TW202214673A - 異源二聚體鬆弛素融合物及其用途 - Google Patents
異源二聚體鬆弛素融合物及其用途 Download PDFInfo
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Abstract
本發明關於異源二聚體鬆弛素融合多肽,具體關於異源二聚體鬆弛素2融合多肽及其用途。因此,本發明提供了鬆弛素融合多肽、核酸分子、載體、宿主細胞、藥物組成物和包含其的套組以及其包括治療方法的用途。本發明之多肽和組成物尤其可用於治療心血管疾病,例如用於治療心臟衰竭。
Description
本發明關於異源二聚體鬆弛素融合物及其用途。特別地,本發明關於鬆弛素-2融合物及其用途。
鬆弛素係屬於胰島素超家族的肽激素。在人類中,該鬆弛素肽家族包括具有高結構相似性但是低序列相似性的七種肽:鬆弛素1、2和3以及胰島素樣肽INSL3、INSL4、INSL5和INSL6。天然存在的鬆弛素由以下組成:藉由兩個鏈間二硫鍵共價連接的A多肽鏈和B多肽鏈。A鏈具有另外的鏈內二硫鍵。鬆弛素基因編碼具有結構B-C-A(由C肽連接的B和A多肽鏈)的激素原。激素原經歷藉由PC1和PC2酶進行的內切蛋白水解切割,從而去除C肽,之後是成熟鬆弛素的分泌。
鬆弛素係已知在妊娠期間介導全身血液動力學改變和腎臟適應性改變之多效激素。鬆弛素還示出具有抗纖維化特性並且在心臟衰竭(例如急性失代償性心臟衰竭(ADHF))中具有有益效果。心臟衰竭與顯著發病率及死亡率相關。其特徵在於複雜的組織重塑,涉及增加的心肌細胞死亡和間質纖維化。鬆弛素激活大量傳訊級聯,該等傳訊級聯已示出在缺血-再灌注和心臟衰竭的環境中是有益的。該等傳訊途徑包括激活磷酸肌醇3-激酶途徑和激活一氧化氮傳訊途徑(Bathgate RA等人 (2013)
Physiol. Rev.[生理學評論] 93 (1): 405-480; Mentz RJ等人 (2013)
Am. Heart J.[美國心臟雜誌]
165 (2): 193-199; Tietjens J等人 (2016)
Heart[心臟] 102: 95-99; Wilson SS等人 (2015)
Pharmacology[藥理學] 35: 315-327)。
已經使用未修飾的重組人鬆弛素-2,即塞鬆弛素(serelaxin)進行了臨床試驗。向住院患者連續靜脈內投與塞鬆弛素改善了心臟、腎臟和肝臟損害及充血的標記(Felker GM等人 (2014)
J. Am. Coll. Cardiol.[美國心臟病學會雜誌] 64 (15): 1591-1598; Metra M等人 (2013)
J. Am. Coll. Cardiol.[美國心臟病學會雜誌] 61 (2): 196-206;
Teerlink JR等人 (2013)
Lancet[柳葉刀] 381 (9860): 29-39)。然而,由於塞鬆弛素從患者循環中快速清除,治療效果係受限的,並且一旦靜脈內注射停止,正面效果迅速消失。另外,在靜脈內接受塞鬆弛素後,大約三分之一患者經歷了顯著血壓降低(> 40 mm Hg),因此必須將劑量減少一半或甚至更多。
WO 2013/004607和WO 2018/138170描述了重組鬆弛素多肽,其中鬆弛素A和鬆弛素B與接頭(linker)肽單鏈融合。WO 2013/004607描述了具有至少5個胺基酸並且少於15個胺基酸的接頭肽的重組鬆弛素。WO 2018/138170描述了具有至少15個胺基酸的接頭肽的重組鬆弛素。
鑒於目前用未修飾的重組鬆弛素進行的有希望的臨床研究,仍然需要另外的重組鬆弛素,該等重組鬆弛素保留了鬆弛素的生物活性並提供了例如延長的半衰期和方便給藥等優點。
本發明關於具有鬆弛素活性之異源二聚體融合物。
因此,在一方面,本發明提供了異源二聚體融合物,其包含:
(i) 與至少一種鬆弛素A鏈多肽或其變體連接的第一異源二聚體化結構域;和
(ii) 與至少一種鬆弛素B鏈多肽或其變體連接的第二異源二聚體化結構域,
其中該第一異源二聚體化結構域與該第二異源二聚體化結構域異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。
在一些實施方式中,藉由一個或多個(例如兩個)鏈間鍵、較佳的是一個或多個(例如兩個)鏈間二硫鍵,將鬆弛素A鏈和鬆弛素B鏈共價結合。在一些實施方式中,鬆弛素A鏈和鬆弛素B鏈並不藉由胺基酸接頭來彼此共價連接。
在一些實施方式中,鬆弛素A鏈係鬆弛素-2A鏈並且鬆弛素B鏈係鬆弛素-2B鏈。
在較佳的實施方式中,第一和第二異源二聚體化結構域源自免疫球蛋白Fc區,例如免疫球蛋白G(IgG)Fc區(「第一Fc區」和「第二Fc區」)。第一和第二Fc區可以包含恒定結構域CH2和/或CH3。較佳的是,第一和第二Fc區包含CH2和CH3。
在替代性實施方式中,第一和第二異源二聚體化結構域源自免疫球蛋白Fab區。
在又另外的替代性實施方式中,第一和第二異源二聚體化結構域異源二聚體化,從而形成平行捲曲螺旋。
在一些實施方式中,將鬆弛素A鏈經由連接子連接至第一異源二聚體化結構域(例如第一Fc區),並且將鬆弛素B鏈經由連接子連接至第二異源二聚體化結構域(例如第二Fc區)。在較佳的實施方式中,一個或較佳的是兩個連接子係多肽。
在一些實施方式中,至少一個連接子係長度為6至40個胺基酸的多肽。較佳的是,兩個連接子皆為長度為6至40個胺基酸的多肽。在較佳的實施方式中,至少一個連接子係長度為21個胺基酸的多肽。在特別較佳的實施方式中,兩個連接子皆為長度為21個胺基酸的多肽。在某些實施方式中,兩個連接子均具有序列GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5]。
在較佳的實施方式中,將第一異源二聚體化結構域(例如第一Fc區)的C-末端連接至鬆弛素A鏈的N-末端,並且將第二異源二聚體化結構域(例如第二Fc區)的C-末端連接至鬆弛素B鏈的N-末端。在替代性實施方式中,將第一異源二聚體化結構域(例如第一Fc區)的N-末端連接至鬆弛素A鏈的C-末端,並且將第二異源二聚體化結構域(例如第二Fc區)的N-末端連接至鬆弛素B鏈的C-末端。
在一些實施方式中,第一和第二異源二聚體化結構域(例如第一和第二Fc區)包含促進異源二聚體化的胺基酸突變和/或修飾,較佳的是,促進非對稱異源二聚體化的胺基酸突變和/或修飾。在較佳的實施方式中,促進異源二聚體化的胺基酸突變係「Fc杵(Knob)」和「Fc臼(Hole)」突變。在特別較佳的實施方式中,「Fc杵」和「Fc臼」突變存在於CH3結構域中。在較佳的實施方式中,第一Fc區包含「Fc杵」突變,並且第二Fc區包含「Fc臼」突變。可替代地,第一Fc區具有「Fc臼」突變,並且第二Fc區具有「Fc杵」突變。較佳的是,促進異源二聚體化的胺基酸突變包含在一個CH3結構域中的「Fc臼」突變Y349C、T366S、L368A和Y407V或其保守性取代;以及在另一個CH3結構域中的「Fc杵」突變S354C和T366W或其保守性取代,其中胺基酸編號係根據如卡巴特中的EU索引進行的。
在本發明之任何方面的實施方式中,鬆弛素-2A鏈多肽包含如SEQ ID NO: 1所示的序列或其變體,並且鬆弛素-2B鏈多肽包含如SEQ ID NO: 2所示的序列或其變體。在一些實施方式中,鬆弛素-2A鏈多肽包含胺基酸突變K9H。
本發明還提供了異源二聚體融合物,其包含:
(i) FcX-con-A融合多肽;和
(ii) FcY-con-B融合多肽,
其中:
A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體;
B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體;
FcY係具有「Fc臼」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變Y349C:T366S:L368A:Y407V或其保守性取代的CH3結構域;
FcX係具有「Fc杵」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變S354C:T366W或其保守性取代的CH3結構域;並且
con係連接子,例如較佳的是具有序列GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5]的連接子多肽,
其中胺基酸編號係根據如卡巴特中的EU索引進行的,其中FcX與FcY異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。
在特別較佳的實施方式中,異源二聚體融合物包含具有SEQ ID NO: 11的胺基酸序列的融合多肽和具有SEQ ID NO: 20的胺基酸序列的融合多肽。
在本發明之任何方面的一些實施方式中,異源二聚體融合物進一步包含一個或多個Fab,視需要其中該異源二聚體融合物包含與第一異源二聚體化結構域(例如第一Fc區)的N-末端連接的一個Fab和與第二異源二聚體化結構域(例如第二Fc區)的N-末端連接的第二Fab。
在本發明之任何方面的一些實施方式中,異源二聚體融合物進一步包含與第一異源二聚體化結構域(例如第一Fc區)的N-末端連接的第二鬆弛素A鏈多肽或其變體和與第二異源二聚體化結構域(例如第二Fc區)的N-末端連接的第二鬆弛素B鏈多肽或其變體,視需要其中將該第二鬆弛素A鏈經由連接子多肽連接至該第一異源二聚體化結構域(例如第一Fc區),並且將該第二鬆弛素B鏈經由連接子多肽連接至該第二異源二聚體化結構域(例如第二Fc區)。
在另一方面,本發明提供了異源二聚體融合物,其包含:
(i) FcX-B-L-A和FcY,視需要FcY-B-L-A;或
(ii) FcY-B-L-A和FcX,視需要FcX-B-L-A;
其中:
FcY係具有「Fc臼」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變Y349C:T366S:L368A:Y407V或其保守性取代的CH3結構域;
FcX係具有「Fc杵」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變S354C:T366W或其保守性取代的CH3結構域;
B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體;
A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體;並且
L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG [SEQ ID NO: 60],
其中胺基酸編號係根據如卡巴特中的EU索引進行的,其中FcX與FcY異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。可替代地,FcX和FcY係如本文所述之非Fc異源二聚體化結構域。在一些實施方式中,將鬆弛素B鏈經由連接子,視需要長度為6至40個胺基酸、例如長度為21個胺基酸的連接子多肽連接至FcX和/或FcY。
在又另一方面,本發明提供了異源二聚體融合物,其包含:
(i) FcX-A-L-B和FcY,視需要FcY-A-L-B;或
(ii) FcY-A-L-B和FcX,視需要FcX-A-L-B;
其中:
FcY係具有「Fc臼」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變Y349C:T366S:L368A:Y407V或其保守性取代的CH3結構域;
FcX係具有「Fc杵」胺基酸突變和/或修飾的免疫球蛋白(例如IgG1)Fc區,較佳的是包含具有胺基酸突變S354C:T366W或其保守性取代的CH3結構域;
A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體;
B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體;並且
L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG [SEQ ID NO: 60],
其中胺基酸編號係根據如卡巴特中的EU索引進行的,其中FcX與FcY異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。可替代地,FcX和FcY係如本文所述之非Fc異源二聚體化結構域。在一些實施方式中,將鬆弛素A鏈經由連接子,視需要長度為6至40個胺基酸、例如長度為21個胺基酸的連接子多肽連接至FcX和/或FcY。
在本發明之任何方面的一些實施方式中,異源二聚體融合物的鬆弛素活性與參考鬆弛素蛋白的鬆弛素活性的比率為約0.001至約10。
在相關方面,本發明提供了編碼本發明之異源二聚體融合物的核酸分子(例如DNA分子)、包含核酸分子的載體、包含載體或核酸的宿主細胞、以及藉由以下方式產生本發明之異源二聚體融合物之方法:培養該等宿主細胞並且收集融合蛋白。
在另一方面,本發明提供了包含本發明之異源二聚體融合物的藥物組成物、包含其的套組(kit)、以及該異源二聚體融合物在療法中的用途,包括治療患有心臟衰竭的受試者之方法。
在所附申請專利範圍中陳述了本發明之多個方面及實施方式。本文還描述了本發明之該等和其他的方面和實施方式。
附圖和序列表說明
鬆弛素
本發明至少部分地基於以下發現:當鬆弛素A鏈和鬆弛素B鏈並不藉由胺基酸接頭來彼此共價連接時,本文所述之異源二聚體融合物可表現出鬆弛素活性。基於WO 2013/004607和WO 2018/138170之揭露內容,這係令人驚訝的,該等文獻描述了重組鬆弛素,其中鬆弛素A和鬆弛素B單鏈融合。本發明之諸位發明人還發現異源二聚體化結構域的異源二聚體化誘導鬆弛素A鏈和鬆弛素B鏈的正確折疊和異源二聚體化(參見實例2)。此外,不同於野生型鬆弛素蛋白,本發明之融合多肽不需要針對生物活性進行內切蛋白水解加工。
如本文所使用,術語「異源二聚體融合物」係指融合多肽的異源二聚體,其中一個融合多肽包含與異源二聚體蛋白(例如鬆弛素A鏈)的第一亞基連接的第一異源二聚體化結構域,並且另一個融合多肽包含與異源二聚體蛋白(例如鬆弛素B鏈)的第二亞基連接的第二異源二聚體化結構域。
本發明之異源二聚體融合物可包含來自選自以下的鬆弛素組的鬆弛素A鏈多肽和鬆弛素B鏈多肽:鬆弛素-1、鬆弛素-2和鬆弛素-3。在較佳的實施方式中,本發明之鬆弛素A鏈多肽係鬆弛素-2A鏈多肽或其變體;並且本發明之鬆弛素B鏈多肽係鬆弛素-2B鏈多肽或其變體。在特定的實施方式中,鬆弛素A鏈多肽包含人鬆弛素-2A鏈多肽或其變體和人鬆弛素-2B鏈多肽或其變體。
術語「鏈」、「多肽」和「肽」在本文中可以互換使用以指藉由肽鍵連接的兩個或更多個胺基酸的鏈。
在一些實施方式中,鬆弛素-2A鏈多肽具有如SEQ ID NO: 1所示的序列或其變體,並且鬆弛素-2B鏈多肽具有如SEQ ID NO: 2所示的序列或其變體。變體可包含一個或多個胺基酸取代、缺失和/或插入。在一些實施方式中,鬆弛素-2A鏈多肽包含選自以下的一個或多個胺基酸突變:K9E、K9H、K9L、K9M、R18E、R18H、R22A、R22I、R22M、R22Q、R22S、R22Y、F23E、F23A和F23I。在較佳的實施方式中,鬆弛素-2A鏈包含胺基酸突變K9H。
鬆弛素A鏈變體和鬆弛素B鏈變體係本領域已知的。此外,技術人員可獲得對鬆弛素A鏈變體和鬆弛素B鏈變體的設計的指導。例如,應當理解的是變體可以保留鬆弛素功能所必需的那些胺基酸。例如,鬆弛素-2B鏈變體可包含保守模體Arg-X-X-X-Arg-X-X-lle(Claasz AA等人 (2002)
Eur. J. Biochem.[歐洲生物化學雜誌]
269 (24): 6287-6293)或Arg-X-X-X-Arg-X-X-Val(Bathgate RA等人
(2013) Physiol Rev.[生理學評論] 93 (1): 405-480)。變體可包含一個或多個胺基酸取代和/或插入。例如,與SEQ ID NO: 62相比,鬆弛素-2B鏈變體可具有一個或多個另外的胺基酸,例如K30和R31以及N-末端V-2、A-1和M-1。可替代地或此外,變體可包含一個或多個胺基酸衍生物。例如,鬆弛素-2B鏈變體的第一胺基酸可以是焦麩胺酸。
在較佳的實施方式中,藉由兩個鏈間二硫鍵,將鬆弛素A鏈和鬆弛素B鏈共價結合(參見實例2)。
鬆弛素家族肽至少部分地藉由激活G蛋白偶聯受體(GPCR)、以及隨後分別藉由Gs蛋白亞基或Gi蛋白亞基刺激或抑制cAMP傳訊途徑來介導它們的生物效應。鬆弛素-2已知激活GPCR RXFP1(也稱為LGR7)並且在較小程度上激活GPCR RXFP2(也稱為LGR8),因此刺激Gs-cAMP依賴性傳訊途徑,導致第二信使分子cAMP的增加。
如本文所使用,術語「鬆弛素活性」係指鬆弛素分子結合鬆弛素受體、和/或激活所述鬆弛素受體和/或引發細胞內傳訊級聯的能力。在其中鬆弛素活性係鬆弛素-2的活性的實施方式中,鬆弛素活性可以是指結合和/或激活受體RXFP1和/或RXFP2的能力。術語「鬆弛素活性」可與「生物活性」互換使用。
藉由測量鬆弛素分子與鬆弛素受體的結合,和/或藉由測量來自與鬆弛素受體結合的下游事件,可測定鬆弛素活性。
可測定體外和/或體內鬆弛素活性。在一些實施方式中,測定體外鬆弛素活性。
藉由測量來自受體被鬆弛素激活的下游的分子的量和/或存在,可測定鬆弛素活性。例如,藉由測量cAMP產生隨後測量受體被鬆弛素激活,可測定鬆弛素活性。用於檢測鬆弛素誘導的cAMP產生之方法係本領域已知的。此類方法包括cAMP ELISA、HTRF cAMP測定和HitHunter®cAMP測定。在一些實施方式中,藉由借助HTRF cAMP測定測量鬆弛素誘導的cAMP產生來測定鬆弛素活性,例如,如在實例3中進行。還可藉由測量一氧化氮(NO)產生隨後測量受體被鬆弛素激活來測定鬆弛素活性。還可藉由測量來自受體被鬆弛素激活的下游的分子的激活來測定鬆弛素活性。例如,藉由測量p42/44 MAPK的激活,可測定鬆弛素活性。
可替代地或此外,藉由測量已知鬆弛素靶基因的激活,可測定鬆弛素活性。例如,藉由測量已知鬆弛素靶基因(即VEGF)在THP-1細胞中的轉錄的激活,可測定鬆弛素活性。測定基因轉錄的激活之方法係本領域已知的並且包括mRNA的定量PCR分析。VEGF mRNA的相對表現可藉由定量即時PCR誘導VEGF轉錄物隨後用鬆弛素孵育THP-1細胞來測量,如Xiao等人 (2013)
Nat Commun.[自然通訊] 4: 1953中所述。
可替代地或此外,藉由測量鬆弛素的一個或多個下游效應,可測定鬆弛素活性。例如,可根據標準方法,藉由超音波心動圖、相對於體重的左心室重量和/或脛骨長度來測量心臟肥大的減少。在另一個實例中,藉由用梅森氏三色染色(Masson's Trichrome Stain)測量纖維化減少,可測定鬆弛素活性。在另一個實例中,藉由測量對結締組織代謝的調節,例如,抑制促纖維化因子(如TGF-β)、抑制成纖維細胞增殖和分化、和/或激活MMP介導的細胞外基質降解,可測定鬆弛素活性(Bathgate RA等人
(2013)
Physiol Rev.[生理學評論] 93 (1): 405-480)。
在一些實施方式中,藉由測量異丙腎上腺素誘導的心臟肥大(測量為相對於脛骨長度的心臟重量)和纖維化(測量為相對於心臟重量的膠原含量)的逆轉,測定鬆弛素活性,例如,如在實例7中進行。
可測定本發明之異源二聚體融合物相對於參考鬆弛素蛋白的活性。在一些實施方式中,參考鬆弛素蛋白係重組蛋白。在較佳的實施方式中,參考鬆弛素蛋白係具有成熟鬆弛素蛋白的鬆弛素A鏈和鬆弛素B鏈陣列的鬆弛素蛋白。具有成熟鬆弛素蛋白的鬆弛素A鏈和鬆弛素B鏈陣列的重組鬆弛素係可商購的。例如,重組人鬆弛素-2、鼠鬆弛素-1和INSL3係從R & D系統公司(R & D Systems)可獲得的(目錄號分別是6586-RN、6637-RN和4544-NS)。
在一些實施方式中,參考鬆弛素蛋白具有與本發明之異源二聚體融合物相同的鬆弛素A鏈和B鏈,或者與本發明之異源二聚體融合物的鬆弛素A鏈和B鏈相差多達10個胺基酸,例如1個或2個胺基酸。在一些實施方式中,參考鬆弛素-2的B鏈的第一胺基酸係D,並且此胺基酸在本發明之異源二聚體融合物的鬆弛素B鏈中缺失。
參考鬆弛素蛋白可以選自:
(i) 重組人鬆弛素-2(本文稱為RELAX0013);和
(ii) 重組鼠鬆弛素-1(本文稱為RELAX0014);和
(iii) 重組Fc融合鬆弛素-2,其中將鬆弛素A和鬆弛素B單鏈融合,並且其中Fc係半衰期延長Fc區(本文稱為RELAX0010並且描述於WO 2018/138170中);和
(iv) 重組Fc融合鬆弛素-2,其中將鬆弛素A和鬆弛素B單鏈融合,並且其中Fc係半衰期延長Fc區(本文稱為RELAX0009並且描述於WO 2018/138170中);和
(v) 重組Fc融合鬆弛素-2,其中將鬆弛素A和鬆弛素B單鏈融合(本文稱為RELAX0126並且描述於WO 2013/004607中);和
(vi) 重組Fc融合鬆弛素-2,其中將鬆弛素A和鬆弛素B單鏈融合(本文稱為RELAX0127並且描述於WO 2013/004607中);以及
(vii) 重組Fc融合鬆弛素,其中將鬆弛素A和鬆弛素B單鏈融合(本文稱為RELAX0128並且描述於WO 2013/004607中)。
在特別較佳的實施方式中,參考鬆弛素蛋白係具有成熟鬆弛素-2蛋白的鬆弛素-2鏈A和鬆弛素-2B鏈陣列的鬆弛素-2蛋白,如在UniProtKB/Swiss-Prot登錄號P04090.1下所揭露的。
如果本發明之異源二聚體融合物顯示出參考鬆弛素蛋白的至少一部分活性,則它們可被認為具有鬆弛素活性。例如,如果融合多肽具有參考鬆弛素蛋白的至少約一半的活性,則它可被認為具有鬆弛素活性。如果所述融合多肽的活性與參考鬆弛素蛋白的活性的比率在約10
-5至約1、約10
-4至約1、約10
-3至約1、約10
-2至約1、約1/50至約1、約1/20至約1、約1/15至約1、約1/10至約1、約1/5至約1、或約½至約1,則本發明之異源二聚體融合物可被認為具有鬆弛素活性。可替代地,如果所述融合多肽的活性與參考鬆弛素蛋白的活性的比率在約1至約10
5、約1至約10
4、約1至約10
3、約1至約100、約1至約50、約1至約20、約1至約15、約1至約10、約1至約5、或約1至約2,則本發明之異源二聚體融合物可被認為具有鬆弛素活性。
在一些實施方式中,異源二聚體融合物的鬆弛素活性與參考鬆弛素蛋白的鬆弛素活性為約0.001至約10。
鬆弛素活性可作為EC50值測定。如本文所使用,術語「EC50」(半數最大有效濃度)係指在指定的暴露時間之後誘導基線和最大值之間的一半的應答的治療化合物的有效濃度。
異源二聚體化結構域
本發明之異源二聚體融合物包含第一異源二聚體化結構域和第二異源二聚體化結構域。在較佳的實施方式中,該第一和第二異源二聚體化結構域源自免疫球蛋白Fc區。
術語「Fc區」定義了免疫球蛋白重鏈的C-末端區,其藉由木瓜蛋白酶消化完整抗體來產生。免疫球蛋白的Fc區通常包含兩個恒定結構域,即CH2結構域和CH3結構域,並且視需要包含CH4結構域。
第一和第二Fc區可以包含免疫球蛋白結構域CH2和/或CH3。在較佳的實施方式中,第一和第二Fc區包含免疫球蛋白結構域CH2和CH3。
Fc區可以源自來自任何物種的免疫球蛋白(例如IgG),較佳的是人的免疫球蛋白(例如人IgG)。在其中Fc區源自IgG的實施方式中,Fc區可以源自任何亞類的IgG(例如IgG1、IgG2、IgG3、IgG4),較佳的是IgG1。較佳的是,第一和第二Fc區源自人IgG1免疫球蛋白。在其他實施方式中,第一和第二Fc區源自人IgG4免疫球蛋白。
在較佳的實施方式中,第一和第二Fc區包含促進異源二聚體化的胺基酸突變和/或修飾。此類修飾可包括將非對稱互補修飾引入第一和第二Fc區中的每一個,使得兩條鏈彼此相容並因此能夠形成異源二聚體,但是每條鏈不能與自身二聚化。此類修飾可涵蓋插入、缺失、保守性和非保守性取代以及重排。摻入此類修飾提供了一種方法,該方法相對於其他不需要的終產物(如同源二聚體),提高了藉由重組細胞培養產生的異源二聚體的產量。
第一和第二Fc區可包含本領域已知的任何促進異源二聚體化的胺基酸突變和/或修飾。修飾的組合可用於最大化組裝效率,同時最小化對抗體穩定性的影響。
在「杵臼(knob in hole)」方法中,可以藉由在接觸殘基之間引入空間位阻來促進異源二聚體化。「突起」藉由用較大的側鏈(例如,酪胺酸或色胺酸)替換來自一個Fc區(「Fc杵」)的介面的一個或多個小的胺基酸側鏈來產生。大小與一個或多個大的側鏈相同或相似的補償「空腔」藉由用具有較小的側鏈的胺基酸(例如,丙胺酸或纈胺酸)替換具有大的側鏈的胺基酸來在另一個Fc區(「Fc臼」)的介面上產生。在以下文獻中詳細描述了「杵臼」修飾,例如Ridgway JB等人 (1996)
Protein Eng.[蛋白質工程] 9 (7) 617-621; Merchant AM等人 (1998)
Nat. Biotechnol.[自然生物技術] 16 (7): 677-681。
可用於產生異源二聚體的其他修飾包括但不限於在兩個Fc區之間產生有利的靜電相互作用的那些。例如,可以將一個或多個帶正電荷的胺基酸引入一個Fc區,並且可以將一個或多個帶負電荷的胺基酸引入另一個Fc區中的相應位置。可替代地或此外,可以修飾Fc區以包括引入能夠形成二硫鍵的半胱胺酸殘基的突變。可替代地或此外,Fc區可包含在鏈之間的介面處對親水性和疏水性殘基的一個或多個修飾,從而使得與同源二聚體的形成相比,異源二聚體的形成在熵和焓方面更有利。
因此,在一些實施方式中,促進異源二聚體化的胺基酸突變和/或修飾在接觸殘基之間產生空間位阻(例如藉由「杵臼」法),在兩個Fc區之間產生有利的靜電相互作用,引入能夠形成二硫鍵的半胱胺酸殘基,和/或修飾在兩個Fc區之間的介面處的親水性和疏水性殘基。
在較佳的實施方式中,促進異源二聚體化的胺基酸突變係「Fc杵」和「Fc臼」突變。在較佳的實施方式中,「Fc杵」和「Fc臼」突變存在於CH3結構域中。
在一些實施方式中,第一和第二Fc區源自人IgG1免疫球蛋白,並且包含具有CH3結構域中的突變的「Fc X」和「Fc Y」,其中「Fc X」和「Fc Y」突變選自表2中所示的組合(或其保守性取代)。
[
表 2]
:「Fc X」和「Fc Y」突變
*其中胺基酸編號係根據如卡巴特中的EU索引進行的。
組合編號 | 一個或多個 Fc X 突變 * | 一個或多個 Fc Y 突變 * |
1 | D399C | K392C |
2 | D399S | K392S |
3 | Y349C | S354C |
4 | Y349C | E356C |
5 | Y349C | E357C |
6 | L351C | S354C |
7 | T394C | V397C |
8 | T366W | T366S: L368A: Y407V |
9 | T366W: D399C | T366S: L368A: K392C: Y407V |
10 | T366W: K392C | T366S: 0099C: L368A: Y407V |
11 | S354C: T366W | Y349C: T366S: L368A: Y407V |
12 | Y349C: T366W | S354C: T366S: L368A: Y407V |
13 | E356C: T366W | Y349C: T366S: L368A: Y407V |
14 | Y349C: T366W | E356C: T366S: L368A: Y41J7V |
15 | E357C: T366W | Y349C: T366S: L368A: Y407V |
16 | Y349C: T366W | E357C: T366S: L368A: Y407V |
17 | S364H/F405A | Y349T/T394F |
18 | T350V/L351Y/F405A/Y407V | T350V/T366L/K392L/T394W |
19 | K360D/D399M/Y407A | E345R/Q347R/T366V/K409V |
