TW202248210A - 抗體介導屈公(chikungunya)病毒中和 - Google Patents
抗體介導屈公(chikungunya)病毒中和 Download PDFInfo
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Abstract
本發明係關於結合且中和屈公病毒(CHIKV)之抗體及其使用方法。
Description
本發明大體上係關於醫學、傳染病及免疫學領域。更特定言之,本發明係關於中和屈公病毒(Chikungunya virus)之抗體。
屈公病毒(CHIKV)係屬於披膜病毒科(
Togaviridaefamily) α病毒屬的一種有包膜之正義RNA病毒且由伊蚊屬(
Aedes)蚊子傳播。成熟的CHIKV病毒粒子含有兩種糖蛋白:E1及E2,其係自前驅物聚合蛋白質p62-E1經蛋白水解裂解而產生。E2在病毒附著方面起作用,而E1介導膜融合以允許病毒進入(Kielian等人, 2010)。對於人類而言,CHIKV感染引起發熱及關節疼痛,此可能很嚴重且在一些情況下持續數年。(Schilte等人, 2013;Sissoko等人, 2009;Staples等人, 2009)。CHIKV在撒哈拉沙漠以南非洲的大部分區域以及在亞洲、歐洲及印度洋與太平洋之部分地區引起爆發。2013年12月,CHIKV首次在西半球中傳播,且在聖馬丁(St. Martin)鑑別出自生病例(CDC 2013)。病毒迅速蔓延至加勒比海幾乎所有的島嶼,以及中美洲、南美洲及北美洲。在不到一年裏,西半球報告超過一百萬例疑似CHIKV病例,且在包括美國在內的超過40個國家有記錄地方性傳播(CDC, 2014)。目前,尚無核准的用於預防或治療CHIKV感染之疫苗或抗病毒療法。
儘管對於人體中針對CHIKV感染之保護性免疫的機制並不完全瞭解,但體液反應控制感染且限制組織損傷(Chu等人, 2013;Hallengard等人, 2014;Hawman等人, 2013;Kam等人,2012b;Lum等人, 2013;Pal等人, 2013)。人類免疫γ-球蛋白在病毒接種長達24小時之後投與時中和培養細胞之感染性且防止小鼠發病(Couderc等人, 2009)。已經描述中和CHIKV感染之若干鼠類單株抗體(mAb)(Brehin等人, 2008;Goh等人, 2013;Masrinoul等人, 2014;Pal等人, 2013;Pal等人, 2014),包括在CHIKV攻擊之後組合使用以治療小鼠或非人類靈長類動物時具有功效的一些單株抗體(Pal等人,2013;Pal等人, 2014)。相比之下,已經報告有限數量之人類CHIKV mAb,其中絕大部分展現適度的中和活性(Fong等人, 2014;Fric等人, 2013;Lee等人, 2011;Selvarajah等人,2013;Warter等人, 2011)。
因此,根據本發明,提供一種偵測個體之屈公病毒感染的方法,其包含(a)使來自該個體之樣品與具有分別來自表3及表4的純系成對之重鏈及輕鏈CDR序列的抗體或抗體片段接觸;及(b)藉由該抗體或抗體片段與該樣品中屈公病毒糖蛋白E2之結合來偵測該樣品中之E2。樣品可為體液,諸如血液、痰液、淚液、唾液、黏液或血清、尿液或糞便。偵測可包含ELISA、RIA或西方墨點法(Western blot)。該方法可進一步包含再次進行步驟(a)及(b)且測定E2含量相較於第一次分析之變化。該抗體可由如表1中所闡述之純系成對之可變序列編碼,或由與如表1中所闡述之純系成對之可變序列具有70%、80%、90%或95%一致性的輕鏈及重鏈可變序列編碼,或具有以如表2中所闡述之純系成對序列為特徵的輕鏈及重鏈可變序列,或與來自表2之純系成對序列具有70%、80%、90%或95%一致性。抗體片段可為重組ScFv(單鏈可變片段)抗體、Fab片段、F(ab')
2片段或Fv片段。抗體可為IgG及/或嵌合抗體。
在另一實施例中,提供一種治療感染屈公病毒之個體,或降低有感染屈公病毒風險之個體之感染可能性的方法,其包含向該個體遞送具有分別來自表3及4之純系成對之重鏈及輕鏈CDR序列的抗體或抗體片段。該抗體可由如表1中所闡述之純系成對之可變序列編碼,或由與如表1中所闡述之純系成對之可變序列具有70%、80%、90%或95%一致性的輕鏈及重鏈可變序列編碼,或具有以如表2中所闡述之純系成對序列為特徵的輕鏈及重鏈可變序列,或與來自表2之純系成對序列具有70%、80%、90%或95%一致性。抗體片段可為重組ScFv(單鏈可變片段)抗體、Fab片段、F(ab')
2片段或Fv片段。該抗體可為IgG及/或嵌合抗體。抗體或抗體片段可在感染之前或感染之後投與。該遞送法可包括抗體或抗體片段之投與,或編碼該抗體或抗體片段之RNA或DNA序列或載體的基因遞送。
在又一實施例中,提供一種單株抗體,其中該抗體係以分別來自表3及表4之純系成對之重鏈及輕鏈CDR序列為特徵。該抗體可由如表1中所闡述之純系成對之可變序列編碼,或由與如表1中所闡述之純系成對之可變序列具有70%、80%、90%或95%一致性的輕鏈及重鏈可變序列編碼,或具有以如表2中所闡述之純系成對序列為特徵的輕鏈及重鏈可變序列,或與來自表2之純系成對序列具有70%、80%、90%或95%一致性。抗體片段可為重組ScFv(單鏈可變片段)抗體、Fab片段、F(ab')
2片段或Fv片段。該抗體可為嵌合抗體,或為靶向除糖蛋白外的屈公病毒抗原之雙特異性抗體。該抗體可為IgG。該抗體或抗體片段進一步包含細胞穿透肽及/或為胞內抗體。
亦提供一種編碼抗體或抗體片段之融合瘤或經工程改造之細胞,其中該抗體或抗體片段係以分別來自表3及表4之純系成對之重鏈及輕鏈CDR序列為特徵。該抗體或抗體片段可由如表1中所闡述之純系成對之可變序列編碼,或由與如表1中所闡述之純系成對之可變序列具有70%、80%、90%或95%一致性的輕鏈及重鏈可變序列編碼,或具有以如表2中所闡述之純系成對序列為特徵的輕鏈及重鏈可變序列,或與來自表2之純系成對序列具有70%、80%、90%或95%一致性。抗體片段可為重組ScFv(單鏈可變片段)抗體、Fab片段、F(ab')
2片段或Fv片段。該抗體可為嵌合抗體及/或IgG。該抗體或抗體片段可進一步包含細胞穿透肽及/或為胞內抗體。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含選自由以下組成之群的重鏈及輕鏈可變序列對:SEQ ID NO:53/54、55/56、57/58、59/60、61/62、63/64、65/66、67/68、70/71、72/73、74/75、76/77、81/82、83/84、85/86、87/88、89/90、91/92、93/94、95/96及97/98。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO:103、104及105之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 187、188及189之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 106、107及108之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO:190、191及192之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 109、110及111之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 193、194及195之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO:112、113及114之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 196、197及198之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO:115、116及117之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 199、200及201之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 118、119及120之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 202、203及204之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 121、122及123之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 205、206及207之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 124、125及126之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 208、209及210之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 130、131及132之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 211、212及213之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 133、134及135之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 214、215及216之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 136、137及138之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 217、218及219之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 139、140及141之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 220、221及222之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 151、152及153之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 223、224及225之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 154、155及156之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 226、227及228之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 157、158及159之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 229、230及231之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 160、161及162之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 232、233及234之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 163、164及165之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 235、236及237之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 166、167及168之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 238、239及240之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 169、170及171之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 241、242及及243之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 172、173及174之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 244、245及246之CDRL1、CDRL2及CDRL3。
在一個實施例中,特異性結合至屈公病毒糖蛋白E2的分離之單株抗體或其抗原結合片段包含胺基酸序列分別為SEQ ID NO: 175、176及177之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 247、248及249之CDRL1、CDRL2及CDRL3。
當在申請專利範圍及/或說明書中與術語「包含」一詞結合使用時,詞語「一個(種)(a/an)」之使用可意謂「一個(種)」,但其亦與「一或多個(種)」、「至少一個(種)」及「一個(種)或多於一個(種)」之含義相符。「約」一詞意謂所陳述數字之加或減5%。
預期本文所描述之任何方法或組合物均可根據本文所描述之任何其他方法或組合物實施。本發明之其他目的、特徵及優勢將自以下[實施方式]而變得顯而易知。然而,應理解,[實施方式]及具體實例雖然指示本發明之特定實施例,但僅以說明方式給出,因為熟習此項技術者由此[實施方式]將對在本發明之精神及範疇內的各種改變及修改變得顯而易知。
本申請案要求2015年4月14日提交之美國臨時申請案第62/147,354號之優先權益,該案之完整內容以引用的方式併入本文中。
本發明係依據美國國家衛生研究院授予之撥款號K08 AI103038、F32 AI096833及U54 AI057157,在政府的支持下作出。政府享有本發明之某些權利。
本發明人分離出中和細胞培養物中之CHIKV感染性且即使在感染之後晚至60小時投與時亦成功地治療接種致死劑量CHIKV之
Ifnar − /-小鼠(缺乏I型干擾素受體)的一大組人類mAb。其將E2之A結構域鑑別為以超強效活性廣泛中和CHIKV感染之mAb識別的主要抗原位點且顯示抑制之主要機制係防止融合。本發明之此等及其他態樣於下文詳細地描述。
I . 屈公病及屈公病毒屈公病係由屈公病毒引起之感染。其特徵在於通常持續二至七天的突然開始發熱,及通常持續數週或數月,而且有時持續數年的關節疼痛。死亡率為1000例中大致1例,且老年人極有可能死亡。該病毒係由伊蚊屬之兩種蚊子傳遞給人類:白紋伊蚊(
A . albopictus)及埃及伊蚊(
A . aegypti)。該病毒之動物貯主包括猴類、鳥類、牛及嚙齒動物。此與登革熱形成對比,登革熱僅以靈長類動物為宿主。
總的來說,最佳預防手段為防治蚊子及避免任何受感染之蚊子的叮咬。尚無已知的特定治療方法,但可使用藥物減輕症狀。休息及補液亦可為有用的。
屈公病之潛伏期在二至十二天範圍內,通常為三至七天。感染者中有72%到97%會出現症狀。症狀包括突然開始,有時分兩階段的發熱,通常持續數天至一週,有時長達十天,通常超過39℃(102℉)且有時達到41℃(104℉),以及劇烈關節疼痛或僵硬,通常持續數週或數月,而且有時持續數年。亦可能存在皮疹(通常為斑丘疹)、肌肉疼痛、頭痛、疲勞、噁心或嘔吐。可能存在眼部炎症,如虹膜睫狀體炎或葡萄膜炎,且可能發生視網膜病變。通常,發熱持續兩天且接著突然結束。不過,頭痛、失眠及極度虛脫會持續不同時間,通常持續約五至七天。
在近期流行期間的觀察結果表明,屈公病毒可在急性感染之後引起長期症狀。在2006年留尼汪(La Reunion)爆發期間,年齡超過45歲之個體中超過50%報告長期肌肉骨骼痛,且在初始感染之後三年,高達60%的人報告長期關節疼痛。在法國進行的輸入性病例研究報告,59%的人在急性感染之後兩年仍遭受關節痛之苦。在意大利局部流行屈公病之後,66%的人在急性感染之後一年報告肌肉疼痛、關節疼痛或乏力。長期症狀並非全新的觀察結果;在1979年爆發之後就觀察到長期關節炎。長期症狀之常用預測指標為年齡之增長及先前的風濕性疾病。此等慢性症狀之成因當前尚未完全瞭解。在報告慢性症狀之人中尚未發現自體免疫性疾病或類風濕性疾病之標記物。然而,由人類及動物模型得到的一些證據表明屈公病毒能夠在宿主內產生慢性感染。在初始發作之後三個月經歷復發性發作之人的肌肉活檢中偵測到病毒抗原。另外,在初始感染之後18個月肌肉骨胳疾病復發期間,在人的滑膜巨噬細胞中發現病毒抗原及RNA。若干動物模型亦表明,屈公病毒可產生持久感染。在小鼠模型中,在接種之後至少16週,特定地在關節相關組織中偵測到病毒RNA且與慢性關節膜炎有關。類似地,另一研究報告,在接種之後數週,於小鼠之關節組織中偵測到病毒報告基因。在非人類靈長類動物模型中,發現屈公病毒在脾中保留至少六週。
屈公病毒係一種具有約11.6kb之正義單股RNA基因組的α病毒。其為勝利基森林病毒(Semliki Forest virus)複合體之一員且與羅斯河病毒(Ross River virus)、奧-奈氏病毒(O'nyong'nyong virus)及勝利基森林病毒密切相關。在美國,其被歸類為C類優先病原體且研究需要III級生物安全防護措施。人類上皮細胞及內皮細胞、原代纖維母細胞及單核細胞源性巨噬細胞在活體外可受納屈公病毒,且病毒複製具有高細胞毒殺性,但對I型及II型干擾素敏感。在活體內,屈公病毒看起來在纖維母細胞、骨胳肌肉祖細胞及肌纖維中複製。
屈公病毒以及引起東部馬腦炎及西部馬腦炎之病毒均為α病毒。屈公病毒一般經由埃及伊蚊之叮咬傳播,但位於巴黎之巴斯德研究所(Pasteur Institute)的近期研究提出,在2005-2006年留尼汪島爆發中的屈公病毒之病毒株引發了有助於由亞洲虎蚊(白紋伊蚊)傳播的突變。
白紋伊蚊之屈公病毒感染係由病毒包膜基因之一(
E1)中的點突變引起。白紋伊蚊對屈公病毒之傳播增強可意謂在存在亞洲虎蚊之其他區域之爆發風險增加。近期在意大利之流行很可能因白紋伊蚊而持續。在非洲,屈公病毒係藉由叢林循環傳播,其中主要存在於其他靈長類動物中之病毒在人類間爆發。
在感染屈公病毒之後,宿主之纖維母細胞產生1型(α及β)干擾素。缺乏干擾素α受體之小鼠在暴露於10
2PFU屈公病毒之後兩至三天內死亡,而野生型小鼠即使在暴露於多達10
6PFU病毒時亦存活。同時,部分1型缺陷型(IFN α/β +/−)小鼠輕度感染且經歷諸如肌肉無力及昏睡之症狀。Partidos等人(2011)利用減毒之活病毒株CHIKV181/25觀察到類似結果。然而,1型干擾素缺陷型(IFN α/β −/−)小鼠暫時失能,且部分1型干擾素缺陷型小鼠沒有任何問題,而不是死亡。
若干研究曾嘗試發現宿主對屈公病感染之反應中所涉及的1型干擾素路徑之上游組分。迄今為止,尚不瞭解屈公病毒特異性病原體相關之分子模式。不過,已發現,IPS-1,又稱為Cardif、MAVS及VISA,係一種重要因子。在2011年,White等人發現,干擾IPS-1使干擾素調控因子3(IRF3)之磷酸化及IFN-β之產生減少。其他研究已發現,IRF3及IRF7係以年齡依賴性方式作用之重要因子。缺乏此兩種調控因子之成年小鼠在感染屈公病毒後死亡。另一方面,若新生兒缺乏此等因子之一,則死於該病毒。
屈公病毒藉由產生NS2(一種降解RBP1且關閉宿主細胞轉錄DNA之能力的非結構性蛋白質)抵消I型干擾素反應。NS2干擾JAK-STAT信號傳導路徑且防止STAT變得磷酸化。
有關屈公病毒之常見實驗室測試包括RT-PCR、病毒分離及血清學測試。病毒分離提供最具決定性之診斷,但耗費一至兩週完成且必須在III級生物安全實驗室中進行。該技術涉及使特定細胞株暴露於來自全血之樣品且鑑別屈公病毒特異性反應。使用巢式引子對之RT-PCR被用於擴增來自全血的若干屈公病毒特異性基因。結果可在一至兩天內測定。
血清學診斷需要的血液量超過其他方法,且使用ELISA分析法來量測屈公病毒特異性IgM含量。結果需要兩至三天,且在其他相關病毒,諸如奧-奈氏病毒及勝利基森林病毒之感染存在下,可能出現假陽性。
鑑別診斷可以包括其他蚊子來源之病毒,諸如登革熱及流感引起之感染。屈公病患者中至少20%在感染之後一年發生慢性復發性多關節痛,而此類症狀在登革熱中不常見。
當前,尚無可用的特定治療方法。減輕症狀之嘗試包括使用NSAID,諸如萘普生(naproxen)或撲熱息痛(paracetamol)(乙醯胺苯酚)及補液。不推薦使用阿司匹林(Aspirin)。在患有關節炎超過兩週之患者中,病毒唑可為有用的。氯喹(chloroquine)之作用尚不清楚。其看起來對急性疾病沒有幫助,但試驗性證據表明,其可能有助於慢性關節炎患者。類固醇看來也無用。
屈公病主要存在於發展中國家。屈公病之流行病學與蚊子、其環境及人類行為有關。蚊子在約5,000年前對於北非不斷變化之氣候的適應使其找出人類儲存水之環境。人類生活環境及蚊子之環境的聯繫極為密切。在流行期間,人類成為該病毒之貯主。在其他時間期間,猴、鳥類及其他脊椎動物充當貯主。
已經描述此病毒之三種基因型:西非基因型、東/中/南非基因型及亞洲基因型。2005年在印度洋及2011年在太平洋島嶼,以及現今在美國發生的爆發性流行在不斷地改變基因型之分佈。
2009年5月28日,在該病毒地方性流行的泰國董里府(Changwat Trang),府醫院決定使感染屈公病毒之母親Khwanruethai Sutmueang (28歲,董里本地人)藉由剖腹產手術分娩一名男嬰,以防母-胎病毒傳播。然而,在嬰兒分娩後,醫生發現該嬰兒已經感染病毒,且將其放入重症監護室,因為該感染使得嬰兒無法自行呼吸或吃奶。醫生推測,該病毒有可能自母親傳播給其胎兒,但未得到實驗室證實。
2013年12月,在聖馬丁之加勒比海島嶼確診屈公病,有66例確診病例及約181例疑似病例。此次爆發在西半球屬首次,該疾病自一群受感染蚊子傳播給人類。到2014年1月,加拿大公共衛生機構(Public Health Agency)報告,在British Virgin Islands、Saint-Barthélemy、Guadeloupe、Dominica、Martinique及French Guyana確診病例。2014年4月,在多米尼加共和國(Dominican Republic),疾病控制與預防中心(Centers for Disease Control and Prevention,CDC)亦確診屈公病。到4月底,其已蔓延至總計14個國家,包括Jamaica、St. Lucia、St. Kitts及Nevis及Haiti在內均聲明流行病。
到2014年5月底,美國已報告超過十例由病毒地方性流行之地區旅行至佛羅里達州(Florida)的人引起之輸入性病例。由加勒比海傳播至美國的屈公病之病毒株最易於由埃及伊蚊傳播。焦點在於,此屈公病之病毒株可突變以使白紋伊蚊載體更高效。若發生此突變,則屈公病毒將為美國造成更嚴重的公共健康問題,因為白紋伊蚊或亞洲虎蚊在美國分佈更廣泛且比埃及伊蚊侵襲性更強。
2014年6月,在巴西確診六例該病毒之病例,兩例出現在聖保羅州(state of São Paulo)坎皮納斯市(city of Campinas)。該六例病例為近期自海地(Haiti)回國之巴西軍隊士兵,其作為聯合國駐海地維和行動成員在海地參與重建工作。坎皮納斯市政當局考慮到其須採取適當行動而官方發佈該資訊。
2014年6月16日,佛羅里達州累積共有42例病例。截至2014年9月11日,波多黎各(Puerto Rico)報告該年之病例數為1,636例。到10月28日,該數字增加至2,974例確診病例,且疑似病例超過10,000例。2014年6月17日,美國密西西比州(state of Mississippi)衛生部官員證實,其正在調查近期旅行至海地的密西西比常駐人口中的首例可能病例。2014年6月19日,該病毒已蔓延至美國喬治亞州(Georgia)。2014年6月24日,美國佛羅里達州波克縣之波因希亞納(Poinciana, Polk County, Florida, USA)報告一例病例。2014年6月25日,美國阿肯色州(state of Arkansas)衛生部證實,來自該州的一個人攜帶有屈公病毒。2014年6月26日,墨西哥哈利斯科州(state of Jalisco)報告一例病例。
2014年7月17日,美國佛羅里達州疾病控制與預防中心報告首例獲得性屈公病例。自2006年起,美國已報告超過200例病例,而且僅為旅行至其他國家的人患病。在美國本土,此為首次病毒由蚊子傳遞給人。2014年9月2日,美國疾病控制與預防中心報告,有七例確診的屈公病例發生於在當地患上該疾病的人。
2014年9月25日,薩爾瓦多(El Salvador)官方當局報告超過30,000例確診的此新型流行病病例。該新型流行病亦出現在牙買加(Jamaica)及巴巴多斯島(Barbados)。到該等國家之旅行者有攜帶該病毒至其自身國家之風險。2014年11月:巴西報告當地傳播一種在美洲尚無記錄的不同屈公病毒株(基因型)。其為非洲基因型,但奇怪的是,無法解釋其為南非基因型抑或西非基因型。新基因型(在美洲)比當前正傳播至美洲的亞洲基因型更嚴重,且對於一種基因型之免疫性無法賦予對其他基因型之免疫性。法屬波利尼西亞(French Polynesia)為正在經歷爆發之區域之一。
2014年11月7日,墨西哥報告在南部恰帕斯州(state of Chiapas)由當地傳播引起的屈公病爆發。該爆發跨越海岸線由瓜地馬拉(Guatemala)邊界蔓延至相鄰瓦哈卡州(state of Oaxaca)。衛生當局報告累積39例實驗室確診病例(到第48週結束時)。未報告疑似病例。2015年1月,哥倫比亞(Colombia)報告90,481例屈公病病例。
II. 單株抗體及其產生 A. 通用方法應瞭解,結合至屈公病毒之單株抗體將具有若干應用。此等應用包括用於偵測及診斷屈公病毒感染之診斷套組的製造,以及用於治療屈公病毒感染。在此等情形中,可將此類抗體與診斷劑或治療劑相關聯,使用其作為競爭性分析中之捕捉劑或競爭劑,或其獨立地使用,而不附加另外的藥劑。該等抗體可經突變或修飾,如以下進一步論述。用於製備及表徵抗體之方法為此項技術中熟知的(參見例如,Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988;美國專利4,196,265)。
用於產生單株抗體(mAb)之方法一般沿著與用於製備多株抗體相同之生產線開始。此兩種方法之第一步驟為適當宿主之免疫接種或因先前天然感染而免疫之個體的鑑別。如此項技術中所熟知的,給定的免疫接種組合物之免疫原性可能不同。因此,通常需要增強宿主免疫系統,此可藉由使肽或多肽免疫原與載體偶合來實現。例示性的較佳載體為匙孔螺血氰蛋白(KLH)及牛血清白蛋白(BSA)。其他白蛋白,諸如卵白蛋白、小鼠血清白蛋白或兔血清白蛋白,亦可用作載體。將多肽綴合至載體蛋白質之方式為此項技術中熟知的且包括戊二醛、間順丁烯二醯亞胺基苯甲醯基-N-羥基琥珀醯亞胺酯、碳化二亞胺及雙重氮化聯苯胺。此項技術中亦熟知,可藉由使用非特異性免疫反應刺激劑(稱為佐劑)來增加特定免疫原組合物之免疫原性。例示性的較佳佐劑包括完全弗氏佐劑(complete Freund's adjuvant)(含有經殺滅之結核分支桿菌(
Mycobacterium tuberculosis)的非特異性免疫反應刺激劑)、不完全弗氏佐劑及氫氧化鋁佐劑。
用於產生多株抗體之免疫原組合物的量取決於免疫原之性質以及用於免疫接種之動物而變化。可使用多種途徑投與免疫原(皮下、肌肉內、皮內、靜脈內及腹膜內)。多株抗體之產生可藉由在免疫接種之後各個時間點取得經免疫接種動物之血樣來進行監測。亦可給與第二次輔助劑注射。重複增強免疫及滴定之過程,直至達到適合滴度。當獲得所需免疫原性程度時,可對經免疫接種之動物抽血且分離血清並儲存,及/或可使用該動物產生MAb。
在免疫接種之後,選擇可能產生抗體之體細胞,具體言之,B淋巴球(B細胞)用於MAb產生方案中。此等細胞可自活檢之脾或淋巴結,或自循環之血液獲得。接著使來自經免疫接種動物之抗體產生B淋巴球與永生骨髓瘤細胞之細胞,一般與經免疫接種之動物屬於同一物種的動物之永生骨髓瘤細胞,或人類或人類/小鼠嵌合細胞融合。適用於產生融合瘤之融合程序中之骨髓瘤細胞較佳不產生抗體,具有高融合效率,且酶不足而使其不能在僅支持所需融合細胞(融合瘤)生長之某些選擇性培養基中生長。熟習此項技術者已知,可以使用多種骨髓瘤細胞(Goding, 第65-66頁, 1986;Campbell, 第75-83頁, 1984)。
用於產生抗體產生脾或淋巴結細胞與骨髓瘤細胞之雜交體的方法通常包含在促進細胞膜融合之一或多種因素(化學試劑或電)存在下,將體細胞與骨髓瘤細胞以2:1比例混合,不過該比例可對應地在約20:1至約1:1間變化。Kohler及Milstein(1975;1976)已經描述使用仙台病毒(Sendai virus)之融合方法,且Gefter等人(1977)已經描述使用聚乙二醇(PEG),諸如37% (v/v) PEG的融合方法。使用電誘導融合方法亦為適合的(Goding, 第71-74頁, 1986)。融合程序通常以約1×10
- 6至1×10
- 8之較低頻率產生有活力的雜交體。然而,此不會造成問題,因為有活力的融合雜交體係藉由在選擇培養基中培養而自輸注的親本細胞(特定言之,通常持續無限分裂的輸注之骨髓瘤細胞)分化。選擇培養基一般為含有阻止核苷酸在組織培養基中從頭合成之試劑的培養基。例示性的較佳試劑為胺基喋呤(aminopterin)、甲胺喋呤(methotrexate)及偶氮絲胺酸。胺基喋呤及甲胺喋呤阻止嘌呤及嘧啶之從頭合成,而偶氮絲胺酸僅阻止嘌呤合成。在使用胺基喋呤或甲胺喋呤情況下,該培養基補充有次黃嘌呤及胸苷作為核苷酸來源(HAT培養基)。在使用偶氮絲胺酸情況下,該培養基補充有次黃嘌呤。若B細胞源為埃-巴二氏病毒(Epstein Barr virus,EBV)轉型之人類B細胞株,則為了除去未與骨髓瘤融合之EBV轉型株,添加烏本苷(Ouabain)。
較佳之選擇培養基為HAT或含烏本苷之HAT。只有能夠操作核苷酸補救路徑之細胞能夠在HAT培養基中存活。骨髓瘤細胞缺乏該補救路徑之關鍵酶,例如次黃嘌呤磷酸核糖轉移酶(HPRT),且其無法存活。B細胞可操作此路徑,但其在培養時壽命有限且一般在約兩週內死亡。因此,只有能在選擇培養基中存活的細胞為由骨髓瘤及B細胞形成之雜交體。當用於融合之B細胞源為EBV轉型之B細胞株時,如此處,亦可將烏本苷用於雜交體之藥物選擇,因為EBV轉型之B細胞易被藥物殺滅,而所用骨髓瘤搭配物應選擇耐烏本苷的。
培養提供一組融合瘤,從中選擇特定融合瘤。通常,融合瘤之選擇係藉由在微量滴定盤中以單一純系之稀釋液培養細胞,隨後測試個別純系上清液(在約兩至三週之後)的所需反應性來進行。分析法應為靈敏、簡單且快速的,諸如放射免疫分析法、酶免疫分析法、細胞毒性分析法、蝕斑分析法、斑點免疫結合分析法及其類似方法。接著所選融合瘤進行連續稀釋或藉由流動式細胞分選進行單細胞分選,並選殖至個別抗體產生細胞株中,該等純系可接著無限繁殖以提供MAb。可採用該等細胞株以兩種基本方式產生MAb。融合瘤樣品可注射至動物(例如,小鼠)體內(通常注射至腹膜腔中)。視情況,在注射之前,用烴,尤其是油,諸如姥鮫烷(四甲基十五烷)使動物預致敏。當以此方式使用人類融合瘤時,最佳向免疫功能不全之小鼠,諸如SCID小鼠進行注射,以防止腫瘤排斥反應。經注射動物產生腫瘤,分泌由融合之細胞雜交體產生之特異性單株抗體。接著可抽取動物之體液,諸如血清或腹水,以提供高濃度MAb。個別細胞株亦可在活體外培養,其中MAb天然地分泌至培養基中,自該培養基可容易地獲得高濃度MAb。或者,可在活體外使用人類融合瘤細胞株以在細胞上清液中產生免疫球蛋白。該等細胞株可適合於在無血清培養基中生長以使回收高純度人類單株免疫球蛋白之能力達到最佳。
必要時,藉由任一方式產生的MAb可使用過濾、離心及各種層析方法,諸如FPLC或親和層析法進一步純化。本發明之單株抗體的片段可自純化之單株抗體,藉由包括用酶(諸如胃蛋白酶或木瓜蛋白酶)消化之方法,及/或藉由化學還原來裂解二硫鍵而獲得。或者,本發明所涵蓋之單株抗體片段可使用自動肽合成儀合成。
預期亦可使用分子選殖方法產生單株抗體。為此,可自融合瘤株分離RNA且藉由RT-PCR獲得抗體基因並選殖至免疫球蛋白表現載體中。或者,由自該等細胞株分離之RNA製備組合免疫球蛋白噬質體文庫且藉由使用病毒抗原淘選來選擇表現適當抗體之噬質體。此方法相較於習知融合瘤技術之優勢在於,可在一輪中產生並篩選出多達約10
4倍之抗體,且由H鏈與L鏈之組合產生新特異性,從而使發現適當抗體之幾率進一步增加。
教示可用於本發明中之抗體之產生的其他美國專利(各自以引用的方式併入本文中)包括美國專利5,565,332,其描述使用組合方法產生嵌合抗體;美國專利4,816,567,其描述重組免疫球蛋白之製備;及美國專利4,867,973,其描述抗體-治療劑綴合物。
B . 本發明之抗體根據本發明之抗體最初可藉由其結合特異性定義,在此情況下,其係針對屈公病毒糖蛋白(GP)。熟習此項技術者藉由使用熟習此項技術者熟知之技術評估給定抗體之結合特異性/親和力,可判定此類抗體是否在本發明之申請專利範圍之範疇內。在一個態樣中,提供具有來自分別如表3及表4中所說明之重鏈及輕鏈之純系成對CDR的單株抗體。此類抗體可使用本文所描述之方法,由以下實例部分中論述之純系產生。
在第二態樣中,該等抗體可藉由其可變序列定義,可變序列包括另外的「構架」區。此等可變序列提供於表1及表2中,其編碼或表示整個可變區。另外,視情況使用以下更詳細地論述之方法,抗體序列可不同於此等序列。舉例而言,核酸序列可不同於以上陳述之彼等序列,不同之處在於:(a)可變區可與輕鏈及重鏈之恆定結構域分隔開;(b)核酸可不同於以上陳述之彼等序列,但不影響由其編碼之殘基;(c)核酸可以給定百分比,例如70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之同源性不同於以上陳述之彼等序列;(d)核酸可由於在高嚴格度條件,如例如低鹽及/或高溫條件(諸如在約50℃至約70℃溫度下由約0.02 M至約0.15 M NaCl所提供)下雜交之能力而不同於以上陳述之彼等序列;(e)胺基酸可以給定百分比,例如80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之同源性不同於以上陳述之彼等序列;或(f)胺基酸可藉由允許保守取代(下文論述)而不同於以上陳述之彼等序列。前述各自適用於表1給出之核酸序列及表2之胺基酸序列。
C.
