 15
<210>424
<211>15
<212>PRT
<213>小家鼠
<400>424
Met Gly Trp Ser Arg Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala
1 5 10 15
<210>425
<211>15
<212>PRT
<213>小家鼠
<400>425
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>426
<211>15
<212>PRT
<213>小家鼠
<400>426
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala
1 5 10 15
<210>427
<211>15
<212>PRT
<213>小家鼠
<400>427
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>428
<211>15
<212>PRT
<213>小家鼠
<400>428
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>429
<211>15
<212>PRT
<213>小家鼠
<400>429
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210>430
<211>15
<212>PRT
<213>小家鼠
<400>430
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>431
<211>15
<212>PRT
<213>小家鼠
<400>431
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>432
<211>15
<212>PRT
<213>小家鼠
<400>432
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>433
<211>15
<212>PRT
<213>小家鼠
<400>433
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>434
<211>15
<212>PRT
<213>小家鼠
<400>434
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>435
<211>15
<212>PRT
<213>小家鼠
<400>435
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>436
<211>15
<212>PRT
<213>小家鼠
<400>436
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln
1 5 10 15
<210>437
<211>15
<212>PRT
<213>小家鼠
<400>437
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>438
<211>15
<212>PRT
<213>小家鼠
<400>438
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>439
<211>16
<212>PRT
<213>小家鼠
<400>439
Met Val Ser Glu Thr His Val Leu Ile Phe Leu Leu Leu Trp Val Ser
1 5 10 15
<210>440
<211>10
<212>PRT
<213>小家鼠
<400>440
Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala
1 5 10
<210>441
<211>15
<212>PRT
<213>小家鼠
<400>441
Ile Gly Trp Ser Tyr Ile Ile Leu Leu Leu Val Ala Thr Ala Thr
1 5 10 15
<210>442
<211>15
<212>PRT
<213>小家鼠
<400>442
Ile Lys Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>443
<211>15
<212>PRT
<213>小家鼠
<400>443
Ile Lys Trp Ser Trp Ile Ser Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>444
<211>15
<212>PRT
<213>小家鼠
<400>444
Lys Gly Gly Ser Cys Val Ser Leu Phe Leu Val Ala Thr Ala Asn
1 5 10 15
<210>445
<211>15
<212>PRT
<213>小家鼠
<400>445
Met Ala Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr
1 5 10 15
<210>446
<211>15
<212>PRT
<213>小家鼠
<400>446
Met Glu Cys Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ala
1 5 10 15
<210>447
<211>19
<212>PRT
<213>小家鼠
<400>447
Met Ile Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Ser Lys
<210>448
<211>19
<212>PRT
<213>小家鼠
<400>448
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Ser Lys
<210>449
<211>19
<212>PRT
<213>小家鼠
<400>449
Met Ser Tyr Ser Leu Gln Leu Leu Arg Met Leu Val Leu Trp Ile Pro
1 5 10 15
Ile Thr Lys
<210>450
<211>4
<212>PRT
<213>小家鼠
<400>450
Leu Val Leu Lys
1
<210>451
<211>15
<212>PRT
<213>小家鼠
<400>451
Met Ala Val Leu Gly Leu Leu Phe Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210>452
<211>15
<212>PRT
<213>小家鼠
<400>452
Met Ala Val Leu Gly Leu Leu Leu Cys Leu Val Thr Phe Pro Ser
1 5 10 15
<210>453
<211>15
<212>PRT
<213>小家鼠
<400>453
Met Asp Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala
1 5 10 15
<210>454
<211>15
<212>PRT
<213>小家鼠
<400>454
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>455
<211>16
<212>PRT