20 | K409D/K392D | D399K/E356K |
21 | K360E/K409W | Q347R/D399V/F405T |
22 | K360E/K409W/Y349C | Q347R/D399V/F405T/S354C |
23 | K370E/K409W | E357N/D399V/F405T |
24 | T366Y | Y407T |
在較佳的實施方式中,「Fc Y」係具有突變Y349C、T366S、L368A和Y407V或其保守性取代的「Fc臼」,並且「Fc X」係具有突變S354C和T366W或其保守性取代的「Fc杵」,其中胺基酸編號係根據如卡巴特中的EU索引進行的。
術語「如卡巴特中的EU索引」係指在Kabat EA等人
(1991) Sequences of Proteins of Immunological Interest [免疫學目的的蛋白質的序列], 第5版, Public Health Service [公共衛生服務], National Institutes of Health [國立衛生研究院], 貝塞斯達, 馬里蘭州中描述的人IgG1 EU抗體的編號系統。本申請引用的所有胺基酸位置均指EU索引位置。
在一些實施方式中,第一Fc區具有「Fc臼」突變,並且第二Fc區具有「Fc杵」突變。在替代性和較佳的實施方式中,第一Fc區具有「Fc杵」突變,並且第二Fc區具有「Fc臼」突變。
應當理解的是,相對於野生型Fc區,該等Fc區可以進一步包含其他胺基酸修飾。可以修飾Fc區以例如增加IgG分子對FcRn的親和力。WO 02/060919揭露了包含具有一個或多個胺基酸修飾的Fc區的經修飾的免疫球蛋白,並且將其藉由引用以其全文併入本文。製備具有一個或多個胺基酸修飾的Fc區之方法係本領域已知的。
在一些實施方式中,第一和/或第二Fc區可以包含一個或多個胺基酸修飾,從而減少或消除Fc區的效應子功能。在一些實施方式中,胺基酸修飾減少或規避了細胞毒性,例如抗體依賴性細胞介導的細胞毒性(ADCC)和補體依賴性細胞毒性(CDC)。
在一些實施方式中,第一和/或第二Fc區可以包含一個或多個胺基酸修飾,從而增加異源二聚體融合物的半衰期。
在一些實施方式中,第一和/或第二Fc區包含以下胺基酸突變組合中的至少一個:
(i) M252Y、S254T和T256E或其保守性取代;
(ii) L234F、L235Q和K322Q或其保守性取代;
(iii) L234F、L235E和P331S或其保守性取代;
(iv) M252Y、S254T、T256E、L234F、L235Q和K322Q或其保守性取代;或
(v) M252Y、S254T、T256E、L234F、L235E和P331S或其保守性取代,
其中胺基酸編號係根據如卡巴特中的EU索引進行的。
在一些實施方式中,第一和/或第二Fc區可以包含胺基酸突變L234F、L235E和P331S或其保守性取代,其中胺基酸編號係根據如卡巴特中的EU索引進行的。
在一些實施方式中,包含「Fc臼」突變的Fc區具有SEQ ID NO: 3所示的序列或其變體,並且包含「Fc杵」突變的Fc區具有SEQ ID NO: 4所示的序列或其變體。
在一些實施方式中,Fc區包含具有回復為Y349的胺基酸突變Y349C的SEQ ID NO: 3變體,和具有回復為S354的胺基酸突變S354C的SEQ ID NO: 4變體,使得Fc區不能形成穩定的二硫鍵。
在一些實施方式中,Fc區包含SEQ ID NO: 3變體和/或SEQ ID NO: 4變體,其中前五個殘基DKTHTCPPC(SEQ ID NO: 69)被修飾。在一些實施方式中,用序列DKTHTACPPC(SEQ ID NO: 70)替換此區域。在替代性實施方式中,用序列GGAGGACPPC(SEQ ID NO: 71)替換此區域。在替代性實施方式中,用序列ACPPC(SEQ ID NO: 72)替換此區域。
在替代性實施方式中,第一和第二異源二聚體化結構域源自免疫球蛋白Fab區。在一些實施方式中,異源二聚體化結構域包含CH1和CL區。已經發現包含L和Fd鏈的Fab區介導有效的異源二聚體化(Schoonjans R等人
.(2000) J. Immunol. [免疫學雜誌] 165 (12): 7050-7057)。因此,在替代性實施方式中,異源二聚體化結構域包含L和Fd鏈。在一些實施方式中,L和Fd鏈異源二聚體化來形成二硫橋穩定的異源二聚體。
在又另外的替代性實施方式中,第一和第二異源二聚體化結構域異源二聚體化,從而形成平行捲曲螺旋。例如,在以下文獻中描述了異源二聚體捲曲螺旋:Aronsson等人
.(2015)
Sci. Rep.[科學報告] 5: 14063。在一些實施方式中,異源二聚體化結構域包含胺基酸突變和/或修飾,從而阻止形成不希望的折疊組裝和/或促進形成平行捲曲螺旋。
第一和第二異源二聚體化結構域(例如第一和第二Fc區)可形成半衰期延長部分。因此,在一些實施方式中,本發明之異源二聚體融合物與參考鬆弛素相比具有延長的半衰期。
如本文所使用,術語「半衰期」用於指血漿中的融合蛋白濃度降低至其原始水平的50%所用的時間。血漿中蛋白質的「半衰期」可取決於不同的因素,例如,蛋白質的大小、其穩定性、其清除率、周轉速率、體內蛋白水解降解、身體或具體組織的吸收率等。測定蛋白質的半衰期之方法係本領域已知的並且在下面的實例中進行了描述。
諸位發明人已示出,具有源自免疫球蛋白Fc的第一和第二異源二聚體化結構域的本發明之異源二聚體融合物在小鼠模型中具有至少5小時的半衰期(參見實例6)。相比之下,IV投與之後,人鬆弛素-2在人體內的半衰期係約0.09 +/- 0.04小時,即5.4 +/- 2.4分鐘(Chen SA等人
.(1993)
Pharm. Res.[藥物研究] 10 (6): 834-838)。
將認識到的是,延長的半衰期係有利的,因為它允許根據安全且便利的給藥方案(例如能以更低的頻率投與的更低的劑量)投與治療蛋白。此外,更低的劑量的實現可提供進一步的優勢,例如,提供改善的安全性特徵和/或激活多種體內作用機制。
連接子
可以藉由連接子多肽將鬆弛素A鏈和B鏈中的一個或兩個連接至它們各自的異源二聚體化結構域。在一些實施方式中,將鬆弛素A鏈經由連接子多肽連接至第一異源二聚體化結構域(例如第一Fc區),並且將鬆弛素B鏈經由連接子多肽連接至第二異源二聚體化結構域(例如第二Fc區)。
連接子多肽可以是任何適合的長度,例如長度為約6至40個胺基酸,較佳的是長度為約6至21個胺基酸。在一些實施方式中,連接子多肽的長度為至少6個胺基酸殘基,較佳的是長度為至少11個胺基酸,較佳的是長度為至少16個胺基酸。在一些實施方式中,連接子多肽的長度為少於40個胺基酸。可以將具有不同或相同長度的連接子多肽用於本發明之異源二聚體融合物的每個臂。在一些實施方式中,至少一個連接子多肽的長度為21個胺基酸。在較佳的實施方式中,兩個連接子多肽的長度均為21個胺基酸。連接子多肽可以具有任何胺基酸序列。可以將具有不同或相同胺基酸組成的連接子多肽用於本發明之異源二聚體融合物的每個臂。
在一些實施方式中,一個或較佳的是兩個連接子多肽包含脯胺酸和丙胺酸重複序列(PA)x(SEQ ID NO: 73),較佳的是其中x係3至15,較佳的是其中該連接子多肽的長度為大於16個胺基酸,較佳的是其中該連接子多肽由以下組成:21個胺基酸序列PAPAPAPAPAPAPAPAPAPAG(SEQ ID NO: 6)。
在一些實施方式中,一個或較佳的是兩個連接子多肽包含甘胺酸和絲胺酸重複序列,例如以下文獻中描述的那些:Chen X等人
(2013)
Adv. Drug. Deliv. Rev.[先進藥物遞送評論] 65 (10): 1357-1369。在一些實施方式中,一個或兩個連接子多肽包含模體(GGGGS)n(SEQ ID NO: 74),其中n可以在1和8之間,例如其中n係4。在一些實施方式中,一個或多個連接子多肽由以下組成:21個胺基酸序列GGGGSGGGGSGGGGSGGGGGS(SEQ ID NO: 5)。在某些實施方式中,兩個連接子多肽由以下組成:21個胺基酸序列GGGGSGGGGSGGGGSGGGGGS(SEQ ID NO: 5)。
在一些實施方式中,一個連接子多肽包含如本文所述之脯胺酸和丙胺酸重複序列,並且另一個連接子多肽包含如本文所述之甘胺酸和絲胺酸重複序列。
可替代地,可以藉由合成連接子多肽,例如聚乙二醇(PEG)聚合物鏈,將鬆弛素A鏈和B鏈中的一個或兩個連接至它們各自的異源二聚體化結構域。因此,可以經由合成連接子,例如聚乙二醇(PEG)聚合物鏈,將鬆弛素A鏈連接至第一異源二聚體化結構域(例如第一Fc區),並且可以經由合成連接子,例如聚乙二醇(PEG)聚合物鏈,將鬆弛素B鏈連接至第二異源二聚體化結構域(例如第二Fc區),其中可以將該合成連接子共價地或非共價地附接至異源二聚體化結構域(例如Fc區)。聚乙二醇化(為PEG聚合物鏈附接至分子的過程)可以根據本領域已知之方法進行。
穩定性
本發明之諸位發明人已示出,本發明之異源二聚體融合物具有意料之外的優越的物理和化學穩定性。因此,在一些實施方式中,本發明之異源二聚體融合物與參考鬆弛素蛋白相比具有優越的物理和/或化學穩定性。
可以藉由測量純度和聚集,例如藉由如實例9中的HP-SEC,測定鬆弛素的物理穩定性。可以藉由測量分子的片段化和修飾,例如藉由如實例9中的LC-MS,測定鬆弛素的化學穩定性。
令人驚訝地,本發明之諸位發明人已示出,與其中鬆弛素A和鬆弛素B單鏈融合(與鬆弛素A和B處於單獨的融合多肽中完全不同)的重組Fc融合鬆弛素相比,本發明之異源二聚體融合物具有優越的物理和化學穩定性。WO 2013/004607描述了與免疫球蛋白Fc區融合的重組單鏈鬆弛素融合多肽,例如,本文稱為RELAX0127和RELAX0128的融合多肽。因此,在一些實施方式中,本發明之異源二聚體融合物與RELAX0127和RELAX0128相比具有優越的物理和/或化學穩定性。
除第一和第二異源二聚體化結構域之外,異源二聚體融合物還可以包含半衰期延長部分。在一些實施方式中,半衰期延長部分係蛋白質半衰期延長部分。蛋白質半衰期延長部分可以選自由以下組成之群組:免疫球蛋白的Fc區、白蛋白結合結構域和血清白蛋白。在另外的實施方式中,半衰期延長部分係蛋白質或肽之外的化學實體,例如聚乙二醇(PEG)聚合物鏈。
半衰期延長部分可以附接在第一或第二異源二聚體化結構域的N-末端或C-末端。在一些實施方式中,半衰期延長部分附接在第一或第二異源二聚體化結構域的N-末端。在其他實施方式中,半衰期延長部分附接在第一或第二異源二聚體化結構域的C-末端。將半衰期延長部分附接至異源二聚體融合物之方法係本領域已知的。例如,半衰期延長部分可藉由化學軛合(conjugation)或重組技術附接。半衰期延長部分可以直接或藉由連接子(例如連接子多肽)附接至異源二聚體融合物。當融合多肽包含蛋白質半衰期延長部分例如Fc區時,連接子多肽的使用可能是特別合適的。
示例性實施方式
本發明之異源二聚體融合物可以具有多種格式和/或序列。
術語「本發明之融合多肽(fusion polypeptide of the invention和fusion polypeptides of the invention)」可以用於指與鬆弛素A鏈融合的第一異源二聚體化結構域,和/或與鬆弛素B鏈融合的第二異源二聚體化結構域。本發明之融合多肽可以是重組融合多肽,即其已由重組DNA技術產生。
在較佳的實施方式中,將第一異源二聚體化結構域(例如第一Fc區)的C-末端連接至鬆弛素A鏈的N-末端,並且將第二異源二聚體化結構域(例如第二Fc區)的C-末端連接至鬆弛素B鏈的N-末端。在一些實施方式中,鬆弛素A鏈多肽和/或鬆弛素B鏈多肽具有游離C-末端。
在替代性實施方式中,將第一異源二聚體化結構域(例如第一Fc區)的N-末端連接至鬆弛素A鏈的C-末端,並且將第二異源二聚體化結構域(例如第二Fc區)的N-末端連接至鬆弛素B鏈的C-末端。在一些實施方式中,鬆弛素A鏈多肽和/或鬆弛素B鏈多肽具有游離N-末端。
本發明之異源二聚體融合物可以進一步包含一個或多個Fab。在一些實施方式中,異源二聚體融合物包含與第一異源二聚體化結構域(例如第一Fc區)的N-末端連接的一個Fab和與第二異源二聚體化結構域(例如第二Fc區)的N-末端連接的第二Fab。
本發明之異源二聚體融合物可以進一步包含第二鬆弛素A鏈多肽或其變體和第二鬆弛素B鏈多肽或其變體。在一些實施方式中,將第二鬆弛素A鏈多肽或其變體連接至第一異源二聚體化結構域(例如第一Fc區)的N-末端,並且將第二鬆弛素B鏈多肽或其變體連接至第二異源二聚體化結構域(例如第二Fc區)的N-末端,視需要其中將該第二鬆弛素A鏈經由連接子(例如連接子多肽)連接至該第一異源二聚體化結構域(例如第一Fc區),並且將該第二鬆弛素B鏈經由連接子(例如連接子多肽)連接至該第二異源二聚體化結構域(例如第二Fc區)。
因此,在一些實施方式中,異源二聚體融合物的格式選自:
(i) FcX-con-A/FcY-con-B(例如參見圖1);
(ii) FcX-con-B/FcY-con-A(例如參見圖1);
(iii) A-con-FcX/B-con-FcY(例如參見圖1);
(iv) B-con-FcX/A-con-FcY(例如參見圖1);
(v) Fab-FcX-con-A/Fab-FcY-con-B(例如參見圖1);
(vi) Fab-FcX-con-B/Fab-FcY-con-A;
(vii) A-con-FcX-con-A/B-con-FcY-con-B(例如參見圖1);
(viii) B-con-FcX-con-B/A-con-FcY-con-A;
(ix) FcX-con-B-L-A和FcY,視需要FcY-con-B-L-A(例如參見圖1);
(x) FcY-con-B-L-A和FcX,視需要FcX-con-B-L-A;
(xi) FcX-con-A-L-B和FcY,視需要FcY-con-A-L-B;以及
(xii) FcY-con-A-L-B和FcX,視需要FcX-con-A-L-B,
其中:
FcY係具有「Fc臼」胺基酸突變和/或修飾的免疫球蛋白Fc區,較佳的是包含具有胺基酸突變Y349C:T366S:L368A:Y407V或其保守性取代的CH3結構域;
FcX係具有「Fc杵」胺基酸突變和/或修飾的Fc區,較佳的是包含具有胺基酸突變S354C:T366W或其保守性取代的CH3結構域;
「con」係連接子多肽;
B係鬆弛素B鏈或其變體;
A係鬆弛素A鏈或其變體;並且
L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG(SEQ ID NO: 60)。
在另一方面,本發明提供了異源二聚體融合物,其包含:
(i) X-B-L-A和Y,視需要Y-B-L-A;或
(ii) Y-B-L-A和X,視需要X-B-L-A;
其中:
X和Y係如本文所述之異源二聚體化結構域;
B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體;
A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體;並且
L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG(SEQ ID NO: 60),
其中X與Y異源二聚體化,並且其中異源二聚體融合物具有鬆弛素活性。
在又另一方面,本發明提供了異源二聚體融合物,其包含:
(i) X-A-L-B和Y,視需要Y-A-L-B或
(ii) Y-A-L-B和X,視需要X-A-L-B,
其中:
X和Y係如本文所述之異源二聚體化結構域;
A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體;
B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體;並且
L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG(SEQ ID NO: 60),
其中X與Y異源二聚體化,並且其中異源二聚體融合物具有鬆弛素活性。
在特別較佳的實施方式中,異源二聚體融合物包含如SEQ ID NO: 11所示的融合多肽Rlx011DD和如SEQ ID NO: 20所示的Rlx014DD。在替代性較佳的實施方式中,異源二聚體融合物包含如SEQ ID NO: 17所示的融合多肽Rlx013DD和如SEQ ID NO: 14所示的Rlx012DD。
在本發明之一方面,提供了異源二聚體融合物,其包含選自表3所示的FcX和FcY組合的融合多肽組合。
[
表 3]
:本發明之異源二聚體融合物中的融合多肽組合
*表1示出了列出的融合多肽的序列。
**在此特定的實施方式中,異源二聚體融合物係IgG,並且包含對應於SEQ ID NO: 54所示的輕鏈的另外的多肽。
異源二聚體融合物 | FcX(杵)融合多肽* | FcY(臼)融合多肽* |
RELAX0019 | Rlx011 | Rlx014 |
RELAX0020 | Rlx013 | Rlx012 |
RELAX0021 | Rlx011b | Rlx014b |
RELAX0022 | Rlx12b | Rlx13b |
RELAX0023 | Rlx011DD | Rlx014DD |
RELAX0024 | Rlx013DD | Rlx012DD |
RELAX0034 | Rlx041H | Rlx014d |
RELAX0039 | Rlx041M | Rlx014DD |
RELAX0040 | Rlx041L | Rlx014DD |
RELAX0041 | Rlx041H | Rlx014DD |
RELAX0043 | Rlx041E | Rlx014DD |
RELAX0046 | Rlx042R | Rlx014DD |
RELAX0052 | Rlx044E | Rlx014DD |
RELAX0053 | Rlx044H | Rlx014DD |
RELAX0054 | Rlx028 | Rlx029 |
RELAX0055 | Rlx030 | Rlx031 |
RELAX0056 | Rlx026 | Rlx027 |
RELAX0063 | Rlx052A | Rlx014DD |
RELAX0069 | Rlx051M | Rlx014DD |
RELAX0070 | Rlx051I | Rlx014DD |
RELAX0071 | Rlx051Q | Rlx014DD |
RELAX0072 | Rlx051A | Rlx014DD |
RELAX0073 | Rlx051Y | Rlx014DD |
RELAX0074 | Rlx051S | Rlx014DD |
RELAX0075 | Rlx052I | Rlx014DD |
RELAX0076 | Rlx052E | Rlx014DD |
RELAX0081 | Rlx020 | Rlx021 |
RELAX0082 | Rlx022 | Rlx023 |
RELAX0083 | Rlx024 | Rlx025 |
RELAX0084 | Rlx026 | Rlx014DD |
RELAX0085 | Rlx011DD | Rlx027 |
RELAX0086 | Rlx020 | Rlx014DD |
RELAX0087 | Rlx011DD | Rlx021 |
RELAX0088 | Rlx055 | FcH01 |
RELAX0091 | Rlx062K | Rlx061H |
RELAX0105 | Rlx020 | Rlx027 |
RELAX0106 | Rlx022 | Rlx027 |
RELAX0107 | Rlx024 | Rlx027 |
RELAX0109 | Rlx020 | Rlx029 |
RELAX0110 | Rlx022 | Rlx029 |
RELAX0111 | Rlx024 | Rlx029 |
RELAX0117 | Rlx076 | Rlx077 |
RELAX0122 | Rlx055 | Rlx056 |
RELAX0123 | Rlx011DD | Rlx014DDdel2aa |
RELAX0124 | Rlx011DD | Rlx014DDdel3aa |
RELAX0130** | R347Rlx011DD | R347Rlx014DD |
在一方面,提供了異源二聚體融合物,其包含SEQ ID NO: 11和SEQ ID NO: 20所示的融合多肽。
在一個替代性方面,提供了異源二聚體融合物,其包含SEQ ID NO: 17和SEQ ID NO: 14所示的融合多肽。
本發明之融合多肽可藉由本領域已知的任何方法產生。在一些實施方式中,本發明之融合多肽藉由在宿主細胞中重組表現編碼融合多肽的核酸分子來產生。
可使用熟悉該項技術者已知之方法來構建含有本發明之核酸分子的表現載體。合適的載體包括例如質體、噬菌粒、噬菌體或病毒載體。
含有本發明之核酸分子的載體可藉由常規技術轉移至宿主細胞。合適的宿主細胞係本領域已知的。在一些實施方式中,宿主細胞係哺乳動物細胞,例如HEK293細胞或CHO細胞。
可藉由常規技術培養轉染的細胞以產生本發明之融合多肽。
一旦已經例如藉由重組表現產生了本發明之融合多肽,則可藉由本領域已知的任何方法將其純化。示例性蛋白質純化技術包括層析法(例如,離子交換層析法、親和力層析法和/或尺寸柱層析法)、離心和差別溶解度。本發明提供了分離的融合多肽,其視需要藉由至少一個純化步驟從細胞培養物中分離。
治療方法
本發明之融合多肽能以在藥物組成物提供。
本發明之藥物組成物可包含一種或多種賦形劑。藥學上可接受的賦形劑係本領域已知的,參見例如Remington's Pharmaceutical Sciences [雷明頓藥物科學](Joseph P. Remington編, 第18版, Mack Publishing Co. [麥克出版公司], 賓夕法尼亞州伊斯頓),將該文獻以其全文併入本文。
本發明涵蓋如下療法,涉及將本發明之融合多肽投與至動物,特別地,哺乳動物,例如人,用於預防、治療或改善與疾病、障礙或感染相關聯的症狀。
因此,本發明之融合多肽或藥物組成物可用在療法中,例如用於治療疾病或障礙。還提供了一種治療疾病或障礙之方法,該方法包括向有需要的受試者或患者投與治療有效量的本發明之融合多肽。該用途或方法可包括投與治療有效的方案,該方案具有比野生型鬆弛素分子的治療有效給藥方案更低頻率的本發明之融合多肽的劑量。
應當理解的是,本發明之融合多肽可用於治療心血管疾病,例如用於治療心臟衰竭。
如本文所使用,術語「心臟衰竭」包括急性心臟衰竭、慢性心臟衰竭(CHF)和急性失代償性心臟衰竭(ADHF)。術語「心臟衰竭」還可包括更具體的診斷,例如,射血分數保留的心臟衰竭(HFpEF)、射血分數中間值心臟衰竭或射血分數降低的心臟衰竭(HFrEF)。
本發明之融合多肽還可用於治療腎臟疾病、肺部疾病和纖維化障礙,例如腎、心臟、肺和肝的纖維化障礙,以及用於傷口癒合(Sherwood OD (2004)
Endocrine Reviews[內分泌評論] 25 (2): 205-234)。本發明之融合多肽還可用於逆轉糖尿病患者的胰島素抗性(Bonner JS等人 (2013)
Diabetes[糖尿病] 62 (9): 3251-3260)。本發明之融合多肽還可以用於不同形式的肺動脈高壓。本發明之融合多肽還可以用於作為以下的結果或原因的障礙:動脈硬度、降低的動脈彈性、降低的動脈順應性和擴張性(包括高血壓)、腎臟疾病、外周動脈疾病、頸動脈和腦血管疾病(即中風和失智)、糖尿病、導致終末器官損傷的微血管疾病、冠狀動脈疾病、和心臟衰竭。
本發明之融合多肽和/或藥物組成物適合用於腸胃外投與至受試者或患者。在一些實施方式中,受試者或患者係哺乳動物,特別地是人。
野生型人鬆弛素-2具有分鐘級的體內半衰期
。因此,它必須藉由在住院患者中連續靜脈內輸注來投與,並且呈現嚴重副作用,包括血壓降低。相比之下,應當理解的是,本發明之融合多肽和/或藥物組成物的實施方式可藉由注射(例如,藉由靜脈內、皮下或肌內注射)投與至受試者或患者。在一些實施方式中,藉由皮下注射投與融合多肽和/或藥物組成物。藉由注射(例如藉由皮下注射)進行的投與為受試者或患者提供了更好的舒適度的益處,並且提供了向醫院環境之外的受試者或患者投與的機會。在一些實施方式中,藉由自我投與來投與融合多肽或藥物組成物。
在一些實施方式中,本發明之融合多肽與野生型鬆弛素相比具有增加的半衰期,其允許基於莫耳濃度的更低的總暴露。例如,能以比野生型鬆弛素更低的頻率投與本發明之融合多肽,因此提供了更便利的給藥方案。
本發明提供了包含本發明之藥物組成物的套組。該套組可包括含有本發明之藥物組成物和說明書的包裝。在一些實施方式中,本發明之藥物組成物以單次劑量小瓶或容器封閉系統(例如,預填充的注射器)配製。視需要,與這樣一個或多個容器相關聯的可以是由管理藥物或生物製品的製造、使用或銷售的政府機構規定的形式的公告,該公告反映該機構針對人投與,對製造、使用或銷售的許可。
如本文所使用,冠詞「一個/種(a和an)」可以是指一個或多於一個/種(例如,至少一個/種)該冠詞的語法賓語。
「約」通常可意味著在給定測量值的性質或精度的情況下測量的量的可接受的誤差程度。示例性誤差程度在給定值或值範圍的百分比(%)內,通常在10%內,更通常在5%內。
本文描述為「包括/包含(comprising)」一個或多個特徵的實施方式也可以被認為係「由這類特徵組成」的相應實施方式的揭露。
如本文所使用的術語「藥學上可接受的」意指由聯邦政府或州政府的監管機構批准的或在美國藥典、歐洲藥典或其他普遍認可的藥典中列出的,用於在動物體內並且更特別地在人體內使用。
濃度、量、體積、百分比和其他數值能以範圍格式來呈現。還應理解的是,此類範圍格式僅僅是為了方便和簡潔而使用,並且應該被靈活地解釋為不僅包括明確列舉為範圍的限值的數值而且包括包含在該範圍內所有單獨的數值或子範圍,就像每個數值和子範圍被明確地列舉一樣。
上述實施方式被理解為說明性實例。設想了另外的實施方式。應當理解的是,關於任何一個實施方式描述的任何特徵可以單獨使用,或者與所描述的其他特徵結合使用,並且還可以與任何其他實施方式的一個或多個特徵,或者任何其他實施方式的任何組合結合使用。此外,在不脫離由所附申請專利範圍限定的本發明之範圍的情況下,也可以採用上面未描述的等效物和修改。
在本揭露的上下文中,本文所述之融合多肽和方法的其他實例和變化對於熟悉該項技術者而言係顯而易見的。
如在所附申請專利範圍中所示的,其他實例和變化在本揭露的範圍內。本文引用的所有文獻均藉由引用以其全文併入本文,包括引用文獻中呈現的所有數據、表、附圖和文本。
實例 實例 1 :重組異源二聚體 Fc 鬆弛素 -2 融合蛋白的產生
已經使用杵臼Fc結構域(Fc杵和Fc臼)的異源二聚體化特性,設計了本文所述之Fc鬆弛素-2融合蛋白,以誘導鬆弛素-2的鏈A和鏈B的正確折疊和異源二聚體化。
更精確地,已經經由連接子將鬆弛素-2鏈A和鏈B遺傳上融合至兩個互補Fc(在Fc的N-和/或C-末端),如圖1所示。然後用兩個表現載體(其包含單Fc-鬆弛素鏈(A和/或B)中的每一個)共轉染CHO細胞。兩個互補Fc部分在CHO細胞內組裝,並因此促進鬆弛素-2的組裝和正確折疊。如在以下實例2中證實,然後在互補Fc鏈之間以及在鏈A和鏈B之間形成二硫鍵,從而重新產生天然鬆弛素-2結構。
異源二聚體Fc鬆弛素-2融合蛋白在上清液中分泌,然後藉由親和力層析法使用自動化系統進行純化,其中蛋白質的Fc區與柱基質結合。
實例 2 : Fc 鬆弛素 -2 杵臼異源二聚體的 LC-MS 分析
對非還原的和還原的去糖基化Fc-鬆弛素-2異源二聚體兩者進行了LC-MS分析。對於去糖基化,將樣本稀釋至1 mg/ml,並使用10 mM Tris-Cl在pH 7.80下緩衝。將肽-N-糖苷酶F(PNGase F)(羅氏公司(Roche))以1單位的酶/50 μg的Fc-鬆弛素-2的濃度添加至樣本中,並在37°C下孵育過夜。對於非還原分析,將樣本在水中稀釋至0.05 mg/ml,並且將20 μL上樣到帶有預切分帽(pre-slit cap)的LC-MS認證的總回收瓶中(沃特世公司(Waters)部件號:186005663CV)。對於還原分析,添加10 mM TCEP,並且將樣本在37°C下再孵育30分鐘,之後進行分析。