抗體序列之工程改造在各種實施例中,出於各種原因,諸如改善表現、改善交叉反應性或降低脫靶結合,可選擇對所鑑別之抗體的序列進行工程改造。以下為用於抗體工程改造之相關技術的大致論述。
可培養融合瘤,接著裂解細胞且提取總RNA。可在RT下使用隨機六聚體以產生RNA之cDNA複本,且接著使用預期可擴增所有人類可變基因序列之PCR引子之多元混合物進行PCR。PCR產物可選殖至pGEM-T Easy載體中,接著藉由自動DNA測序,使用標準載體引子進行測序。結合及中和之分析可使用自融合瘤上清液收集且藉由使用蛋白質G管柱之FPLC純化的抗體進行。
重組全長IgG抗體係藉由將來自選殖載體之重鏈及輕鏈Fv DNA次選殖至IgG質體載體中,轉染至293 Freestyle細胞或CHO細胞中來產生,且純化抗體係自293或CHO細胞上清液收集。
在與最終cGMP製造方法相同之宿主細胞及細胞培養方法中產生的抗體之快速可用性有可能縮短方法進展程式之持續時間。Lonza開發出使用彙集的在CDACF培養基中生長之轉染物的一種通用方法,用於在CHO細胞中快速產生少量(最多50 g)抗體。儘管比實際瞬時系統略慢,但優勢包括較高產物濃度及與產生細胞株相同之宿主及方法的使用。在拋棄式生物反應器中表現模型抗體之GS-CHO池之生長及生產率的實例:在以分批進料模式操作之拋棄式袋式生物反應器培養(5 L工作體積)時,在轉染9週內達到2 g/L之採集抗體濃度。
抗體分子將包含由例如mAb蛋白水解裂解產生之片段(諸如F(ab')、F(ab')
2),或可例如經由重組方式產生的單鏈免疫球蛋白。此類抗體衍生物為單價的。在一個實施例中,此類片段可彼此組合,或與其他抗體片段或受體配位體組合以形成「嵌合」結合分子。很明顯,此類嵌合分子可含有能夠結合至同一分子之不同抗原決定基的取代基。
在相關實施例中,抗體為所揭示之抗體之衍生物,例如包含與所揭示之抗體(例如,嵌合抗體或CDR移植抗體)中之CDR序列相同之CDR序列的抗體。或者,可希望進行修飾,諸如將保守變化引入抗體分子中。在進行該等變化時,可考慮胺基酸之親水指數。在此項技術中一般瞭解胺基酸之親水指數在賦予蛋白質相互作用生物功能方面之重要性(Kyte及Doolittle, 1982)。公認胺基酸之相對親水性促成所得蛋白質之二級結構,該二級結構又界定蛋白質與其他分子(例如酶、受質、受體、DNA、抗體、抗原及其類似物)之相互作用。
在此項技術中亦瞭解,可基於親水性有效進行類似胺基酸之取代。美國專利4,554,101(以引用的方式併入本文中)陳述,藉由鄰近胺基酸之親水性調節的蛋白質之最大局部平均親水性與該蛋白質之生物特性相關。如美國專利4,554,101中詳述的,已經指定胺基酸殘基以下親水值:鹼性胺基酸:精胺酸(+3.0)、離胺酸(+3.0)及組胺酸(-0.5);酸性胺基酸:天冬胺酸(+3.0±1)、麩胺酸(+3.0±1)、天冬醯胺(+0.2)及麩醯胺酸(+0.2);親水性、非離子性胺基酸:絲胺酸(+0.3)、天冬醯胺(+0.2)、麩醯胺酸(+0.2)及蘇胺酸(-0.4);含硫胺基酸:半胱胺酸(-1.0)及甲硫胺酸(-1.3);疏水性、非芳族胺基酸:纈胺酸(-1.5)、白胺酸(-1.8)、異白胺酸(-1.8)、脯胺酸(-0.5±1)、丙胺酸(-0.5)及甘胺酸(0);疏水性、芳族胺基酸:色胺酸(-3.4)、苯丙胺酸(-2.5)及酪胺酸(-2.3)。
應瞭解,一種胺基酸可經具有類似親水性之另一胺基酸取代且產生在生物學或免疫學上改變之蛋白質。在該等變化中,用親水值在±2內之胺基酸取代較佳,用親水值在±1內之彼等胺基酸取代尤佳,且用親水值在±0.5內之彼等胺基酸取代甚至更佳。
如上文所概述,胺基酸取代一般係基於胺基酸側鏈取代基之相對相似性,例如其疏水性、親水性、電荷、大小及其類似特性。考慮各種前述特徵之例示性取代為熟習此項技術者所熟知的,且包括:精胺酸及離胺酸;麩胺酸及天冬胺酸;絲胺酸及蘇胺酸;麩醯胺酸及天冬醯胺;以及纈胺酸、白胺酸及異白胺酸。
本發明亦涵蓋同型修飾。藉由修飾Fc區以使其具有不同之同型,可實現不同功能。舉例而言,改變成IgG
1可增加抗體依賴性細胞毒性,轉變成A類可改善組織分佈,且轉變成M類可改善價態。
經修飾抗體可藉由熟習此項技術者已知之任何技術製備,包括經由標準分子生物技術表現,或多肽之化學合成。重組表現之方法闡述於本文件中其他地方。
D . 單鏈抗體單鏈可變片段(scFv)係免疫球蛋白重鏈及輕鏈之可變區與短(通常為絲胺酸、甘胺酸)連接子連接在一起的融合物。儘管移除恆定區且引入連接肽,但此嵌合分子保留原始免疫球蛋白之特異性。此修飾通常未改變特異性。歷史上產生此等分子係為了幫助噬菌體呈現,其中其特別適宜以單一肽形式表現抗原結合結構域。或者,scFv可直接由來源於融合瘤的次選殖之重鏈及輕鏈產生。單鏈可變片段缺乏在完整抗體分子中所發現的恆定Fc區,且因此無法使用常用結合位點(例如,蛋白質A/G)來純化抗體。此等片段通常可使用蛋白質L純化/固定,因為蛋白質L與κ輕鏈之可變區相互作用。
可撓性連接子一般包含促進螺旋及轉角之胺基酸殘基,諸如丙胺酸、絲胺酸及甘胺酸。然而,其他殘基亦可起作用。Tang等人(1996)使用噬菌體呈現作為自蛋白質連接子文庫快速選擇單鏈抗體(scFv)之定製連接子的一種方式。構建隨機連接子文庫,其中重鏈及輕鏈可變結構域之基因係藉由編碼具有不同組成之18個胺基酸之多肽的片段連接。將scFv組庫(大約5×10
6個不同成員)呈現於絲狀噬菌體上且用半抗原進行親和力選擇。所選變體群展現結合活性之顯著增加,同時保持相當大的序列多樣性。隨後篩選1054種個別變體得到催化活性scFv,其係以可溶形式高效產生的。序列分析揭露在V
HC末端之後兩個殘基之連接子中的保守脯胺酸及在其他位置處之大量精胺酸及脯胺酸作為所選繫鏈(tether)之唯一常見特徵。
本發明之重組抗體亦可涉及允許受體二聚合或多聚合之序列或部分。此類序列包括衍生自IgA之該等序列,其允許與J鏈一起形成多聚體。另一多聚合結構域為Gal4二聚合結構域。在其他實施例中,該等鏈可用允許兩個抗體組合的諸如生物素/抗生素蛋白之試劑修飾。
在獨立實施例中,單鏈抗體可藉由使用非肽連接子或化學單元連接受體輕鏈及重鏈來產生。大體而言,輕鏈及重鏈將在不同細胞中產生,純化,且隨後以適當方式(亦即,重鏈之N末端經由適當化學橋接附接至輕鏈之C末端)連接在一起。
使用交聯試劑形成分子橋接,將兩個不同分子,例如穩定劑及凝聚劑之官能基系在一起。然而,預期會產生相同類似物之二聚體或多聚體或包含不同類似物之雜聚物複合體。為了以逐步方式連接兩種不同化合物,可使用異雙官能交聯劑消除不想要的均聚物形成。
例示性異雙官能交聯劑含有兩個反應性基團:一個與一級胺基團(例如,N-羥基丁二醯亞胺)反應,且另一個與硫醇基(例如,吡啶基二硫化物、順丁烯二醯亞胺、鹵素等)反應。經由一級胺反應性基團,該交聯劑可與一種蛋白質(例如,選定抗體或片段)之離胺酸殘基反應,且經由硫醇反應性基團,已經繫栓至第一蛋白質上的交聯劑與另一蛋白質(例如,選擇性試劑)之半胱胺酸殘基(游離硫氫基)反應。
較佳採用在血液中具有合理穩定性之交聯劑。已知眾多類型的含有二硫鍵之連接子,其可成功地用於綴合靶向劑及治療劑/預防劑。含有位阻性二硫鍵之連接子可證明在活體內得到較大穩定性,從而防止靶向肽在到達作用部位之前釋放。因此此等連接子為一組連接試劑。
另一交聯試劑為SMPT,其為含有藉由鄰近苯環及甲基「空間位阻」之二硫鍵的雙官能交聯劑。咸信二硫鍵之位阻起到保護該鍵免受可存在於組織及血液中之硫醇根陰離子(諸如谷胱甘肽)侵襲的功能,且藉此有助於防止綴合物在將附接試劑遞送至目標位點之前解偶合。
與許多其他已知之交聯試劑相同,SMPT交聯試劑能夠交聯諸如半胱胺酸之SH或一級胺(例如,離胺酸之ε胺基)之官能基。另一可能的交聯劑類型包括含有可裂解二硫鍵之異雙官能光反應性疊氮苯,諸如磺基丁二醯亞胺基-2-(對疊氮基水楊醯胺基)乙基-1,3'-二硫代丙酸酯。N-羥基-琥珀醯亞胺基與一級胺基反應且疊氮苯(在光解後)與任何胺基酸殘基發生非選擇性反應。
除受阻交聯劑外,亦可根據本發明採用非受阻連接子。除含有或產生保護性二硫化物外,其他有用交聯劑包括SATA、SPDP及2-亞胺基硫雜環戊烷(Wawrzynczak及Thorpe, 1987)。在此項技術中充分瞭解此類交聯劑之使用。另一實施例涉及使用可撓性連接子。
美國專利4,680,338描述可用於產生配位體與含胺聚合物及/或蛋白質之綴合物,尤其用於形成抗體與螯合劑、藥物、酶、可偵測標記及其類似物之綴合物的雙官能連接子。美國專利5,141,648及5,563,250揭示含有在多種溫和條件下可裂解之不穩定鍵的可裂解綴合物。此連接子特別適用於所關注之試劑可直接鍵接至該連接子且裂解導致活性劑之釋放的情形。特定應用包括將游離胺基或游離硫氫基添加至蛋白質,諸如抗體或藥物。
美國專利5,856,456提供用於將多肽成分連接至融合蛋白,例如單鏈抗體之肽連接子。該連接子為至多約50個胺基酸長度,含有出現至少一次之帶電胺基酸(較佳為精胺酸或離胺酸),繼之以脯胺酸,且以較大穩定性及較少聚集為特徵。美國專利5,880,270揭示可用於多種免疫診斷及分離技術中的含胺氧基之連接子。
E . 胞內抗體在一特定實施例中,抗體為適於在細胞內部起作用之重組抗體,此類抗體稱為「胞內抗體」。此等抗體可藉由多種機制,諸如藉由改變細胞內蛋白質運輸、干擾酶功能及阻斷蛋白質-蛋白質或蛋白質-DNA相互作用來干擾目標功能。以許多方式,其結構模擬或類似上文所論述之單鏈及單結構域抗體的結構。實際上,單一轉錄物/單鏈為允許在目標細胞中細胞內表現並且使蛋白質轉運越過細胞膜更可行的重要特徵。然而,需要另外的特徵。
影響胞內抗體治療之實施的兩個主要問題為遞送,包括細胞/組織靶向;及穩定性。就遞送而言,已經採用多種方法,諸如組織引導之遞送、使用細胞類型特異性啟動子、基於病毒之遞送,及使用細胞穿透肽/膜易位肽。就穩定性而言,該方法一般係藉由蠻力法篩選,包括涉及噬菌體呈現且可以包括共同序列之序列成熟或發展的方法,或更具引導性之修飾,諸如插入穩定序列(例如,Fc區、伴隨蛋白序列、白胺酸拉鏈)及二硫化物置換/修飾。
胞內抗體可能需要之另外的特徵為用於細胞內靶向之信號。已設計出可使胞內抗體(或其他蛋白質)靶向亞細胞區域,諸如細胞質、胞核、粒線體及ER之載體,且其等可自商品購得(Invitrogen Corp.;Persic等人, 1997)。
由於能夠進入細胞,胞內抗體具有其他類型之抗體無法達成的另外用途。就本發明抗體而言,與活細胞中之MUC1細胞質域相互作用的能力可干擾與MUC1 CD有關之功能,諸如信號傳導功能(結合至其他分子)或寡聚物形成。特定言之,預期此類抗體可用於抑制MUC1二聚體形成。
F . 純化在某些實施例中,本發明之抗體可經純化。如本文中所用,術語「純化」意圖指可與其他組分分離之組合物,其中相對於其天然可獲得之狀態,蛋白質純化至任何程度。因此,純化之蛋白質亦指脫離其可天然出現之環境的蛋白質。當使用術語「實質上純化」時,此名稱將指這樣一種組合物,其中蛋白質或肽形成該組合物之主要組分,諸如蛋白質在該組合物中佔約50%、約60%、約70%、約80%、約90%、約95%或更高百分比。
蛋白質純化技術係熟習此項技術者熟知的。此等技術一方面涉及細胞環境粗品部分分離成多肽及非多肽部分。當多肽與其他蛋白質分離時,所關注之多肽可進一步使用層析技術及電泳技術純化以達到部分或完全純化(或純化至均質)。特別適合於製備純肽之分析方法為離子交換層析法、排阻層析法、聚丙烯醯胺凝膠電泳、等電聚焦。用於蛋白質純化之其他方法包括用硫酸銨、PEG、抗體及其類似物沈澱,或藉由熱變性,隨後離心;凝膠過濾、逆相層析、羥磷灰石層析及親和層析;及此類及其他技術之組合。
在純化本發明之抗體時,可能需要在原核或真核表現系統中表現該多肽且使用變性條件提取蛋白質。可使用結合至多肽之標記部分的親和管柱自其他細胞組分純化多肽。如此項技術中一般所知,咸信執行多個純化步驟之次序可改變,或可省略某些步驟,且仍為適用於製備實質上純化之蛋白質或肽的方法。
通常,利用結合抗體Fc部分之試劑(亦即,蛋白質A)分級分離完整抗體。或者,可以使用抗原同時純化及選擇適當抗體。此類方法通常利用結合至支撐物,諸如管柱、過濾器或珠粒之選擇劑。抗體結合至支撐物,移除污染物(例如,洗掉)且藉由施加條件(鹽、熱等)釋放抗體。
熟習此項技術者根據本發明將獲知用於定量蛋白質或肽之純化程度的多種方法。此等方法包括例如,測定活性部分之比活性,或藉由SDS/PAGE分析評估一個部分內的多肽量。用於評估一個部分之純度的另一方法係計算該部分之比活性,將其與初始提取物之比活性相比較,且由此計算純度。用於表示活性之量的實際單位當然取決於選擇用於跟蹤純化之特定分析技術及表現之蛋白質或肽是否展現可偵測之活性。
已知多肽之遷移有時會隨SDS/PAGE之不同條件而明顯變化(Capaldi等人
,1977)。因此,應理解,在不同電泳條件下,純化或部分純化之表現產物的表觀分子量可變化。
III . 屈公病毒感染之主動 / 被動免疫及治療 / 預防 A . 調配物及投與本發明提供包含抗屈公病毒抗體及用於產生該等抗體之抗原的醫藥組合物。此類組合物包含預防或治療有效量之抗體或其片段,或肽免疫原,及醫藥學上可接受之載劑。在一個具體實施例中,術語「醫藥學上可接受」意指經聯邦政府或洲政府之監管機構批准或在美國藥典或其他公認之藥典中列出適用於動物,且更特定言之適用於人類。術語「載劑」係指與治療劑一起投與之稀釋劑、賦形劑或媒劑。此類醫藥載劑可為無菌液體,諸如水及油,包括石油、動物、植物或合成來源之油,諸如花生油、大豆油、礦物油、芝麻油及其類似物。當經靜脈內投與醫藥組合物時,水為特定載劑。亦可採用生理食鹽水溶液及右旋糖水溶液及甘油溶液作為液體載劑,特別是對於可注射溶液而言。其他適合之醫藥賦形劑包括澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻穀、麵粉、白堊、矽膠、硬脂酸鈉、甘油單硬脂酸酯、滑石、氯化鈉、脫脂奶粉、甘油、丙烯、乙二醇、水、乙醇及其類似物。
若需要,組合物亦可含有少量濕潤劑或乳化劑,或pH緩衝劑。此等組合物可呈溶液、懸浮液、乳液、錠劑、丸劑、膠囊、散劑、持續釋放調配物及其類似物之形式。經口調配物可以包括標準載劑,諸如醫藥級甘露醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、纖維素、碳酸鎂等。適合藥劑之實例描述於「Remington's Pharmaceutical Sciences」中。此類組合物將含有預防或治療有效量的較佳呈純化形式之抗體或其片段,以及適量載劑,以便提供適合向患者投與之形式。調配物應適合投與模式之要求,該投與模式可為經口、靜脈內、動脈內、頰內、鼻內、噴霧、支氣管吸入或藉由機械通氣遞送。
亦設想活疫苗,其中抗體(如所揭示之該等抗體)係在有感染屈公病毒風險之個體中活體內產生。E1及E2之序列在所附序列表中以SEQ ID NO:253-276列出。此類疫苗可調配用於非經腸投與,例如調配用於經由皮內、靜脈內、肌肉內、皮下或甚至腹膜內途徑注射。涵蓋藉由皮內及肌肉內途徑投與。或者,疫苗可藉由局部途徑,例如藉由鼻滴液、吸入或藉由噴霧器直接投與黏膜。醫藥上可接受之鹽包括酸鹽及與無機酸(諸如氫氯酸或磷酸)或有機酸(諸如乙酸、草酸、酒石酸、扁桃酸及其類似酸)形成的該等鹽。與游離羧基形成之鹽亦可衍生自無機鹼,諸如鈉、鉀、銨、鈣或鐵氫氧化物;及有機鹼,諸如異丙胺、三甲胺、2-乙胺基乙醇、組胺酸、普魯卡因(procaine)及其類似物。
抗體之被動轉移,稱為人工獲得性被動免疫,一般涉及使用靜脈內或肌肉內注射。抗體之形式可為人類或動物血漿或血清、用於靜脈內(IVIG)或肌肉內(IG)使用的彙集之人類免疫球蛋白、來自免疫接種或由疾病恢復之供體的高滴度人類IVIG或IG,及單株抗體(MAb)。此類免疫一般僅持續較短時段,且亦有超敏反應及血清疾病,尤其由非人類起源之球蛋白引起之超敏反應及血清疾病的潛在風險。然而,被動免疫提供即時保護。抗體將以適於注射(亦即,無菌及可注射)之載劑調配。
大體而言,本發明組合物之成分係單獨或混合在一起以單位劑型形式(例如以乾燥凍乾粉末或無水濃縮物形式)於指示活性劑之量的密閉密封容器(諸如安瓿或藥囊)中提供。當意圖藉由輸注投與組合物時,其可用含有無菌醫藥級水或生理食鹽水之輸液瓶來施配。當藉由注射投與組合物時,可提供具有注射用無菌水或生理食鹽水之安瓿,以使該等成分可在投與前混合。
本發明之組合物可調配為中性或鹽形式。醫藥學上可接受之鹽包括與陰離子形成之鹽,諸如衍生自氫氯酸、磷酸、乙酸、草酸、酒石酸等之鹽;及與陽離子形成之鹽,諸如衍生自氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣、氫氧化鐵、異丙胺、三乙胺、2-乙胺基乙醇、組胺酸、普魯卡因等之鹽。
IV . 抗體 綴合物本發明之抗體可連接到至少一種試劑以形成抗體綴合物。為了增加抗體分子作為診斷劑或治療劑之功效,通常連接或共價結合至少一個所需分子或部分,或與之形成複合體。此類分子或部分可為(但不限於)至少一個效應子或報告子分子。效應子分子包含具有所需活性,例如細胞毒性活性之分子。已經附接至抗體之效應子分子的非限制性實例包括毒素、抗腫瘤劑、治療性酶、放射性核素、抗病毒劑、螯合劑、細胞因子、生長因子及寡聚核苷酸或多聚核苷酸。相比之下,報告子分子定義為可使用分析法偵測的任何部分。已經綴合至抗體之報告子分子的非限制性實例包括酶、放射性標記、半抗原、螢光標記、磷光分子、化學發光分子、發色團、光親和性分子、著色粒子或配位體,諸如生物素。
抗體綴合物一般較佳用作診斷劑。抗體診斷劑一般分為兩類:用於活體外診斷,諸如用於多種免疫分析法中之診斷劑;及用於活體內診斷方案之診斷劑,一般稱為「抗體引導之成像」。此項技術中已知許多適當成像劑,以及其附接至抗體之方法(參見例如,美國專利5,021,236、4,938,948及4,472,509)。所用成像部分可為順磁性離子、放射性同位素、螢光染料、NMR可偵測之物質及X射線成像劑。
在順磁性離子之情況下,可例如提及諸如鉻(III)、錳(II)、鐵(III)、鐵(II)、鈷(II)、鎳(II)、銅(II)、釹(III)、鈣(III)、鐿(III)、釓(III)、釩(II)、鋱(III)、鏑(III)、鈥(III)及/或鉺(III)之離子,其中釓尤佳。可用於其他情形,諸如X射線成像之離子包括(但不限於)鑭(III)、金(III)、鉛(II)且尤其是鉍(III)。
在用於治療及/或診斷應用之放射性同位素之情況下,可提及砹
211、
14碳、
51鉻、
36氯、
57鈷、
58鈷、銅
67、
152Eu、鎵
67、
3氫、碘
123、碘
125、碘
131、銦
111、
59鐵、
32磷、錸
186、錸
188、
75硒、
35硫、鎝
99m及/或釔
90。
125I通常較佳用於某些實施例中,且鎝
99m及/或銦
111亦由於能量低及適用於遠程偵測而通常較佳。本發明之放射性標記之單株抗體可根據此項技術中熟知之方法製備。舉例而言,單株抗體可藉由與碘化鈉及/或碘化鉀及化學氧化劑(諸如次氯酸鈉)或酶氧化劑(諸如乳過氧化酶)接觸而碘化。根據本發明之單株抗體可用鎝
99m藉由配位體交換法,例如藉由用亞錫溶液還原高鎝酸鹽,將經還原之鎝螯合至葡聚糖凝膠管柱上且將抗體施加至此管柱上來進行標記。或者,可以使用直接標記技術,例如藉由溫育高鎝酸鹽、還原劑(諸如SNCl
2)、緩衝溶液(諸如鄰苯二甲酸鈉-鉀溶液)及該抗體。通常用於使以金屬離子形式存在之放射性同位素結合至抗體的中間官能基為二伸乙三胺五乙酸(DTPA)或伸乙基二胺四乙酸(EDTA)。
在預期用作綴合物之螢光標記中包括Alexa 350、Alexa 430、AMCA、BODIPY 630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、Cascade Blue、Cy3、Cy5, 6-FAM、異硫氰酸螢光素、HEX、6-JOE、俄勒岡綠(Oregon Green) 488、俄勒岡綠500、俄勒岡綠514、太平洋藍(Pacific Blue)、REG、若丹明綠(Rhodamine Green)、若丹明紅、腎造影劑(Renographin)、ROX、TAMRA、TET、四甲基若丹明及/或德克薩斯紅(Texas Red)。
本發明所涵蓋之另一類抗體綴合物為預期主要在活體外使用的該等綴合物,其中抗體連接至在與發色基質接觸時產生著色產物的二級結合配位體及/或酶(酶標籤)。適合酶之實例包括尿素酶、鹼性磷酸酶、(辣根)氫過氧化酶或葡萄糖氧化酶。較佳之二級結合配位體為生物素及抗生素蛋白及抗生蛋白鏈菌素化合物。此類標記之使用為熟習此項技術者熟知的且描述於例如美國專利3,817,837、3,850,752、3,939,350、3,996,345、4,277,437、4,275,149及4,366,241中。