<213>小家鼠
<400>455
Met Gly Arg Leu Thr Phe Ser Phe Leu Leu Leu Leu Pro Val Pro Ala
1 5 10 15
<210>456
<211>15
<212>PRT
<213>小家鼠
<400>456
Met Gly Trp Ser Cys Val Leu Leu Phe Leu Val Ser Gly Thr Ala
1 5 10 15
<210>457
<211>15
<212>PRT
<213>小家鼠
<400>457
Met Gly Trp Ser Trp Ile Phe Phe Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>458
<211>15
<212>PRT
<213>小家鼠
<400>458
Met Gly Trp Ser Trp Ile Phe Leu Phe Phe Leu Ser Gly Thr Ala
1 5 10 15
<210>459
<211>15
<212>PRT
<213>小家鼠
<400>459
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Ser Ala
1 5 10 15
<210>460
<211>15
<212>PRT
<213>小家鼠
<400>460
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>461
<211>15
<212>PRT
<213>小家鼠
<400>461
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala
1 5 10 15
<210>462
<211>15
<212>PRT
<213>小家鼠
<400>462
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210>463
<211>15
<212>PRT
<213>小家鼠
<400>463
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala
1 5 10 15
<210>464
<211>15
<212>PRT
<213>小家鼠
<400>464
Met Gly Trp Ser Trp Val Phe Leu Ser Phe Leu Ser Gly Thr Ala
1 5 10 15
<210>465
<211>16
<212>PRT
<213>小家鼠
<400>465
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ile Ser
1 5 10 15
<210>466
<211>15
<212>PRT
<213>小家鼠
<400>466
Met Ala Val Val Thr Gly Lys Gly Leu Pro Ser Pro Lys Leu Glu
1 5 10 15
<210>467
<211>15
<212>PRT
<213>小家鼠
<400>467
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr
1 5 10 15
<210>468
<211>11
<212>PRT
<213>小家鼠
<400>468
Met Gln Leu Gly His Leu Leu Pro Asp Gly Ser
1 5 10
<210>469
<211>16
<212>PRT
<213>小家鼠
<400>469
Arg Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
<210>470
<211>4
<212>PRT
<213>小家鼠
<400>470
Leu Ile Leu Lys
1
<210>471
<211>4
<212>PRT
<213>小家鼠
<400>471
Leu Val Leu Lys
1
<210>472
<211>5
<212>PRT
<213>人工的
<220>
<223>连接肽
<400>472
Gln Ile Trp Asn Asn
1 5
<210>473
<211>19
<212>PRT
<213>小家鼠
<400>473
Met Glu Ser Gln Asn His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>474
<211>19
<212>PRT
<213>小家鼠
<400>474
Met Glu Ser Gln Thr His Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>475
<211>19
<212>PRT
<213>小家鼠
<400>475
Met Glu Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
Val Asp Gly
<210>476
<211>19
<212>PRT
<213>小家鼠
<400>476
Met Glu Ser Gln Thr Gln Val Leu Ile Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>477
<211>19
<212>PRT
<213>小家鼠
<400>477
Met Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Ala Cys Ala
<210>478
<211>19
<212>PRT
<213>小家鼠
<400>478
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Thr Cys Gly
<210>479
<211>19
<212>PRT
<213>小家鼠
<400>479
Met Glu Thr Asp Pro Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>480
<211>19
<212>PRT
<213>小家鼠
<400>480
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>481
<211>19
<212>PRT
<213>小家鼠
<400>481
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>482
<211>19
<212>PRT
<213>小家鼠
<400>482
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Ser Thr Gly
<210>483
<211>19
<212>PRT
<213>小家鼠
<400>483
Met Glu Thr His Ser Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
Val Glu Gly
<210>484
<211>23
<212>PRT
<213>小家鼠
<400>484
Met Gly Phe Lys Met Glu Ser His Thr Gln Ala Phe Val Phe Ala Phe
1 5 10 15
Leu Trp Leu Ser Val Asp Gly
20
<210>485
<211>16
<212>PRT
<213>小家鼠
<400>485