使用與Xevo G2-XS Q-TOF儀器偶聯的ACQUITY I-Class UPLC(沃特世公司,米爾福德(Milford),麻塞諸塞州)進行實驗,兩者均使用UNIFI科學資訊系統進行操作。對於LC系統,溶劑A係含有0.1%甲酸的水,並且溶劑B係含有0.1%甲酸的乙腈(兩者均為UPLC-MS級,全清公司(BioSolve))。將UV檢測器設置為在220 nm和280 nm的波長下進行測量,並且將小瓶放置在維持4°C溫度的樣本室中。將1 μL的體積注射到反相ACQUITY UPLC蛋白質BEH C4柱、300Å孔柱(沃特世公司部件號:186004495)上,並且使用經6分鐘從5%至75%的溶劑B的遞增梯度洗脫蛋白質。
藉由輸注50% 2-丙醇中的2 μg/μL碘化鈉,從500-5000 m/z校準質譜儀,並且lockspray係200 pg/μL白胺酸腦啡肽(Leucine Enkephalin)。按正電離作用模式和靈敏度分析儀模式操作儀器,關鍵設置如下:毛細管電壓 = 3.0 V;樣本錐電壓 = 40 V;源溫度 = 120°C;去溶劑化溫度 = 450°C;錐孔氣流量 = 120 L/h;去溶劑化氣流量 = 1000 L/h;質量範圍 = 500-5000 m/z,掃描時間 = 1.0 sec。
在UNIFI軟體中處理數據。光譜係從其中洗脫目的蛋白的層析圖中的保留時間合併的。原始數據係使用針對大分子的MaxEnt1演算法減去並且解卷積的背景。將實驗數據與理論序列的質量進行比較,在理論序列中,對於非還原分析考慮了二硫鍵,並且對於還原分析考慮了游離半胱胺酸。在肽-N-糖苷酶F去糖基化後,還考慮了天冬醯胺(+1 Da)的脫醯胺化。
LC-MS分析證實,在互補Fc鏈之間以及在鏈A和鏈B之間形成二硫鍵,從而重新產生天然鬆弛素-2結構。作為實例,圖2A示出了RELAX0019和RELAX0023的LC-MS數據。非還原分析證實,對於RELAX0019和RELAX0023形成了預期質量分別為58932 Da和59361 Da的異源二聚體:未檢測到同源二聚體。還原分析(圖2B)證實了兩條鏈的序列同一性,並且示出它們不具有修飾。
用來鑒定二硫鍵的非還原肽作圖
將異源二聚體Fc-鬆弛素(50 μg)放置到清潔樣本管中,並且在17 μL的100 mM磷酸鈉(pH 7.0)中稀釋。藉由添加0.5 μL的5 mg/ml碘乙醯胺,隨後在室溫下孵育20分鐘,實現游離半胱胺酸的烷基化。在烷基化後,再添加2.5 μL的100 mM磷酸鈉緩衝液(pH 7.0)和2.5 μL的氯化鈉。藉由添加40 μL 8.0 M鹽酸胍,並且在37°C下孵育30分鐘,使蛋白質變性。藉由添加125 μL的100 mM磷酸鈉緩衝液(pH 7.0),隨後添加0.5 μL的40 mM EDTA,實現稀釋。將內切蛋白酶Lys-C(和光化學公司(Wako Chemicals))以1 mg/ml的濃度在水中重構,並且將5 μL添加至Fc-鬆弛素-2中。在37°C下進行消化持續2小時,在這個時間後,添加另外的5 μL Lys-C,並且再繼續孵育2小時。對於肽分析,將42.5 μL的樣本轉移至UPLC小瓶中,並且添加2.5 μL的水。對於二硫鍵的還原,將2.5 μL的500 mM DTT添加至樣本的另一42.5 μL等分試樣中,並在室溫下放置15分鐘,之後進行LC-MS分析。
使用與Xevo G2-XS Q-TOF儀器偶聯的ACQUITY I-Class UPLC(沃特世公司,米爾福德,麻塞諸塞州)進行肽的分析,兩者均使用UNIFI科學資訊系統進行操作。對於LC系統,溶劑A係含有0.1%甲酸的水,並且溶劑B係含有0.1%甲酸的乙腈(兩者均為UPLC-MS級,全清公司)。將UV檢測器設置為在214 nm的波長下進行測量,並且將小瓶放置在維持4°C溫度的樣本室中。將10 μl的體積注射到反相ACQUITY BEH C18300 Å孔柱(沃特世公司部件號:186003687)上,並且使用經73.5分鐘從5%至37% B,然後經另外的2.5分鐘增加至60% B的溶劑B的遞增梯度洗脫蛋白質。在77.5分鐘後,將柱保持在95% B下持續5分鐘。
藉由輸注50% 2-丙醇中的2 μg/μL碘化鈉,從100-2600 m/z校準質譜儀,並且lockspray係200 pg/μL白胺酸腦啡肽。按正電離作用模式和靈敏度分析儀模式操作儀器,關鍵設置如下:毛細管電壓 = 3.0 V;樣本錐電壓 = 25 V;源溫度 = 100°C;去溶劑化溫度 = 250°C;錐孔氣流量 = 0 L/h;去溶劑化氣流量 = 500 L/h;質量範圍 = 100-2600 m/z,掃描時間 = 0.5 sec。
藉由輸入具有預期二硫鍵的序列並且進行檢索用於匹配Lys-C產生的肽,在UNIFI軟體中處理數據。將在不存在和存在還原劑的情況下獲得的層析圖覆蓋,從而驗證所鑒定的二硫鍵鍵合的肽一旦還原就不再觀察到。
鑒定出與摻入鏈A和鏈B兩者的二硫鍵鍵合的鬆弛素-2肽的預期質量相匹配的肽,如圖3的頂部所示(SLSLSPGGGGGSGGGGSGGGGSGGGGGSQLYSALANKCCHVGCTK = LCGRELVRAQIAICGMSTWS = RSLARFC(分別為SEQ ID NO 75-77),包括3個二硫鍵在內的預期質量6836.23 Da)。圖3(A-D)示出了對於RELAX0019此肽的鑒定,並且證實了當添加還原劑時不再觀察到該肽:小圖A和B示出了在不存在和存在DTT的情況下的提取離子層析圖,並且小圖C和D示出了肽的相應質譜。圖3(E-H)示出了對於RELAX0023相同肽的鑒定,並且證實了當添加還原劑時不再觀察到該肽:小圖E和F示出了在不存在和存在DTT的情況下的提取離子層析圖,並且小圖G和H示出了肽的相應質譜。該等數據證實,鬆弛素鏈A和鏈B係藉由異源二聚體RELAX0019和RELAX0023內的二硫鍵來相互作用的。
實例 3 : Fc- 鬆弛素 -2 融合蛋白的體外活性(基於細胞的 cAMP 活性測定)
藉由以下方法測試如上所述產生的鬆弛素-2融合多肽的生物活性,例如刺激一種或多種細胞受體應答。
從迪世科沃科斯公司(DiscoverX)購買表現在CHO細胞中產生的人或小鼠受體的穩定細胞系。
- cAMP Hunter™ CHO-K1 RXFP1 Gs,細胞系(迪世科沃科斯公司目錄號95-0127C2)
- cAMP Hunter™ CHO-K1 RXFP2 Gs細胞系(迪世科沃科斯公司目錄號95-0140C2)
- cAMP Hunter™ CHO-K1 mRXFP1 Gs細胞系(迪世科沃科斯公司目錄號95-0180C2)
該等受體的激活導致下游的cAMP第二信使的產生,該第二信使可以在功能活性測定中測得。
使用以下基於牛血清白蛋白(BSA)的測定緩衝液進行常規cAMP測定:補充有0.1% BSA(西格瑪公司(Sigma)# A9418)和0.5 mM IBMX(西格瑪公司# I7018)的漢克氏(Hanks)平衡鹽溶液(西格瑪公司# H8264),用1 M NaOH調整至pH 7.4。
將表現目的受體的細胞的凍結的冷凍小瓶在水浴中迅速解凍,轉移到預加溫的細胞培養基中並且以240 xg旋轉5分鐘。將細胞以優化的濃度(例如3.33 x 10
4個細胞/mL的hRXFP1)重新懸浮在細胞培養基中,並且將30 µL細胞懸液添加至聚-D-離胺酸塗覆的384孔板(格瑞納公司(Greiner)# 781946)中,並允許黏附過夜。第二天,將培養基從板中移去並用5 uL測定緩衝液替換。使用非接觸式液體分配器(ECHO™,Labcyte公司(Labcyte)),將測試重組肽或Fc融合樣本的11點連續稀釋液添加到細胞中。所有樣本稀釋液均製作一式兩份。向每個孔中添加另外的5 µL測定緩衝液,並將板在室溫下孵育30分鐘。
使用可商購的cAMP動態G
SHTRF套組(Cisbio公司(Cisbio),目錄號62AM4PEJ),遵循按照製造商的建議的兩步方案來測量cAMP水平。簡要地說,藉由將抗cAMP穴狀化合物(供體螢光團)和cAMP-d2(受體螢光團)各1/20稀釋於提供在該套組中的軛合與裂解緩衝液中而單獨地將它們製成。將5 µL抗cAMP穴狀化合物添加到測定板的所有孔中,並且將5 µL cAMP-d2添加到除了非特異性結合(NSB)孔之外的所有孔中,向其中添加軛合與裂解緩衝液。將板在室溫下孵育一小時,然後在Envision(珀金埃爾默公司(Perkin Elmer))上使用320 nm的激發波長以及620 nm和665 nm的發射波長進行讀數。如製造商的指南中所述將數據轉化成% ΔF然後轉化為最大天然促效劑應答的激活%,並且藉由4-參數邏輯擬合進行分析以測定EC50值。在hRXFP1細胞的情況下,將該等結果與重組h鬆弛素-2(R & D系統公司(R & D Systems),目錄號6586 RN)的相應結果進行比較;在mRXFP1細胞的情況下,與m鬆弛素-1(R & D系統公司,目錄號6637-RN)的相應結果進行比較;以及在hRXFP2細胞的情況下,與INSL3(R & D系統公司,目錄號4544-NS)的相應結果進行比較。
使用統計分析軟體(GraphPad Prism, 第6版)進行數據分析。
測試的構建體的生物活性在表4和圖4中提供。表4已總結了來自幾個測定的重組人鬆弛素-2和融合多肽兩者的平均EC50測量值。
RELAX0013、RELAX0014和RELAX0010係參考蛋白,其中RELAX0013係重組人鬆弛素-2,RELAX0014係重組鼠鬆弛素-1,並且RELAX0010係單鏈融合蛋白,其包含鏈A、15個胺基酸的接頭、鏈B、15個胺基酸的連接子以及含有SEQ ID NO. 8的胺基酸序列的Fc,描述於WO 2018/138170中。
[
表 4]
:異源二聚體Fc鬆弛素融合多肽的生物活性(n:重複序列的數量)。
名稱 | n | EC50 hRXFP1 ( M ) | EC50 mRXFP1 ( M ) | EC50 hRXFP2 ( M ) |
RELAX0013 | 23 | 1.15E-12 | 7.54E-13 | 1.75E-09 |
RELAX0014 | 23 | 4.47E-12 | 2.37E-12 | 1.78E-12 |
RELAX0010 | 10 | 8.3E-12 | 7.64E-12 | 2.88E-07 |
RELAX0019 | 8 | 3.57E-11 | 9.10E-12 | 3.42E-08 |
RELAX0020 | 4 | 4.41E-11 | 2.79E-11 | 3.54E-08 |
RELAX0023 | 11 | 3.77E-11 | 3.27E-11 | 3.24E-08 |
RELAX0024 | 2 | 4.60E-11 | 1.56E-11 | 4.26E-08 |
RELAX0021 | 4 | 8.27E-11 | 4.14E-11 | 未測試 |
RELAX0022 | 2 | 4.74E-11 | 3.28E-11 | 未測試 |
RELAX0091 | 2 | 5.88E-11 | 2.88E-11 | > 1.09E-7 |
RELAX0117 | 6 | 1.06E-11 | 1.74E-11 | 1.61E-08 |
從表4中呈現的結果可以得出結論,測試的異源二聚體Fc鬆弛素融合蛋白的效力不如單鏈融合RELAX0010或重組人鬆弛素-2肽,但它們仍保留了高水平的生物活性(在人RXFP1細胞系中,範圍從約10 pM至約80 pM)。
該等結果示出了鬆弛素A鏈和B鏈可以融合至任一/兩個末端(連接子可以附接至鬆弛素鏈的N或C末端)以及異源二聚體Fc(X或Y)的任一鏈,並保留生物活性。因此,本文所述之異源二聚體Fc鬆弛素融合蛋白的格式構成了用於產生長半衰期活性鬆弛素的穩健格式。
用來穩定異源二聚體Fc的二硫鍵的存在並不影響融合蛋白的效力(比較RELAX0023與RELAX0021以及RELAX0024與RELAX0022)。
使用的兩個上鉸鏈區(GGAGGA(SEQ ID NO: 78)和天然DKTHT(SEQ ID NO: 79))並不影響效力(比較RELAX0023與RELAX0019以及RELAX0024與RELAX0020)。上鉸鏈的確切胺基酸序列對於融合蛋白的活性並不重要。
實例 4 :在異源二聚體鬆弛素 -2Fc 融合蛋白中連接子組成和長度的影響
連接子可以由甘胺酸和絲胺酸殘基(GS)組成,或可以由脯胺酸和丙胺酸重複序列(PA)組成。本文使用的連接子的長度為6至21個殘基。長GS連接子的實例係:GGGGSGGGGSGGGGSGGGGGS(SEQ ID NO: 5)(21個胺基酸)。長PA連接子的實例係:PAPAPAPAPAPAPAPAPAPAG(SEQ ID NO: 6)(21個胺基酸)。
可以將具有不同長度和組成的連接子放置在異源二聚體鬆弛素-2Fc融合多肽的每條Fc鏈上。
具有多種連接子的異源二聚體鬆弛素-2Fc融合蛋白的實例示於表5中。此表還顯示了關於以下的資訊:可開發性/可製造性(在從細胞培養上清液進行蛋白A捕獲後,單體的/非聚集的鬆弛素-2Fc融合蛋白的表現產量和百分比)以及生物活性。
[
表 5]
:在小規模表現期間,連接子對異源二聚體Fc鬆弛素-2融合蛋白的生物活性和可開發性特性的影響。
名稱 | 表現產量( mg/l ) | % 單體 | n | EC50 hRXFP1 ( M ) | EC50 mRXFP1 ( M ) | EC50 hRXFP2 ( M ) |
RELAX0013 | 23 | 1.15E-12 | 7.54E-13 | 1.75E-09 | ||
RELAX0014 | 23 | 4.47E-12 | 2.37E-12 | 1.78E-12 | ||
RELAX0010 | 無數據 | 無數據 | 10 | 8.3E-12 | 7.64E-12 | 2.88E-07 |
RELAX0019 | 147 | 78 | 25 | 5.81E-11 | 2.24E-11 | 4.40E-08 |
RELAX0023 | 無數據 | 無數據 | 15 | 3.32E-11 | 1.36E-11 | 4.20E-08 |
RELAX0081 | 164 | 82 | 3 | 4.51E-11 | 4.73E-11 | 4.92E-08 |
RELAX0082 | 226 | 83 | 3 | 5.68E-11 | 4.90E-11 | 3.81E-08 |
RELAX0083 | 83 | 94 | 6 | 2.81E-11 | 1.34E-11 | 2.42E-08 |
RELAX0056 | 466 | 75 | 4 | 3.87E-11 | 3.27E-11 | 6.48E-08 |
RELAX0054 | 6 | 89 | 2 | 2.89E-11 | 1.59E-11 | 1.53E-08 |
RELAX0055 | 9 | 92 | 2 | 1.88E-11 | 1.51E-11 | 3.39E-08 |
RELAX0084 | 91 | 93 | 2 | 5.34E-11 | 3.48E-11 | 1.20E-08 |
RELAX0085 | 261 | 81 | 2 | 6.37E-11 | 3.09E-11 | 4.67E-08 |
RELAX0086 | 150 | 92 | 2 | 4.49E-11 | 2.68E-11 | 4.88E-08 |
RELAX0087 | 179 | 82 | 2 | 4.89E-11 | 3.48E-11 | 3.63E-08 |
RELAX0105 | 231 | 76 | 2 | 7.12E-11 | 1.49E-11 | 3.33E-08 |
RELAX0106 | 269 | 76 | 2 | 6.96E-11 | 1.98E-11 | 4.94E-08 |
RELAX0107 | 301 | 77 | 2 | 8.09E-11 | 3.87E-11 | 1.22E-07 |
RELAX0109 | 60 | 33 | 3 | 1.72E-09 | 8.22E-10 | |
RELAX0110 | 61 | 34 | 3 | 1.88E-09 | 1.11E-09 | > 6.07E-8 |
RELAX0111 | 60 | 36 | 3 | 1.93E-09 | 1.24E-09 | > 6.06E-8 |
連接子的長度和組成確實對分子的可開發性方面有影響。如表5所示,具有小於或等於16個胺基酸的PA連接子的異源二聚體鬆弛素-2Fc融合多肽並未很好表現。相比之下,21個殘基長的PA連接子顯著增加了表現產量。具有GS連接子的構建體的表現產量更一致。
具有短且非對稱的(不同的)連接子的異源二聚體鬆弛素-2Fc融合蛋白保留了效力。僅在具有低單體含量的融合蛋白(RELAX0109、RELAX0110和RELAX0111)中觀察到生物活性降低。
實例 5 :鬆弛素 -2 序列中的點突變
將鬆弛素單點突變類似物製備為異源二聚體Fc鬆弛素-2融合蛋白。表6示出了保留效力和有利的可開發性特性的此類分子的實例。
靶向的天然殘基帶正電荷並且可能易於蛋白水解,但並不參與鬆弛素與其受體的結合。
例如,R22X類似物異源二聚體Fc鬆弛素-2融合蛋白似乎一貫具有改善的可開發性/可製造性特性。
[
表 6]
:在小規模表現期間,保留效力和有利的可開發性特性的鬆弛素-2類似物的實例。
名稱 | 表現產量( mg/l ) | % 單體 | n | EC50 hRXFP1 ( M ) | EC50 mRXFP1 ( M ) | EC50 hRXFP2 ( M ) |
RELAX0013 | 23 | 1.15E-12 | 7.54E-13 | 1.75E-09 | ||
RELAX0014 | 23 | 4.47E-12 | 2.37E-12 | 1.78E-12 | ||
RELAX0019 | 147 | 78 | 25 | 5.81E-11 | 2.24E-11 | 4.40E-08 |
RELAX0039 | 188.0 | 87 | 2 | 6.54E-11 | 4.25E-11 | 1.08E-07 |
RELAX0040 | 128.8 | 88 | 2 | 5.92E-11 | 2.92E-11 | > 1.27E-7 |
RELAX0041 | 162.5 | 82 | 2 | 6.22E-11 | 3.17E-11 | 1.18E-07 |
RELAX0043 | 160.2 | 79 | 2 | 7.98E-11 | 5.58E-11 | > 1.58E-7 |
RELAX0052 | 162.4 | 81 | 4 | 9.67E-11 | 5.69E-11 | 1.05E-07 |
RELAX0053 | 181.0 | 80 | 2 | 7.15E-11 | 4.36E-11 | > 1.79E-7 |
RELAX0063 | 157.2 | 84 | 2 | 1.96E-10 | 4.46E-11 | > 1.38E-7 |
RELAX0069 | 163.0 | 86 | 3 | 5.76E-11 | 3.69E-11 | > 1.62E-7 |
RELAX0070 | 145.5 | 91 | 3 | 6.67E-11 | 5.02E-11 | 1.07E-07 |
RELAX0071 | 174.7 | 85 | 3 | 6.87E-11 | 3.93E-11 | 1.15E-07 |
RELAX0072 | 232.3 | 78 | 2 | 8.53E-11 | 4.03E-11 | > 2.3E-7 |
RELAX0073 | 174.7 | 87 | 3 | 5.70E-11 | 4.15E-11 | 8.63E-08 |
RELAX0074 | 170.0 | 88 | 2 | 5.45E-11 | 4.53E-11 | 9.21E-08 |
RELAX0075 | 144.4 | 79 | 3 | 9.47E-11 | 6.14E-11 | >1.43E-7 |
表6中呈現的結果證明,在鬆弛素-2鏈A的胺基酸序列中的一些可變性係容許的,並不損失效力,同時保留了有利的可開發性特性。
實例 6 : Fc- 鬆弛素 -2 融合蛋白的 PK 曲線
使用鬆弛素ELISA測定和/或cAMP測定,確定鬆弛素-2融合多肽的藥物動力學(PK)曲線。藉由皮下(SC)和/或靜脈內(IV)途徑,以6 mg/kg向6-10週齡雄性C57BL/6J(Jax)小鼠(傑克遜實驗室(Jackson Laboratories))投與鬆弛素-2融合多肽。對於IV途徑投與,在藥物投與後5分鐘、30分鐘和60分鐘,隨後是3小時和/或6小時和/或8小時和24小時,隨後是一系列的最少1天間隔至最多21天,收集血清樣本。對於SC途徑投與,遵循相似的時間表,其中在前8小時內以更低頻率進行收集;例如,在30分鐘時收集第一樣本,然後是在3小時、8小時、24小時、30小時和48小時,隨後是一系列的最少1天間隔至最多21天進行收集。藉由心臟穿刺將樣本收集到血清管中,並在室溫下保持15至30分鐘,然後在收集的30分鐘內以10000 rpm離心10分鐘。將等分的樣本儲存在< -80°C並且稍後藉由ELISA或cAMP活性測定進行測試。
對於大多數分子,使用抗h鬆弛素-2捕獲物(預塗覆的人鬆弛素-2 Quantikine ELISA套組,R & D系統公司,目錄號DRL200)和抗人Fc檢測抗體(用HRP標記的AU003)在ELISA中測試PK樣本,但RELAX0010(描述於WO 2018/138170中)除外,其係使用抗人Fc捕獲物和抗h鬆弛素-2檢測物(使用來自人鬆弛素-2 ELISA套組(R & D系統公司,目錄號DRL200)的多株HRP標記的抗體)在ELISA中進行測試的。在兩個測定中,用100 μL RD1-19測定稀釋劑在室溫下封閉塗覆有捕獲抗體的板,持續一小時。將50 μL的標準品或樣本添加至每個孔中,並在室溫下孵育兩小時。吸出樣本,並將孔用測定洗滌緩衝液洗滌三次。每個孔添加50 μL HRP標記的檢測抗體,在抗人Fc特異性檢測的情況下在PBS/1% BSA中以1 : 1000稀釋,或在抗h鬆弛素-2檢測的情況下未經稀釋就使用。在室溫下孵育1小時並且三次洗滌後,添加50 μL/孔的TMB(SureBlue Reserve KPL 53-00-03),並且一旦發生顏色變化,藉由添加50 μL/孔的TMB終止溶液(KPL 50-85-06)來終止反應。
在基於細胞的 cAMP 活性測定中的 PK 樣本的生物活性。
測試如上所述從動物收集的血清樣本的生物活性,從而測量功能性鬆弛素-2,以評估Fc-鬆弛素-2融合多肽的完整性。從迪世科沃科斯公司購買表現在CHO細胞中產生的人RXFP1受體的穩定細胞系。此受體的激活導致下游的cAMP第二信使的產生,該第二信使可以在功能活性測定中測得。
使用以下基於牛血清白蛋白(BSA)的測定緩衝液進行cAMP測定:補充有0.1% BSA(西格瑪公司# A9418)和0.5 mM IBMX(西格瑪公司# I7018)的漢克氏平衡鹽溶液(西格瑪公司# H8264),用1 M NaOH調整至pH 7.4。
將鬆弛素-2融合多肽或重組鬆弛素-2肽(R & D系統公司,目錄號6586-RN)的劑量溶液稀釋在測定緩衝液中,並且將非接觸式液體分配器(ECHO,Labcyte公司)用於產生四種基質濃度的11點標準曲線。使用的基質係來自模擬劑量動物的空白血清,並且按兩倍所需濃度手動添加至孔中,並允許添加細胞。將測試樣本從血清管轉移至384孔源板,將其藉由非接觸式液體分配器(ECHO,Labcyte公司)用於在測定緩衝液中建立四種稀釋液。所有樣本稀釋液均製作一式兩份。
將表現hRXFP1的細胞的凍結的冷凍小瓶在水浴中迅速解凍,轉移到預加溫的細胞培養基中並且以240 xg旋轉5分鐘。將細胞重新懸浮在8 mL細胞培養基中,接種在含有10 mL培養基的T75燒瓶中,並允許貼壁過夜。第二天,使用accutase分離細胞,並且以240 xg旋轉5分鐘。將所得的細胞沈澱以優化的濃度重新懸浮,並且使用組合液滴分配器(Combi-drop dispenser)將2.5 µL細胞懸液添加至測定板的每個孔中。
使用可商購的cAMP動態2 HTRF套組(Cisbio公司,目錄號62AM4PEJ),遵循按照製造商的建議的兩步方案來測量cAMP水平。簡要地說,藉由將抗cAMP穴狀化合物(供體螢光團)和cAMP-d2(受體螢光團)各1/20稀釋於提供在該套組中的軛合與裂解緩衝液中而單獨地將它們製成。將2.5 µL抗cAMP穴狀化合物添加到測定板的所有孔中,並且將2.5 µL cAMP-d2添加到除了非特異性結合(NSB)孔之外的所有孔中,向其中添加軛合與裂解緩衝液。將板在室溫下孵育一小時,然後在Envision(珀金埃爾默公司)上使用320 nm的激發波長以及620 nm和665 nm的發射波長進行讀數。如製造商的指南中所述將數據轉化成% ΔF,並且從標準曲線的線性部分計算樣本值。
結果和結論
圖5示出了來自一系列體內PK實驗的數據的總結,其中將Fc-鬆弛素-2多肽IV投與至小鼠。針對5分鐘時間點,將數據歸一化。
IV投與之後,人鬆弛素-2在人體內的半衰期係約0.09 +/- 0.04小時,即5.4 +/- 2.4分鐘(Chen等人1993)。與天然鬆弛素-2相比,重組鬆弛素Fc融合多肽均顯示出半衰期改善。與其中鬆弛素鏈與接頭連接的那些Fc-鬆弛素多肽(示例為RELAX0010和RELAX0009)相比,其中鬆弛素A鏈和B鏈連接至不同異源二聚體Fc鏈的Fc-鬆弛素多肽(示例為RELAX0019、RELAX0023、RELAX0034、RELAX0046和RELAX0117)具有改善的PK特性。然而,由於含接頭的分子RELAX0088和RELAX0122兩者均顯示出良好的體內穩定性,鬆弛素鏈A和鏈B之間的連接接頭的存在本身與Fc-鬆弛素多肽在體內的快速消除沒有直接關係。
在此研究中意料之外的是,與Fc-鬆弛素融合多肽RELAX0010和RELAX0009相比,異源二聚體Fc-鬆弛素融合多肽(RELAX0019、RELAX0023、RELAX0034、RELAX0046、RELAX0117、RELAX0088和RELAX0122)均具有顯著改善的藥物動力學特性。
實例 7 :藉由 RELAX0019 和 RELAX0023 逆轉已建立的肥大和纖維化
經由微型泵將異丙腎上腺素(15 mg/kg/天)輸注到C57B6小鼠中,持續10天以誘導心臟肥大和纖維化。將以相同持續時間輸注有媒介物的小鼠用作基線對照。10天後,移除微型泵,並且給予小鼠含有r鬆弛素-2(500 ug/kg/天)的新微型泵,或小鼠接受RELAX0019(20 mg/kg)或RELAX0023(20 mg/kg)的兩次每週一次(QW)皮下注射中的第一次。14天治療期後,將小鼠處死,並且收集它們的心臟用於分析肥大和纖維化。在移除媒介物微型泵後,收集來自基線對照小鼠的心臟。將肥大確定為相對於脛骨長度的心臟重量的量度,並且藉由定量相對於心臟重量的膠原含量來建立纖維化。在此模型中,輸注異丙腎上腺素顯著誘導了肥大和纖維化兩者。RELAX0019和RELAX0023的QW給藥使異丙腎上腺素誘導的肥大返回至基線水平,與r鬆弛素-2的恒定輸注一樣。所有鬆弛素治療還將心臟纖維化減少了超過50%。對於每組,N = 8。**p < 0.01,***p < 0.001,****p < 0.0001
重組鬆弛素Fc融合蛋白RELAX0019和RELAX0023能夠以與天然h鬆弛素-2類似的方式逆轉肥大和纖維化(圖6)。
實例 8 :使用桿狀病毒 ELISA 評估 Fc- 鬆弛素 -2 蛋白的非特異性結合。