將分子位點特異性附接至抗體之又一已知方法包含使抗體與基於半抗原之親和標記反應。本質上,基於半抗原之親和標記與抗原結合位點中之胺基酸反應,由此破壞此位點且阻斷特異性抗原反應。然而,由於其因抗體綴合物引起抗原結合之損失,此可能為不利的。
亦可使用含有疊氮基之分子,經由低強度紫外光產生之反應性亞氨體中間物而與蛋白質形成共價鍵(Potter及Haley, 1983)。特定言之,已使用嘌呤核苷酸之2-疊氮基類似物及8-疊氮基類似物作為定點光探針以鑑別粗細胞提取物中之核苷酸結合蛋白(Owens及Haley, 1987;Atherton等人
,1985)。2-疊氮基核苷酸及8-疊氮基核苷酸亦用於定位純化蛋白質之核苷酸結合結構域(Khatoon等人
,1989;King等人
,1989;Dholakia等人
,1989)且可用作抗體結合劑。
此項技術中已知用於將抗體附接或綴合至其綴合物部分之若干方法。一些附接方法涉及使用金屬螯合劑錯合物,採用例如有機螯合劑,諸如二伸乙三胺五乙酸之酸酐(DTPA);伸乙基三胺四乙酸;N-氯-對甲苯磺醯胺;及/或四氯-3α-6α-二苯基甘脲-3附接至抗體(美國專利4,472,509及4,938,948)。單株抗體亦可與酶在諸如戊二醛或高碘酸鹽之偶合劑存在下反應。帶有螢光素標記物之綴合物係在此等偶合劑存在下或藉由與異硫氰酸鹽反應來製備。在美國專利4,938,948中,乳房腫瘤之成像係使用單株抗體實現且可偵測成像部分使用諸如甲基-對羥基苯甲亞胺酸酯或N-琥珀醯亞胺基-3-(4-羥苯基)丙酸酯之連接子結合至抗體。
在其他實施例中,涵蓋藉由使用不改變抗體組合位點之反應條件,在免疫球蛋白Fc區中選擇性引入硫氫基進行免疫球蛋白之衍生化。揭示的根據此方法產生之抗體綴合物展現改善之耐久性、特異性及敏感性(美國專利5,196,066,以引用的方式併入本文中)。文獻中亦已揭示效應子或報告子分子之位點特異性附接,其中該報告子或效應子分子係綴合至Fc區中之碳水化合物殘基(O'Shannessy等人
,1987)。據報告,此方法製造出在診斷上及治療上頗具前景之抗體,該等抗體當前處於臨床評價中。
V . 免疫偵測方法在又其他實施例中,本發明涉及用於結合、純化、移除、定量及以其他方式大體上偵測屈公病毒及其相關抗原的免疫偵測方法。儘管該等方法可在傳統意義上應用,但另一用途將為疫苗及其他病毒儲備液之品質控制及監測,其中可使用根據本發明之抗體評估病毒中H1抗原之量或完整性(亦即,長期穩定性)。或者,可以使用該等方法針對適當/所需反應性型態篩選各種抗體。
一些免疫偵測方法包括例如酶連免疫吸附劑分析法(ELISA)、放射免疫分析法(RIA)、免疫放射分析法、螢光免疫分析法、化學發光分析法、生物發光分析法及西方墨點法。特定言之,亦提供用於偵測及定量針對樣品中之特定寄生蟲抗原決定基之屈公病毒抗體的競爭性分析法。各種有用免疫偵測方法之步驟已描述於科學文獻中,諸如Doolittle及Ben-Zeev(1999)、Gulbis及Galand
(1993)、De Jager等人(1993)及Nakamura等人(1987)。大體而言,免疫結合方法包括獲得懷疑含有屈公病毒之樣品,及視具體情況在有效允許免疫複合體形成之條件下,使該樣品與根據本發明之第一抗體接觸。
此等方法包括用於自樣品純化屈公病毒或相關抗原之方法。該抗體較佳連接至諸如呈管柱矩陣形式之固體支撐物,且將懷疑含有屈公病毒或抗原組分之樣品施加到固定之抗體上。不想要的組分將自該管柱洗掉,留下與固定之抗體形成免疫複合體的屈公病毒抗原,接著藉由自管柱移出有機體或抗原進行收集。
免疫結合方法亦包括用於偵測及定量樣品中屈公病毒或相關組分之量以及偵測及定量在該結合方法期間形成之任何免疫複合體的方法。此處,將獲得懷疑含有屈公病毒或其抗原之樣品,且使該樣品與結合屈公病毒或其組分之抗體接觸,隨後偵測及定量在特定條件下形成之免疫複合體之量。就抗原偵測而言,所分析之生物樣品可為懷疑含有屈公病毒或屈公病毒抗原之任何樣品,諸如組織切片或試樣、均質化組織提取物、生物流體(包括血液及血清),或分泌物,諸如糞便或尿液。
使所選生物樣品與抗體在有效條件下接觸一段足以允許免疫複合體(主要免疫複合體)形成之時間一般為僅僅將抗體組合物添加至樣品中且培育該混合物一段長到足以使該等抗體與存在之屈公病毒或抗原形成免疫複合體(亦即,結合至屈公病毒或抗原)之時間的問題。此後,一般洗滌樣品-抗體組合物,諸如組織切片、ELISA盤、點漬墨或西方墨點,以移除任何非特異性結合之抗體物質,使得僅在主要免疫複合體內特異性結合之該等抗體得到偵測。
大體而言,免疫複合體形成之偵測為此項技術中熟知的且可藉由應用眾多方法實現。此等方法一般係基於標記或標記物,諸如該等放射性標籤、螢光標籤、生物標籤及酶標籤中之任一者的偵測。關於使用此類標記之專利包括美國專利3,817,837、3,850,752、3,939,350、3,996,345、4,277,437、4,275,149及4,366,241。當然,可藉由使用如此項技術中已知的二級結合配位體,諸如二次抗體及/或生物素/抗生素蛋白配位體結合佈置發現另外的優勢。
用於偵測之抗體本身可連接至可偵測標記,其中接著僅僅偵測此標記,由此測定組合物中主要免疫複合體之量。或者,可藉助於對抗體具有結合親和力之第二結合配位體偵測主要免疫複合體內結合之第一抗體。在此等情況下,該第二結合配位體可連接至可偵測標記。該第二結合配位體本身通常為一種抗體,其因此可被稱為「二級」抗體。主要免疫複合體與經標記之二級結合配位體或抗體在有效條件下接觸一段足以允許二級免疫複合體形成之時間。接著一般洗滌該等二級免疫複合體以移除任何非特異性結合之經標記二級抗體或配位體,且接著偵測二級免疫複合體中之殘留標記。
其他方法包括藉由兩步法偵測主要免疫複合體。使用第二結合配位體,諸如對抗體具有結合親和力之抗體,形成如上文所描述之二級免疫複合體。洗滌之後,使二級免疫複合體與對第二抗體具有結合親和力之第三結合配位體或抗體再次在有效條件下接觸一段足以允許形成免疫複合體(三級免疫複合體)之時間。第三配位體或抗體連接至可偵測標記,從而允許偵測由此形成之三級免疫複合體。若需要,此系統可提供信號放大。
一種免疫偵測方法使用兩種不同抗體。第一生物素化抗體用於偵測目標抗原,且接著第二抗體用於偵測附接至生物素複合體的生物素。在該方法中,首先在含有第一步驟抗體之溶液中培育待測試之樣品。若存在目標抗原,則一些抗體結合至抗原而形成生物素化抗體/抗原複合體。抗體/抗原複合體接著藉由在具有抗生蛋白鏈菌素(或抗生素蛋白)、生物素化DNA及/或互補生物素化DNA之連續溶液中培育以進行擴增,其中每一步驟添加另外的生物素位點至抗體/抗原複合體中。重複擴增步驟,直至達到適合擴增程度,此時,在含有針對生物素之第二步驟抗體的溶液中培育樣品。此第二步驟抗體例如用酶標記,該酶可藉由使用色原體受質之組織酶學偵測抗體/抗原複合體之存在。在適當擴增情況下,可產生在宏觀上可見之綴合物。
另一已知的免疫偵測方法利用了免疫-PCR(聚合酶鏈反應)方法。該PCR方法在與生物素化DNA一起培育之前類似於Cantor方法,不過改用多輪抗生蛋白鏈菌素及生物素化DNA培育,用低pH或高鹽緩衝液洗滌DNA/生物素/抗生蛋白鏈菌素/抗體複合體以釋放出抗體。接著使用所得洗滌溶液在適合引子及適當對照物存在下進行PCR反應。至少在理論上,可利用PCR之巨大擴增能力及特異性偵測單抗原分子。
A . ELISA免疫分析法在其最簡單且最直接之意義上講為結合分析法。某些較佳的免疫分析法為此項技術中已知的各種類型之酶連免疫吸附劑分析法(ELISA)及放射免疫分析法(RIA)。使用組織切片進行之免疫組織化學偵測亦為特別有用的。然而,易於理解的是,偵測不限於此類技術,且亦可使用西方墨點法、點漬墨法、FACS分析及其類似方法。
在一種例示性ELISA中,將本發明之抗體固定至展現蛋白質親和力之選定表面上,諸如聚苯乙烯微量滴定盤之孔中。接著,將懷疑含有屈公病毒或屈公病毒抗原之測試組合物添加至該等孔。在結合及洗滌移除非特異性結合之免疫複合體之後,可偵測經結合之抗原。偵測可藉由添加連接至可偵測標記之另一抗屈公病毒抗體實現。此類ELISA為簡單的「夾心ELISA」。偵測亦可藉由添加第二抗屈公病毒抗體,隨後添加對該第二抗體具有結合親和力之第三抗體實現,其中該第三抗體連接至可偵測標記。
在另一例示性ELISA中,將懷疑含有屈公病毒或屈公病毒抗原之樣品固定至孔表面上且接著與本發明之抗屈公病毒抗體接觸。在結合及洗滌移除非特異性結合之免疫複合體之後,偵測經結合之抗屈公病毒抗體。在初始抗屈公病毒抗體連接至可偵測標記情況下,可直接偵測免疫複合體。再次,使用對第一抗屈公病毒抗體具有結合親和力之第二抗體偵測免疫複合體,其中第二抗體連接至可偵測標記。
無論採用何種形式,ELISA均具有某些共同特徵,諸如塗佈、培育及結合、洗滌移除非特異性結合之物質,及偵測經結合之免疫複合體。下文中描述此等步驟。
在用抗原或抗體塗佈盤時,一般將該盤之孔與抗原或抗體溶液培育隔夜或指定的數小時時間。接著洗滌該盤之孔以移除不完全吸附之材料。接著,該等孔之任何殘留可用表面利用對測試抗血清呈抗原中性之非特異性蛋白質「塗佈」。此等蛋白質包括牛血清白蛋白(BSA)、酪蛋白或奶粉溶液。該塗佈允許阻斷固定表面上之非特異性吸附位點且因此減小由該表面上抗血清之非特異性結合引起的背景。
在ELISA中,可能更常用的是,使用二級或三級偵測方式而非直接程序。因此,在蛋白質或抗體結合至孔,用非反應性材料塗佈以減小背景且洗滌以移除未結合之材料之後,使固定表面與待測試之生物樣品在有效允許免疫複合體(抗原/抗體)形成的條件下接觸。免疫複合體之偵測則需要經標記之二級結合配位體或抗體,及二級結合配位體或抗體與經標記之三級抗體或第三結合配位體之組合。
「有效允許免疫複合體(抗原/抗體)形成之條件下」意謂,該等條件較佳包括用諸如BSA、牛γ球蛋白(BGG)或磷酸鹽緩衝生理食鹽水(PBS)/Tween之溶液稀釋抗原及/或抗體。此等添加之試劑亦往往有助於減小非特異性背景。
「適合」條件亦意謂,培育係在足以允許有效結合之溫度或時間段下進行。培育步驟通常為較佳在約25℃至27℃之溫度下約1至2至約4小時,或可在約4℃下隔夜。
在ELISA中之所有培育步驟之後,洗滌接觸之表面,以便移除未形成複合體之材料。較佳洗滌程序包括用諸如PBS/Tween或硼酸鹽緩衝液之溶液洗滌。在測試樣品與最初結合之材料之間形成特定免疫複合體且隨後洗滌之後,可測定甚至微量免疫複合體之存在。
為提供偵測方式,第二或第三抗體將具有相關標記以允許偵測。較佳此標記將為在與適當發色受質一起培育時顯色的酶。因此,舉例而言,需要使第一及第二免疫複合體與尿素酶、葡萄糖氧化酶、鹼性磷酸酶或氫過氧化酶綴合抗體在促進其他免疫複合體形成之發生的時間及條件下接觸或培育(例如,在室溫下於含PBS之溶液,諸如PBS-Tween中培育2小時)。
在與經標記抗體一起培育且隨後洗滌以移除未結合之材料之後,例如藉由與發色受質,諸如脲,或溴甲酚紫,或2,2'-次偶氮基-二(3-乙基-苯并噻唑啉-6-磺酸(ABTS))或H
2O
2(在過氧化酶作為酶標記之情況下)一起培育,來對標記之量進行定量。接著,藉由例如使用可見光譜分光光度計量測所產生之顏色的色度來實現定量。
在另一實施例中,本發明涵蓋使用競爭性形式。此特別適用於偵測樣品中之屈公病毒抗體。在基於競爭之分析法中,藉由置換已知量之經標記抗體或分析物的能力測定未知量之分析物或抗體。因此,信號之可定量損失指示樣品中未知抗體或分析物之量。
此處,本發明人提出使用經標記屈公病毒單株抗體來測定樣品中屈公病毒抗體之量。基本形式將包括使已知量之屈公病毒單株抗體(連接至可偵測標記)與屈公病毒抗原或粒子接觸。屈公病毒抗原或有機體較佳附接至支撐物。在經標記單株抗體結合至支撐物之後,添加樣品且在允許樣品中之任何未標記抗體與經標記單株抗體競爭且因此置換經標記單株抗體的條件下進行培育。藉由量測喪失之標記或殘留標記(且自經結合標記之初始量中減去該標記),可測定結合至支撐物之未標記抗體的量且因此測定樣品中存在之抗體量。
B . 西方墨點法西方墨點法(或者,蛋白質免疫墨點法)為用於偵測給定組織勻漿或提取物樣品中之特定蛋白質的分析技術。其使用凝膠電泳,藉由多肽之長度(變性條件)或藉由蛋白質之3-D結構(天然/非變性條件)來分離天然或變性之蛋白質。接著將蛋白質轉印至膜(通常為硝化纖維素或PVDF)上,在其中使用目標蛋白質特異性抗體探測(偵測)該等蛋白質。
樣品可獲自完整組織或細胞培養物。在大多數情況下,首先使用摻混機(對於較大樣品體積)、使用均質機(較小體積)或藉由音波處理,以機械方式分解固體組織。亦可藉由以上機械方法之一打開細胞。然而,應注意,細菌、病毒或環境樣品可為蛋白質之來源且因此西方墨點法並不僅僅侷限於細胞研究。可採用選定之清潔劑、鹽及緩衝劑促進細胞溶解及溶解蛋白質。通常添加蛋白酶及磷酸酶抑制劑以防止樣品被其自身酶消化。組織準備通常係在較冷溫度下進行以避免蛋白質變性。
使用凝膠電泳分離樣品中之蛋白質。蛋白質之分離可藉由等電點(pI)、分子量、電荷或此等因素之組合進行。分離之性質取決於樣品之處理及凝膠之性質。此為測定蛋白質之極有用方式。亦可使用二維(2-D)凝膠,其在兩個維度上擴散來自單一樣品之蛋白質。蛋白質在第一維度上係根據等電點(使其具有中性淨電荷之pH)分離,且在第二維度上根據其分子量分離。
為了使蛋白質可用於抗體偵測,將其自凝膠內移至由硝化纖維素或聚偏二氟乙烯(PVDF)製成之膜上。將該膜置放於凝膠頂部上,且在其頂部上置放一疊濾紙。將該整個疊層置放於緩衝溶液中,該緩衝溶液在毛細作用下使蛋白質與其一起在濾紙上向前移動。用於轉印蛋白質之另一方法稱為電墨點法(electroblotting)且使用電流將蛋白質自凝膠拉至PVDF或硝化纖維素膜中。蛋白質自凝膠內移至膜上,同時維持其在凝膠內所具有之組織。此墨點法之結果是,蛋白質暴露於薄表面層上以進行偵測(參見下文)。膜之兩個種類係針對其非特異性蛋白質結合特性(亦即,同等地結合所有蛋白質)選擇。蛋白質結合係基於疏水相互作用,以及膜與蛋白質之間之帶電相互作用。相較於PVDF,硝化纖維素膜更便宜,但要脆弱得多且無法經受住反覆探測。蛋白質自凝膠轉印至膜之均一性及總體效用可藉由用考馬斯亮藍(Coomassie Brilliant Blue)或麗春紅染料(Ponceau S dye)對膜染色來檢查。一旦轉印,即使用經標記初級抗體偵測蛋白質,或使用未標記初級抗體,隨後使用經標記蛋白質A或結合至初級抗體Fc區之二級經標記抗體間接偵測蛋白質。
C . 免疫組織化學分析本發明之抗體亦可與製備用於免疫組織化學(IHC)研究之新鮮冷凍及/或福馬林固定、石蠟包埋之組織塊一起使用。由此等顆粒試樣製備組織塊之方法已成功地用於先前針對各種預後因子之IHC研究中且為熟習此項技術者熟知的(Brown等人, 1990;Abbondanzo等人, 1990;Allred等人, 1990)。
簡言之,可藉由以下方式製備冷凍切片:在小塑料膠囊中,在室溫下使50 ng冷凍「粉碎」組織在磷酸鹽緩衝生理食鹽水(PBS)中復水;藉由離心使粒子集結成團;將其再懸浮於黏性包埋介質(OCT)中;倒轉膠囊及/或再藉由離心使其集結成團;在-70℃異戊烷中急速冷凍;切割塑料膠囊及/或移出冷凍之組織圓柱;將組織圓柱固定於低溫薄片切片機夾盤上;及/或自膠囊切割25-50個連續切片。或者,可使用完整的冷凍組織樣品進行連續切片切割。
永久性切片可藉由類似方法製備,該方法涉及在塑料微量離心管中使50 mg樣品復水;集結成團;再懸浮於10%福馬林中固定4小時;洗滌/集結成團;再懸浮於溫熱的2.5%瓊脂中;集結成團;在冰水中冷卻以使瓊脂變硬;自管中移出組織/瓊脂塊;使該塊滲入及/或包埋於石蠟中;及/或切割多達50個永久性連續切片。又,可代之以完整組織樣品。
D . 免疫偵測套組在又其他實施例中,本發明涉及與以上描述之免疫偵測方法一起使用的免疫偵測套組。由於抗體可用於偵測屈公病毒或屈公病毒抗原,故該套組中可包括該等抗體。因此,免疫偵測套組將在適合容器構件中包含結合至屈公病毒或屈公病毒抗原之第一抗體,及視情況使用之免疫偵測試劑。
在某些實施例中,屈公病毒抗體可預先結合至固體支撐物,諸如管柱矩陣及/或微量滴定盤之孔。該套組中之免疫偵測試劑可呈多種形式,包括與給定抗體關聯或連接至給定抗體之該等可偵測標記。亦涵蓋與二級結合配位體關聯或附接至二級結合配位體之可偵測標記。例示性二級配位體為對第一抗體具有結合親和力之二級抗體。
用於本發明套組中之其他適合的免疫偵測試劑包括兩組分試劑,其包含對第一抗體具有結合親和力之二級抗體,以及對第二抗體具有結合親和力之第三抗體,該第三抗體連接至可偵測標記。如上所述,此項技術中已知多種例示性標記且所有此類標記均可結合本發明使用。
該等套組可進一步包含具有屈公病毒或屈公病毒抗原之適當等分之組合物,無論經標記抑或未標記,均可用於製備供偵測分析法用之標準曲線。該等套組可含有呈完全綴合形式、呈中間物形式或呈有待該套組之使用者綴合之獨立部分形式的抗體-標記綴合物。該等套組之組分可包裝於水性介質中或以凍乾形式包裝。
該等套組之容器構件一般包括至少一個小瓶、試管、燒瓶、瓶、注射器,或可放入抗體或較佳適宜等分之其他容器構件。本發明之套組通常亦包括用於容納該抗體、抗原及任何其他試劑容器的呈緊密限制形式以供商業銷售的構件。此類容器可以包括保持所需小瓶之射出模製或吹塑模製塑料容器。
VI. 實例包括以下實例以展示較佳實施例。熟習此項技術者應理解,以下實例中所揭示之技術代表本發明人所發現的在實施例之實踐中作用良好之技術,且因此可視為構成其實踐之較佳模式。然而,熟習此項技術者應理解,根據本發明,在不背離本發明之精神及範疇的情況下可對所揭示之具體實施例作出許多改變且仍獲得相同或相似結果。
實例 1 - 材料及方法 人類 mAb 之分離 .PBMC係在斯里蘭卡(Sri Lanka)記錄的有症狀之CHKV感染之後約5年自人類獲得。在384孔盤中,在CpG存在下,用EBV轉型B細胞。使用活CHIKV疫苗株181/25病毒作為抗原,藉由ELISA篩選由所得B細胞淋巴母細胞之細胞株得到的上清液中人類CHKV特異性結合抗體之存在。收集轉型之B細胞且使其與骨髓瘤細胞株融合,分配至培養盤中且擴增,並藉由在含有烏本苷之次黃嘌呤-胺基喋呤-胸苷培養基中生長進行選擇。藉由單細胞分選來選殖融合瘤。收集由在無血清培養基中生長之經選殖融合瘤得到的上清液,藉由蛋白質G層析法自澄清培養基純化且濃縮。
中和分析法 .使用CHKV病毒複製子(VRP)或代表不同基因及地理型態之4種活屈公病毒中之每一種來測試純化之IgG mAb蛋白質的中和活性。藉由基於含有CHIKV病毒株SL15649(GenBank:GU189061.1)基因組序列之全長cDNA的質體,使用基於PCR之選殖方法產生三質體CHIKV複製子輔助系統,由此產生編碼GFP之VRP。將VRP與mAb稀釋液一起培育,接著接種至Vero 81細胞單層上,保持18小時;用螢光成像系統鑑別經感染細胞及總細胞(用核標記物鑑別)。為了測定mAb寬度(breadth)及中和效力,本發明人使用四種代表性活病毒株,其中每一CHIKV基因型至少一個代表,包括三種基因型各自的一種原型病毒以及來自當前加勒比海爆發之一個病毒株。中和活性係在病灶減少中和測試中測定。在37℃下,將純化之人類mAb之連續稀釋液與100個病灶形成單位之CHIKV一起培育1小時。在96孔盤中,將MAb-病毒複合體添加至Vero細胞中,且接著在細胞固定之後,使用免疫過氧化酶偵測來偵測蝕斑,並使用ImmunoSpot 5.0.37微觀分析儀(Cellular Technologies Ltd)進行定量。與在不存在抗體情況下接種CHIKV之孔比較之後,使用非線性回歸分析計算EC
50值。
E2 ELISA .在大腸桿菌中產生重組CHIKV E2胞外域蛋白質(對應於CHIKV-LR2006病毒株)且使其吸附至微量滴定盤上。施加人類mAb,接著用生物素綴合之山羊抗人類IgG偵測經結合CHKV特異性mAb。
競爭結合分析法 .本發明人藉由在Octet Red生物感測器(ForteBio)中抗體對競爭結合至含有附接至抗Penta-His生物感測器尖端(ForteBio #18-5077)之聚組胺酸標籤的CHIKV-LR2006 E2胞外域蛋白質而鑑別出結合至同一主要抗原位點之抗體組。
用於抗原決定基定位之丙胺酸掃描突變誘發 .對帶有C末端V5標籤之CHIKV包膜蛋白表現構建體(病毒株S27,Uniprot Reference #Q8JUX5)進行丙胺酸掃描突變誘發以產生全面突變文庫。引子經設計成在包膜蛋白之E2、6K及E1區域內的每一殘基(結構性聚合蛋白質中之殘基Y326至H1248)均突變成丙胺酸;丙胺酸密碼子突變成絲胺酸。總計產生910種CHIKV包膜蛋白突變體。使用免疫螢光結合分析法,使用以高通量流式細胞儀偵測之細胞螢光來測試mAb與每一構建體之結合的損失。