Met Gly Val Pro Thr Gln Leu Leu Leu Leu Trp Leu Thr Val Arg Cys
1 5 10 15
<210>486
<211>19
<212>PRT
<213>小家鼠
<400>486
Met Ile Ala Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Cys
<210>487
<211>19
<212>PRT
<213>小家鼠
<400>487
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
Ile Ile Cys
<210>488
<211>19
<212>PRT
<213>小家鼠
<400>488
Met Lys Phe Pro Ser Gln Leu Leu Leu Leu Leu Leu Phe Gly Ile Pro
1 5 10 15
Met Ile Cys
<210>489
<211>19
<212>PRT
<213>小家鼠
<400>489
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Cys
<210>490
<211>19
<212>PRT
<213>小家鼠
<400>490
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Thr Arg Tyr
<210>491
<211>19
<212>PRT
<213>小家鼠
<400>491
Met Asn Met Leu Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Ala
1 5 10 15
Gly Lys Cys
<210>492
<211>19
<212>PRT
<213>小家鼠
<400>492
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ala Ile Gly
<210>493
<211>19
<212>PRT
<213>小家鼠
<400>493
Met Arg Cys Leu Ala Glu Phe Leu Arg Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ala Thr Gly
<210>494
<211>19
<212>PRT
<213>小家鼠
<400>494
Met Arg Cys Ser Leu Gln Phe Leu Gly Val Leu Met Phe Trp Ile Ser
1 5 10 15
Val Ser Gly
<210>495
<211>19
<212>PRT
<213>小家鼠
<400>495
Met Arg Phe Ser Ala Gln Leu Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Ser Thr Ala
<210>496
<211>19
<212>PRT
<213>小家鼠
<400>496
Met Arg Pro Ser Ile Gln Phe Leu Gly Leu Leu Leu Phe Trp Leu His
1 5 10 15
Ala Gln Cys
<210>497
<211>19
<212>PRT
<213>小家鼠
<400>497
Met Arg Val Leu Ala Glu Leu Leu Gly Leu Leu Leu Phe Cys Phe Leu
1 5 10 15
Val Arg Cys
<210>498
<211>19
<212>PRT
<213>小家鼠
<400>498
Met Arg Val Leu Pro Glu Phe Leu Gly Leu Leu Leu Leu Trp Ile Ser
1 5 10 15
Val Arg Cys
<210>499
<211>19
<212>PRT
<213>小家鼠
<400>499
Met Ser Ile Ser Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210>500
<211>19
<212>PRT
<213>小家鼠
<400>500
Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210>501
<211>19
<212>PRT
<213>小家鼠
<400>501
Met Ser Val Pro Thr Gln Leu Leu Ala Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210>502
<211>19
<212>PRT
<213>小家鼠
<400>502
Met Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Gly Cys
<210>503
<211>19
<212>PRT
<213>小家鼠
<400>503
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Ala Arg Cys
<210>504
<211>19
<212>PRT
<213>小家鼠
<400>504
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
Ser Thr Gly
<210>505
<211>19
<212>PRT
<213>小家鼠
<400>505
Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser
1 5 10 15
Ser Arg Gly
<210>506
<211>18
<212>PRT
<213>小家鼠
<400>506
Met Val Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Ser
1 5 10 15
Arg Gly
<210>507
<211>19
<212>PRT
<213>小家鼠
<400>507
Met Val Ser Thr Ser Gln Leu Leu Gly Leu Leu Leu Phe Trp Thr Ser
1 5 10 15
Ser Arg Gly
<210>508
<211>16
<212>PRT
<213>小家鼠
<400>508
Pro Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln Ser Arg Cys
1 5 10 15
<210>509
<211>18
<212>PRT
<213>小家鼠
<400>509
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>510
<211>18
<212>PRT
<213>小家鼠
<400>510
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>511
<211>18
<212>PRT
<213>小家鼠
<400>511
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>512
<211>18
<212>PRT
<213>小家鼠
<400>512
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
His Ser
<210>513
<211>18
<212>PRT
<213>小家鼠
<400>513