在CHO細胞中表現RELAX蛋白,並且如上所述進行純化。為評估單株抗體的非特異性結合而開發的桿狀病毒ELISA(參考文獻:Hotzel等人,2012 mAbs 4: 6, 753-760)適於確定具有修飾的Fc-鬆弛素多肽的非特異性結合,由此不是計算「BV分數」(桿狀病毒板吸光度/空白板吸光度),而是分別針對桿狀病毒板和空白板將非特異性結合計算為相對於背景的信號(其中背景係在不存在Fc-鬆弛素多肽的情況下獲得的值)。引入該量度以反映一些Fc肽與塗覆的和未塗覆的(空白)板的非特異性結合增加(與單株抗體相比)。在PBS(Gibco公司14190-086)+ 0.5% BSA(西格瑪公司A9576)中以100 nM或10 nM製備每種蛋白質的製劑,並將其一式兩份用於96孔Nunc Maxisorp F板上的ELISA測定,該板在4°C下用50 µL/孔的50 mM碳酸鈉中的1%桿狀病毒提取物(BV板)或用50 mM碳酸鈉(空白板)塗覆過夜。在用PBS洗滌後,將板在室溫下用300 µL/孔的PBS + 0.5% BSA封閉1小時,並用PBS洗滌三次。添加50 µL/孔的PBS + 0.5% BSA(背景)或RELAX蛋白稀釋液,並且在室溫下孵育1 h。在PBS中洗滌三次後,以50 µL/孔添加在PBS + 0.5% BSA中以1 : 5000稀釋的檢測抗體(抗人Fc-特異性-HRP 西格瑪公司A0170)。將樣本在室溫下孵育1小時並且將板在PBS中洗滌三次。然後以50 µL/孔添加HRP底物-TMB(SureBlue Reserve KPL 53-00-03),並且在顏色變化後,藉由添加50 µL/孔的0.5M硫酸來終止反應。在450 nm處測量吸光度並確定每個樣本的非特異性結合。將非特異性結合(相對於背景的倍數結合)定義為在Fc鬆弛素-2蛋白存在時和在Fc鬆弛素-2蛋白不存在時(背景)的非特異性結合的比率。在100 nM或10 nM的2種不同濃度下測試的Fc-鬆弛素-2蛋白的數據示於表7中。
[
表 7]
:桿狀病毒ELISA中Fc-鬆弛素融合蛋白在100 nM和10 nM處的結合(-001、002、003係指同一蛋白的不同批次)
融合名稱 | 100 nM處的非特異性結合BV板(信號/背景) | 100 nM處的非特異性結合空白板(信號/背景) | 10 nM處的非特異性結合BV板(信號/背景) | 10 nM處的非特異性結合空白板(信號/背景) |
RELAX0019-001 | 2.0 | 1.8 | 1.0 | 1.2 |
RELAX0019-002 | 1.5 | 1.9 | 1.1 | 1.1 |
RELAX0020 | 2.2 | 2.5 | 1.1 | 1.3 |
RELAX0021 | 2.7 | 5.3 | 1.0 | 2.0 |
RELAX0022 | 4.9 | 8.2 | 1.3 | 2.9 |
RELAX0023-001 | 1.7 | 1.8 | 1.0 | 1.0 |
RELAX0023-002 | 2.4 | 3.7 | 1.1 | 0.8 |
RELAX0024 | 1.8 | 5.3 | 0.9 | 1.5 |
RELAX0039 | 6.3 | 3.2 | 1.7 | 1.8 |
RELAX0040 | 7.5 | 3.0 | 2.6 | 2.1 |
RELAX0041 | 7.0 | 4.4 | 1.9 | 2.0 |
RELAX0043 | 3.7 | 1.6 | 1.3 | 1.3 |
RELAX0052 | 2.9 | 1.1 | 1.5 | 1.3 |
RELAX0053 | 5.5 | 3.8 | 1.7 | 2.2 |
RELAX0054 | 3.2 | 4.1 | 1.5 | 1.8 |
RELAX0055 | 1.4 | 4.6 | 0.7 | 1.7 |
RELAX0056 | 5.4 | 9.1 | 1.3 | 1.2 |
RELAX0069 | 1.7 | 1.8 | 1.1 | 6.5 |
RELAX0070 | 2.7 | 3.2 | 0.9 | 1.3 |
RELAX0071 | 1.3 | 1.7 | 0.8 | 0.9 |
RELAX0072 | 1.4 | 2.4 | 0.7 | 1.3 |
RELAX0073 | 1.7 | 1.6 | 0.7 | 1.1 |
RELAX0074 | 1.4 | 1.8 | 0.9 | 1.5 |
RELAX0075 | 4.7 | 7.9 | 3.3 | 4.8 |
RELAX0076 | 3.3 | 5.0 | 1.5 | 3.6 |
RELAX0081 | 3.2 | 4.9 | 0.8 | 1.5 |
RELAX0082 | 3.4 | 6.1 | 1.0 | 2.9 |
RELAX0083 | 2.9 | 5.7 | 2.6 | 1.5 |
RELAX0084 | 3.2 | 7.8 | 1.2 | 1.7 |
RELAX0085 | 5.4 | 12.3 | 1.4 | 2.2 |
RELAX0086 | 3.1 | 7.2 | 1.3 | 1.6 |
RELAX0087 | 4.1 | 17.3 | 1.4 | 2.7 |
RELAX0088-001 | 3.5 | 5.6 | 1.4 | 1.4 |
RELAX0088-002 | 1.9 | 2.2 | 1.1 | 0.8 |
RELAX0091 | 5.6 | 39.3 | 1.6 | 6.8 |
RELAX0105 | 12.9 | 8.3 | 2.4 | 1.1 |
RELAX0106 | 14.6 | 8.3 | 2.4 | 1.0 |
RELAX0107 | 11.6 | 7.0 | 1.8 | 0.9 |
RELAX0109 | 27.1 | 19.7 | 5.8 | 2.5 |
RELAX0110 | 26.8 | 23.9 | 8.3 | 2.6 |
RELAX0111 | 29.0 | 24.3 | 7.0 | 2.9 |
RELAX0117 | 18.5 | 47.4 | 3.0 | 8.2 |
RELAX0122 | 2.2 | 2.4 | 1.1 | 0.7 |
RELAX0123 | 2.5 | 4.8 | 1.1 | 0.9 |
RELAX0124-001 | 1.8 | 1.7 | 1.1 | 0.7 |
RELAX0124-002 | 6.4 | 4.6 | 1.5 | 0.9 |
RELAX0126-001 | 20.0 | 41.5 | 10.2 | 16.9 |
RELAX0126-002 | 21.3 | 40.4 | 10.9 | 14.3 |
RELAX0127 | 23.5 | 42.8 | 13.3 | 19.8 |
RELAX0128 | 23.5 | 42.4 | 13.2 | 19.2 |
RELAX0130 | 2.2 | 6.1 | 1.1 | 1.6 |
RELAX0010-001 | 6.3 | 13.7 | 1.5 | 5.0 |
RELAX0010-002 | 6.0 | 13.2 | 1.8 | 4.2 |
RELAX0010-003 | 2.4 | 21.0 | 0.8 | 7.7 |
RELAX0009 | 17.8 | 22.2 | 4.8 | 21.5 |
如表7和圖7中所示,當使用GS連接子將鬆弛素鏈附接至C-末端時,異源二聚體鬆弛素-2Fc融合多肽表現出更低的非特異性結合。一些非對稱的PA連接子、某些點突變和鬆弛素鏈在N-末端處的定位,特別是在二價分子(RELAX0117)的情況下,增加了與空白板和BV塗覆板兩者的非特異性結合。在高(100 nM)和低(10 nM)濃度兩者下,與BV塗覆板相比,一些具有特別高非特異性結合的Fc-鬆弛素蛋白表現出與空白板的更大的非特異性結合。儘管對照分子 - 含接頭的二價RELAX0009、RELAX0010、RELAX0126、RELAX0127和RELAX0128均證明了高非特異性結合,但是鬆弛素的鏈A和鏈B之間接頭的存在和二價本身都不驅動高非特異性結合,如可以藉由RELAX0122的低非特異性結合所證明。
實例 9 :溶液中的穩定性
使用高效尺寸排阻層析法(HP-SEC)和液相層析法-質譜法(LC-MS)評估RELAX0023的穩定性,並且與RELAX0127和RELAX0128進行比較。藉由對280 nm處的吸光度進行檢測的HP-SEC可用於測量純度、聚集和片段化。將分子緩衝液交換至優化的配製物組成物中,然後濃縮至高達10 mg/mL。將所有樣本放置在應激溫度條件(40°C)下,持續長達4週。在1、2和4週的時間點,收集樣本並注射到尺寸排阻柱,並且以固定流速用水性流動相等度洗脫。與較小的分子相比,較大的分子在更大程度上從尺寸排阻柱的孔排除,並因此更早洗脫。將早於單體峰洗脫的峰記錄為聚集體。將在單體峰後洗脫的峰(不包括緩衝液相關峰)記錄為片段。將結果記錄為純度百分比、聚集體百分比和片段百分比,並且示於圖8中。RELAX0023係最穩定的分子,其純度損失率%僅為0.1%/月,而RELAX0128和RELAX0127分別為7.7%和9.3%。RELAX0127和RELAX0128兩者示出了聚集的跡象,然而,RELAX0023的聚集水平並未增加,表明更好的物理溶液穩定性。片段化似乎係純度損失的主要因素,其中RELAX0127具有6.6%片段化/月,而RELAX0128為6.8%。RELAX0023僅具有0.7%/月的片段化率。同時,在40°C下儲存4週後,RELAX0128的總峰面積從22403下降至18216(降低19%),而RELAX0127從22225下降至18823(降低15%)。總峰面積的這一顯著損失以及高片段化率表明這兩種分子可能存在高度化學降解。應指出,總面積的這一損失對於這兩種分子的層析圖曲線具有很大影響。這解釋了為什麼儘管儲存後聚集體峰面積出現明顯增加,但RELAX0128和RELAX0127在4週時與之前的時間點相比顯示出更低的聚集體百分比。相比之下,RELAX0023的總峰面積僅下降了0.03%,從21828下降至21761,表明與RELAX0128和RELAX0127相比具有更好的穩定性曲線。
使用還原質量分析,藉由LC-MS進一步驗證了分子的片段化,表明在40°C下儲存後,RELAX0127和RELAX0128的片段峰在強度方面有所增加(圖9A)。相比之下,RELAX0023的片段峰在應激後保持不變。還原條件下的質譜還顯示出RELAX0127和RELAX0128隨時間的修飾,這藉由峰向更大質量的位移和峰的加寬從而表明更大的異質性來證明(圖9B)。相比之下,RELAX0023的完整質譜保持不變,表明沒有發生修飾。此研究表明與RELAX0127和RELAX0128相比,RELAX0023具有優越的物理和化學穩定性。
實例 10 :石蟹獼猴中的 RELAX0023 的 PK 曲線
使用基於ELISA的夾心免疫測定,確定石蟹獼猴中的RELAX0023的藥物動力學(PK)曲線。向隨機分配至4組(3隻動物/組)的共12隻雌性石蟹獼猴投與RELAX0023。分別向組1、2和3中的動物SC投與0.1、1和10 mg/kg的RELAX0023。向組4中的動物藉由IV推注給予10 mg/kg的RELAX0023。在藥物投與後0.25小時、1小時、2小時、4小時、8小時、24小時、48小時、96小時、7天、14天和21天收集血清樣本。
將測定板用山羊抗人IgG抗體塗覆並與來自組1-4動物的石蟹獼猴血清一起孵育。藉由與HRP軛合的抗鬆弛素抗體檢測與板結合的RELAX0023。在添加至板之前,將石蟹獼猴血清以1 : 10稀釋。在100%血清中,定量下限係0.010 µg/mL,並且定量上限係0.300 µg/mL。
結果和結論
圖10示出了在單次劑量後石蟹獼猴中的RELAX0023的平均血清濃度-時間曲線。在SC投與單次劑量後,RELAX0023在0.01至10 mg/kg的劑量範圍內表現出線性PK。觀察到C
max的劑量成比例增加。對於0.1、1和10 mg/kg SC劑量組,平均C
max值分別是0.400、4.69、34.8 µg/mL。從0.1 mg/kg至10 mg/kg SC組也觀察到AUC
0-last值的劑量成比例增加。對於0.1、1和10 mg/kg SC劑量組,平均AUC
0-last值分別是2.01、25.5、193 µg天/mL。總體而言,RELAX0023 PK在0.1 mg/kg至10 mg/kg的範圍內呈線性,其中平均CL/F為51.0 mL/天/kg,平均t
1/2為3.07天。RELAX0023的SC生體可用率估計為88.2%。
無
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圖 1]示出了根據本發明一些實施方式的異源二聚體融合物之示例性格式。異源二聚體融合物的每種融合多肽的格式以FcX、FcY、A、B、con和L給出,其中FcX(「Fc杵」)和FcY(「Fc臼」)係兩個包含促進異源二聚體化的胺基酸突變和/或修飾的Fc區;A(「Rlx A」)和B(「Rlx B」)係鬆弛素A鏈和鬆弛素B鏈多肽;「con」係連接子多肽;L係接頭多肽,HC X和HC Y - 抗體的重鏈,LC - 抗體的輕鏈,鉸鏈 - 抗體的鉸鏈區,並且Fab係抗體的Fab片段。
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圖 2]示出了RELAX0019和RELAX0023之LC-MS分析A) 示出了完整分子的質量的RELAX0019和RELAX0023去糖基化和非還原分析;B) 示出了單獨的Fc融合鏈(杵-鬆弛素鏈A和臼-鬆弛素鏈B)的質量的RELAX0019和RELAX0023去糖基化和還原分析。
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圖 3]示出了藉由使用LC-MS的非還原肽作圖,RELAX0019和RELAX0023的C-末端肽之分析。在頂部小圖中示出了具有由線代表的預測二硫鍵的C-末端肽之胺基酸序列。小圖A和E - 在不存在還原劑(-DTT)的情況下,C-末端肽之提取離子層析圖。小圖C和G - 在不存在還原劑的情況下,C-末端肽的解卷積質譜。小圖B和F - 在存在還原劑(+DTT)的情況下的提取離子層析圖,以及小圖D和H - 在存在還原劑的情況下的解卷積質譜。圖3按出現順序分別揭露了SEQ ID NO 75、77和76。
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圖 4]示出了在表現重組人RXFP1的細胞中藉由cAMP誘導測量的本發明一些異源二聚體融合物之體外生物活性。
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圖 5]示出了來自一系列ELISA實驗之體內藥物動力學(PK)曲線,其中將本發明之異源二聚體融合物靜脈內投與至小鼠。將數據歸一化為在5 min時間點(T1)處的% cMax。
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圖 6]示出了在用RELAX0019和RELAX0023治療的小鼠中,異丙腎上腺素誘導的心臟纖維化和肥大之逆轉。示出了以下的纖維化和肥大的水平:(1) 媒介物(基線)、(2) 異丙腎上腺素、(3) 異丙腎上腺素 + 鬆弛素-2、(4) 異丙腎上腺素 + RELAX0019和 (5) 異丙腎上腺素 + RELAX0023。
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圖 7]示出了在桿狀病毒(BV)ELISA測定中,本發明之異源二聚體融合物之體外非特異性結合。
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圖 8]示出了儲存後溶液中RELAX0023、RELAX0127和RELAX0128的純度損失、聚集和片段化之百分比。
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圖 9]示出了藉由還原LC-MS分析評估的溶液中RELAX0023、RELAX0127和RELAX0128隨時間之穩定性。A) 總離子層析圖B) 還原分子的質譜
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圖 10]示出了在靜脈內和皮下注射後石蟹獼猴中RELAX0023的PK曲線。
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圖 11]示出了編碼本發明多肽中的一些之核苷酸序列。(按出現順序分別為SEQ ID NO 80-140)。
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表 1]
:序列表上鉸鏈區以斜體表示,鬆弛素A以底線表示,鬆弛素B以雙底線表示,FC區以粗體表示。
SEQ ID NO: | 構建體 | 胺基酸序列 |
1 | 鬆弛素A | QLYSALANKCCHVGCTKRSLARFC |
2 | 鬆弛素B | SWMEEVIKLCGRELVRAQIAICGMSTWS |
3 | FcH01 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
4 | FcK01 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
5 | Con01 | GGGGSGGGGSGGGGSGGGGGS |
6 | Con02 | PAPAPAPAPAPAPAPAPAPAG |
7 | RELAX0009 | SWMEEVIKLCGRELVRAQIAICGMSTWSGGGGSGGGGSGGGGS QLYSALANKCCHVGCTKRSLARFCAAAGGGGSGGGGSGGGGSGGGGSA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
8 | RELAX0010 | DKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGS QLYSALANKCCHVGCTKRSLARFCGGGGSGGGGSGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
9 | Rlx011 | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
10 | Rlx011b | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
11 | Rlx011DD | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
12 | Rlx012 | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
13 | Rlx012b | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
14 | Rlx012DD | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
15 | Rlx013 | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
16 | Rlx013b | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
17 | Rlx013DD | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
18 | Rlx014 | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
19 | Rlx014b | GGAGGA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
20 | Rlx014DD | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
21 | Rlx020 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
22 | Rlx021 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
23 | Rlx022 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
24 | Rlx023 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
25 | Rlx024 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGGS QLYSALANKCCHVGCTKRSLARFC |
26 | Rlx025 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
27 | Rlx026 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAPAPAPAPAPAPAPAPAPAGS QLYSALANKCCHVGCTKRSLARFC |
28 | Rlx027 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAPAPAPAPAPAPAPAPAPAGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
29 | Rlx028 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAPAPAPAPAPAPAGS QLYSALANKCCHVGCTKRSLARFC |
30 | Rlx029 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAPAPAPAPAPAPAGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
31 | Rlx030 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAPAPAPAPAGS QLYSALANKCCHVGCTKRSLARFC |
32 | Rlx031 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAPAPAPAPAGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
33 | Rlx041E | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANECCHVGCTKRSLARFC |
34 | Rlx041H | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANHCCHVGCTKRSLARFC |
35 | Rlx041L | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANLCCHVGCTKRSLARFC |
36 | Rlx041M | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANMCCHVGCTKRSLARFC |
37 | Rlx044E | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKESLARFC |
38 | Rlx044H | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKHSLARFC |
39 | Rlx051A | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAAFC |
40 | Rlx051I | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAIFC |
41 | Rlx051M | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAMFC |
42 | Rlx051Q | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAQFC |
43 | Rlx051S | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLASFC |
44 | Rlx052E | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAREC |
45 | Rlx052I | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARIC |
46 | Rlx055 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWSGGGSGGGSG QLYSALANKCCHVGCTKRSLARFC |
47 | Rlx056 | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWSGGGSGGGSG QLYSALANKCCHVGCTKRSLARFC |
48 | Rlx061H | SWMEEVIKLCGRELVRAQIAICGMSTWSAAAGGGGSGGGGSGGGGSGGGGSA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
49 | Rlx062K | QLYSALANKCCHVGCTKRSLARFCAAAGGGGSGGGGSGGGGSGGGGSA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
50 | Rlx076 | QLYSALANKCCHVGCTKRSLARFCAAAGGGGSGGGGSGGGGSGGGGSA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
51 | Rlx077 | SWMEEVIKLCGRELVRAQIAICGMSTWSAAAGGGGSGGGGSGGGGSGGGGSA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
52 | Rlx014DDdel2aa | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMST |
53 | Rlx014DDdel3aa | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMS |
54 | R347 L | ELVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFSGSKSGNTASLTISGQAEDEADYYCSSYTSSSTLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQTHEGSTVEKTVAPTECS |
55 | R347Rlx011DD | EVQLLESGGGLVQPGGSLRLSCTTSGFTFNTYAMSWVRQAPGKGLEWLSGINNNGRTAFYADSVKGRFTISRDNSKNTLYLQINSLRADDTAVYFCAKDVRFIAVPGDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARFC |
56 | R347Rlx014DD | EVQLLESGGGLVQPGGSLRLSCTTSGFTFNTYAMSWVRQAPGKGLEWLSGINNNGRTAFYADSVKGRFTISRDNSKNTLYLQINSLRADDTAVYFCAKDVRFIAVPGDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