中和機制 .在附著至Vero 81細胞之前或之後,使MAb與VRP相互作用,且接著如關於VRP中和分析法所描述,對細胞進行染色、成像及分析以測定mAb在哪一階段發揮抗病毒作用。如補充實驗程序中所詳述,進行內源性融合及外源性融合分析法。
小鼠中之活體內保護研究 .在無病原體動物設施中飼養Ifnar
-/-小鼠且在A-BSL3設施中進行感染實驗。在麻醉下進行腳掌注射。對於預防研究,在腳掌中皮下接種10 FFU之CHIKV-LR之前1天,藉由向6週齡Ifnar
-/-小鼠腹膜內注射來投與人類mAb。對於治療研究,在投與單次劑量的指定劑量個別人類mAb或人類mAb組合之前24、48或60小時,遞送10 FFU之CHIKV-LR。
人類個體及周圍血液細胞分離 .提供在2006年10月感染CHIKV且在其他方面健康之成年個體。CHIKV感染之症狀與自斯里蘭卡訪問一年返回一致,在訪問期間,患者處於城市區域(主要在科倫坡(Colombo))及鄉村環境,包括雨林及海岸區域。患者在訪問過程中經歷多次昆蟲叮咬,但在整個停留過程中保持良好健康情況。在返回美國時,個體因發熱(102℉)持續三天而出現在主治醫師前。患者報告同時發生肘部及手指之兩側關節疼痛,以及背部及腹部上出現凸起的不癢皮疹,伴隨廣泛性「身體痛」及頭痛。在陳述時,其看起來良好且無急性病痛。輕度、泛白的丘疹在整個背部、胸部及腹部蔓延(參見圖4)。注意到輕度結膜炎。骨骼檢查發現明顯手指、膝部及肘部腫脹觸痛,沒有出現紅斑或積液。肌肉強度及受影響關節之活動範圍完整,但關節移動引起疼痛。
抽取血液進行CBC、血清學測試及瘧疾抹片,且允許患者離開。白細胞計數為4.0×10
4個細胞/mm
3,血容比為41%且血小板計數為180,000個/mm
3。總淋巴球計數為1.0×10
4個細胞/mm
3。瘧疾抹片及血清學測試呈陰性,且將患者嘗試性診斷為患有病因未知之病毒疾病。
患者兩週後返回診所,無發熱但存在持久關節痛,主要集中在手指。患者描述較之其前一次問診期間疼痛及僵硬無好轉且可能惡化。患者報告,屈公病毒爆發係在先前旅行之區域中發生。抽取血液且分離出血清,並送至CDC進行PCR及血清學測試,由此確定屈公病毒感染之診斷。
2012年4月,在指示感染五年半之後,在美國生活時,在中間時間段不知道暴露於CHIKV或其他致關節炎α病毒的情況下,藉由在Ficoll上密度梯度分離來分離周邊血液單核細胞(PBMC)。冷凍保存細胞且儲存於液氮中直至研究。有關自個體募集及收集血液樣品之方案得到位於教堂山(Chapel Hill)之北卡羅萊納大學(University of North Carolina)及範德比爾特大學醫學中心(Vanderbilt University Medical Center)審查委員會批准。
人類融合瘤之產生 .在37℃下迅速解凍冷凍保存之PBMC樣品並洗滌,隨後用埃-巴二氏病毒轉型,如(Smith等人, 2012)所描述。培養物在37℃及5% CO
2下培育10天且使用VRP中和分析法及ELISA針對上清液中細胞分泌之CHIKV特異性抗體之存在進行篩選。本發明人使用同一血液樣品之獨立等分試樣進行了兩次獨立轉型。
在第一次轉型中,本發明人產生每份培養物含有平均42個經轉型B細胞集落的3,840份培養物(10×384孔盤),估計總共有約161,000個別B細胞集落。為了篩選在BSL2條件下針對CHIKV展示中和活性之抗體,本發明人開發出使用表現綠色螢光蛋白作為報告子之CHIKV複製子(VRP)進行的高通量螢光減少中和分析法。VRP為呈現天然病毒糖蛋白但缺乏全長病毒基因組,且因此不能產生感染性後代之病毒粒子(Vander Veen等人, 2012)。本發明人使用由2006年自斯里蘭卡分離之病毒株SL15649得到的VRP(Morrison等人, 2011)。SL15649係與感染供體之病毒株同時期產生且很可能具有極其類似之序列。由此實驗,本發明人經上清液鑑別出以90%抑制作用來介導中和的160個B細胞培養物,表明總B細胞中病毒特異性B細胞之頻率為0.099%(約1/1,000)。此等細胞株中總計有60個抑制程度>98%,且在第二次篩選中,該60個細胞株中有58個細胞株之上清液含有在ELISA中結合至細胞培養物產生之CHIKV(病毒株181/25)的抗體被捕捉在免疫測定盤上。本發明人選出該58個細胞株中具有最高中和及結合活性的35個細胞株進行融合瘤融合,在融合及接種之後以病毒結合上清液鑑別出22個融合瘤,並成功地分離出14個純系用於進一步研究。在第二次轉型中,本發明人產生每份培養物含有平均38個經轉型B細胞集落的1,536份培養物(4×384孔盤),估計總共有約58,000個供測試的個別B細胞集落,表明病毒特異性B細胞頻率為0.1%(亦為約1/1,000)。在此實驗中,其使用針對結合至CHIKV病毒株181/25之ELISA之初級篩選,而不是先前的中和測試。本發明人鑑別出ELISA光學密度信號為背景值四倍的60個細胞株,選出在ELISA中具有最高光學密度信號之30個B細胞株進行融合,在融合及接種之後經病毒結合上清液鑑別出18個融合瘤,並成功地分離出16個純系用於進一步研究。
與骨髓瘤細胞融合. 如所描述(Smith等人, 2012),將來自具有能夠中和CHIKV感染性之上清液之孔的細胞與HMMA2.5非分泌性骨髓瘤細胞融合。藉由在含有烏本苷之次黃嘌呤-胺基喋呤-胸苷(HAT)培養基中生長來選擇所得融合瘤,使用FACSAria III細胞分選儀(BD Biosciences),藉由單細胞FACS以生物方式進行選殖,並擴增。
人類 mAb 之 產生及純化 .藉由三輪限制性稀釋,或根據製造商之說明書,用ClonePix裝置(Molecular Devices)選殖含有融合瘤產生CHIKV特異性抗體之孔。一旦獲得個別純系,即擴增每一融合瘤直至在75 cm
2燒瓶中達到50%匯合。對於抗體表現,用細胞刮刀收集細胞,在無血清培養基(來自Invitrogen之GIBCO Hybridoma-SFM,12045084)中洗滌,並均等地分入四個含有250 mL無血清培養基之225 cm
2燒瓶(Corning, 431082)中。培育細胞21天,隨後藉由離心使培養基變澄清,並使其通過0.2 µm無菌過濾器。藉由蛋白質G層析法(GE Life Sciences,蛋白質G HP管柱)自澄清培養基純化抗體。
細胞 .將BHK-21細胞(ATCC CCL-10)維持在補充有10%胎牛血清(FBS)及10%磷酸胰醣(Sigma)之α最低必需培養基(αMEM;Gibco)中。Vero 81細胞(ATCC CCL-81)維持在補充有5% FBS之αMEM中。所有細胞之培養基均補充有0.29 mg/mL L-麩醯胺酸(Gibco)、100 U/mL青黴素(Gibco)、100 μg/mL鏈黴素(Gibco)及500 ng/mL兩性黴素B。細胞在37℃下維持在含5% CO
2之潮濕氛圍中。
CHIKV VRP 質體構建體之產生 .三質體CHIKV複製子輔助系統係使用基於PCR之選殖方法,由含有CHIKV病毒株SL15649(Genbank:GU189061.1)基因組序列之全長cDNA的質體得到。使用兩步法構建CHIKV複製子基因組,該方法涉及產生CHIKV全長結構盒經多選殖位點(MCS)取代之中間選殖載體。將增強之綠色螢光蛋白(eGFP)次選殖至此質體之多選殖位點中以產生pMH41(CHIKV SL15649 eGFP複製子)。兩質體輔助系統之構建包括多步驟選殖方法,該方法首先涉及經由移除大部分(6,891 nt) CHIKV非結構盒產生全長結構基因輔助質體。全長結構盒進一步再分入兩個構建體中:pMH38(CHIKV SL15649衣殼輔助質體),其依序包含衣殼基因序列及唯一AvrII限制位點;及pMH39(CHIKV SL15649糖蛋白輔助質體),其含有衣殼RNA結合結構域之框內缺失,繼之以完整包膜糖蛋白(E3-E1)編碼序列。
重組 CHIKV p62 - E1 之 產生 .使用293fectin試劑(Invitrogen)將含有CHIKV p62(亦即,E3[aa S1-R64]-E2[aa S1-E361]-16個胺基酸之連接子-E1[aa Y1-Q411],繼之以His標籤)之質體(Voss等人, 2010)轉染至293F細胞中。培育72小時之後,移出上清液,且再培養細胞72小時。將合併之上清液裝載至鎳瓊脂糖珠粒管柱(GoldBio)上且用咪唑溶離。使用Superdex S200凝膠過濾管柱(GE Life Sciences)進一步純化蛋白質。彙集含有CHIKV p62-E1蛋白質之溶離份,冷凍且在-80℃下儲存。
CHIKV 病毒株 SL15649 源性 VRP 儲備液之產生 .VRP儲備液係根據範德比爾特大學環境、衛生及安全系以及範德比爾特生物安全評審委員會批准之方案,在經認證的3級生物安全(BSL3)設施中在生物安全櫥櫃中由重組CHIKV質體回收。藉由用NotI-HF消化使三種SL15649複製子系統質體線性化,藉由苯酚-氯仿萃取進行純化,並在使用mMessage mMachine SP6轉錄套組(Life Technologies)之轉錄反應中使用其作為模板,以在活體外產生加帽之全長RNA轉錄物。使用GenePulser電穿孔器,藉由電穿孔將病毒RNA轉錄物引入BHK21細胞中。在電穿孔之後24小時,收集含有VRP之培養物上清液;藉由以855×g離心20分鐘使上清液變澄清,等分且在-80℃下儲存。藉由使用Vero81細胞,以20%之VRP儲備液及10%之第1代培養物上清液進行連續傳代,由此評價該等儲備液中能繁殖之重組病毒,在其感染之後72小時檢查細胞病變效應(CPE)。當在最後一代中未偵測到CPE時,認為儲備液通過此安全性測試。接著將儲備液自BSL3實驗室移出。
VRP 中和及 GFP 報告子分析法 .將Vero 81細胞(2.25×10
3個細胞/孔)接種於384孔盤之孔中且在37℃下培育24小時。在37℃下,將純融合瘤上清液或純化之mAb之連續稀釋液與在病毒稀釋緩衝液(VDB;含有20 mM HEPES且補充有1%FBS之RPMI培養基)中MOI為約5個感染單位/細胞之VRP一起培育1小時且接著將其吸附至細胞。在37℃下培育細胞18小時,用Hoechst染色劑染色以標記核,且在Vanderbilt高通量篩選設施處,使用ImageXpress Micro XL成像系統(Molecular Devices)成像。使用MetaXpress軟體(Molecular Devices)以每孔兩個視域定量細胞總數及感染CHIKV之細胞(藉由GFP表現標記)。對於每一抗體,使用非線性回歸測定在95%信賴區間下之EC
50值以使用R統計程式(R.C. Team, 2014)擬合單獨的對數生長曲線。
製備病毒儲備液作為抗原用於 ELISA .用NotI-HF使CHIKV疫苗株181/25之感染性純系質體(Levitt等人, 1986及Mainou等人, 2013)線性化且在活體外使用mMessage mMachine SP6轉錄套組(Life Technologies)進行轉錄。藉由電穿孔將病毒RNA引入BHK21細胞中。24小時後收集培養物上清液,藉由以855×g離心20分鐘使其變澄清,等分且在-80℃下儲存。
病毒捕捉 ELISA 用於融合瘤篩選 .藉由用在0.1 M Na
2CO
3及0.1 M NaHCO
3pH 9.3結合緩衝液中製備的1 µg/mL純化之小鼠mAb CHK-187(Pal等人, 2013)塗佈分析盤來使抗體結合至病毒粒子,使用其塗佈ELISA盤(Nunc 242757)且在4℃下培育隔夜。將盤與阻斷緩衝液(1%乳粉及2%山羊血清於含Tween 20之PBS[PBS-T]中)一起培育1小時之後,用PBS-T洗滌盤五次,且與25 µL來自感染CHIKV疫苗株181/25之BHK21細胞單層的培養物上清液一起培育。在室溫下培育1小時之後,用PBS洗滌盤10次,且將10 µL B細胞培養物上清液添加至每孔25 µL阻斷緩衝液中。在室溫下培育盤1小時,隨後用PBS-T洗滌五次。將綴合至鹼性磷酸酶之二級抗體(山羊抗人類Fc;Meridian Life Science, W99008A)以1:5,000稀釋度施加於每孔25 µL阻斷緩衝液中,且在室溫下培育盤1小時。在用PBS-T洗滌五次之後,以每孔25 µL添加磷酸酶受質溶液(含1 mg/mL磷酸酶受質之1 M Tris胺基甲烷[Sigma, S0942]),且在室溫下培育盤2小時,隨後在405 nm下使用Biotek盤讀取器測定光學密度。
CHIKV 特異性對照人類 mAb .在一些分析法中,使用兩種先前已描述之人類CHIKV特異性mAb,即5F10及8B10(Warter等人, 2011)作為陽性對照物。在293F細胞(Invitrogen)中,在用含有5F10及8B10抗體可變基因區之序列優化之cDNA(基於由Cheng-I Wang及Alessandra Nardin提供之序列(Singapore Immunology Network, A*STAR, Singapore))的IgG1表現質體(Lonza)轉染之後,表現此等mAb。
針對結合至 E2 蛋白質之 mAb 的 ELISA .如所描述(Pal等人, 2013),在大腸桿菌中產生重組CHIKV E2胞外域蛋白質(對應於CHIKV-LR2006病毒株)且將其吸附至微量滴定盤(100 µL,2 µg/mL E2蛋白質溶液於0.1 M Na
2CO
3、0.1 M NaHCO
3及0.1% NaN
3[pH 9.3]中)上,在4℃下保持隔夜。用含有0.05% Tween-20之PBS沖洗盤三次,且在37℃與阻斷緩衝液(PBS、0.05% Tween-20及2%[w/v]BSA)一起培育1小時。在室溫下,將初級人類mAb(在阻斷緩衝液中稀釋至10 µg/mL)添加至孔中,保持1小時。用含有0.05% Tween-20之PBS沖洗盤三次,且依序添加二級抗體(在阻斷緩衝液中以1/20,000稀釋的對小鼠血清蛋白質具有極低交叉反應性之生物素綴合之山羊抗人類IgG(H及L鏈)(Jackson ImmunoResearch Laboratories))及抗生蛋白鏈菌素綴合之辣根過氧化酶(在含0.05% Tween-20之PBS中稀釋;Vector Laboratories),各自在室溫下保持1小時,且在各步驟間進行盤沖洗。用PBS沖洗四次之後,在室溫下將盤與100 µL TMB(3,3',5,5'-四甲基聯苯胺)發色受質溶液(Dako)一起培育5分鐘,且藉由添加2 N H
2SO
4停止反應。使用ELISA盤讀取器,以450 nm下之光學密度確定產物強度。
藉由表面電漿子共振量測親和力 .如所描述(Austin等人, 2012),使用Biacore T100儀器對純化之人類mAb與CHIKV蛋白質之相互作用進行動力學分析。對於完整IgG與可溶性CHIKV p62-E1之相互作用,將抗人類IgG抗體(GE Life Sciences)固定至S系列CM5晶片上且用於捕捉抗CHIKV抗體或對照抗體(hu-WNV E16)。以65 μL/min將CHIKV p62-E1注射至表面上,保持180秒,且使其解離1000秒,隨後在每次循環之間用3 M MgCl
2再生。一些抗體不結合至單體E1蛋白質,因此本發明人測試其與VLP之結合。對於用CHIKV VLP進行之動力學量測,固定抗小鼠IgG抗體(GE Life Sciences)以捕捉具有亞奈莫耳濃度親和力之一組小鼠抗CHIKV抗體,又使用該等抗體捕捉CHIKV VLP。以65 μL/min將抗CHIKV IgG或Fab注射至晶片表面上,保持180秒,且使其解離1000秒,隨後在每次循環之間用10 mM甘胺酸(pH 1.7)再生。所有資料均使用Biacore評價軟體(1.1.1版)及全局1:1朗格繆爾(Langmuir)曲線擬合進行處理。結果係由至少三次獨立實驗獲得。
用於病灶減少中和測試中之病毒株.
為了測定mAb寬度及中和效力,本發明人使用四種代表性病毒株,其中每一CHIKV基因型至少一個代表,包括三種基因型各自的一種原型病毒以及來自當前加勒比海爆發之一個病毒株。病毒株LR2006_OPY1(LR)(CHIKV東/中/南非[ECSA]基因型)係由Stephen Higgs(Manhattan, KS)提供。病毒株NI 64 IbH 35(西非基因型)以及病毒株RSU1及99659(亞洲基因型;在2014年自英屬維爾京島(British Virgin Islands)的個體分離(Lanciotti及Valadere, 2014))係由Robert Tesh(World Reference Center for Emerging Viruses and Arboviruses, Galveston, TX)提供。
用感染性 CHIKV 進行之 病灶減少中和測試 ( FRNT ).在37℃下,將純化之人類mAb之連續稀釋液與100個病灶形成單位(FFU)之CHIKV一起培育1小時。在96孔盤中,將MAb-病毒複合體添加至Vero細胞中。培育90分鐘之後,用含1%(w/v)甲基纖維素且補充有2% FBS之改良型伊格爾培養基(Modified Eagle Media,MEM)覆蓋細胞。細胞培育18小時且用含1%多聚甲醛之PBS固定。細胞在補充有0.1%皂素及0.1%牛血清白蛋白(BSA)之PBS中依序用500 ng/mL鼠類CHK-11(Pal等人, 2013)及辣根過氧化酶(HRP)綴合之山羊抗小鼠IgG培育。使用TrueBlue過氧化酶受質(KPL)觀測感染CHIKV之病灶且使用ImmunoSpot 5.0.37微觀分析儀(Cellular Technologies Ltd)定量。與在不存在抗體情況下接種CHIKV之孔比較之後,使用非線性回歸分析計算EC
50值。
生物膜干涉測量術競爭結合分析法.
將含有聚組胺酸標籤之CHIKV-LR2006 E2胞外域蛋白質(20 μg/mL)固定至抗Penta-His生物感測器尖端(ForteBio #18-5077)上,保持2分鐘。測定動力學緩衝液(kinetics buffer,KB;1×PBS、0.01% BSA及0.002% Tween 20)中之基線信號1分鐘之後,將生物感測器尖端浸入含有濃度為100 μg/mL之初級抗體的孔中,保持5分鐘,且接著浸入含有濃度為100 μg/mL之競爭性mAb之孔中,保持5分鐘。藉由將在初始mAb複合體之後施加之競爭性mAb的最大信號與單獨競爭性mAb之最大信號相比較來測定在第一mAb存在下競爭性mAb之結合百分比。若競爭性mAb之最大結合降低至<30%之單獨結合親和力,則判斷抗體競爭結合至同一位點。若競爭性mAb之最大結合為非競爭結合之>70%,則認為抗體係非競爭性的。30%至70%程度之非競爭性結合被視為中間競爭。
突變誘發抗原決定基定位 .對帶有C末端V5標籤之CHIKV包膜蛋白表現構建體(病毒株S27,Uniprot Reference #Q8JUX5)進行丙胺酸掃描突變誘發以產生全面突變文庫。引子經設計成包膜蛋白之E2、6K及E1區域內的每一殘基(結構聚合蛋白質中之殘基Y326至H1248)均突變成丙胺酸;丙胺酸密碼子突變成絲胺酸(Fong等人, 2014)。總體而言,產生910個CHIKV包膜蛋白突變體(98.5%覆蓋度),確定序列且排列在384孔盤中。在384孔盤中,用CHIKV突變文庫轉染HEK-293T細胞且培育22小時。將細胞固定於含4%多聚甲醛(Electron Microscopy Sciences)之PBS加鈣及鎂(PBS+/+)中且用在10%正常山羊血清NGS;Sigma)中稀釋的0.25至1.0 µg/mL純化之mAb或2.5 µg/mL純化之Fab片段染色。使用獨立免疫螢光滴定曲線,測定針對野生型CHIKV包膜蛋白之初級抗體濃度以確保信號在偵測之直線範圍內。使用含3.75 µg/mL AlexaFluor488綴合之二級抗體(Jackson ImmunoResearch Laboratories)之10% NGS偵測抗體。用不含鎂及鈣之PBS(PBS-/-)洗滌細胞兩次且將其再懸浮於含0.1% BSA(Sigma)之Cellstripper(Cellgro)中。使用高通量流式細胞儀(HTFC,Intellicyt)偵測平均細胞螢光度。藉由用模擬轉染之對照物減去該信號且針對來自野生型轉染之對照物的信號進行標準化,相對於野生型蛋白質反應性計算抗體針對每一突變純系之反應性。若相應丙胺酸突變不與測試mAb反應,但與其他CHIKV抗體反應,則將胺基酸鑑別為mAb結合所需的。此逆向篩選(counter-screen)策略有助於排除摺疊異常或具有表現缺陷之突變體(Christian等人, 2013;Paes等人, 2009;及Selvarajah等人, 2013)。使用PyMol軟體在CHIKV包膜蛋白晶體結構(單體PDB ID #3N41及三聚體PDB ID #2XFB)上觀測抗體結合所需之胺基酸。
附著前後之中和分析.