Met Gly Trp Ser Trp Ile Phe Leu Leu Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>514
<211>18
<212>PRT
<213>小家鼠
<400>514
Met Gly Trp Ser Trp Val Phe Leu Ser Phe Leu Ser Gly Thr Ala Val
1 5 10 15
Leu Ser
<210>515
<211>18
<212>PRT
<213>小家鼠
<400>515
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Ile Ile
1 5 10 15
Asn Ser
<210>516
<211>18
<212>PRT
<213>小家鼠
<400>516
Met Lys Leu Trp Leu Asn Trp Ile Leu Leu Val Ala Leu Leu Asn Ile
1 5 10 15
Gln Cys
<210>517
<211>18
<212>PRT
<213>小家鼠
<400>517
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Val
1 5 10 15
His Cys
<210>518
<211>19
<212>PRT
<213>小家鼠
<400>518
Met Leu Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Gly
1 5 10 15
Val His Cys
<210>519
<211>18
<212>PRT
<213>小家鼠
<400>519
Met Met Val Leu Ser Leu Leu Tyr Leu Leu Thr Ala Leu Pro Gly Ile
1 5 10 15
Leu Ser
<210>520
<211>18
<212>PRT
<213>小家鼠
<400>520
Met Asn Phe Gly Leu Ser Leu Ile Phe Leu Val Leu Ile Leu Lys Val
1 5 10 15
Gln Cys
<210>521
<211>14
<212>PRT
<213>小家鼠
<400>521
Met Gln Leu Gly His Leu Leu Pro Asp Gly Ser Val Asn Ser
1 5 10
<210>522
<211>19
<212>PRT
<213>小家鼠
<400>522
Met Val Ser Glu Thr His Val Leu Ile Phe Leu Leu Leu Trp Val Ser
1 5 10 15
Val His Cys
<210>523
<211>19
<212>PRT
<213>小家鼠
<400>523
Arg Ser Val Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Val Asn Ser
<210>524
<211>18
<212>PRT
<213>小家鼠
<400>524
Met Glu Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
Tyr Ser
<210>525
<211>18
<212>PRT
<213>小家鼠
<400>525
Met Glu Trp Ser Arg Val Phe Ile Phe Leu Leu Ser Val Thr Ala Val
1 5 10 15
His Ser
<210>526
<211>18
<212>PRT
<213>小家鼠
<400>526
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Val
1 5 10 15
His Ser
<210>527
<211>18
<212>PRT
<213>小家鼠
<400>527
Met Glu Trp Ser Trp Val Phe Leu Phe Leu Leu Ser Leu Thr Ser Val
1 5 10 15
His Ser
<210>528
<211>19
<212>PRT
<213>小家鼠
<400>528
Met Gly Arg Leu Thr Phe Ser Phe Leu Leu Leu Leu Pro Val Pro Ala
1 5 10 15
Val Leu Ser
<210>529
<211>18
<212>PRT
<213>小家鼠
<400>529
Met Gly Trp Ser Cys Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210>530
<211>18
<212>PRT
<213>小家鼠
<400>530
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Asn Val
1 5 10 15
His Ser
<210>531
<211>18
<212>PRT
<213>小家鼠
<400>531
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210>532
<211>18
<212>PRT
<213>小家鼠
<400>532
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>533
<211>18
<212>PRT
<213>小家鼠
<400>533
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>534
<211>18
<212>PRT
<213>小家鼠
<400>534
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ser Thr Ala Thr Val
1 5 10 15
His Ser
<210>535
<211>18
<212>PRT
<213>小家鼠
<400>535
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210>536
<211>18
<212>PRT
<213>小家鼠
<400>536
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
His Ser
<210>537
<211>18
<212>PRT
<213>小家鼠
<400>537
Met Gly Trp Ser Cys Ile Ile Leu Ile Leu Val Ala Ala Ala Thr Val
1 5 10 15
Gln Phe
<210>538
<211>18
<212>PRT
<213>小家鼠
<400>538
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Arg Ala Thr Val
1 5 10 15
His Ser
<210>539
<211>18
<212>PRT
<213>小家鼠
<400>539
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210>540
<211>18
<212>PRT
<213>小家鼠
<400>540
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210>541
<211>18
<212>PRT
<213>小家鼠
<400>541