57 | RELAX0126 | DKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGSP QLYSALANKCCHVGCTKRSLARFCGGGSGGGSG SWMEEVIKLCGRELVRAQIAICGMSTWS |
58 | RELAX0127 | DKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGSGGSP QLYSALANKCCHVGCTKRSLARFCGGGSGGGSG SWMEEVIKLCGRELVRAQIAICGMSTWS |
59 | RELAX0128 | DKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGSGGSGGSP QLYSALANKCCHVGCTKRSLARFCGGGSGGGSG SWMEEVIKLCGRELVRAQIAICGMSTWS |
60 | 接頭01 | GGGSGGGSGG |
61 | Rlx052A | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLARAC |
62 | RELAX0013 B鏈 | D SWMEEVIKLCGRELVRAQIAICGMSTWS |
63 | RELAX0013 A鏈 | QLYSALANKCCHVGCTKRSLARFC |
64 | RELAX0014 B鏈 | MRVSEEWMDGFIRMCGREYARELIKICGASVGR |
65 | RELAX0014 A鏈 | ESGGLMSQQCCHVGCSRRSIAKLYC |
66 | Rlx042R | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCRVGCTKRSLARFC |
67 | Rlx014d | DKTHTA CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS SWMEEVIKLCGRELVRAQIAICGMSTWS |
68 | Rlx051Y | DKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGGS QLYSALANKCCHVGCTKRSLAYFC |
無
<![CDATA[<110> 英商梅迪繆思有限公司(MEDIMMUNE LIMITED)]]> <![CDATA[<120> 異源二聚體鬆弛素融合物及其用途]]> <![CDATA[<130> 201011]]> <![CDATA[<140>]]> <![CDATA[<141>]]> <![CDATA[<150> 63/040,250]]> <![CDATA[<151> 2020-06-17]]> <![CDATA[<160> 140 ]]> <![CDATA[<170> PatentIn 3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 24]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> 未知序列的描述:鬆弛素A序列]]> <![CDATA[<400> 1]]> Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 <![CDATA[<210> 2]]> <![CDATA[<211> 28]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> 未知序列的描述:鬆弛素B序列]]> <![CDATA[<400> 2]]> Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 <![CDATA[<210> 3]]> <![CDATA[<211> 226]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 3]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly 225 <![CDATA[<210> 4]]> <![CDATA[<211> 226]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 4]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly 225 <![CDATA[<210> 5]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 5]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Gly Ser 20 <![CDATA[<210> 6]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 6]]> Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 1 5 10 15 Pro Ala Pro Ala Gly 20 <![CDATA[<210> 7]]> <![CDATA[<211> 312]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 7]]> Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala 35 40 45 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 50 55 60 Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 65 70 75 80 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Cys Pro Pro Cys Pro 85 90 95 Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 100 105 110 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 115 120 125 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 130 135 140 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 145 150 155 160 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 165 170 175 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 180 185 190 Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 195 200 205 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 210 215 220 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 225 230 235 240 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 245 250 255 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 260 265 270 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 275 280 285 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 290 295 300 Lys Ser Leu Ser Leu Ser Pro Gly 305 310 <![CDATA[<210> 8]]> <![CDATA[<211> 309]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 8]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Gly 260 265 270 Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile 275 280 285 Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly 290 295 300 Met Ser Thr Trp Ser 305 <![CDATA[<210> 9]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 9]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 10]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 10]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 11]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 11]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 12]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 12]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 13]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 13]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 14]]> <![CDATA[<211> 275]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 14]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <![CDATA[<210> 15]]> <![CDATA[<211> 276]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 15]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <![CDATA[<210> 16]]> <![CDATA[<211> 276]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 16]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <![CDATA[<210> 17]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 17]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 18]]> <![CDATA[<211> 276]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 18]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <![CDATA[<210> 19]]> <![CDATA[<211> 276]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 19]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <![CDATA[<210> 20]]> <![CDATA[<211> 275]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 20]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <![CDATA[<210> 21]]> <![CDATA[<211> 266]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 21]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 <![CDATA[<210> 22]]> <![CDATA[<211> 270]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 22]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu 245 250 255 Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 270 <![CDATA[<210> 23]]> <![CDATA[<211> 261]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 23]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys 260 <![CDATA[<210> 24]]> <![CDATA[<211> 265]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 24]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met 225 230 235 240 Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile 245 250 255 Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 <![CDATA[<210> 25]]> <![CDATA[<211> 256]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 25]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 225 230 235 240 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 245 250 255 <![CDATA[<210> 26]]> <![CDATA[<211> 260]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 26]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 225 230 235 240 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 245 250 255 Ser Thr Trp Ser 260 <![CDATA[<210> 27]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 27]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 225 230 235 240 Ala Pro Ala Pro Ala Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 28]]> <![CDATA[<211> 275]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 28]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 225 230 235 240 Ala Pro Ala Pro Ala Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <![CDATA[<210> 29]]> <![CDATA[<211> 266]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 29]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 <![CDATA[<210> 30]]> <![CDATA[<211> 270]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 30]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 225 230 235 240 Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu 245 250 255 Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 270 <![CDATA[<210> 31]]> <![CDATA[<211> 261]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 31]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Pro Ala Pro Ala Pro Ala Pro Ala Gly Ser Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys 260 <![CDATA[<210> 32]]> <![CDATA[<211> 265]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 32]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Pro Ala Pro Ala Pro Ala Pro Ala Gly Ser Ser Trp Met 225 230 235 240 Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile 245 250 255 Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 <![CDATA[<210> 33]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 33]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Glu Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 34]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 34]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 His Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 35]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 35]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Leu Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 36]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 36]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Met Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 37]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 37]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Glu Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 38]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 38]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys His Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 39]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 39]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ala Phe Cys 260 265 270 <![CDATA[<210> 40]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 40]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ile Phe Cys 260 265 270 <![CDATA[<210> 41]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 41]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Met Phe Cys 260 265 270 <![CDATA[<210> 42]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 42]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Gln Phe Cys 260 265 270 <![CDATA[<210> 43]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 43]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ser Phe Cys 260 265 270 <![CDATA[<210> 44]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 44]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Glu Cys 260 265 270 <![CDATA[<210> 45]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 45]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Ile Cys 260 265 270 <![CDATA[<210> 46]]> <![CDATA[<211> 308]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 46]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gln Leu Tyr Ser 275 280 285 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu 290 295 300 Ala Arg Phe Cys 305 <![CDATA[<210> 47]]> <![CDATA[<211> 308]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 47]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gln Leu Tyr Ser 275 280 285 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu 290 295 300 Ala Arg Phe Cys 305 <![CDATA[<210> 48]]> <![CDATA[<211> 273]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 48]]> Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ala Ala Ala Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 50 55 60 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 65 70 75 80 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 85 90 95 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 100 105 110 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 115 120 125 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 130 135 140 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 145 150 155 160 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 165 170 175 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 180 185 190 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 195 200 205 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 210 215 220 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 225 230 235 240 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 245 250 255 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 260 265 270 Gly <![CDATA[<210> 49]]> <![CDATA[<211> 269]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 49]]> Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser 20 25 30 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 35 40 45 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 50 55 60 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 65 70 75 80 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 85 90 95 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 100 105 110 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 115 120 125 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 130 135 140 Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser 145 150 155 160 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 165 170 175 Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val 180 185 190 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 195 200 205 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 210 215 220 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 225 230 235 240 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 245 250 255 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 260 265 <![CDATA[<210> 50]]> <![CDATA[<211> 314]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 50]]> Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser 20 25 30 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 35 40 45 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 50 55 60 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 65 70 75 80 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 85 90 95 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 100 105 110 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 115 120 125 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 130 135 140 Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser 145 150 155 160 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 165 170 175 Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val 180 185 190 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 195 200 205 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 210 215 220 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 225 230 235 240 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 245 250 255 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly 260 265 270 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 275 280 285 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 290 295 300 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 305 310 <![CDATA[<210> 51]]> <![CDATA[<211> 322]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 51]]> Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ala Ala Ala Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 50 55 60 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 65 70 75 80 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 85 90 95 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 100 105 110 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 115 120 125 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 130 135 140 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 145 150 155 160 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 165 170 175 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 180 185 190 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 195 200 205 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 210 215 220 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 225 230 235 240 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 245 250 255 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 260 265 270 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 275 280 285 Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys 290 295 300 Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr 305 310 315 320 Trp Ser <![CDATA[<210> 52]]> <![CDATA[<211> 273]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 52]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr <![CDATA[<210> 53]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 53]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 <![CDATA[<210> 54]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 54]]> Glu Leu Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser 85 90 95 Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125 Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130 135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <![CDATA[<210> 55]]> <![CDATA[<211> 494]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 55]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Gly Ile Asn Asn Asn Gly Arg Thr Ala Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Asp Val Arg Phe Ile Ala Val Pro Gly Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys 465 470 475 480 Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 485 490 <![CDATA[<210> 56]]> <![CDATA[<211> 498]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 56]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Gly Ile Asn Asn Asn Gly Arg Thr Ala Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Asp Val Arg Phe Ile Ala Val Pro Gly Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys 465 470 475 480 Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr 485 490 495 Trp Ser <![CDATA[<210> 57]]> <![CDATA[<211> 292]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 57]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Pro Gln Leu Tyr Ser Ala Leu Ala Asn Lys 225 230 235 240 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly 245 250 255 Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp Met Glu Glu Val Ile Lys 260 265 270 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 275 280 285 Ser Thr Trp Ser 290 <![CDATA[<210> 58]]> <![CDATA[<211> 295]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 58]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Pro Gln Leu Tyr Ser Ala Leu 225 230 235 240 Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg 245 250 255 Phe Cys Gly Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp Met Glu Glu 260 265 270 Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile 275 280 285 Cys Gly Met Ser Thr Trp Ser 290 295 <![CDATA[<210> 59]]> <![CDATA[<211> 298]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 59]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys Gly Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp 260 265 270 Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln 275 280 285 Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 290 295 <![CDATA[<210> 60]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 60]]> Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 1 5 10 <![CDATA[<210> 61]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 61]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Ala Cys 260 265 270 <![CDATA[<210> 62]]> <![CDATA[<211> 29]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 62]]> Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 <![CDATA[<210> 63]]> <![CDATA[<211> 24]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 63]]> Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 <![CDATA[<210> 64]]> <![CDATA[<211> 33]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 64]]> Met Arg Val Ser Glu Glu Trp Met Asp Gly Phe Ile Arg Met Cys Gly 1 5 10 15 Arg Glu Tyr Ala Arg Glu Leu Ile Lys Ile Cys Gly Ala Ser Val Gly 20 25 30 Arg <![CDATA[<210> 65]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 65]]> Glu Ser Gly Gly Leu Met Ser Gln Gln Cys Cys His Val Gly Cys Ser 1 5 10 15 Arg Arg Ser Ile Ala Lys Leu Tyr Cys 20 25 <![CDATA[<210> 66]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 66]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys Arg Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <![CDATA[<210> 67]]> <![CDATA[<211> 276]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 67]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <![CDATA[<210> 68]]> <![CDATA[<211> 271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 68]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Tyr Phe Cys 260 265 270 <![CDATA[<210> 69]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 69]]> Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 <![CDATA[<210> 70]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 70]]> Asp Lys Thr His Thr Ala Cys Pro Pro Cys 1 5 10 <![CDATA[<210> 71]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 71]]> Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys 1 5 10 <![CDATA[<210> 72]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 72]]> Ala Cys Pro Pro Cys 1 5 <![CDATA[<210> 73]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (1)..(30) ]]> <![CDATA[<223>此序列可能涵蓋3-15個“Pro Ala”重複單元]]> <![CDATA[<400> 73]]> Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 1 5 10 15 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 20 25 30 <![CDATA[<210> 74]]> <![CDATA[<211> 40]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (1)..(40) ]]> <![CDATA[<223>此序列可能涵蓋1-8個“Gly Gly Gly Gly Ser”重複單元]]> <![CDATA[<400> 74]]> 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 Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser 35 40 <![CDATA[<210> 75]]> <![CDATA[<211> 45]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多肽]]> <![CDATA[<400> 75]]> Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser 20 25 30 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys 35 40 45 <![CDATA[<210> 76]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 76]]> Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 1 5 10 15 Ser Thr Trp Ser 20 <![CDATA[<210> 77]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 77]]> Arg Ser Leu Ala Arg Phe Cys 1 5 <![CDATA[<210> 78]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 78]]> Gly Gly Ala Gly Gly Ala 1 5 <![CDATA[<210> 79]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成肽]]> <![CDATA[<400> 79]]> Asp Lys Thr His Thr 1 5 <![CDATA[<210> 80]]> <![CDATA[<211> 72]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> 未知序列的描述:鬆弛素A序列]]> <![CDATA[<400> 80]]> cagctctact cagcgctcgc taataagtgt tgtcatgtgg gatgcacaaa gcggtctctc 60 gccagattct gc 72 <![CDATA[<210> 81]]> <![CDATA[<211> 84]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> 未知序列的描述:鬆弛素B序列]]> <![CDATA[<400> 81]]> agctggatgg aagaagtgat taaactgtgt ggccgcgaac tggtgcgcgc gcagattgcg 60 atttgcggca tgagcacctg gagc 84 <![CDATA[<210> 82]]> <![CDATA[<211> 678]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 82]]> gacaagaccc atacatgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaaaagc 660 ttgtccctga gccccggc 678 <![CDATA[<210> 83]]> <![CDATA[<211> 678]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 83]]> gacaagaccc atacatgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaaaagc 660 ttgtccctga gccccggc 678 <![CDATA[<210> 84]]> <![CDATA[<211> 927]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 84]]> gataaaaccc atacctgccc gccgtgcccg gcgccggaac tgctgggcgg cccgagcgtg 60 tttctgtttc cgccgaaacc gaaagatacc ctgatgatta gccgcacccc ggaagtgacc 120 tgcgtggtgg tggatgtgag ccatgaagat ccggaagtga aatttaactg gtatgtggat 180 ggcgtggaag tgcataacgc gaaaaccaaa ccgcgcgaag aacagtataa cagcacctat 240 cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa agaatataaa 300 tgcaaagtga gcaacaaagc gctgccggcg ccgattgaaa aaaccattag caaagcgaaa 360 ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccgcgatga actgaccaaa 420 aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 480 tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 540 gatggcagct tttttctgta tagcaaactg accgtggata aaagccgctg gcagcagggc 600 aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 660 ctgagcctga gcccgggcaa aggcggcggc ggcagcggcg gcggcggcag cggcggcggc 720 ggcagccagc tgtatagcgc gctggcgaac aaatgctgcc atgtgggctg caccaaacgc 780 agcctggcgc gcttttgcgg cggcggcggc agcggcggcg gcggcagcgg cggcggcggc 840 agcagctgga tggaagaagt gattaaactg tgtggccgcg aactggtgcg cgcgcagatt 900 gcgatttgcg gcatgagcac ctggagc 927 <![CDATA[<210> 85]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 85]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 86]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 86]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 87]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 87]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagattc tgc 813 <![CDATA[<210> 88]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 88]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 89]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 89]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 90]]> <![CDATA[<211> 825]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 90]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <![CDATA[<210> 91]]> <![CDATA[<211> 828]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 91]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <![CDATA[<210> 92]]> <![CDATA[<211> 828]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 92]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <![CDATA[<210> 93]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 93]]> gacaagaccc ayacmtgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagattc tgc 813 <![CDATA[<210> 94]]> <![CDATA[<211> 828]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 94]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <![CDATA[<210> 95]]> <![CDATA[<211> 828]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 95]]> ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <![CDATA[<210> 96]]> <![CDATA[<211> 825]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 96]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <![CDATA[<210> 97]]> <![CDATA[<211> 798]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 97]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg tggagggggc 720 ggatcccagc tctactcagc gctcgctaat aagtgttgtc atgtgggatg cacaaagcgg 780 tctctcgcca gattctgc 798 <![CDATA[<210> 98]]> <![CDATA[<211> 810]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 98]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg tggagggggc 720 ggatccagct ggatggaaga agtgattaaa ctgtgtggcc gcgaactggt gcgcgcgcag 780 attgcgattt gcggcatgag cacctggagc 810 <![CDATA[<210> 99]]> <![CDATA[<211> 783]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 99]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggaggtggc tctggtggag ggggcggatc ccagctctac 720 tcagcgctcg ctaataagtg ttgtcatgtg ggatgcacaa agcggtctct cgccagattc 780 tgc 783 <![CDATA[<210> 100]]> <![CDATA[<211> 795]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 100]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggaggtggc tctggtggag ggggcggatc cagctggatg 720 gaagaagtga ttaaactgtg tggccgcgaa ctggtgcgcg cgcagattgc gatttgcggc 780 atgagcacct ggagc 795 <![CDATA[<210> 101]]> <![CDATA[<211> 768]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 101]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg tggagggggc ggatcccagc tctactcagc gctcgctaat 720 aagtgttgtc atgtgggatg cacaaagcgg tctctcgcca gattctgc 768 <![CDATA[<210> 102]]> <![CDATA[<211> 780]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 102]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg tggagggggc ggatccagct ggatggaaga agtgattaaa 720 ctgtgtggcc gcgaactggt gcgcgcgcag attgcgattt gcggcatgag cacctggagc 780 <![CDATA[<210> 103]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 103]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc acctgctccc gcaccagccc ctgctcccgc accagcccct 720 gctcccgcac cagccggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagattc tgc 813 <![CDATA[<210> 104]]> <![CDATA[<211> 825]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 104]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc acctgctccc gcaccagccc ctgctcccgc accagcccct 720 gctcccgcac cagccggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <![CDATA[<210> 105]]> <![CDATA[<211> 798]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 105]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc agctcctgct cccgcaccag cccctgctcc cgcaccagcc 720 ggatcccagc tctactcagc gctcgctaat aagtgttgtc atgtgggatg cacaaagcgg 780 tctctcgcca gattctgc 798 <![CDATA[<210> 106]]> <![CDATA[<211> 810]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 106]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc agctcctgct cccgcaccag cccctgctcc cgcaccagcc 720 ggatccagct ggatggaaga agtgattaaa ctgtgtggcc gcgaactggt gcgcgcgcag 780 attgcgattt gcggcatgag cacctggagc 810 <![CDATA[<210> 107]]> <![CDATA[<211> 783]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 107]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc accagcccct gctcccgcac cagccggatc ccagctctac 720 tcagcgctcg ctaataagtg ttgtcatgtg ggatgcacaa agcggtctct cgccagattc 780 tgc 783 <![CDATA[<210> 108]]> <![CDATA[<211> 795]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 108]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc accagcccct gctcccgcac cagccggatc cagctggatg 720 gaagaagtga ttaaactgtg tggccgcgaa ctggtgcgcg cgcagattgc gatttgcggc 780 atgagcacct ggagc 795 <![CDATA[<210> 109]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 109]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatga gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 110]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 110]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatca ctgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 111]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 111]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaattt gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 112]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 112]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatat gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 113]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 113]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaaggagtc tctcgccaga ttctgc 816 <![CDATA[<210> 114]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 114]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcactc tctcgccaga ttctgc 816 <![CDATA[<210> 115]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 115]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccgccttc tgc 813 <![CDATA[<210> 116]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 116]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccatcttc tgc 813 <![CDATA[<210> 117]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 117]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccatgttc tgc 813 <![CDATA[<210> 118]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 118]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcccagttc tgc 813 <![CDATA[<210> 119]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 119]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcctccttc tgc 813 <![CDATA[<210> 120]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 120]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcctacttc tgc 813 <![CDATA[<210> 121]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 121]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagagag tgc 813 <![CDATA[<210> 122]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 122]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagaatc tgc 813 <![CDATA[<210> 123]]> <![CDATA[<211> 924]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 123]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ctcctggatg gaggaggtta tcaagctgtg tggacgcgaa 780 ctggtgcgcg ctcagatcgc gatatgcggg atgtccacat ggtcaggcgg cggcagcggc 840 ggcggcagcg gccagctcta ctcagcgctc gctaataagt gttgtcatgt gggatgcaca 900 aagcggtctc tcgccagatt ctgc 924 <![CDATA[<210> 124]]> <![CDATA[<211> 924]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 124]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ctcctggatg gaggaggtta tcaagctgtg tggacgcgaa 780 ctggtgcgcg ctcagatcgc gatatgcggg atgtccacat ggtcaggcgg cggcagcggc 840 ggcggcagcg gccagctcta ctcagcgctc gctaataagt gttgtcatgt gggatgcaca 900 aagcggtctc tcgccagatt ctgc 924 <![CDATA[<210> 125]]> <![CDATA[<211> 819]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 125]]> tcctggatgg aagaagtgat caagctctgc ggcagagaac tcgtgcgggc ccagatcgct 60 atctgcggca tgtctacttg gagcgcggcc gcgggtggag gtggatccgg aggaggtgga 120 agcggaggag gtggaagcgg aggaggtgga agcgcttgtc ctccatgccc ggcgcctgag 180 ttcgagggcg gaccctccgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 240 tcccggaccc ccgaagtgac ctgcgtggtg gtggacgtgt cccacgagga ccctgaagtg 300 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 360 gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggactgg 420 ctgaacggca aagagtacaa gtgcaaggtc tccaacaagg ccctgcccgc ctccatcgaa 480 aagaccatct ccaaggccaa gggccagccc cgcgagcctc aggtgtgcac actgcccccc 540 agccgggaag agatgaccaa gaaccaggtg tccctgtcct gtgccgtgaa aggcttctac 600 ccctccgata tcgctgtgga atgggagtcc aacggccagc ccgagaacaa ctacaagacc 660 accccccctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gaccgtggac 720 aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 780 aaccactaca cccagaagtc tctgtccctg agccccggc 819 <![CDATA[<210> 126]]> <![CDATA[<211> 807]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 126]]> cagctgtact ctgccctggc caacaagtgt tgccacgtgg gctgcaccaa gagatccctg 60 gccagattct gtgcggccgc gggtggaggt ggatccggag gaggtggaag cggaggaggt 120 ggaagcggag gaggtggaag cgcttgtcct ccatgcccgg cgcctgagtt cgagggcgga 180 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 240 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 300 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 360 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 420 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 480 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 540 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 600 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 660 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 720 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 780 cagaagtctc tgtccctgag ccccggc 807 <![CDATA[<210> 127]]> <![CDATA[<211> 942]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 127]]> cagctgtact ctgccctggc caacaagtgt tgccacgtgg gctgcaccaa gagatccctg 60 gccagattct gtgcggccgc gggtggaggt ggatccggag gaggtggaag cggaggaggt 120 ggaagcggag gaggtggaag cgcttgtcct ccatgcccgg cgcctgagtt cgagggcgga 180 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 240 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 300 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 360 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 420 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 480 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 540 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 600 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 660 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 720 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 780 cagaagtctc taagcttgag ccccggcgga ggtggtggaa gcggaggagg tggctctgga 840 gggggtggaa gcggaggtgg aggtggatcc cagctctact cagcgctcgc taataagtgt 900 tgtcatgtgg gatgcacaaa gcggtctctc gccagattct gc 942 <![CDATA[<210> 128]]> <![CDATA[<211> 966]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 128]]> tcctggatgg aagaagtgat caagctctgc ggcagagaac tcgtgcgggc ccagatcgct 60 atctgcggca tgtctacttg gagcgcggcc gcgggtggag gtggatccgg aggaggtgga 120 agcggaggag gtggaagcgg aggaggtgga agcgcttgtc ctccatgccc ggcgcctgag 180 ttcgagggcg gaccctccgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 240 tcccggaccc ccgaagtgac ctgcgtggtg gtggacgtgt cccacgagga ccctgaagtg 300 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 360 gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggactgg 420 ctgaacggca aagagtacaa gtgcaaggtc tccaacaagg ccctgcccgc ctccatcgaa 480 aagaccatct ccaaggccaa gggccagccc cgcgagcctc aggtgtgcac actgcccccc 540 agccgggaag agatgaccaa gaaccaggtg tccctgtcct gtgccgtgaa aggcttctac 600 ccctccgata tcgctgtgga atgggagtcc aacggccagc ccgagaacaa ctacaagacc 660 accccccctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gaccgtggac 720 aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 780 aaccactaca cccagaagtc tctaagcttg agccccggcg gaggtggtgg aagcggagga 840 ggtggctctg gagggggtgg aagcggaggt ggaggtggat ccagctggat ggaagaagtg 900 attaaactgt gtggccgcga actggtgcgc gcgcagattg cgatttgcgg catgagcacc 960 tggagc 966 <![CDATA[<210> 129]]> <![CDATA[<211> 819]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 129]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacc 819 <![CDATA[<210> 130]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 