將Vero 81細胞(ATCC CCL-81;約7.5×10
3個細胞/孔)接種於96孔盤之孔中且在37℃下培育約24小時。對於附著前分析法,在4℃下,在病毒稀釋緩衝液(VDB)中製備mAb之稀釋液且在4℃下與VRP一起預培育1小時。在4℃下,將抗體-病毒複合體添加至預先冷卻的Vero 81細胞中,保持1小時。藉由用VDB洗滌三次移除未吸附之病毒,且在37℃下,在完全培養基中培育細胞18小時。附著後分析法係以類似方式進行,不過相同MOI之VRP首先在4℃下吸附至Vero 81細胞上,保持1小時,藉由用病毒稀釋緩衝液洗滌三次移除未結合之VRP,且細胞與含有mAb連續稀釋液之預先冷卻的VDB一起在4℃下培育1小時。藉由用VDB洗滌三次移除未結合之mAb,且在37℃下,在完全培養基中培育細胞18小時。如關於VRP中和分析法所述對細胞進行染色、成像及分析,其中每孔四個視域,得到總計約800至1,000個細胞用於分析每一樣品之GFP表現。
融合抑制分析法 .使用FFWO分析法評估病毒與質膜之融合(Edwards及Brown, 1986)。將Vero 81細胞(約3.75×10
3個細胞/孔)接種於96孔盤之孔中且在37℃下培育約24小時。用結合培養基(補充有1% FBS,25 mM HEPES[pH 7.4]及20 mM NH
4Cl之RPMI 1640,用以防止經由內體融合感染)洗滌細胞一次且在4℃下,在結合培養基中培育15分鐘。在結合培養基中稀釋含有VRP之接種物且在4℃下與細胞一起培育1小時。藉由用結合培養基洗滌兩次來移除未結合之VRP。在4℃下,將mAb於VDB中之連續稀釋液與細胞一起培育1小時,且藉由用VDB洗滌兩次來移除未結合之mAb。在37℃下,藉由添加預溫熱之融合培養基(RPMI 1640、1% FBS、25 mM HEPES及30 mM丁二酸,pH 5.5),保持2分鐘,以誘導FFWO。在平行孔中,在37℃下添加對照培養基(RPMI 1640、1% FBS、25 mM HEPES,pH 7.4),保持兩分鐘。移除培養基且在補充有5% FBS、20 mM NH
4Cl(用以確保僅經由pH依賴性質膜融合發生感染)及25 mM HEPES[pH 7.4]之DMEM中培育細胞。在感染後18小時,如所述對細胞進行染色、成像及分析,其中每孔四個視域,得到總計約800至1,000個細胞用於分析每一樣品之GFP表現。
小鼠中之活體內保護研究 .本研究係嚴格遵照美國國家衛生研究院實驗室動物護理及使用指南(Guide for the Care and Use of Laboratory Animals)中之建議進行。方案得到華盛頓大學醫學院實驗動物管理及使用委員會(Institutional Animal Care and Use Committee)批准(保證號:A3381-01)。在華盛頓大學醫學院的無病原體動物設施中飼養Ifnar
-/-小鼠且感染實驗係在A-BSL3設施中在華盛頓大學動物研究委員會批准下進行。在用鹽酸氯胺酮及甲苯噻嗪(xylazine)誘導及維持麻醉下進行腳掌注射。對於預防研究,在腳掌中皮下接種在含1%熱滅活FBS之HBSS中稀釋的10 FFU之CHIKV-LR前1天,藉由腹膜內注射向6週齡Ifnar
-/-小鼠投與人類mAb。對於治療研究,在投與單次劑量的指定劑量個別人類mAb或人類mAb組合之前24、48或60小時,遞送10 FFU之CHIKV-LR。
實例 2 - 結果 CHIKV 特異性人類 mAb 之分離. 本發明人自2006年於斯里蘭卡獲得CHIKV感染且呈現發熱、關節痛及皮疹之單一個體(圖4)分離出一組mAb。臨床病程以及B細胞轉型及篩選程序提供於線上方法中。其在兩個獨立實驗中對自天然感染五年半之後之供體收集之單一血液樣品獲得的B細胞進行轉型。其觀察到總計1,000個總B細胞中約1個之病毒特異性B細胞頻率且由分泌結合至病毒之抗體的B細胞株產生30個穩定融合瘤。該mAb組含有多個亞類之IgG,其中24種IgG1、三種IgG2及兩種IgG3;一種由於融合瘤生長較差而不確定(表5)。
mAb 中和作用之評估 .十八種mAb針對亞洲CHIKV病毒株SL15649-GFP病毒報告子粒子(VRP)展現中和活性且EC
50值<40 ng/mL,其中有十一種展現超強效抑制活性(定義為EC
50值<10 ng/mL,表5)。四種mAb具有較弱抑制活性(EC
50值在0.1至5 µg/mL範圍內),且八種mAb在最高測試濃度下不具有抑制活性(EC
50值>10 µg/mL)。
中和活性之寬度. 本發明人使用高通量病灶減少中和測試(FRNT)測定針對東/中/南非(ECSA)基因型(LR2006 OPY1[LR]病毒株)、西非基因型(NI 64 IbH 35病毒株)及亞洲基因型(RSU1及99659[2014年加勒比海]病毒株)之代表性感染性CHIKV病毒株的每一抗體之EC
50值(Pal等人, 2013)。二十五種mAb針對至少一種CHIKV病毒株展現中和活性(EC
50值<10 µg/mL),其中八種mAb展現在強效範圍內之中和作用(EC
50值在10至99 ng/mL之間)且十三種mAb展現在超強效範圍內之中和作用(EC
50值<10 ng/mL)(表5)。出於比較目的,本發明人亦測試先前報告的針對全部三種基因型之人類mAb 5F10及8B10,且在每一情形中,EC
50值均>100 ng/mL(範圍161-1337)。在大多數情況下,本發明人分離之mAb針對來自全部三個基因型之病毒展現相對類似之中和活性。六種mAb(2B4、2H1、4J21、4N12、5M16及9D14)以超強效活性抑制來自全部三個基因型之病毒(EC
50值<10 ng/mL)。此等資料指示,單一個體可產生超強效且具有廣泛中和作用之多種CHIKV特異性抗體。
結合至 E2 蛋白質. CHIKV E2蛋白質為鼠類(Goh等人, 2013;Lum等人, 2013)、非人類靈長類動物(Kam等人, 2014)及人類(Fong等人, 2014;Kam等人, 2012a;Kam等人, 2012b;Selvarajah等人, 2013)體液反應之主要目標。本發明人測試人類mAb與大腸桿菌中表現之E2蛋白質胞外域之單體形式的結合(Pal等人, 2013)。九種mAb較強地結合至E2胞外域,六種展現中度結合,一種結合較弱,且有14種無法結合超過背景(表5)。在活體外結合純化之E2蛋白質的能力與中和效力沒有直接相關性(表5)。使用表面電漿子共振分析法測試一小組17種人類mAb與來源於哺乳動物細胞之p62-E1蛋白質的結合(Voss等人, 2010)。所有mAb結合均在nM範圍內,且K
D值為0.5至20 nM。結合動力學之差異與抗原特異性或功能活性不相關(表S1)。
競爭結合研究. 為了鑑別重組E2蛋白質中由不同中和性mAb識別之不重疊抗原區域,本發明人使用定量競爭結合分析法。為比較,其亦評價四種先前所描述之鼠類mAb(CHK-84、CHK-88、CHK-141及CHK-265)(Pal等人, 2013)及先前所描述之人類mAb 5F10(Warter等人, 2011)(圖5)。競爭模式為複合體,而且三個主要競爭組係顯而易見的,本發明人將其指定為組1(紅色方框)、組2(藍色方框)或組3(綠色方框)。本發明人亦確定含有單一人類mAb 5F19之第四組(橙色方框)。此等競爭研究表明,存在由特異性抗體識別之三個主要抗原區域。
使用丙胺酸掃描突變誘發進行抗原決定基定位. 本發明人使用丙胺酸掃描突變誘發文庫結合基於細胞之表現及流式細胞術來鑑別CHIKV病毒株S27(ECSA基因型)之E2及E1蛋白質中抗體結合所需之胺基酸(Fong等人, 2014)(圖6A-D)。一小組20種人類mAb中抗體結合至CHIKV糖蛋白所需之殘基列於表6中。影響此20種mAb之結合的突變以病毒株S27與表示此研究中使用之所有CHIKV基因型之病毒株之全長E2序列比對指示(圖1A)。E2中影響結合之胺基酸主要位於結構域A與B之溶劑暴露區域,以及連接結構域A與B之β-帶狀連接體之弓形結構1及2中(Voss等人, 2010)(圖1A)。比較藉由結合損失實驗,使用丙胺酸掃描突變誘發及競爭結合分析所鑑別之抗原位點(圖5)證實,競爭組1及2大體上對應於在結構域A及弓形結構內之位點,而組3對應於結構域B中之區域。
抗原區域之結構分析. 結構域A與B及弓形結構中大量不同的表面殘基接觸至少一種mAb(圖1B-C)。E2中之兩個主要抗原區域負責多種mAb之結合。第一區位於結構域A中胺基酸58與80之間,且含有推定的受體結合結構域(RBD)(Sun等人, 2014;Voss等人, 2010)。第二區位於結構域B中胺基酸190與215之間。兩個序列區域均從病毒包膜突出且位於E2三聚體頂點附近(圖6A-D及7)。
中和機制 .本發明人使用展示一定抑制活性範圍之mAb進行附著前後中和分析法。正如預期的,全部五種測試mAb當與VRP一起預培育時均高效地中和感染(圖2A)。不過,mAb 4B8即使在高濃度下亦未完全中和VRP,表示有一部分CHIKV病毒粒子對此mAb具有抗性;在使用對應於三種不同CHIKV基因型之存活CHIKV病毒株進行的分析法中亦觀察到此模式(資料未示出)。相比之下,mAb 3E23、4J21、5M16及9D14當在附著之前投與時,會完全中和感染。全部五種人類mAb當在附著之後添加時亦中和CHIKV感染,但本發明人觀察到三種不同的活性模式(圖2A)。MAb 4B8當在附著後添加時不能完全中和且抗性病毒粒子之分率大於在附著前中和之後所觀察之分率。無論在附著之前抑或之後添加,MAb 9D14均以類似效率中和VRP。MAb 3E23、4J21及5M16展示VRP之完全中和,但附著後之中和效率低於附著前添加之中和效率。當在附著之前或之後添加時,mAb 2H1及4N12亦高效中和VRP(圖8)。
測試五種超高效中和性mAb(3E23、4B8、4J21、5M16或9D14)之外源性融合(Fusion-from-without,FFWO)分析法揭露全部抑制融合(Edwards及Brown, 1986)。正如預期的,當經mAb預處理之病毒粒子用在中性pH下緩衝之培養基連續培育時,觀察到極少甚至無感染(圖2B)。在不存在抗體處理之情況下,短脈衝之酸性pH緩衝之培養基產生受感染細胞,指示病毒包膜與質膜之間融合。值得注意的是,全部五種人類mAb均抑制質膜融合及感染,其中mAb 9D14在此分析法中展現最大效力。此等研究表明,超高效之中和性mAb阻止CHIKV融合。
MAb 在活體內 之 預防作用.本發明人在利用6週齡高度免疫缺乏之Ifnar
-/-小鼠之致死感染模型中測試展現不同中和活性水準之一小組mAb(表7)。在皮下注射致死劑量之CHIKV-LR2006之前24小時,用單次50 µg劑量(約3 mg/kg)之人類抗CHIKV mAb或西尼羅河病毒(West Nile virus)特異性同型對照mAb(WNV hE16)預處理小鼠。用同型對照mAb處理之所有小鼠在接種後4天死於感染。用mAb 4B8、4J21或5M16預處理完全保護Ifnar
-/-小鼠,而用mAb 3E23或9D14處理則部分保護感染之動物,且存活率為67%(圖3A)。意外的是,在活體外具有較弱中和作用之mAb 2D12保護83%之動物。
在活體內 MAb 暴露後療法 .用致死劑量之CHIKV-LR2006接種Ifnar
-/-小鼠且接著在病毒接種之後24小時,投與單次50 µg(約3 mg/kg)劑量之代表性mAb。此等mAb之治療性投與提供完全之保護作用,而同型對照mAb不提供保護作用(圖3B)。為了進一步確定功效之治療窗,在用CHIKV-LR2006攻擊之後48小時,向Ifnar
-/-小鼠投與單次250 µg(約14 mg/kg)劑量之代表性mAb。用5M16、4J21及4B8處理分別保護85%、50%及12.5%之動物(圖3C)。值得注意地,當以500 µg(約28 mg/kg)劑量使用時,用4N12之單藥療法在60小時之後續時間點保護100%之動物(圖3D)。此等資料確定,人類mAb可保護免受CHIKV誘導之死亡影響,即使在確定感染之後一定時間間隔時。
類似地,在WT小鼠中進行研究以評估人類mAb對CHIKV急性及慢性關節炎之影響。在感染之後第1天或第3天投與MAb且在感染之後D3、D5或D28分析病毒負荷或RNA。取決於檢查之組織及時間,1H12或4J14提供最顯著之病毒保護作用。4N12在此等分析法中亦提供顯著保護作用。
在活體內之組合 mAb 療法.鑒於在用單一抗CHIKV mAb處理之動物中進行活體內抗性選擇之可能性(Pal等人, 2013),本發明人測試兩種抗CHIKV人類mAb之組合是否能保護小鼠免受致死性攻擊。其基於個別mAb在活體外之效力來選擇中和性mAb對。在接種之後60小時,向Ifnar
-/-小鼠投與單次組合抗體治療劑量(各250 µg,總計約28 mg/kg)的最有效mAb。儘管一些mAb組合([4J21+2H1]及[4J21+5M16])提供極少或不提供保護作用,但其餘組合([4J21+4N12])在此極遲時間點引起63%存活率(圖3D)。因此,組合mAb療法即使在此等動物感染之24至36小時內投與時,亦保護高度免疫功能不全之小鼠免受致死性CHIKV感染。在此情形中,4N12與4J21之組合的作用不如其作為單藥療法,不過在單藥療法實驗中4N12之劑量(500 µg)為組合療法中4N12組分之劑量(250 µg)的兩倍。
表
S1.藉由SPR值量測的人類CHIKV抗體結合抗原之動力學,ka、kd、KD為平均值±標準差。KD = kd/ka;t
1/2= (ln(2)/kd)60。
實例 3 - 討論本發明人報導自單一個體分離一組不同的天然存在之人類mAb,其中大部分識別CHIKV E2蛋白質且在活體外展示顯著中和活性並在活體內展示治療功效。作為一種類別,大部分抑制性抗體亦展現較寬活性,中和來自全部三個CHIKV基因型之病毒,包括當前在加勒比海流行之病毒株。在此研究中分離的人類CHIKV特異性mAb中大部分在低於100 ng/mL之濃度下中和病毒,且有許多在低於10 ng/mL下展現抑制活性。此活性高於本發明人在先前有關針對其他致病性人類病毒,包括H1、H2、H3或H5流感病毒(Hong等人, 2013;Krause等人, 2012;Krause等人, 2011a;Krause等人, 2011b;Krause等人, 2010;Thornburg等人, 2013;Yu等人, 2008)、登革熱病毒(Messer等人, 2014;Smith等人, 2013a;Smith等人, 2014;Smith等人, 2013b;Smith等人, 2012)及其他病毒之人類mAb之研究中所觀察的活性。許多人類CHIKV mAb之效力類似於或超過在反覆增強免疫及親和力成熟之後產生的同類最佳鼠類中和性CHIKV mAb之效力(Fong等人, 2014;Fric等人, 2013;Pal等人, 2013;Warter等人, 2011)。針對CHIKV之大部分其他中和性人類mAb實質上不夠強效(Fong等人, 2014;Selvarajah等人, 2013;Warter等人, 2011)。單一先前報導之人類CHIKV特異性mAb(IM-CKV063)展示與此處報導之超強效中和性mAb類似之活性(Fong等人, 2014)。
本發明人藉由不同的中和性測試CHIKV mAb觀察到E2中抗原決定基識別模式之多樣性。利用丙胺酸取代之CHIKV糖蛋白進行的精細抗原決定基定位顯示,E2中三個結構區域之識別與mAb介導之中和作用有關:結構域A,其含有推定的RBD(Sun等人, 2013;Voss等人, 2010);結構域B,其接觸並遮蔽E1中之融合環(Voss等人, 2010);及β-帶狀連接體之弓形結構1及2,其含有酸敏感性區域且連接結構域A與B(Voss等人, 2010)。在定位至E2中之抗原決定基的抗體中,主體(競爭組1及2中之抗體)優先識別結構域A以及弓形結構1及2中之位點,而一小組(競爭組3中)識別結構域B中之位點。此等資料表明,結構域A中之表面暴露區域及該等弓形結構為引起人類中和抗體反應之主要抗原位點。本發明人得出結論,結構域A中之高度保守區域及弓形結構2可能引起廣泛保護性免疫反應且充當抗原決定基聚焦疫苗設計的引人注目之候選物。
值得注意地,關鍵E2結構域中幾乎四分之一的表面暴露殘基看起來與來自單一個體之一或多種mAb接合。主要抗原位點上功能不同之結合模式的存在係藉由兩個觀察結果表明:(a)一些mAb結合至類似抗原決定基,但展現的抑制活性存在若干數量級之變化;及(b)結合至E2蛋白質之中和能力與親和力之間存在極少相關性。七種最強效之中和性人類mAb(2H1、3E23、4B8、4J21、4N12、5M16及9D14)很可能經由防止pH依賴性結構變化,由此防止核衣殼穿透至細胞質中,而在附著之後的步驟中抑制CHIKV感染(Kielian等人, 2010)。
由於在小鼠中之治療功效看來在非人類靈長類動物之實驗誘發感染及關節炎中預測治療結果(Pal等人, 2013;Pal等人, 2014),故此處之資料表明,用CHIKV特異性人類mAb預防人類將防止感染。鑒於有關用單藥療法選擇抗性變體之問題(Pal等人, 2013),使用靶向E2不同區域之超強效中和性抗體的組合療法可能為所需的。可靶向在爆發期間患嚴重疾病風險明顯增加之患者群,包括具有嚴重潛伏性醫學病狀之患者(例如,懷孕晚期女性、免疫功能不全者及老年患者)。其他臨床測試計劃確定中和性人類mAb是否能預防或改善確定的人類關節疾病。
表 1 - 抗體可變區之核苷酸序列
表 2 - 抗體可變區之蛋白質序列
表 3 - 重鏈 CDR 序列
表 4 - 輕鏈 CDR 序列
表 5 - 屈公病毒特異性人類單株抗體之特徵
1抗體之次序反映在針對不同基因型之臨床CHIKV分離株的中和分析法中抗體之效力程度及寬度。
2免疫球蛋白同型、亞型及輕鏈使用係藉由ELISA確定。NT指示由於B細胞株之生長不良而未測試。
3(-)表示無可偵測之結合[OD <0.1];(+/-)表示較弱結合[OD 0.31-0.499];(++)表示中度結合[OD 0.5-0.99];(+++)表示較強結合[OD >1.0]。
4所示值表示由兩個或兩個以上獨立實驗得到的組合資料。
5中和50%病毒之濃度(ng/mL)(EC
50)。(>)指示EC
50值超過測試的最高mAb濃度(10 µg/ml)。N.D.=未進行。
表 6 - 屈公病毒特異性人類單株抗體之主要抗原位點
1抗體之次序反映在針對不同基因型之臨床CHIKV分離株的中和分析法中抗體之效力程度及寬度。
2所示值表示由兩個獨立實驗得到的組合資料。Low binding指示在用於評估競爭之生物感測器上mAb不完全結合至E2。NT指示由於Ab在ELISA中不結合E2胞外域而未測試;NSF Ab指示mAb供應不足。
3NotReact指示mAb不與野生型包膜蛋白反應且在此系統中無法測試。NoReduct指示mAb結合至野生型E蛋白質,但對於任何突變體未觀察到可再現地減少。DA指示結構域A;DB指示結構域B;Arch指示弓形結構1、弓形結構2或兩者。
4在先前的cryo-EM重建中藉由與mAb接觸而鑑別的殘基。
表 7 - 屈公病毒特異性人類單株抗體之活體外中和效力及寬度
1抗體之次序反映在針對不同基因型之臨床CHIKV分離株的中和分析法中抗體之效力程度及寬度。
2中和50%病毒之濃度(ng/mL)(EC
50)。(>)指示EC
50值超過測試的最高mAb濃度(10 µg/ml)。N.D.=未進行。
本文中所揭示及主張之所有組合物及/或方法均可根據本發明製備及執行,無需過多實驗。雖然已根據較佳實施例描述本發明之組合物及方法,但熟習此項技術者應清楚變化可在不背離本發明之概念、精神及範疇的情況下應用於本文所述之組合物及方法及方法之步驟或步驟順序中。更特定言之,顯而易知在化學上及生理上相關之某些藥劑可取代本文所描述之藥劑,同時獲得相同或類似結果。熟習此項技術者顯而易知的所有該等類似取代及修改視為在由隨附申請專利範圍所界定的本發明之精神、範疇及概念內。
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CHKV MAb | 配位體 | ka (10 6M-1 s-1) | kd (10 -4s-1) | KD (nM) | t 1/2(min) |
5M16 | p62-E1 | 1.09±0.02 | 1.13±0.02 | 1.03±0.01 | 102±2 |
5M16 Fab | VLP | 1.19±0.01 | 0.84±0.13 | 7.07±1.06 | 137±21 |
4J21 | p62-E1 | 1.19±0.02 | 0.62±0.04 | 0.54±0.31 | 186±11 |
4J21 Fab | VLP | 1.58±0.03 | 14.2±0.29 | 9.00±0.03 | 8±0.2 |
3E23 | p62-E1 | 3.18±2.43 | 2.67±0.87 | 6.11±1.41 | 43±19 |
3E23 Fab | VLP | 0.203±0.03 | 3.93±0 40 | 19.6±3.16 | 29±3 |
4B8 | p62-E1 | 2.98±2.98 | 5.06±1.10 | 5.57±1.10 | 23±5 |
4B8 Fab | VLP | 0.60±0.04 | 3.33±0.30 | 5.60±0.46 | 35±3 |
5N23 | p62-E1 | 2.98±0.75 | 2.40±0.66 | 0.87±0.37 | 48±17 |
1 L1 | p62-E1 | 0.88±0.44 | 2.73±0.36 | 3.79±2.10 | 42± 6 |
2C2 | P62-E1 | 1.54±0.65 | 6.08±1.45 | 4.59±2.32 | 19±6 |
2D 12 | p62-E1 | 17.5±1.64 | 5.41±4.97 | 0.49±0.08 | 13±4 |
4N12 | p62-E1 | 1.24±0.02 | 1.18±0.01 | 0.95±0.02 | 98±1 |
5O14 | p62-E1 | 0.79±0.02 | 9.11±0.19 | 1.15±0.01 | 13±0.3 |
9D14 | p62-E1 | 2.70±0.90 | 2.82±0.14 | 1.13±0.40 | 41±2 |
8G18 | P62-E1 | 3.90±0.21 | 1.88±0.11 | 0.48±0.02 | 62±3 |
4J14 | p62-E1 | 1.61±0.47 | 15.3±2.52 | 9.94±2.64 | 8±1 |
5F | p62-E1 | 2.61±0.04 | 50.9±0.75 | 19.5±0.2 | 2±0.03 |
3A2 | p62-E1 | 2.12±0.02 | 10.1±0.12 | 4.78±0.08 | 11±0.1 |
1M9 | p62-E1 | 1.86±0.99 | 3.98±0.26 | 2.48±0.99 | 29±2 |
3B4 | p62-E1 | 2.91±0.09 | 1.56±0.11 | 0.54±0.02 | 74±5 |
8B | p62-E1 | 0.99±0.03 | 2.74±0.10 | 2.77±0.18 | 42±2 |
8E22 | P62-E1 | 0.48±0.02 | 2.0±0.13 | 4.22±0.42 | 58±4 |
純系 | 可變區序列 | SEQ ID NO: |
1H12重鏈 | CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCCTCTGGTTACAGCTTTACCAGCTACGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCACTTACAAAGGTTACACACAGTATGCACAGAACTTCCAGGGCAGAGTCACCATCACCACAGACACACCCGCGACTACAGTCTATATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGCGCGAGAGTTCTTTCCGAGACTGGTTATTTCTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 2 |
1H12輕鏈 | CAGGCTGTGGTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGTACTGGGAGCAGCTCCAACATCGGGGCAGATTATAATGTACACTGGTACCAGCTGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGCTTCGGTATTCGGCGGAGGGACCAAACTGACCGTCCTAG | 3 |
2B4重鏈 | caggtgcagctggtgcaatctgggtctgagttgaagaagcctgggGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACAGTTTCACTAGCTATTCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGGATGGGATGGATCGACACCAACACTGGGAACCCAACCTATGCCCAGGACTTCGCAGGACGGTTTGTCTTCTCCTTGGACACCTCTGTCACCACGGCATATCTGCAGATCAGCAGCCTAAAGGCTGGGGACACTGCCGTTTATTACTGTGCAACATATTATGTTGACCTTTGGGGGAGTTATCGCCAAGACTACTACGGTATGGACGTCTGGGGCCAC | 4 |
2B4輕鏈 | cagtctgtgctgactcagccaccctcagcgtctgggacccccgggcagagggtcaccatCTCTTGTTCTGGAGGGAGCTCCAACATCGGGAGTAATCCTGTAAATTGGTACCAGATGGTCCCAGGAACGGCCCCCAAACTCCTCCTCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAATGGACTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGTATGGGATGACAGCCTGAGTGGCCGTTGGGTGTTCGGCGGAGGGACCAAGGTGACCGTCCTA | 5 |
2H1重鏈 | CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCGTCTGGTTACACCTTTACCAGTTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCACTTACAATGGTGACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCACCTTGACAACAGAGACATCCACGAGCACAGCCTACATGGAGCTGAGGCGCCTGAGATCTGACGACACGGCCGTTTACTACTGTGCGAGAGATTTTGAATTTCCCGGAGATTGTAGTGGTGGCAGCTGCTACTCCAGGTTCATCTACCAGCACAACGACATGGACGTCTGGGGCCACGGGACCCTGGTCACCGTCTCCTCAGCAAGC | 6 |
2H1輕鏈 | CAGGCTGTGGTGACTCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATCATTATGTATCCTGGTACCAGCACCTCCCGGGAACAGCCCCCAAACTCCTCATTTATGACAATTATAAGCGACCCTCAGTGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCGCGTCAGCCACCCTGGGCATCATCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCAGCCTGAGTGCTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA | 7 |
3E23重鏈 | CAGGTGCAGCTGGTGCAGTCGGGCCCAGGACTGGTGAAGCCTTCGGACACCCTGTCCCTCACCTGCAGTGTCTCAAGTGACGCCCTCCGCAGCAGGAGTTATTACTGGGGCTGGGTCCGCCAGCCCCCCGGGAAGGGATTGGAGTGGATTGGGACTGTCTCTTATAGTGGGGGCACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCGTGTCGGTGGACACGTCCAAGAACCACTTCTCCCTGAGGTTGAACTCTGTGACCGCCGCAGACGCGGCTGTTTATTACTGTGCGAGATCTTATTTCTATGATGGCAGTGGTTACTACTACCTGAGCTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 8 |
3E23輕鏈 | CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGCTTCCAGCACTGGAGCAGTCACCAGTGGTCACTATCCAAACTGGTTCCAGCAGAAACCTGGACAACCACCCAGGGCCCTGATTTATAGCACAGACAACAAGCACTCCTGGACCCCTGCCCGGTTCTCAGGCTCCCTCCTAGGGGTCAAGGCTGCCCTGACACTGTCAGATGTACAGCCTGAGGACGAGGCTGACTATTACTGCCTGCTCCATTTTGGTGGTGTCGTGGTCTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 9 |
3N23重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGTGTCTGGATTCACCTTCAGTAACTATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGACTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAGTGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGGGTGACTACGTTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 10 |
3N23輕鏈 | GACATTGTGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAGTTGCCGGGCCAGTCAGAGCATTCCCAGCTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTACATCCACTTTGGAAGCTGGGGTCCCATCACGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAATACGGGGATATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA | 11 |
4J14重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACTTCCAGCACTTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGCAGCATCCCTGTCTTTGCTACAGTAAACTACGCACAGAAGTTCCAGGGCAGACTCACGATTACCGCGGACGAATCCACGAGCACAGTTTACATGGAACTGAGCAGCCTGAGATCTGAGGACACGGCCGTTTATTTCTGTGCGAGCCCCTATTGTAGTAGTATGAACTGCTATACGACCTTTTACTACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 12 |
4J14輕鏈 | CAGGCTGTGGTGACTCAGCCTGCCTCCGTGTTTGGGTTTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACTTTGGTACTTATAACTATGTCTCTTGGTACCAGCAACACCCAGGCCAAGCCCCCAAACTCATGATTTTTGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTTCTTATTACTGCAGCTCCTATACAAGCGGCAGCACTCTCTACGGCGGAGGGACCAAGCTGACCGTCCTG | 13 |
4J21重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACAGTTTCACTAGCTATTCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCCTGAGTGGATGGGATGGATCGACACCAACACTGGGAACCCAACCTATGCCCAGGACTTCGCAGGACGGTTTGTCTTCTCCTTGGACACCTCTGTCACCACGGCATATCTGCAGATCAGCAGCCTAAAGGCTGGGGACACTGCCGTTTATTACTGTGCAACATATTATGTTGACCTTTGGGGGAGTTATCGCCAAGACTACTACGGTATGGACGTCTGGGGCCACGGGACCCTGGTCACCGTCTCCTCA | 14 |
4J21輕鏈 | CAGTCTGTGGTGACTCAGCCACCCTCAGTGTCTGGGACCCCCGGGCAGGGGGTCACCATCTCTTGTTCTGGAGGGAGCTCCAACATCGGGAGTAATCCTGTAAATTGGTACCAGATGGTCCCAGGAACGGCCCCCAAACTCCTCCTCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAATGGACTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGTATGGGATGACAGCCTGAGTGGCCGTTGGGTGTTCggcggagggaccaagctgaccgtccta | 15 |
4N12重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACATCCTCAGTAAATTATCCGTGCACTGGGTGCGACAGGCTCCTGGAAAAGGACTTGAATGGATGGGAGGTTCTGAACGTGAAGATGGCGAAACAGTCTACGCACAGAAGTTCCAGGGCAGAATCAGCTTGACCGAGGACACATCTATAGAGACAGCCTACATGGAGCTGAGCAGCCTGAGTTCTGAGGACACGGCCGTGTATTATTGTGCAACAGGAGGCTTCTGGAGTATGATTGGGGGAAATGGAGTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 16 |
4N12輕鏈 | CAGGCTGTGGTGACTCAGTCTCCATCGTCCCTGCCTGCATCTGTAGGAGACAGGGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATAATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTGAGCGCCTGATCTATGGAACCTCCAATTTGCAGAGTGGGGTCCCGTCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCCCACGTTCGGCCGCGGGACCAAGGTGGAAATCAAA | 17 |