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>542
<211>18
<212>PRT
<213>小家鼠
<400>542
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>543
<211>18
<212>PRT
<213>小家鼠
<400>543
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>544
<211>19
<212>PRT
<213>小家鼠
<400>544
Met Gly Trp Ser Phe Leu Pro Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210>545
<211>18
<212>PRT
<213>小家鼠
<400>545
Met Gly Trp Ser Arg Ile Phe Leu Phe Leu Leu Ser Ile Thr Ala Val
1 5 10 15
His Cys
<210>546
<211>18
<212>PRT
<213>小家鼠
<400>546
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>547
<211>18
<212>PRT
<213>小家鼠
<400>547
Met Gly Trp Ser Trp Ile Phe Pro Phe Leu Leu Ser Gly Thr Ala Val
1 5 10 15
His Cys
<210>548
<211>18
<212>PRT
<213>小家鼠
<400>548
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Phe
<210>549
<211>18
<212>PRT
<213>小家鼠
<400>549
Met Gly Trp Ser Tyr Ile Ile Phe Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>550
<211>18
<212>PRT
<213>小家鼠
<400>550
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
His Ser
<210>551
<211>18
<212>PRT
<213>小家鼠
<400>551
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
His Ser
<210>552
<211>18
<212>PRT
<213>小家鼠
<400>552
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Val
1 5 10 15
Asn Ser
<210>553
<211>18
<212>PRT
<213>小家鼠
<400>553
Met Arg Trp Ser Cys Ile Ile Leu Phe Leu Val Ala ThrAla Thr Val
1 5 10 15
His Ser
<210>554
<211>16
<212>PRT
<213>人工的
<220>
<223>接头8
<400>554
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
<210>555
<211>26
<212>PRT
<213>人工的
<220>
<223>接头9
<400>555
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25
<210>556
<211>17
<212>PRT
<213>人工的
<220>
<223>接头10
<400>556
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly
<210>557
<211>27
<212>PRT
<213>人工的
<220>
<223>接头11
<400>557
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25
<210>558
<211>38
<212>DNA
<213>人工的
<220>
<223>插入唯一的HindIII和KasI限制性位点
<400>558
aagcttcaac aggggagagt gttgaaggga gaggcgcc 38
Claims (11)
1.用于在包含表达质粒的真核宿主细胞中重组产生异源多肽的方法，其特征在于
a)表达质粒在5’至3’方向包含
aa)启动子，
ab)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1，
ac)编码第二多肽的核酸，该核酸包含
i)编码所述异源多肽的核酸，
ii)编码接头的核酸，
iii)编码免疫球蛋白片段的核酸，
ad)包含聚腺苷酸化信号的3’非翻译区，
b)将表达质粒导入真核宿主细胞，
c)在适合表达第二多肽的条件下培养宿主细胞，
d)将第二多肽从培养基中回收。
2.根据权利要求1所述的方法，其特征在于所述的第二多肽包含在异源多肽后的接头并且在接头后是作为第二多肽羧基端部分的免疫球蛋白片段。
3.根据权利要求1或2所述的方法，其特征在于第二多肽含有位于编码所述异源多肽的核酸5′的编码单个氨基酸或二肽或肽QIWNN(SEQ IDNO：472)或其片段的额外核酸。
4.根据权利要求1至3任一项中所述的方法，其特征在于免疫球蛋白片段获自IgG或IgE。
5.根据权利要求1至4任一项中所述的方法，其特征在于真核细胞是哺乳动物细胞。
6.根据权利要求5所述的方法，其特征在于哺乳动物细胞是CHO细胞、NS0细胞、Sp2/0细胞、COS细胞、K562细胞、BHK细胞、PER.C6细胞或HEK细胞。
7.根据权利要求1至6任一项中所述的方法，其特征在于接头是选自SEQ ID NO：06、07、08、09、10、139、140、554、555、556和557的肽或多肽。
8.根据权利要求1至7任一项中所述的方法，其特征在于免疫球蛋白片段包含a)免疫球蛋白重链的CH1-、CH2-、CH3-结构域和铰合区或免疫球蛋白轻链的CL-结构域，和b)免疫球蛋白重链可变结构域或轻链可变结构域的片段。
9.根据权利要求1至7任一项中所述的方法，其特征在于免疫球蛋白片段仅包含恒定结构域。
10.质粒，其在5’至3’方向包含
a)启动子，
b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列根据第二多肽的头两个氨基酸而选自表1；
c)编码第二多肽的核酸，该核酸包含
i)编码异源多肽的核酸，
ii)编码接头的核酸，
iii)编码免疫球蛋白片段的核酸；
d)包含聚腺苷酸化信号的3’非翻译区。
11.用来制备质粒的配套元件，用于在包含所述质粒的真核细胞中表达异源多肽，其在5’至3’方向包含
a)启动子，
b)编码第一多肽的核酸，其中所述第一多肽的氨基酸序列选自SEQID NO：36、37、319、320、321、322、323、324、325、326、327、328和329，
c)编码第二多肽的核酸，该核酸包含
i)编码肽QIWNN(SEQ ID NO：472)或其氨基端部分的核酸，
ii)包含至少一个限制性切割位点的克隆位点，
iii)编码选自SEQ ID NO：06、07、08、09、10、139、140、554、555、556和557的接头的核酸，
iv)编码免疫球蛋白片段的核酸；