130]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagc 816 <![CDATA[<210> 131]]> <![CDATA[<211> 1482]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 131]]> gaggtgcagc tgctcgagtc agggggaggc ttggtacagc cgggggggtc cctgagactc 60 tcctgtacaa cctctggatt cacctttaac acgtatgcca tgagttgggt ccgccaggct 120 ccagggaagg ggctggaatg gctctcaggt attaataaca atggtcggac tgcattctac 180 gcagactccg tgaagggccg cttcaccatc tccagagaca actccaaaaa cacactttat 240 ctgcaaatta atagtctgag agcggacgac acggccgttt atttctgtgc gaaagatgtc 300 agatttatcg cagtgcctgg tgactcctgg ggccagggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggccccca gcagcaagag caccagcggc 420 ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc 540 ggcctgtaca gcctgagcag cgtggtgaca gtgccaagca gcagcctggg cacccagacc 600 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaagaccca cacctgtcct ccatgcccgg cgcctgagtt cgagggcgga 720 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 780 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 840 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 900 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 960 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 1020 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 1080 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 1140 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 1260 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 1320 cagaagtctc taagcttgag ccccggcgga ggtggtggaa gcggaggagg tggctctgga 1380 gggggtggaa gcggaggtgg aggtggatcc cagctctact cagcgctcgc taataagtgt 1440 tgtcatgtgg gatgcacaaa gcggtctctc gccagattct gc 1482 <![CDATA[<210> 132]]> <![CDATA[<211> 1494]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 132]]> gaggtgcagc tgctcgagtc agggggaggc ttggtacagc cgggggggtc cctgagactc 60 tcctgtacaa cctctggatt cacctttaac acgtatgcca tgagttgggt ccgccaggct 120 ccagggaagg ggctggaatg gctctcaggt attaataaca atggtcggac tgcattctac 180 gcagactccg tgaagggccg cttcaccatc tccagagaca actccaaaaa cacactttat 240 ctgcaaatta atagtctgag agcggacgac acggccgttt atttctgtgc gaaagatgtc 300 agatttatcg cagtgcctgg tgactcctgg ggccagggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggccccca gcagcaagag caccagcggc 420 ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc 540 ggcctgtaca gcctgagcag cgtggtgaca gtgccaagca gcagcctggg cacccagacc 600 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaagaccca cacctgtcct ccatgcccgg cgcctgagtt cgagggcgga 720 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 780 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 840 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 900 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 960 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 1020 aaggccaagg gccagccccg cgagcctcag gtgtgcacac tgccccccag ccgggaagag 1080 atgaccaaga accaggtgtc cctgtcctgt gccgtgaaag gcttctaccc ctccgatatc 1140 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200 ctggactccg acggctcatt cttcctggtg tccaagctga ccgtggacaa gtcccggtgg 1260 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 1320 cagaagtctc taagcttgag ccccggcgga ggtggtggaa gcggaggagg tggctctgga 1380 gggggtggaa gcggaggtgg aggtggatcc agctggatgg aagaagtgat taaactgtgt 1440 ggccgcgaac tggtgcgcgc gcagattgcg atttgcggca tgagcacctg gagc 1494 <![CDATA[<210> 133]]> <![CDATA[<211> 648]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 133]]> gagctcgtgt tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60 tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120 cacccaggca aagcccccaa actcatgatt tatgatgtca gtaagcggcc ctcaggggtt 180 tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240 caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cactttggta 300 ttcggcggag ggaccaagct gaccgtccta ggtcagccca aggctgcccc ctcggtcact 360 ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420 agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480 gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540 tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600 catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 648 <![CDATA[<210> 134]]> <![CDATA[<211> 876]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 134]]> gataaaaccc atacctgccc gccgtgcccg gcgccggaac tgctgggcgg cccgagcgtg 60 tttctgtttc cgccgaaacc gaaagatacc ctgatgatta gccgcacccc ggaagtgacc 120 tgcgtggtgg tggatgtgag ccatgaagat ccggaagtga aatttaactg gtatgtggat 180 ggcgtggaag tgcataacgc gaaaaccaaa ccgcgcgaag aacagtataa cagcacctat 240 cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa agaatataaa 300 tgcaaagtga gcaacaaagc gctgccggcg ccgattgaaa aaaccattag caaagcgaaa 360 ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccgcgatga actgaccaaa 420 aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 480 tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 540 gatggcagct tttttctgta tagcaaactg accgtggata aaagccgctg gcagcagggc 600 aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 660 ctgagcctga gcccgggcaa aggcggcagc ccgcagctgt atagcgcgct ggcgaacaaa 720 tgctgccatg tgggctgcac caaacgcagc ctggcgcgct tttgcggcgg cggcagcggc 780 ggcggcagcg gcagctggat ggaagaagtg attaaactgt gtggccgcga actggtgcgc 840 gcgcagattg cgatttgcgg catgagcacc tggagc 876 <![CDATA[<210> 135]]> <![CDATA[<211> 885]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 135]]> gataagacac acacctgtcc tccatgtcct gctccagaac tgctcggcgg accctctgtg 60 ttcctgtttc ctccaaagcc taaggacacc ctgatgatct ctcggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc tcacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 240 agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggctaag 360 ggccagcctc gggaacctca ggtttacaca ctgcctccat ctcgggacga gctgaccaag 420 aatcaggtgt ccctgacctg cctggtcaag ggcttctacc cttccgatat cgccgtggaa 480 tgggagtcca atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg acagtggaca agtctcggtg gcagcagggc 600 aacgtgttct cctgttctgt gatgcacgag gccctgcaca accactacac ccagaagtcc 660 ctgtctctgt cccctggaaa aggcggttct ggtggctctc ctcagctgta ctctgccctg 720 gccaacaagt gttgtcacgt gggctgcacc aagcggtccc tggctagatt ttgtggcggt 780 ggaagtggcg gcggatccgg ctcttggatg gaagaggtta tcaagctgtg cggcagagaa 840 ctcgtgcggg cccagatcgc tatctgtggc atgtccacct ggtcc 885 <![CDATA[<210> 136]]> <![CDATA[<211> 894]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 136]]> gataagacac atacctgtcc tccatgtcct gctccagagc tgctcggagg cccttccgtg 60 tttctgttcc ctccaaagcc taaggacacc ctgatgatct ctcggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc tcacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 240 agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggccaag 360 ggccagccta gggaacccca ggtttacacc ttgcctccat ctcgggacga gctgaccaag 420 aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagtcta atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg acagtggaca agtccagatg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca atcactacac ccagaagtcc 660 ctgtctctgt cccctggcaa aggtggcagc ggaggttccg gaggatctcc tcagctgtac 720 tctgccctgg ccaacaagtg ttgccacgtg ggctgcacca agagatccct ggccagattt 780 tgtggcggcg gatctggcgg aggttccggc tcttggatgg aagaagtgat caagctctgc 840 ggcagagaac tcgtgcgggc ccagatcgct atctgcggca tgtctacctg gtcc 894 <![CDATA[<210> 137]]> <![CDATA[<211> 516]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 137]]> ttcaattggt acgtggacgg cgtggaagtg cacaacgcca agaccaagcc cagagaggaa 60 cagtacaact ccacctaccg ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg 120 aacggcaaag agtacaagtg caaggtctcc aacaaggccc tgcccgcctc catcgaaaag 180 accatctcca aggccaaggg ccagccccgc gagcctcagg tgtacacact gccccccagc 240 cgggaagaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaagg cttctacccc 300 tccgatatcg ctgtggaatg ggagtccaac ggccagcccg agaacaacta caagaccacc 360 ccccctgtgc tggactccga cggctcattc ttcctgtact ccaagctgac cgtggacaag 420 tcccggtggc agcagggcaa cgtgttctcc tgctccgtga tgcacgaggc cctgcacaac 480 cactacaccc agaagtctct gtccctgagc cccggc 516 <![CDATA[<210> 138]]> <![CDATA[<211> 828]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 138]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <![CDATA[<210> 139]]> <![CDATA[<211> 816]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 139]]> gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcga 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <![CDATA[<210> 140]]> <![CDATA[<211> 813]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列的描述:合成多核苷酸]]> <![CDATA[<400> 140]]> gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagagcg tgc 813
Claims (37)
- 一種異源二聚體融合物,其包含: (i) 與至少一種鬆弛素A鏈多肽或其變體連接的第一異源二聚體化結構域;和 (ii) 與至少一種鬆弛素B鏈多肽或其變體連接的第二異源二聚體化結構域, 其中該第一異源二聚體化結構域與該第二異源二聚體化結構域異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。
- 如請求項1所述之異源二聚體融合物,其中藉由至少一個鏈間二硫鍵,將該鬆弛素A鏈多肽和該鬆弛素B鏈多肽共價結合。
- 如請求項1或2所述之異源二聚體融合物,其中該鬆弛素A鏈和該鬆弛素B鏈並不藉由胺基酸接頭來彼此共價連接。
- 如前述請求項中任一項所述之異源二聚體融合物,其中該鬆弛素A鏈係鬆弛素-2A鏈並且該鬆弛素B鏈係鬆弛素-2B鏈。
- 如前述請求項中任一項所述之異源二聚體融合物,其中將該鬆弛素A鏈經由連接子連接至該第一異源二聚體化結構域,並且將該鬆弛素B鏈經由連接子連接至該第二異源二聚體化結構域,視需要其中一個或較佳的是兩個連接子係多肽。
- 如請求項5所述之異源二聚體融合物,其中一個或較佳的是兩個連接子的長度為6至40個胺基酸,例如一個或較佳的是兩個連接子的長度為21個胺基酸。
- 如前述請求項中任一項所述之異源二聚體融合物,其中該第一和第二異源二聚體化結構域源自免疫球蛋白Fc區(分別是「第一Fc區」和「第二Fc區」),視需要其中該第一和第二Fc區包含恒定結構域CH2和CH3。
- 如請求項7所述之異源二聚體融合物,其中將該第一Fc區的C-末端連接至該鬆弛素A鏈的N-末端並且將該第二Fc區的C-末端連接至該鬆弛素B鏈的N-末端。
- 如請求項7或8所述之異源二聚體融合物,其中該第一和第二Fc區包含促進異源二聚體化的胺基酸突變和/或修飾,視需要其中該等促進異源二聚體化的胺基酸突變係「Fc杵」和「Fc臼」突變,例如存在於CH3結構域中的「Fc杵」和「Fc臼」突變。
- 如請求項7至9中任一項所述之異源二聚體融合物,其中該第一和第二Fc區源自人IgG1免疫球蛋白。
- 如請求項10所述之異源二聚體融合物,其中該等促進異源二聚體化的胺基酸突變包含: a. 在一個CH3結構域中的「Fc臼」突變Y349C、T366S、L368A和Y407V;和 b. 在另一個CH3結構域中的「Fc杵」突變S354C和T366W, 其中胺基酸編號係根據如卡巴特中的EU索引進行的。
- 如請求項11所述之異源二聚體融合物,其中: a. 該第一Fc區包含「Fc杵」突變並且該第二Fc區包含「Fc臼」突變;或 b. 該第二Fc區包含「Fc杵」突變並且該第一Fc區包含「Fc臼」突變。
- 如請求項10至12中任一項所述之異源二聚體融合物,其中該第一和/或第二Fc區包含胺基酸突變L234F、L235E和P331S,其中胺基酸編號係根據如卡巴特中的EU索引進行的。
- 如請求項4至13中任一項所述之異源二聚體融合物,其中該鬆弛素-2A鏈多肽包含如SEQ ID NO: 1所示的序列或其變體,並且該鬆弛素-2B鏈多肽包含如SEQ ID NO: 2所示的序列或其變體 。
- 如請求項14所述之異源二聚體融合物,其中該鬆弛素-2A鏈多肽包含胺基酸突變K9H、K17M或K17I。
- 如請求項5至15中任一項所述之異源二聚體融合物,其中兩個連接子均具有序列GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5]。
- 一種異源二聚體融合物,其包含: (i) FcX-con-A融合多肽;和 (ii) FcY-con-B融合多肽, 其中: A係鬆弛素A鏈或其變體,例如鬆弛素-2A鏈或其變體; B係鬆弛素B鏈或其變體,例如鬆弛素-2B鏈或其變體; FcY係包含人IgG1免疫球蛋白的恒定結構域CH2和CH3的Fc區,並且包含「Fc臼」胺基酸突變和/或修飾,較佳的是胺基酸突變Y349C: T366S:L368A:Y407V; FcX係具有「Fc杵」胺基酸突變和/或修飾、較佳的是包含人IgG1免疫球蛋白的恒定結構域CH2和CH3的Fc區,並且包含「Fc杵」胺基酸突變和/或修飾,較佳的是胺基酸突變S354C:T366W;並且 con係連接子多肽,較佳的是具有序列GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5], 其中胺基酸編號係根據如卡巴特中的EU索引進行的,其中FcX與FcY異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。
- 如前述請求項中任一項所述之異源二聚體融合物,其中該異源二聚體融合物包含具有SEQ ID NO: 11的胺基酸序列的融合多肽和具有SEQ ID NO: 20的胺基酸序列的融合多肽。
- 如請求項8至18中任一項所述之異源二聚體融合物,其中該異源二聚體融合物進一步包含一個或多個Fab,視需要其中該異源二聚體融合物包含與該第一Fc區的N-末端連接的一個Fab和與該第二Fc區的N-末端連接的第二Fab。
- 如請求項8至19中任一項所述之異源二聚體融合物,其中異源二聚體進一步包含與該第一Fc區的N-末端連接的第二鬆弛素A鏈多肽或其變體和與該第二Fc區的N-末端連接的第二鬆弛素B鏈多肽或其變體,視需要其中將該第二鬆弛素A鏈經由連接子多肽連接至該第一Fc區,並且將該第二鬆弛素B鏈經由連接子多肽連接至該第二Fc區。
- 一種異源二聚體融合物,其包含: (i) FcX-B-L-A和FcY,視需要FcY-B-L-A;或 (ii) FcY-B-L-A和FcX,視需要FcX-B-L-A; 其中: FcY係具有「Fc臼」胺基酸突變和/或修飾的免疫球蛋白Fc區,較佳的是包含具有胺基酸突變Y349C:T366S:L368A:Y407V的CH3結構域; FcX係具有「Fc杵」胺基酸突變和/或修飾的免疫球蛋白Fc區,較佳的是包含具有胺基酸突變S354C:T366W的CH3結構域; B係鬆弛素B鏈或其變體,例如鬆弛素2B鏈或其變體; A係鬆弛素A鏈或其變體,例如鬆弛素2A鏈或其變體;並且 L係接頭多肽,較佳的是具有胺基酸序列GGGSGGGSGG [SEQ ID NO: 60], 其中胺基酸編號係根據如卡巴特中的EU索引進行的,其中FcX與FcY異源二聚體化,並且其中該異源二聚體融合物具有鬆弛素活性。
- 如請求項21所述之異源二聚體融合物,其中將該鬆弛素B鏈經由連接子,視需要長度為6至40個胺基酸、例如長度為21個胺基酸的連接子多肽連接至FcX和/或FcY。
- 如前述請求項中任一項所述之異源二聚體融合物,其中該異源二聚體融合物的鬆弛素活性與參考鬆弛素蛋白的鬆弛素活性的比率為約0.001至約10。
- 一種核酸分子,其編碼如前述請求項中任一項所述之異源二聚體融合物。
- 一種載體,其包含如請求項24所述之核酸分子。
- 一種宿主細胞,其包含如請求項25所述之載體或如請求項24所述之核酸分子。
- 一種產生如請求項1至23中任一項所述之異源二聚體融合物之方法,該方法包括培養如請求項26所述之宿主細胞,並且收集融合蛋白。
- 一種藥物組成物,其包含如請求項1至23中任一項所述之異源二聚體融合物和藥學上可接受的賦形劑。
- 如請求項1至23中任一項所述之異源二聚體融合物或如請求項28所述之藥物組成物,用於在療法中使用。
- 如請求項1至23中任一項所述之異源二聚體融合物或如請求項28所述之藥物組成物,用於治療患有心臟衰竭的受試者,其中將該異源二聚體融合物或藥物組成物投與至該受試者。
- 用於如請求項29或30所述使用的異源二聚體融合物,或用於如請求項29或30所述使用的藥物組成物,其中藉由皮下注射將該異源二聚體融合物或藥物組成物投與至該受試者。
- 如請求項29至31中任一項所述使用的異源二聚體融合物,或如請求項29至31中任一項所述使用的藥物組成物,其中藉由自我投與來投與該融合多肽或藥物組成物。
- 一種套組,其包含如請求項28所述之藥物組成物。
- 一種治療患有疾病或障礙的受試者之方法,該方法包括將如請求項1至23中任一項所述之異源二聚體融合物或如請求項28所述之藥物組成物投與至該受試者。
- 一種治療患有心臟衰竭的受試者之方法,該方法包括將如請求項1至23中任一項所述之異源二聚體融合物或如請求項28所述之藥物組成物投與至該受試者。
- 如請求項34或35所述之方法,其中藉由皮下注射將該異源二聚體融合物或藥物組成物投與至該受試者。
- 如請求項34至36中任一項所述之方法,其中藉由自我投與來投與該異源二聚體融合物或藥物組成物。
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