5M16重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGAGTTTCCTGCAAGGCATCTGGGTACACCTTCACCAGTTACTTTATGCACTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGCGATAACTTATCCTGGTGGTGGTAGCCCATCCTACGCACCGCAGTTCCAGGGCAGACTCACCATGACCGACGACACGTCCGCGACCACAGTCTACATGGACCTGAGTGACCTGACTTCTAAAGACACGGCCGTGTATTACTGTGCGAGAGGTGCCCACCGTTCCATTGGGACGACCCCCCTTGACTCGTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCAAGCTTCAAGGG | 18 |
5O14重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGACGCGTGGTCCAGGCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTATGTATGGCGTCCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGAATGATGGATCTAAAGAATACTATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAGGAACACGTTGTATCTGCAAATGAACAGCCTGAGAGTCGACGACACGGCAGTGTATTTTTGTGCGAGAGATGGAATTCCTGACCCTGAACGCGGTGACTACGGGGGCTTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 19 |
5O14輕鏈 | CAGACTGTGGTGACTCAGTTTCCATCCTCCCCGTTTGCATCTGTAGGAGACGGAGTCACCATCACTTGCCGGGCAAGGCAGAGCATTAGCAGTTATGTTAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATTTACGCTACATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCGGTCTGCAACCTGAAGATTTTGCAACATACTACTGTCAACAGAGTTACAGTTTTCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC | 20 |
8G18重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTCAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGCCCTCTGGAGGCACCTTCAACAACAATGGGATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGCATCGTCCCGAACTTTGGAACCCCAACCTATGGACAAGACTTCCAGGGCAGAGTCACGATCACCGCGGACGAATCTACGAGCACAGTCTTCTTGGAGCTGACCAGACTGAGATCTGACGACACGGCCGTTTATTTCTGTGCGCGAGGTCGCACGGCGGTGACTCCGATGCAATTGGGTTTACAGTTCTACTTTGACTTCTGGGGCCGGGGAACCCTGGTCACCGTCTCCTCA | 21 |
8G18輕鏈 | cagactgtggtgactCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTTCTGCCAACAGTGGAGCAGTCACCAGTGATTACTATCCAAACTGGTTCCAGCAGAAACCTGGACAAGCACCCAGGGCACTGATTTATAGTGCAAGCAACAAATTCTCCTGGACGCCTGCCCGGTTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACACTGTCAGGTGCGCAGCCTGAGGACGAGGCTGAGTATTACTGCCTGGTCTACTCTGGTGATGGTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCC | 22 |
1I9重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCCGGGGCCTCAGTGAAGGTCTCCTGCAAGACTTCTGGATATACGTTCACCGACAACTCTGTACACTGGGTGCGACAGGCCCCTGGACAAGGGTTTGAGTGGATGGGACGGATCAACCCTAACACTGGTGTCTCAACTTCTGCCCAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAACCTACATGGAGCTGAGCAGTTTGAGATCTGACGACACGGCCGTCTATTACTGTGCGAGAGAGGAGAACGATAGTAGTGGGTATTACCTTTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA | 23 |
1I9輕鏈 | CAGATTGTGGTGACTCAGTCTCCATCCTCCCTGTTTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGGAGAGTGGGGTCCCATCAAGGTTCGGTGGCAGTAGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGGACCCCGTGGACGTTCGGCCAAGGGACCAAGGTGGACATCAAA | 24 |
1L1重鏈 | CAGGTGCAGCTGGTGCAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCAGTATTAGTGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGGAGTGGCTTGCACTCATTTATTGGGATGATGATAAGCGCTACAGCCCATCTCTGAAGAGCAGGCTCACCATCACCAAGGACACCTCCGAAAACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGTGCACACAGTATGACTAAAGGCGGGGCTATCTATGGTCAGGCCTACTTTGAATACTGGGGCCAGGGAACCCTGGTC | 25 |
1L1輕鏈 | CCATCTCCTGCACTGGAACCAGACAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATCATTTATGATGTCACTGATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGCCTCCAAGTCTGCCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCAGCAGCACTCTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 26 |
1M9重鏈 | caggtccagctggtacagtctggggctgaggtgaagaagcctggGGCCTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACACCCTCACTGAATTATCCATGCACTGGGTGCGACAGGCTCCTGGAAAAGGCCTAGAGTGGATGGGAGGTTTTGAGCCTGAAGATGGTGAAACAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCGAGGACACATCTAGAGACACAGCCTACATGGAGCTGAGTAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTACAACAGATCAGGTCTACTATCGTTCGGGGAGTTATTCTGGATATGTTGACTACTGGGGCCAGGGAACCCTGGTC | 27 |
1O5重鏈 | caggtccagctggtgcagtctggggctgaggtgaagaagcctgggtCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGACGCACCTTCAGCAGCTATGTTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTCTGTTTGGTACAGCAAACTACGCACAGAAATTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTCTATTACTGTGCGAGGGGCGCCCAGCTATATTACAATGATGGTAGTGGTTACATTTTTGACTACTGGGGCCAGGGAGCCCTGGTC | 28 |
1O6重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGCCTGAGGTGAAGAAGCCTGGGACCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTCAGCTTTATTAGCTCTGCTGTGCAGTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGATGGATCGTCGTTGCCAGTGCTAACACAAACTACGCACAGAAGTTCCGGGAAAGAGTCACCATTACTAGGGACATGTCCACAAACACAGCCTATATGGAACTGACCAGCCTGAGATCCGAGGACACGGCCGTTTATTACTGTGCGGCAGAGCACCGGTCCCCTTGTAGTGGTGGTGATAGCTGCTACAGTCTCTACTACGGTATGGACGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 29 |
2A2重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTTCCGCCTGGGGGGTCCCTGAGACTGTCCTGTACAGCCTCTGGATTCACCGTTAGTAACTATGGCATGAGCTGGGTCCGCCAGACTCCAGGGAAGGGGCTGGAGTGGGTCTCAACTATTAGTACTAGTAGTGGTAGAACATTCTACGCAGACTCCGTGGAGGGCCGGTTCACCATCTCCGGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGTCGAAGACACGGCCGTATATTACTGTGCGAAAGGCCCGTTCGGGGGCGACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 30 |
2A2輕鏈 | CAGGCTGTGGTGACTCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGCCATCTACTTAGCCTGGTATCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTGGCAACTGGCAGTACACTTTTGGCCAGGGGACCAAACTGGAGATCAAA | 31 |
2C2重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCCTGGTACAGCCTGGCAGGTCCCTGACACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGTTTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCTTGGAGTGGGTCGCAGGTATTAGTTGGAATAGTGGTAGCGTAGGCTATGCGGACTCTATGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATTAACAGTCTGAGAGCTGAGGACACGGCCTTATATTACTGTGCAAAAGCATTCTGGTTCGGGGAGTTATCGGGTTACGGTATGGACGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 32 |
2C2輕鏈 | CAGGCTGTGGTGACTCAGCCTCCCTCCGCGTCCGGGTTTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTAGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATAATTTATGCGGTCACTAGGCGGCCCTCAGGGGTCCCTGAGCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCACCTCATATGCAGGCAACAACAAGGATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA | 33 |
2D12重鏈 | CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACAGCTTTAACATCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAACTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGACCACTTTGGGGGGAATTTTACTATGATATCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 34 |
2D12輕鏈 | CAGGCTGTGGTGACTCAGTCTCCAGGCACCCTGTCCTTGTCTCCAGGGGAAAGAGCCACCCTCTCTTGCAGGGCCAGTCAGAGTGTTAGCAGCGGGTACTCAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAAAAGGGCCGCTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCTGTTTGCTACCTCACCTCCGCCCTTCGGCCAAGGGACACGACTGGAGATTAAA | 35 |
3A2重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAATTATGTTATGGAGTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGCAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGTTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGATCAGAGTGGGAGTCTTCCTATGGTTCGGGGAATTATTATACAGATTACTTCTACTACTACGCTATGGACGTCTGGGGCCCAGGGACCCTGGTCACCGTCTCCTCA | 36 |
3A2輕鏈 | CAGGCTGTGGTGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAATCAGAGCCTCCTGCGTGGTATTAGATACAACTATTTGGATTGGTACCTGCAGAAACCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGCCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCTACCACCTTCGGCCAAGGGACACGACTGGAGATTAAA | 37 |
3B4重鏈 | CAGGTGCAGCTGGAGGAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGCTGACCTGTTCCTTCTCTGGGTTCTCACTCACCACTACTGGAGTGACTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCTTGGAGTGGCTTGCACTCATTTATTGGGATGATGATAAGCGCTACAGCCCATCTCTGAAGAGCAGGCTCACCATCACCAAGGACACCTCCAAAAACCAGGTGGTCCTTACCATGACCAACATGGACCCTGTGGACACTGCCACATATTACTGTGCGCACTCCACCGGCTACTATGATAGTAGTGGCTATCGAGGGGCCCTTGATGCTTTTGCTGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 38 |
3B4輕鏈 | CAGATTGTGGTGACTCAGTTTCCAGACTCCCCGGCTGTGTCTTTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACCACTCCAACAATAAAAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAACCTGCTCATTTACTGGGCATCTGCCCGACAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA | 39 |
3E23重鏈 | CAGGTGCAGCTGGTGCAGTCGGGCCCAGGACTGGTGAAGCCTTCGGACACCCTGTCCCTCACCTGCAGTGTCTCAAGTGACGCCCTCCGCAGCAGGAGTTATTACTGGGGCTGGGTCCGCCAGCCCCCCGGGAAGGGATTGGAGTGGATTGGGACTGTCTCTTATAGTGGGGGCACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCGTGTCGGTGGACACGTCCAAGAACCACTTCTCCCTGAGGTTGAACTCTGTGACCGCCGCAGACGCGGCTGTTTATTACTGTGCGAGATCTTATTTCTATGATGGCAGTGGTTACTACTACCTGAGCTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 40 |
3E23輕鏈 | CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGCTTCCAGCACTGGAGCAGTCACCAGTGGTCACTATCCAAACTGGTTCCAGCAGAAACCTGGACAACCACCCAGGGCCCTGATTTATAGCACAGACAACAAGCACTCCTGGACCCCTGCCCGGTTCTCAGGCTCCCTCCTAGGGGTCAAGGCTGCCCTGACACTGTCAGATGTACAGCCTGAGGACGAGGCTGACTATTACTGCCTGCTCCATTTTGGTGGTGTCGTGGTCTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 41 |
3H5重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTTCAACGTCTGGATTCACCTTCAGGATGTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCCGTTATTTTTAACGATGGAGTTAAGAAATATTATGGAGACGCCGTGAAGGGCCGATTCACCGTCTCCAGAGACAATTCCAGGAACACCCTGTATCTGGAAATGAAAAGCCTGAGAGTCGACGACACGGCTGCCTACTACTGTGCGAGAGACGGGATTCCTGACCCCGAACGCGGTGACTACGGGGGCTTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 42 |
3H5輕鏈 | CAGACTGTGGTGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACACAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTACCAGTTATTTAAACTGGTATCAGCAGAAACCAGGAAAAGCCCCAAAGCTCCTCATCTATGCTACATCCAGTTTGCAAAGTGGGCTCCCCTCAAGGTTCAGTGGCAGTGGCTATGGGACAGAATTCACTCTCACCATCAGTGGTCTGCAACCTGAAGATTTTGCAACATACTACTGTCAACAGAGTTACAGTTTTCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAAATGGATA | 43 |
3I21重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAACCTCTGGATTCATCTTTGATGATTATGCCATGTACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGAAACATAGCCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATTTGGAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGTAAAAGATCTTTACGGGTACGATATTTTGACTGGTAATGGATATGATTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 44 |
3I21輕鏈 | CAGGCTGTGGTGACTCAGTCTTCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCAAAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAA | 45 |
3K11重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCCCCTGCAAGGCTTCTGGAGACACCCTCAGTTACTACGGAATCACTTGGGTGCGACGGGCCCCTGGACAAGGGCTTGAGTGGATGGGACAGATCATCCCTTTCTTTGCTACAACAATCTCCGCACAGAAGTTCCAGGGCAGACTCACCATGACCGCGGAAGAATCCACGAGCACTGGCTACATGGAGCGCACATTTTACATGGACTTGAGTAGCCTTAGACCTGAGGACACGGCCGTATACTACTGTGCGGGGGGCTACTATGGTTCGGGGAGTTCGGGCGACTACGGTTTGGACGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 46 |
3K11輕鏈 | CAGGCTGTGGTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTAAACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTTCGGGAGTCTTCGGAACTGGGACCGAGGTCACCGTCCTA | 47 |
4B8重鏈 | CAGGTGCAGCTGGTGCAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTGACGTGCGCTGTTTCTGGTGACTCCATCGGCAGTAGAAGTTTCTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGAAGTATCTATTATAATGGGACCACCTACTACAAGCCGTCCCTCAAGAGTCGAGTCACCATATCCCTAGACACGTCCAAGAACCAGTTCTCCCTGAGGCTGAGCTCTCTGACCGCCACAGACACGGGTGTCTATTACTGTGCGCGGGCGCCAACCTACTGTAGTCCTTCCAGCTGCGCAGTTCACTGGTACTTCAATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCCTCA | 48 |
4B10重鏈 | CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGCTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACATATTTACCAAATATGGTATCAGTTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGGTGGGATGGATCAGCGCTTACAATGAAAACACAAACTATGCAGAGAAGTTCCAGGGCAGAGTCACCTTGACCACAGATGCATCCACGAGCACGGCCTACATGGAGCTGAGGAACCTGAGATCTGACGACACGGCCGTATACTTCTGTGCGAGAGAAGTCTGGTTCGCGGAGTATATTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA | 49 |
8E22輕鏈 | CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTTCTGCCAACAGTGGAGCAGTCACCAGTGATTACTATCCAAACTGGTTCCAGCAGAAACCTGGACAAGCACCCAGGGCACTGATTTATAGTGCAAGCAACAAATTCTCCTGGACGCCTGCCCGGTTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACACTGTCAGGTGCGCAGCCTGAGGACGAGGCTGAGTATTACTGCCTGGTCTACTCTGGTGATGGTGTGGTTTTC GGCGGAGGGACCAAGCTGACCGTCCTAA | 50 |
9A11輕鏈 | CAGTCTGTGGTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGCTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCGTGATTTATGATGTCGCTAATCGGCCCTCAGGGATTTCTGACCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCGGCTCATATACCAGCGACGTCTCGCCGGTTTTCAGCGGGGGGACCAAGCTGACCGTCCTCA | 51 |
9D14重鏈 | CAGGTGCAGCTGGTGCAGTCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGCTTTCCTGCAAGGCTTCTGGATACACCTTCACAAGTCATCCTATGAATTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACACCAAGACTGGGAACCTAACTTATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCTTGGACACCTCTGTCAGGACGGCGTATCTGCAGATCAGCGGCCTAAAGGCTGAGGACACTGCCATTTATTACTGTGCGAGAGATGAGTATAGTGGCTACGATTCGGTAGGGGTGTTCCGTGGTTCTTTTGACGACTTCTACGGTATGGACGTCTGGGGCCAAGGGACCCTGGTCACCGTCTCCTCA | 52 |
純系 | 可變區序列 | SEQ ID NO: |
1H12重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYGISWVRQAPGQGLEWMGWISTYKGYTQYAQNFQGRVTITTDTPATTVYMELRSLRSDDTAVYYCARVLSETGYFYYYYYGMDVWGQGTLVTVSS | 53 |
1H12輕鏈 | QAVVTQPPSVSGAPGQRVTISCTGSSSNIGADYNVHWYQLLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSASVFGGGTKLTVL | 54 |
2B4重鏈 | QVQLVQSGSELKKPGASVKVSCKASGYSFTSYSINWVRQAPGQGPEWMGWIDTNTGNPTYAQDFAGRFVFSLDTSVTTAYLQISSLKAGDTAVYYCATYYVDLWGSYRQDYYGMDVWGH | 55 |
2B4輕鏈 | QSVLTQPPSASGTPGQRVTISCSGGSSNIGSNPVNWYQMVPGTAPKLLLYTNNQRPSGVPDRFSGSKSGTSASLAINGLQSEDEADYYCAVWDDSLSGRWVFGGGTKVTVL | 56 |
2H1重鏈 | QVQLVQSGAEVKKPGASVRVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISTYNGDTNYAQKFQGRVTLTTETSTSTAYMELRRLRSDDTAVYYCARDFEFPGDCSGGSCYSRFIYQHNDMDVWGHGTLVTVSSAS | 57 |
2H1輕鏈 | QAVVTQPPSVSAAPGQKVTISCSGSSSNIGNHYVSWYQHLPGTAPKLLIYDNYKRPSVIPDRFSASKSGASATLGIIGLQTGDEADYYCGTWDSSLSAVVFGGGTKLTVL | 58 |
3E23重鏈 | QVQLVQSGPGLVKPSDTLSLTCSVSSDALRSRSYYWGWVRQPPGKGLEWIGTVSYSGGTYYNPSLQSRVTVSVDTSKNHFSLRLNSVTAADAAVYYCARSYFYDGSGYYYLSYFDSWGQGTLVTVSS | 59 |
3E23輕鏈 | QAVVTQEPSLTVSPGGTVTLTCASSTGAVTSGHYPNWFQQKPGQPPRALIYSTDNKHSWTPARFSGSLLGVKAALTLSDVQPEDEADYYCLLHFGGVVVFGGGTKLTVL | 60 |
3N23重鏈 | QVQLVQSGGGVVQPGRSLRLSCAVSGFTFSNYAMHWVRQAPGKGLDWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQVNSLRAEDTAVYYCARGDYVLDYWGQGTLVTVSS | 61 |
3N23輕鏈 | DIVMTQSPSSLSASVGDRVTISCRASQSIPSYLNWYQQKPGKAPKVLIYATSTLEAGVPSRFSGSGSGTDFTLTITSLQPEDFATYYCQQSYNTGIFTFGPGTKVDIK | 62 |
4J14重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGGTSSTYAISWVRQAPGQGLEWMGGSIPVFATVNYAQKFQGRLTITADESTSTVYMELSSLRSEDTAVYFCASPYCSSMNCYTTFYYFDFWGQGTLVTVSS | 63 |
4J14輕鏈 | QAVVTQPASVFGFPGQSITISCTGTSSDFGTYNYVSWYQQHPGQAPKLMIFDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEASYYCSSYTSGSTLYGGGTKLTVL | 64 |
4J21重鏈 | QVQLVQSGSELKKPGASVKVSCKASGYSFTSYSINWVRQAPGQGPEWMGWIDTNTGNPTYAQDFAGRFVFSLDTSVTTAYLQISSLKAGDTAVYYCATYYVDLWGSYRQDYYGMDVWGHGTLVTVSS | 65 |
4J21輕鏈 | QSVVTQPPSVSGTPGQGVTISCSGGSSNIGSNPVNWYQMVPGTAPKLLLYTNNQRPSGVPDRFSGSKSGTSASLAINGLQSEDEADYYCAVWDDSLSGRWVFGGGTKLTVL | 66 |
4N12重鏈 | QVQLVQSGAEVKKPGASVKVSCKVSGYILSKLSVHWVRQAPGKGLEWMGGSEREDGETVYAQKFQGRISLTEDTSIETAYMELSSLSSEDTAVYYCATGGFWSMIGGNGVDYWGQGTLVTVSS | 67 |
4N12輕鏈 | QAVVTQSPSSLPASVGDRVTITCRASQDIRNNLGWYQQKPGKAPERLIYGTSNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGRGTKVEIK | 68 |
5M16重鏈 | QVQLVQSGAEVKKPGASVRVSCKASGYTFTSYFMHWVRQAPGQGLEWMAITYPGGGSPSYAPQFQGRLTMTDDTSATTVYMDLSDLTSKDTAVYYCARGAHRSIGTTPLDSWGQGTLVTVSSASFK | 69 |
5O14重鏈 | QVQLVQSGGRVVQAGRSLRLSCAASGFTFSMYGVHWVRQAPGKGLEWVAVIWNDGSKEYYGDSVKGRFTISRDNSRNTLYLQMNSLRVDDTAVYFCARDGIPDPERGDYGGLDYWGQGTLVTVSS | 70 |
5O14輕鏈 | QTVVTQFPSSPFASVGDGVTITCRARQSISSYVNWYQQKPGKAPKLLIYATSSLQSGVPSRFSGSGYGTDFTLTISGLQPEDFATYYCQQSYSFPRTFGQGTKVEIK | 71 |
8G18重鏈 | QVQLVQSGAQVKKPGSSVKVSCKPSGGTFNNNGISWVRQAPGQGLEWMGGIVPNFGTPTYGQDFQGRVTITADESTSTVFLELTRLRSDDTAVYFCARGRTAVTPMQLGLQFYFDFWGRGTLVTVSS | 72 |
8G18輕鏈 | QTVVTQEPSLTVSPGGTVTLTCSANSGAVTSDYYPNWFQQKPGQAPRALIYSASNKFSWTPARFSGSLLGGKAALTLSGAQPEDEAEYYCLVYSGDGVVFGGGTKLTV | 73 |
1I9重鏈 | QVQLVQSGAEVKKPGASVKVSCKTSGYTFTDNSVHWVRQAPGQGFEWMGRINPNTGVSTSAQKFQGRVTMTRDTSISTTYMELSSLRSDDTAVYYCAREENDSSGYYLWGQGTLVTVSS | 74 |
1I9輕鏈 | QIVVTQSPSSLFASVGDRVTITCRASQSISTYLNWYQQKPGKAPKLLIYAASSLESGVPSRFGGSRSGTDFTLTISSLQPEDFATYYCQQSYRTPWTFGQGTKVDIK | 75 |