d)包含聚腺苷酸化信号的3’非翻译区。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05023003.6 | 2005-10-21 | ||
| EP05023003 | 2005-10-21 | ||
| EP06010665 | 2006-05-24 | ||
| EP06010665.5 | 2006-05-24 | ||
| PCT/EP2006/010067 WO2007045465A1 (en) | 2005-10-21 | 2006-10-19 | Method for the recombinant expression of a polypeptide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101292036A true CN101292036A (zh) | 2008-10-22 |
| CN101292036B CN101292036B (zh) | 2016-04-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200680039291.9A Active CN101292036B (zh) | 2005-10-21 | 2006-10-19 | 用于重组表达多肽的方法 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US7807409B2 (zh) |
| EP (1) | EP1941043B1 (zh) |
| JP (1) | JP4860702B2 (zh) |
| KR (1) | KR101030612B1 (zh) |
| CN (1) | CN101292036B (zh) |
| AR (1) | AR056138A1 (zh) |
| AT (1) | ATE505552T1 (zh) |
| AU (1) | AU2006303440B2 (zh) |
| BR (1) | BRPI0617688A2 (zh) |
| CA (1) | CA2624893C (zh) |
| DE (1) | DE602006021335D1 (zh) |
| IL (1) | IL189420A (zh) |
| TW (1) | TW200732472A (zh) |
| WO (1) | WO2007045465A1 (zh) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103773770A (zh) * | 2012-10-18 | 2014-05-07 | 高峰 | 一种可分泌的绿色荧光蛋白及其在重组蛋白高产表达细胞株筛选方面的应用 |
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| US7579157B2 (en) | 2003-07-10 | 2009-08-25 | Hoffmann-La Roche Inc. | Antibody selection method against IGF-IR |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977598A (zh) * | 2009-11-05 | 2017-07-25 | 弗·哈夫曼-拉罗切有限公司 | 糖基化重复基序分子缀合物 |
| CN107119073A (zh) * | 2011-12-22 | 2017-09-01 | 弗·哈夫曼-拉罗切有限公司 | 表达载体元件组合、新的生产用细胞产生方法及其在重组产生多肽中的用途 |
| CN103773770A (zh) * | 2012-10-18 | 2014-05-07 | 高峰 | 一种可分泌的绿色荧光蛋白及其在重组蛋白高产表达细胞株筛选方面的应用 |
| CN113789339A (zh) * | 2014-07-03 | 2021-12-14 | 豪夫迈·罗氏有限公司 | 多肽表达系统 |
| CN106922148A (zh) * | 2014-07-29 | 2017-07-04 | 瑟勒提斯公司 | 用于癌症免疫疗法的ror1(ntrkr1)特异性的嵌合抗原受体 |
| CN106661557A (zh) * | 2014-08-11 | 2017-05-10 | 豪夫迈·罗氏有限公司 | 用于增加真核细胞的比生产率的方法 |
| CN106661557B (zh) * | 2014-08-11 | 2022-01-18 | 豪夫迈·罗氏有限公司 | 用于增加真核细胞的比生产率的方法 |
| CN112739713A (zh) * | 2018-06-25 | 2021-04-30 | 华盛顿大学 | 有力的且选择性的白介素模拟物的从头设计 |
| CN113136400A (zh) * | 2020-01-17 | 2021-07-20 | 普莱柯生物工程股份有限公司 | 一种高效表达外源蛋白的cho细胞株的构建方法及其应用 |
| CN113136400B (zh) * | 2020-01-17 | 2022-09-09 | 普莱柯生物工程股份有限公司 | 一种表达外源蛋白的cho细胞株的构建方法及其应用 |
| CN116583273A (zh) * | 2020-10-14 | 2023-08-11 | 维里迪安治疗公司 | 用于治疗甲状腺眼病的组合物和方法 |
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| IL189420A0 (en) | 2008-06-05 |
| CN101292036B (zh) | 2016-04-13 |
| JP4860702B2 (ja) | 2012-01-25 |
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| KR101030612B1 (ko) | 2011-04-20 |
| IL189420A (en) | 2014-06-30 |
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| CA2624893A1 (en) | 2007-04-26 |
| AU2006303440B2 (en) | 2011-09-08 |
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| EP1941043A1 (en) | 2008-07-09 |
| CA2624893C (en) | 2015-03-17 |
| US20070117185A1 (en) | 2007-05-24 |
| AR056138A1 (es) | 2007-09-19 |
| KR20080049115A (ko) | 2008-06-03 |
| WO2007045465A1 (en) | 2007-04-26 |
| JP2009509558A (ja) | 2009-03-12 |
| US7807409B2 (en) | 2010-10-05 |
| ATE505552T1 (de) | 2011-04-15 |
| BRPI0617688A2 (pt) | 2011-06-07 |
| EP1941043B1 (en) | 2011-04-13 |
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