1L1重鏈 | QVQLVQSGP.TLVKPTQTLTLTCTFSGFSLSISGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSRLTITKDTSENQVVLTMTNMDPVDTATYYCAHSMTKGGAIYGQAYFEYWGQGTLV | 76 |
1L1輕鏈 | PSPALEPDSDVGGYNYVSWYQQHPGKAPKLIIYDVTDRPSGVSNRFSASKSANTASLTISGLQAEDEADYYCSSYTSSST | 77 |
1M9重鏈 | QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFEPEDGETIYAQKFQGRVTMTEDTSRDTAYMELSSLRSEDTAVYYCTTDQVYYRSGSYSGYVDYWGQGTLV | 78 |
1O5重鏈 | QVQLVQSGAEVKKPGSSVKVSCKASGRTFSSYVISWVRQAPGQGLEWMGGIIPLFGTANYAQKFQGRVTITADESTSTAYMELSSLRSDDTAVYYCARGAQLYYNDGSGYIF DYWGQGALV | 79 |
1O6重鏈 | QVQLVQSGPEVKKPGTSVKVSCKASGFSFISSAVQWVRQARGQRLEWIGWIVVASANTNYAQKFRERVTITRDMSTNTAYMELTSLRSEDTAVYYCAAEHRSPCSGGDSCYSLYYGMDVWGQGTLVTVSS | 80 |
2A2重鏈 | QVQLVQSGGGLVPPGGSLRLSCTASGFTVSNYGMSWVRQTPGKGLEWVSTISTSSGRTFYADSVEGRFTISGDNSKNTLYLQMNSLRVEDTAVYYCAKGPFGGDFDYWGQGTLVTVSS | 81 |
2A2輕鏈 | QAVVTQSPATLSLSPGERATLSCRASQSVAIYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRGNWQYTFGQGTKLEIK | 82 |
2C2重鏈 | QVQLVQSGGGLVQPGRSLTLSCAASGFTFDVYAMHWVRQAPGKGLEWVAGISWNSGSVGYADSMKGRFTISRDNAKNSLYLQINSLRAEDTALYYCAKAFWFGELSGYGMDVWGQGTLVTVSS | 83 |
2C2輕鏈 | QAVVTQPPS.ASGFPGQSVTISCTGTSSDVGSYNYVSWYQQHPGKAPKLIIYAVTRRPSGVPERFSGSKSGNTASLTVSGLQAEDEADYYCTSYAGNNKDVFGTGTKVTVL | 84 |
2D12重鏈 | QVQLVQSGAEVKKPGASVKVSCKASGYSFNIYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARPLWGEFYYDIWGQGTLVTVSS | 85 |
2D12輕鏈 | QAVVTQSPGTLSLSPGERATLSCRASQSVSSGYSAWYQQKPGQAPRLLIYGASKRAAGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQLFATSPPPFGQGTRLEIK | 86 |
3A2重鏈 | QVQLVQSGGGVVQPGRSLRLSCAASGFTFSNYVMEWVRQAPGKGLEWVAVISYDGSNKYYADSVK.GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSEWESSYGSGNYYTDYFYYYAMDVWGPGTLVTVSS | 87 |
3A2輕鏈 | QAVVTQSPLSLPVTPGEPASISCRSNQSLLRGIRYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSATDFTLKISRVEAEDVGVYYCMQALQTPTTFGQGTRLEIK | 88 |
3B4重鏈 | QVQLEESGPTLVKPTQTLTLTCSFSGFSLTTTGVTVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHSTGYYDSSGYRGALDAFAVWGQGTLVTVSS | 89 |
3B4輕鏈 | QIVVTQFPDSPAVSLGERATINCKSSQSVLYHSNNKNYLAWYQQKPGQPPNLLIYWASARQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK | 90 |
3E23重鏈 | QVQLVQSGPGLVKPSDTLSLTCSVSSDALRSRSYYWGWVRQPPGKGLEWIGTVSYSGGTYYNPSLQSRVTVSVDTSKNHFSLRLNSVTAADAAVYYCARSYFYDGSGYYYLSYFDSWGQGTLVTVSS | 91 |
3E23輕鏈 | QAVVTQEPS.LTVSPGGTVTLTCASSTGAVTSGHYPNWFQQKPGQPPRALIYSTDNKHSWTPARFSGSLLGVKAALTLSDVQPEDEADYYCLLHFGGVVVFGGGTKLTVL | 92 |
3H5重鏈 | QVQLVQSGGGVVQPGRSLRLSCSTSGFTFRMYGMHWVRQAPGKGLEWVAVIFNDGVKKYYGDAVKGRFTVSRDNSRNTLYLEMKSLRVDDTAAYYCARDGIPDPERGDYGGLDYWGQGTLVTVSS | 93 |
3H5輕鏈 | QTVVTQSPSSLSASVGDTVTITCRASQSITSYLNWYQQKPGKAPKLLIYATSSLQSGLPSRFSGSGYGTEFTLTISGLQPEDFATYYCQQSYSFPRTFGQGTKVEMD | 94 |
3I21重鏈 | QVQLVQSGGGLVQPGRSLRLSCATSGFIFDDYAMYWVRQAPGKGLEWVSGISWNSGNIAYADSVKGRFTISRDNAKNSLYLEMNSLRAEDTALYYCVKDLYGYDILTGNGYDYWGQGTLVTVSS | 95 |
3I21輕鏈 | QAVVTQSSLSLPVTPGEPASISCRSSQSLLQSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPPTFGQGTKVEIK | 96 |
3K11重鏈 | QVQLVQSGAEVKKPGSSVKVPCKASGDTLSYYGITWVRRAPGQGLEWMGQIIPFFATTISAQKFQGRLTMTAEESTSTGYMERTFYMDLSSLRPEDTAVYYCAGGYYGSGSSGDYGLDVWGQGTLVTVSS | 97 |
3K11輕鏈 | QAVVTQPPS.VSGAPGQRVTISCTGSSSNIGAGYDVNWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSGVFGTGTEVTVL | 98 |
4B8重鏈 | QVQLVQSGPGLVKPSETLSLTCAVSGDSIGSRSFYWGWIRQPPGKGLEWIGSIYYNGTTYYKPSLKSRVTISLDTSKNQFSLRLSSLTATDTGVYYCARAPTYCSPSSCAVHWYFNLWGRGTLVTVSS | 99 |
4B10重鏈 | QVQLVQSGAELKKPGASVKVSCKASGYIFTKYGISWLRQAPGQGLEWVGWISAYNENTNYAEKFQGRVTLTTDASTSTAYMELRNLRSDDTAVYFCAREVWFAEYIYWGQGTLVTVSS | 100 |
9A11輕鏈 | QSVVTQPASVSGSPGQSITISCTGTSSDVGAYNYVSWYQQHPGKAPKLVIYDVANRPSGISDRFSGSKSGNTASLTISGLQAEDEADYYCGSYTSDVSPVFSGGTKLTVL | 101 |
9D14重鏈 | QVQLVQSGSELKKPGASVKLSCKASGYTFTSHPMNWVRQAPGQGLEWMGWINTKTGNLTYAQGFTGRFVFSLDTSVRTAYLQISGLKAEDTAIYYCARDEYSGYDSVGVFRGSFDDFYGMDVWGQGTLVTVSS | 102 |
抗體 | CDRH1 (SEQ ID NO: ) | CDRH2 (SEQID NO: ) | CDRH3 (SEQ ID NO: ) |
1H12 | GYSFTSYG (103) | ISTYKGYT (104) | ARVLSETGYFYYYYYGMDV (105) |
2B4 | GYSFTSYS (106) | IDTNTGNP (107) | ATYYVDLWGSYRQDYYGMDV (108) |
2H1 | GYTFTSYG (109) | ISTYNGDT (110) | ARDFEFPGDCSGGSCYSRFIYQHNDMDV (111) |
3E23 | SDALRSRSYY (112) | VSYSGGT (113) | ARSYFYDGSGYYYLSYFDS (114) |
3N23 | GFTFSNYA (115) | IWYDGSNK (116) | ARGDYVLDY (117) |
4J14 | GGTSSTYA (118) | SIPVFATV (119) | ASPYCSSMNCYTTFYYFDF (120) |
4J21 | GYSFTSYS (121) | IDTNTGNP (122) | ATYYVDLWGSYRQDYYGMDV (123) |
4N12 | GYILSKLS (124) | SEREDGET (125) | ATGGFWSMIGGNGVDY (126) |
5M16 | GYTFTSYF (127) | TYPGGGSP (128) | ARGAHRSIGTTPLDS (129) |
5O14 | GFTFSMYG (130) | IWNDGSKE (131) | ARDGIPDPERGDYGGLDY (132) |
8G18 | GGTFNNNG (133) | IVPNFGTP (134) | ARGRTAVTPMQLGLQFYFDF (135) |
1I9 | GYTFTDNS (136) | INPNTGVS (137) | AREENDSSGYYL (138) |
1L1 | GFSLSISGVG (139) | IYWDDDK (140) | AHSMTKGGAIYGQAYFEY (141) |
1M9 | GYTLTELS (142) | FEPEDGET (143) | TTDQVYYRSGSYSGYVDY (144) |
1O5 | GRTFSSYV (145) | IIPLFGTA (146) | ARGAQLYYNDGSGYIFDY (147) |
1O6 | GFSFISSA (148) | IVVASANT (149) | AAEHRSPCSGGDSCYSLYYGMDV (150) |
2A2 | GFTVSNYG (151) | ISTSSGRT (152) | AKGPFGGDFDY (153) |
2C2 | GFTFDVYA (154) | ISWNSGSV (155) | AKAFWFGELSGYGMDV (156) |
2D12 | GYSFNIYG (157) | ISAYNGNT (158) | ARPLWGEFYYDI (159) |
3A2 | GFTFSNYV (160) | ISYDGSNK (161) | ARSEWESSYGSGNYYTDYFYYYAMDV (162) |
3B4 | GFSLTTTGVT (163) | IYWDDDK (164) | AHSTGYYDSSGYRGALDAFAV (165) |
3E23 | SDALRSRSYY (166) | VSYSGGT (167) | ARSYFYDGSGYYYLSYFDS (168) |
3H5 | GFTFRMYG (169) | IFNDGVKK (170) | ARDGIPDPERGDYGGLDY (171) |
3I21 | GFIFDDYA (172) | ISWNSGNI (173) | VKDLYGYDILTGNGYDY (174) |
3K11 | GDTLSYYG (175) | IIPFFATT (176) | TAVYYCAGGYYGSGSSGDYGLDV (177) |
4B8 | GDSIGSRSFY (178) | IYYNGTT (179) | ARAPTYCSPSSCAVHWYFNL (180) |
4B10 | GYIFTKYG (181) | ISAYNENT (182) | AREVWFAEYIY (183) |
9D14 | GYTFTSHP (184) | INTKTGNL (185) | ARDEYSGYDSVGVFRGSFDDFYGMDV (186) |
抗體 | CDRL1 (SEQ ID NO: ) | CDRL2 (SEQID NO: ) | CDRL3 (SEQ ID NO: ) |
1H12 | SSNIGADYN (187) | GNT (188) | QSYDSSLSASV (189) |
2B4 | SSNIGSNP (190) | TNN (191) | AVWDDSLSGRWV (192) |
2H1 | SSNIGNHY (193) | DNY (194) | GTWDSSLSAVV (195) |
3E23 | TGAVTSGHY (196) | STD (197) | LLHFGGVVV (198) |
3N23 | QSIPSY (199) | ATS (200) | QQSYNTGIFT (201) |
4J14 | SSDFGTYNY (202) | DVS (203) | SSYTSGSTLYGGG (204) |
4J21 | SSNIGSNP (205) | TNN (206) | AVWDDSLSGRWV (207) |
4N12 | QDIRNN (208) | GTS (209) | LQHNSYPPT (210) |
5O14 | QSISSY (211) | ATS (212) | QQSYSFPRT (213) |
8G18 | SGAVTSDYY (214) | SAS (215) | LVYSGDGVV (216) |
1I9 | QSISTY (217) | AAS (218) | QQSYRTPWT (219) |
1L1 | DSDVGGYNY (220) | DVT (221) | SSYTSSSTLV (222) |
2A2 | QSVAIY (223) | DAS (224) | QQRGNWQYT (225) |
2C2 | SSDVGSYNY (226) | AVT (227) | TSYAGNNKDV (228) |
2D12 | QSVSSGY (229) | GAS (230) | QLFATSPPP (231) |
3A2 | QSLLRGIRYNY (232) | LGS (233) | MQALQTPTT (234) |
3B4 | QSVLYHSNNKNY (235) | WAS (236) | QQYYSTPYT (237) |
3E23 | TGAVTSGHY (238) | STD (239) | LLHFGGVVV (240) |
3H5 | QSITSY (241) | ATS (242) | QQSYSFPRT (243) |
3I21 | QSLLQSNGYNY (244) | LGS (245) | MQALQTPPT (246) |
3K11 | SSNIGAGYD (247) | GNN (248) | QSYDSSLSGSGV (249) |
9A11 | SSDVGAYNY (250) | DVA (251) | GSYTSDVSPV (252) |
mAb 1 | IgG 亞類 2 | λ/κ 輕鏈 2 | 結合至 E2 胞外域之 ELISA (10 µg/mL) 3 | 針對 CHIKV VRP ( 病毒株 SL15649) 4 之中和作用 EC 50(ng/mL) 5 [95%信賴區間] |
2H1 | IgG2 | λ | ++ | 8 [6 - 10] |
4N12 | IgG2 | κ | - | 8 [7 - 10] |
2B4 | IgG1 | λ | ++ | 14 [11 - 17] |
4J21 | IgG1 | λ | ++ | 5 [4 - 6] |
5M16 | IgG1 | κ | +++ | 5 [4 - 6] |
9D14 | IgG1 | λ | +++ | 6 [5 - 7] |
1H12 | IgG1 | λ | +++ | 17 [14 - 20] |
8E22 | IgG1 | λ | ++ | 17 [14 - 19] |
8G18 | IgG1 | λ | ++ | 17 [14 - 19] |
10N24 | IgG1 | κ | - | 21 [17 - 26] |
8I4 | IgG1 | κ | +++ | 8 [5 - 14] |
3N23 | IgG1 | κ | - | 25 [21 - 30] |
5O14 | IgG1 | κ | +++ | 38 [30 - 47] |
4J14 | IgG1 | λ | ++ | 23 [20 - 26] |
3E23 | IgG2 | λ | - | 11 [9 - 13] |
1L1 | IgG1 | λ | +/- | 18 [15 - 22] |
3B4 | IgG3 | κ | - | > |
4B8 | IgG1 | λ | +++ | 0.6 [0.4 - 0.8] |
4G20 | IgG1 | λ | - | 95 [60 - 160] |
1O5 | IgG1 | λ | - | 138 [110 - 170] |
1O6 | IgG3 | λ | - | 5,200 [4,100 - 6,600] |
2L5 | NT | NT | - | 4,600 [2,400 - 9,500] |
3A2 | IgG1 | κ | +++ | 1,300 [830 - 1,900] |
5F19 | IgG1 | λ | +++ | > |
1M9 | IgG1 | κ | - | > |
1I9 | IgG1 | κ | - | > |
4B10 | IgG1 | κ | - | > |
2C2 | IgG1 | λ | - | > |
2D12 | IgG1 | κ | - | > |
5N23 | IgG1 | λ | +++ | > |
鼠類 CHK-152 | IgG2c | κ | - | 3 [2 - 4] |
mAb 1 | 針對純化之 E2 蛋白 質之競爭結合組 2 | 突變誘發定位 | |
E2 結構域 3 | 當變成丙胺酸時觀察到結合減少的 E2 殘基 | ||
2H1 | Low binding | E2-DA | R80、T116 |
4N12 | NT | Arch | D250 |
2B4 | Low binding | NoReduct ## | - |
4J21 | Low binding | NoReduct | - |
5M16 | 2 | Arch | G253 |
9D14 | 2 | NoReduct | - |
1H12 | 1/2 | DA/B、Arch | T58、D59、D60、R68、D71、I74、D77、T191、N193、K234 |
8E22 | Low binding | DA、Arch | H62、W64、R68、H99、D117、I255 |
8G18 | Low binding | DA | H62、W64、D117 |
10N24 | NT | DA、B | W64、D71、R80、T116、D117、I121、N187、I190 |
8I4 | NSF Ab | DB、Arch | M171、Q184、I190、N193、V197、R198、Y199、G209、L210、K215、K234、V242、I255 |
3N23 | NT | DA、Arch | D60、R68、G98、H170、M171、K233、K234 |
5O14 | 2 | NoReduct | - |
4J14 | Low binding | DA/B | D63、W64、T65、R80、I121、A162、N193 |
3E23 | NT | DA | W64 |
1L1 | Low binding | Arch | G253 |
3B4 | NT | DB | V192、Q195 |
4B8 | 2 | NoReduct | - |
4G20 | NT | DB | D174、R198、Y199、K215 |
1O5 | NT | DA | W64、T65 |
1O6 | 2 | DA | R80 |
2L5 | NT | NoReduct | - |
3A2 | 3 | DB | I190、R198、Y199、G209、L210、T212 |
5F19 | 4 | DA | H18 |
1M9 | NT | DA、Arch | R36、H62、R80、Q146、E165、E166、N231、D250、H256 |
1I9 | NT | E2 | 不確定 |
4B10 | NT | NoReduct | - |
2C2 | NT | NoReduct | 不確定 |
2D12 | NT | E2 | 不確定 |
5N23 | 1 | DA、Arch | E24、D117、I121 |
鼠類 CHK-152 | NT | E2-DA、E2-DB | D59、W235、A11、M74、G194、N193、T212、H232 4 |
mAb 1 | 針對指定基因型及病毒株之 CHKV 的 中和作用 * EC 50, ng/mL 2 (95%信賴區間) | |||
西非基因型 | ECSA 基因型 | 亞洲基因型 | ||
NI 64 IbH 35 病毒株 | LR2006 OPY1 (LR) 病毒株 | RSUI 病毒株 | 2014 年加勒比海 99659 病毒株 | |
2H1 | 3.7 (3.3-4.3) | 5.6 (4.9-6.3) | 5.9 (5.3-6.7) | 5.5 (4.7-6.5) |
4N12 | 2.5 (2.0-3.1) | 4.0 (3.3-5.0) | 6.5 (5.7-7.3) | 7.3 (5.9-9.2) |
2B4 | 3.2 (2.8-3.7) | 5.6 (4.6-6.7) | 6.5 (5.6-7.7) | 7.0 (6.0-8.2) |
4J21 | 5.2 (4.3-6.4) | 7.4 (6.6-8.3) | 7.7 (7.0-8.6) | 7.2 (5.3-9.8) |
5M16 | 6. 0 (5.5-6.6) | 5.9 (5.0-6.8) | 8.4 (6.7-10.4) | 11.7 (9.7-14.1) |
9D14 | 2.1 (1.6-2.7) | 2.9 (2.3-3.7) | 6.3 (4.7-8.4) | 86.0 (31.5-235) |
1H12 | 3.0 (2.5-3.5) | 7.5 (6.7-8.4) | 11.7 (9.3-14.8) | 11.6 (8.2-16.2) |
8E22 | 8.2 (7.0-9.7) | 7.2 (6.4-8.3) | 42.5 (30.8-58.5) | 138.9 (64.7-298) |
8G18 | 4.7 (4.1-5.3) | 7.3 (6.3-8.4) | 34.9 (24.9-48.9) | 52.4 (24.1-114) |
10N24 | 7.9 (6.9-9.0) | 9.5 (8.2-11.0) | 15.9 (13.2-19.2) | 23.6 (18.3-30.5) |
8I4 | 6.9 (3.8-12.3) | 6.2 (4.5-8.4) | 153 (78-299) | > |
3N23 | 6.0 (5.0-7.2) | 10.1 (8.9-11.5) | 14.1 (11.6-17.1) | 8.7 (7.0-10.9) |
5O14 | 6.7 (5.5-8.3) | 12.1 (10.9-13.5) | 17.3 (14.2-21.1) | 6.2 (5.3-7.2) |
4J14 | 12.9 (11.2-15.0) | 17.7 (16.1-19.4) | 23.1 (20-27) | 23.0 (18.5-28.4) |
3E23 | 19.4 (15.2-25.0) | 18.7 (16.3-21.5) | 36.0 (30.3-42.9) | 38.0 (30.3-47.5) |
1L1 | 18.6 (15.5-22.4) | 24.2 (21.3-27.5) | 34.3 (29-40.7) | N.D. |
3B4 | 18.7 (10.7-32.8) | 29.6 (18.7-46.8) | 271 (144-511) | N.D. |
4B8 | 22.8 (12.4-41.8) | 28.1 (19.8-39.9) | 234 (142-386) | N.D. |
4G20 | 22.3 (17.3-29.0) | 34.9 (28.2-43.8) | 131.4 (88.5-195) | N.D. |
1O5 | 30.1 (22.6-35.3) | 37.6 (32.6-43.4) | 48.9 (37.8-63.2) | N.D. |
1O6 | 61.7 (50.8-74.8) | 57.5 (48.8-68.1) | N.D. | N.D. |
2L5 | 1,076 (748-1,548) | 2,361 (1,460-3,819) | 5,632 (3,904-8,128) | N.D. |
3A2 | 1,566 (1,111-2,207) | 1,396 (952-2,046) | > | N.D. |
5F19 | > | 9,064 (2,911-28,249) | > | N.D. |
1M9 | > | > | 6,187 (2,795-13,709) | N.D. |
1I9 | > | > | > | N.D. |
4B10 | > | > | > | N.D. |
2C2 | > | > | > | N.D. |
2D12 | > | > | > | N.D. |
5N23 | > | > | > | N.D. |
鼠類 CHK-152 |
以下附圖形成本說明書之一部分且包括在此以進一步展示本發明之某些態樣。參照此等附圖中之一或多個,結合本文中呈現之具體實施例之詳細說明,可更好地理解本發明。
圖 1A - C . 對於 mAb 結合至關重要的 E2 殘基之結構分析 .(圖1A)
來自此研究中所使用之CHIKV病毒株之E2的序列比對。病毒株名稱示於左側(S27,SEQ ID NO: 1,寄存編號AF369024.2;SL15649,寄存編號GU189061;LR2006_OPY1,寄存編號DQ443544.2;99659,寄存編號KJ451624;RSU1,寄存編號HM045797.1;NI 64 IbH35,寄存編號HM045786.1)。序列上方之數字對應於成熟E2蛋白質中之胺基酸位置。與病毒株S27相同之胺基酸以短劃線指示。由CHIKV E2/E1雜二聚體之晶體結構(Voss等人, 2010)確定的E2之結構域描繪於序列比對上方的圖中且以顏色編碼(藍綠色:結構域A,紫色:β-帶狀連接體,綠色:結構域B,粉紅色:結構域C,灰褐色:晶體結構中不存在之區域)。藉由丙胺酸掃描突變誘發測定的丙胺酸取代破壞mAb結合之殘基位置以每一特定抗體之比對上方帶顏色編碼之點指示。影響多種抗體之結合的殘基係以帶漸變灰色之方形指示,其中灰色之色度越深,則在該殘基處受丙胺酸取代影響之抗體的數量越多。(圖1B)定位於成熟包膜糖蛋白複合體之晶體結構(PDB ID 3N41)上的mAb結合所需殘基之位置。顯示單一E1/E2雜二聚體之帶狀跡線的側視圖,其中E1呈淺藍綠色且E2之結構域如A圖中著色。抗體結合所需之胺基酸側鏈以空間填充形式顯示且20種個別抗體各自之顏色編碼係遵循A圖中之圖例。影響多種抗體之結合的殘基係以灰色之色度描繪,其中色度越暗,則在該殘基處受丙胺酸取代影響之抗體的數量越多(圖例示於左側)。(圖1C)由圖1B中之結構旋轉90°得到的E1/E2雜二聚之俯視圖。
圖 2A - B . 人類抗 CHIKV mAb 之 中和機制 .(圖2A) 附著前後之中和分析。使SL15649 VRP (i)在添加至預先冷卻的Vero細胞中之前,與所示mAb(包括CHK-152,一種陽性對照mAb)一起在4℃下培育1小時,接著藉由三次洗滌移除未結合之病毒(附著前;實心圓)或(ii)吸附至預先冷卻的Vero細胞上,在4℃下保持1小時,隨後在4℃下添加指定mAb,保持1小時(附著後;空心圓)。(圖2B)
FFWO分析。將SL15649 VRP吸附至預先冷卻的Vero細胞上,在4℃下保持1小時,隨後添加所示mAb(包括CHK-152,一種陽性對照鼠類mAb),保持1小時。移除未結合之病毒,且在37℃下,使細胞暴露於低pH值培養基(pH 5.5;實心圓)2分鐘以引起病毒在質膜處之融合。作為陰性對照,在37℃下使細胞暴露於中性pH培養基(pH 7.4;空心圓)2分鐘。對於圖2A及圖2B,在37℃下培育細胞,直至感染之後18小時,且使用螢光顯微鏡檢查對GFP陽性細胞進行定量。合併來自兩個獨立實驗之資料,每一實驗係一式三份進行。
圖 3A - D . 針對 Ifnar -/- 小鼠致死性 CHIKV 感染的人類 mAb 療法 .(圖3A)在CHIKV致死性攻擊
之前24小時,藉由腹膜內注射向小鼠投與50 µg指定CHIKV特異性mAb或對照mAb(每種測試mAb,
n=3至6隻小鼠)。(圖3B)在CHIKV致死性攻擊
之後24小時,藉由腹膜內注射向小鼠投與50 µg指定CHIKV特異性mAb或對照mAb(每種測試mAb,
n=4至6隻小鼠)。(圖3C) 在CHIKV致死性攻擊
之後48小時,藉由腹膜內注射向小鼠投與250 µg指定CHIKV特異性mAb或對照mAb(每種測試mAb,n=7至10隻小鼠)。(圖3D)在CHIKV致死性攻擊
之後60小時,藉由腹膜內注射向小鼠投與250 µg指定CHIKV特異性mAb對或對照mAb(每個測試mAb組合,
n=8隻小鼠,4J21+2H1除外,其為
n=3)。對於利用4J21或4N12之單藥療法,給與500 µg之單次劑量(每種測試mAb,
n=4至5隻小鼠)。
圖 4 . 在急性表現時之丘疹 .個體因發熱(102℉)持續三天,同時肘部及手指發生兩側關節疼痛,及皮疹而出現在主治醫師面前。醫生記下整個背部、胸部及腹部出現凸起的不癢、泛白之丘疹(照片示於圖中)。
圖 5 . mAb 競爭組之鑑別 .使用基於Octet之生物膜干涉測量術進行之定量競爭結合被用於將mAb指定至競爭組。將覆蓋有固定之CHIKV-LR2006 E2胞外域的抗Penta-His生物感測器尖端浸入含有初級mAb之孔中,隨後浸入含有競爭性mAb之孔中。所示值為在第一mAb存在下競爭性mAb之結合百分比(藉由比較在第一mAb複合體之後施加之競爭性mAb的最大信號與單獨競爭性mAb之最大信號而測定)。若競爭性mAb之最大結合降低至其非競爭結合之<30%,則判斷mAb完全競爭結合至同一位點(黑色方形),或若競爭性mAb之結合降低至其非競爭結合之<70%,則判斷mAb展現部分完成(灰色方形)。若競爭性mAb之最大結合為其非競爭結合之>70%,則mAb視為非競爭性的(白色方形)。鑑別出四個競爭結合組,以著色方框指示。藉由丙胺酸掃描突變誘發而發現的mAb之相應主要抗原位點(表1及圖1A-C)概述於競爭矩陣右側數欄中。DA指示結構域A;DB指示結構域B,e指示弓形結構1及2;NT指示未測試;NotReact指示mAb不與野生型包膜蛋白反應;NoReduct指示mAb結合至野生型E蛋白,但關於任何突變體沒有注意到可再現地減少。合併來自一個實驗之資料,其中每一單獨mAb有多個讀數且mAb與每一競爭性抗體之組合有單一讀數。
圖 6A-
D . CHIKV MAb 之 高解析度抗原決定基定位 .(A) 構建包含910個E2/E1突變之CHIKV包膜蛋白的丙胺酸掃描突變文庫,其中每個氨基酸獨立地突變成丙胺酸。每一突變陣列盤的每個孔含有一個具有指定取代的突變。示出反應性結果之代表性384孔盤。每一盤上包括八個陽性對照孔(野生型E2/E1)及八個陰性對照孔(模擬轉染)。(B)對於抗原決定基定位,測試表現CHIKV包膜突變文庫之人類HEK-293T細胞與所關注mAb(此處顯示為MAb 4G20)之免疫反應性且使用Intellicyt高通量流式細胞儀進行量測。相對於野生型CHIKV E2/E1反應性<30%,又對於不同CHIKV E2/E1 MAb具有>70%反應性之純系首先鑑別為對MAb結合至關重要。(C)四種個別殘基之突變減少4G20結合(紅色條柱)但不會大幅影響其他構形依賴性MAb(灰色條柱)或兔多株抗體(rPAb,來自IBT Bioservices之禮物)的結合。條柱表示至少兩個重複實驗之資料點的平均值及範圍。(D) PRNT50<1,000 ng/ml之中和性MAb的抗原決定基定位於E2/E1之三聚體晶體結構(PDB Entry 2XFC)上。所有中和抗原決定基均定位於E2/E1之充分暴露的膜遠端結構域。為清楚起見,每一個別E2/E1雜二聚體次單元以不同顏色顯示。E2結構域A與B中含有多種MAb之關鍵抗原決定基殘基的高免疫原性區域在E2之單一次單元上以紅色勾勒。
圖 7 . 對於 定位於競爭組之抗體的 mAb 結合至關重要之 E2 殘基的結構分析 .定位於E1/E2之晶體結構(PDB ID 2XFB)上的來自不同競爭組之人類或小鼠mAb結合所需殘基之位置(圖1A-C)。E1/E2三聚體之空間填充模型,其中E1呈白色且E2單體分別呈淺灰色、深灰色或黑色。抗體結合所需之殘基係根據其所屬競爭組進行顏色編碼。紅色指示殘基D117及I121,其為5N23結合所需的,且屬於競爭組1。藍色指示殘基R80及G253,其為I06或5M16結合所需的,屬於競爭組2。綠色指示殘基Q184、S185、I190、V197、R198、Y199、G209、L210、T212及I217,其為CHK-285、CHK-88或3A2結合所需的,且屬於競爭組3。橙色指示殘基H18,其為5F19結合所需的,且屬於競爭組4。紫色指示殘基E24、A33、L34、R36、V50、D63、F100、T155,其為5N23、CHK-84或CHK-141結合所需的,且屬於競爭組1及2。藍綠色指示殘基T58、D59、D60、R68、I74、D77、T191、N193及K234,其為1H12結合所需的,且屬於競爭組2及3。棕色指示殘基D71,其為CHK-84及1H12結合所需的,且屬於競爭組1、2及3。黃色指示除殘基D71之外皆包含推定受體結合結構域(RBD)的殘基(T58、D71、N72、I74、P75、A76、D77、S118及R119),其屬於競爭組1、2及3。上圖顯示三聚體之鳥眼圖,中間圖顯示三聚體自上圖中之結構沿x軸旋轉45°得到的成角度之側視圖,且下圖顯示三聚體自中間圖中之結構沿x軸旋轉45°得到的側視圖。
圖 8 . 兩種人類抗 CHIKV mAb 2H1 或 4N12 之 中和機制 .附著前後之中和分析。使CHIKV病毒株SL15649病毒複製子(virus replicon particle,VRP)(1)在添加至預先冷卻的Vero細胞中之前,與所示mAb(2H1或4N12)一起培育,接著藉由三次洗滌來移除未結合之病毒(附著前;實心圓)或(2)吸附至預先冷卻的Vero細胞上,隨後添加指定mAb(附著後;空心圓)。當在附著之前或之後添加時,此等mAb均中和。
圖 9 . B6 小鼠急性疾病模型 .相較於在D+3時對照抗體處理,在第1天給與CHO細胞產生之重組抗體使踝部中的病毒減少。實驗係在4週齡WT小鼠中於皮下接種10
3FFU之CHIKV-LR之後進行。在D+1給與抗體且在D+3收集組織以藉由病灶形成分析進行滴定。
圖 10 . B6 小鼠急性疾病模型 .在第3天全身性給與在CHO細胞中產生的CHKV mAb 4N12使踝部中之病毒滴度降低。實驗係在4週齡WT小鼠中於皮下接種10e3 FFU之CHIKV-LR之後進行。在D+3給與抗體且在D+5收集組織以藉由病灶形成分析進行滴定。
圖 11.
B6 小鼠慢性疾病模型. 在第3天全身性給與在CHO細胞中產生之CHKV mAb在第28天使踝部中之病毒基因組當量減小。實驗係在4週齡WT小鼠中於接種10e3 FFU之CHIKV-LR之後進行。在D+3給與抗體(300 µg)且在D+28收集組織以藉由qRT-PCR進行分析。
圖 12 . INFNAR 基因敲除致死性疾病小鼠模型 .在感染後60小時全身性給與在CHO細胞中產生的CHKV mAb使存活率增加。實驗係在4至5週齡IFNAR-/-小鼠中於皮下接種10e3 FFU之CHIKV-LR之後進行。在感染之後60小時給與抗體且跟蹤21天之死亡情況。
圖 13 . 融合瘤產生之 CHIKV 特異性 mAb ( 『原始』 ) 或重組 CHIKV 特異性 mAb ( 『新』 ) 之 中和曲線 .中和曲線係在BHK21細胞中進行。在37℃下,將100 FFU之CHIKV-LR與指定mAb混合1小時,隨後添加至BHK21細胞中。藉由病灶形成分析確定感染。
圖 14 . 融合瘤產生之抗體與重組 CHO 細胞產生之抗體的半數最大有效抑制濃度 ( EC
50 ; ng / mL ) 的比較 .融合瘤產生之抗體與重組產生之抗體的資料類似。
圖 15 . 呈 胺基酸形式的 E1 與 E2 蛋白質以及編碼該等蛋白質之基因之核苷酸的比對 .蛋白質之Genbank寄存編號與病毒株一起列出。提供來自原型組東.中.南非(ECSA)之病毒的三個病毒株,兩個亞洲病毒株及一個西非病毒株。此等抗體在所有病毒株中交叉反應。
<![CDATA[<110> 美國凡德貝爾大學(VANDERBILT UNIVERSITY)]]> <![CDATA[<120> 抗體介導屈公(CHIKUNGUNYA)病毒中和]]> <![CDATA[<140> ]]> <![CDATA[<141> ]]> <![CDATA[<150> US 62/147,354]]> <![CDATA[<151> 2015-04-14]]> <![CDATA[<160> 276 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 1]]> Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Gly Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Ile Pro Ala Asp Ala Gly Arg 65 70 75 80 Ala Gly Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Ser Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Lys Glu Leu Pro Cys Ser Thr Tyr Val Gln Ser Asn 145 150 155 160 Ala Ala Thr Ala Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Leu Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Ser Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Gly Ser Asn Glu 195 200 205 Gly Leu Ile Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Ile His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Met Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Ser Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Thr His Lys Lys Glu Val Val Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Ala Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Val Val Val Ser Val Ala Ser Phe Ile Leu Leu Ser Met Val Gly Met 370 375 380 Ala Val Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420 <![CDATA[<210> 2]]> <![CDATA[<211> 378]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 2]]> caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cctctggtta cagctttacc agctacggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcactt acaaaggtta cacacagtat 180 gcacagaact tccagggcag agtcaccatc accacagaca cacccgcgac tacagtctat 240 atggagctga ggagcctgag atctgacgac acggccgtgt attactgcgc gagagttctt 300 tccgagactg gttatttcta ctactactac tacggtatgg acgtctgggg ccaagggacc 360 ctggtcaccg tctcctca 378 <![CDATA[<210> 3]]> <![CDATA[<211> 334]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 3]]> caggctgtgg tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgtactg ggagcagctc caacatcggg gcagattata atgtacactg gtaccagctg 120 cttccaggaa cagcccccaa actcctcatc tatggtaaca ccaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240 caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtgcttcg 300 gtattcggcg gagggaccaa actgaccgtc ctag 334 <![CDATA[<210> 4]]> <![CDATA[<211> 312]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 4]]> gcctcagtga aggtctcctg caaggcttct ggatacagtt tcactagcta ttctatcaac 60 tgggtgcgac aggcccctgg acaagggcct gagtggatgg gatggatcga caccaacact 120 gggaacccaa cctatgccca ggacttcgca ggacggtttg tcttctcctt ggacacctct 180 gtcaccacgg catatctgca gatcagcagc ctaaaggctg gggacactgc cgtttattac 240 tgtgcaacat attatgttga cctttggggg agttatcgcc aagactacta cggtatggac 300 gtctggggcc ac 312 <![CDATA[<210> 5]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 5]]> cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60 tcttgttctg gagggagctc caacatcggg agtaatcctg taaattggta ccagatggtc 120 ccaggaacgg cccccaaact cctcctctat actaataatc agcggccctc aggggtccct 180 gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcaa tggactccag 240 tctgaggatg aggctgatta ttactgtgca gtatgggatg acagcctgag tggccgttgg 300 gtgttcggcg gagggaccaa ggtgaccgtc cta 333 <![CDATA[<210> 6]]> <![CDATA[<211> 411]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 6]]> caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgagggtc 60 tcctgcaagg cgtctggtta cacctttacc agttatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcactt acaatggtga cacaaactat 180 gcacagaagt tccagggcag agtcaccttg acaacagaga catccacgag cacagcctac 240 atggagctga ggcgcctgag atctgacgac acggccgttt actactgtgc gagagatttt 300 gaatttcccg gagattgtag tggtggcagc tgctactcca ggttcatcta ccagcacaac 360 gacatggacg tctggggcca cgggaccctg gtcaccgtct cctcagcaag c 411 <![CDATA[<210> 7]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 7]]> caggctgtgg tgactcagcc gccctcagtg tctgcggccc caggacagaa ggtcaccatc 60 tcctgctctg gaagcagctc caacattggg aatcattatg tatcctggta ccagcacctc 120 ccgggaacag cccccaaact cctcatttat gacaattata agcgaccctc agtgattcct 180 gaccgattct ctgcctccaa gtctggcgcg tcagccaccc tgggcatcat cggactccag 240 actggggacg aggccgatta ttactgcgga acatgggata gcagcctgag tgctgtggta 300 ttcggcggag ggaccaagct gaccgtccta 330 <![CDATA[<210> 8]]> <![CDATA[<211> 381]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 8]]> caggtgcagc tggtgcagtc gggcccagga ctggtgaagc cttcggacac cctgtccctc 60 acctgcagtg tctcaagtga cgccctccgc agcaggagtt attactgggg ctgggtccgc 120 cagccccccg ggaagggatt ggagtggatt gggactgtct cttatagtgg gggcacctac 180 tacaacccgt ccctccagag tcgagtcacc gtgtcggtgg acacgtccaa gaaccacttc 240 tccctgaggt tgaactctgt gaccgccgca gacgcggctg tttattactg tgcgagatct 300 tatttctatg atggcagtgg ttactactac ctgagctact ttgactcctg gggccaggga 360 accctggtca ccgtctcctc a 381 <![CDATA[<210> 9]]> <![CDATA[<211> 327]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 9]]> caggctgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60 acctgtgctt ccagcactgg agcagtcacc agtggtcact atccaaactg gttccagcag 120 aaacctggac aaccacccag ggccctgatt tatagcacag acaacaagca ctcctggacc 180 cctgcccggt tctcaggctc cctcctaggg gtcaaggctg ccctgacact gtcagatgta 240 cagcctgagg acgaggctga ctattactgc ctgctccatt ttggtggtgt cgtggtcttc 300 ggcggaggga ccaagctgac cgtccta 327 <![CDATA[<210> 10]]> <![CDATA[<211> 348]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 10]]> caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag tgtctggatt caccttcagt aactatgcca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggactg ggtggcagtt atatggtatg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaagtga acagcctgag agccgaggac acggctgtgt attactgtgc gaggggtgac 300 tacgttcttg actactgggg ccagggaacc ctggtcaccg tctcctca 348 <![CDATA[<210> 11]]> <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 11]]> gacattgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcagttgcc gggccagtca gagcattccc agctatttaa attggtatca acagaaacca 120 gggaaagccc ctaaggtcct gatctatgct acatccactt tggaagctgg ggtcccatca 180 cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcaccag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacaata cggggatatt cactttcggc 300 cctgggacca aagtggatat caaa 324 <![CDATA[<210> 12]]> <![CDATA[<211> 378]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 12]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg cacttccagc acttatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggc agcatccctg tctttgctac agtaaactac 180 gcacagaagt tccagggcag actcacgatt accgcggacg aatccacgag cacagtttac 240 atggaactga gcagcctgag atctgaggac acggccgttt atttctgtgc gagcccctat 300 tgtagtagta tgaactgcta tacgaccttt tactactttg acttctgggg ccagggaacc 360 ctggtcaccg tctcctca 378 <![CDATA[<210> 13]]> <![CDATA[<211> 327]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 13]]> caggctgtgg tgactcagcc tgcctccgtg tttgggtttc ctggacagtc gatcaccatc 60 tcctgcactg gaaccagcag tgactttggt acttataact atgtctcttg gtaccagcaa 120 cacccaggcc aagcccccaa actcatgatt tttgatgtca gtaatcggcc ctcaggggtt 180 tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240 caggctgagg acgaggcttc ttattactgc agctcctata caagcggcag cactctctac 300 ggcggaggga ccaagctgac cgtcctg 327 <![CDATA[<210> 14]]> <![CDATA[<211> 381]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 14]]> caggtgcagc tggtgcagtc tgggtctgag ttgaagaagc ctggggcctc agtgaaggtt 60 tcctgcaagg cttctggata cagtttcact agctattcta tcaactgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggatgg atcgacacca acactgggaa cccaacctat 180 gcccaggact tcgcaggacg gtttgtcttc tccttggaca cctctgtcac cacggcatat 240 ctgcagatca gcagcctaaa ggctggggac actgccgttt attactgtgc aacatattat 300 gttgaccttt gggggagtta tcgccaagac tactacggta tggacgtctg gggccacggg 360 accctggtca ccgtctcctc a 381 <![CDATA[<210> 15]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 15]]> cagtctgtgg tgactcagcc accctcagtg tctgggaccc ccgggcaggg ggtcaccatc 60 tcttgttctg gagggagctc caacatcggg agtaatcctg taaattggta ccagatggtc 120 ccaggaacgg cccccaaact cctcctctat actaataatc agcggccctc aggggtccct 180 gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcaa tggactccag 240 tctgaggatg aggctgatta ttactgtgca gtatgggatg acagcctgag tggccgttgg 300 gtgttcggcg gagggaccaa gctgaccgtc cta 333 <![CDATA[<210> 16]]> <![CDATA[<211> 369]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 16]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggata catcctcagt aaattatccg tgcactgggt gcgacaggct 120 cctggaaaag gacttgaatg gatgggaggt tctgaacgtg aagatggcga aacagtctac 180 gcacagaagt tccagggcag aatcagcttg accgaggaca catctataga gacagcctac 240 atggagctga gcagcctgag ttctgaggac acggccgtgt attattgtgc aacaggaggc 300 ttctggagta tgattggggg aaatggagtg gactactggg gccagggaac cctggtcacc 360 gtctcctca 369 <![CDATA[<210> 17]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 17]]> caggctgtgg tgactcagtc tccatcgtcc ctgcctgcat ctgtaggaga cagggtcacc 60 atcacttgcc gggcaagtca ggacattaga aataatttag gctggtatca gcagaaacca 120 gggaaagccc ctgagcgcct gatctatgga acctccaatt tgcagagtgg ggtcccgtca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt accctcccac gttcggccgc 300 gggaccaagg tggaaatcaa a 321 <![CDATA[<210> 18]]> <![CDATA[<211> 380]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 18]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgagagtt 60 tcctgcaagg catctgggta caccttcacc agttacttta tgcactgggt gcgacaggcc 120 cctggacaag gacttgagtg gatggcgata acttatcctg gtggtggtag cccatcctac 180 gcaccgcagt tccagggcag actcaccatg accgacgaca cgtccgcgac cacagtctac 240 atggacctga gtgacctgac ttctaaagac acggccgtgt attactgtgc gagaggtgcc 300 caccgttcca ttgggacgac cccccttgac tcgtggggcc agggaaccct ggtcaccgtc 360 tcctcagcaa gcttcaaggg 380 <![CDATA[<210> 19]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 19]]> caggtgcagc tggtgcagtc tgggggacgc gtggtccagg ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt atgtatggcg tccactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggaatg atggatctaa agaatactat 180 ggagactccg tgaagggccg attcaccatc tccagagaca attccaggaa cacgttgtat 240 ctgcaaatga acagcctgag agtcgacgac acggcagtgt atttttgtgc gagagatgga 300 attcctgacc ctgaacgcgg tgactacggg ggcttggact actggggcca gggaaccctg 360 gtcaccgtct cctca 375 <![CDATA[<210> 20]]> <![CDATA[<211> 322]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 20]]> cagactgtgg tgactcagtt tccatcctcc ccgtttgcat ctgtaggaga cggagtcacc 60 atcacttgcc gggcaaggca gagcattagc agttatgtta attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatttacgct acatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggata tgggacagat ttcactctca ccatcagcgg tctgcaacct 240 gaagattttg caacatacta ctgtcaacag agttacagtt ttcctcgaac gttcggccaa 300 gggaccaagg tggaaatcaa ac 322 <![CDATA[<210> 21]]> <![CDATA[<211> 381]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 21]]> caggtgcagc tggtgcagtc tggggctcag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagc cctctggagg caccttcaac aacaatggga tcagttgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggc atcgtcccga actttggaac cccaacctat 180 ggacaagact tccagggcag agtcacgatc accgcggacg aatctacgag cacagtcttc 240 ttggagctga ccagactgag atctgacgac acggccgttt atttctgtgc gcgaggtcgc 300 acggcggtga ctccgatgca attgggttta cagttctact ttgacttctg gggccgggga 360 accctggtca ccgtctcctc a 381 <![CDATA[<210> 22]]> <![CDATA[<211> 325]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 22]]> cagactgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60 acctgttctg ccaacagtgg agcagtcacc agtgattact atccaaactg gttccagcag 120 aaacctggac aagcacccag ggcactgatt tatagtgcaa gcaacaaatt ctcctggacg 180 cctgcccggt tctcaggctc cctccttggg ggcaaagctg ccctgacact gtcaggtgcg 240 cagcctgagg acgaggctga gtattactgc ctggtctact ctggtgatgg tgtggttttc 300 ggcggaggga ccaagctgac cgtcc 325 <![CDATA[<210> 23]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 23]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ccggggcctc agtgaaggtc 60 tcctgcaaga cttctggata tacgttcacc gacaactctg tacactgggt gcgacaggcc 120 cctggacaag ggtttgagtg gatgggacgg atcaacccta acactggtgt ctcaacttct 180 gcccagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacaacctac 240 atggagctga gcagtttgag atctgacgac acggccgtct attactgtgc gagagaggag 300 aacgatagta gtgggtatta cctttggggt cagggaaccc tggtcaccgt ctcctca 357 <![CDATA[<210> 24]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 24]]> cagattgtgg tgactcagtc tccatcctcc ctgtttgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc acctatttaa attggtatca gcaaaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tggagagtgg ggtcccatca 180 aggttcggtg gcagtagatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagga ccccgtggac gttcggccaa 300 gggaccaagg tggacatcaa a 321 <![CDATA[<210> 25]]> <![CDATA[<211> 366]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 25]]> caggtgcagc tggtgcagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60 acctgcacct tctctgggtt ctcactcagt attagtggag tgggtgtggg ctggatccgt 120 cagcccccag gaaaggccct ggagtggctt gcactcattt attgggatga tgataagcgc 180 tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccga aaaccaggtg 240 gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacacagt 300 atgactaaag gcggggctat ctatggtcag gcctactttg aatactgggg ccagggaacc 360 ctggtc 366 <![CDATA[<210> 26]]> <![CDATA[<211> 276]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 26]]> ccatctcctg cactggaacc agacagtgac gttggtggtt ataactatgt ctcctggtac 60 caacaacacc caggcaaagc ccccaaactc atcatttatg atgtcactga tcggccctca 120 ggggtttcta atcgcttctc tgcctccaag tctgccaaca cggcctccct gaccatctct 180 gggctccagg ctgaggacga ggctgattat tactgcagct catatacaag cagcagcact 240 ctggttttcg gcggagggac caagctgacc gtccta 276 <![CDATA[<210> 27]]> <![CDATA[<211> 363]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 27]]> caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggata caccctcact gaattatcca tgcactgggt gcgacaggct 120 cctggaaaag gcctagagtg gatgggaggt tttgagcctg aagatggtga aacaatctac 180 gcacagaagt tccagggcag agtcaccatg accgaggaca catctagaga cacagcctac 240 atggagctga gtagcctgag atctgaggac acggccgtct attactgtac aacagatcag 300 gtctactatc gttcggggag ttattctgga tatgttgact actggggcca gggaaccctg 360 gtc 363 <![CDATA[<210> 28]]> <![CDATA[<211> 363]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 28]]> caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtc 60 tcctgcaagg cttctggacg caccttcagc agctatgtta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatccctc tgtttggtac agcaaactac 180 gcacagaaat tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgacgac acggccgtct attactgtgc gaggggcgcc 300 cagctatatt acaatgatgg tagtggttac atttttgact actggggcca gggagccctg 360 gtc 363 <![CDATA[<210> 29]]> <![CDATA[<211> 390]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 29]]> caggtgcagc tggtgcagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60 tcctgcaagg cttctggatt cagctttatt agctctgctg tgcagtgggt gcgacaggct 120 cgtggacaac gccttgagtg gataggatgg atcgtcgttg ccagtgctaa cacaaactac 180 gcacagaagt tccgggaaag agtcaccatt actagggaca tgtccacaaa cacagcctat 240 atggaactga ccagcctgag atccgaggac acggccgttt attactgtgc ggcagagcac 300 cggtcccctt gtagtggtgg tgatagctgc tacagtctct actacggtat ggacgtctgg 360 ggccaaggga ccctggtcac cgtctcctca 390 <![CDATA[<210> 30]]> <![CDATA[<211> 354]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 30]]> caggtgcagc tggtgcagtc tgggggaggc ttggttccgc ctggggggtc cctgagactg 60 tcctgtacag cctctggatt caccgttagt aactatggca tgagctgggt ccgccagact 120 ccagggaagg ggctggagtg ggtctcaact attagtacta gtagtggtag aacattctac 180 gcagactccg tggagggccg gttcaccatc tccggagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agtcgaagac acggccgtat attactgtgc gaaaggcccg 300 ttcgggggcg actttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354 <![CDATA[<210> 31]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 31]]> caggctgtgg tgactcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttgcc atctacttag cctggtatca acagaaacct 120 ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cagtttatta ctgtcagcag cgtggcaact ggcagtacac ttttggccag 300 gggaccaaac tggagatcaa a 321 <![CDATA[<210> 32]]> <![CDATA[<211> 369]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 32]]> caggtgcagc tggtgcagtc tgggggaggc ctggtacagc ctggcaggtc cctgacactc 60 tcctgtgcag cctctggatt cacctttgat gtttatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcttggagtg ggtcgcaggt attagttgga atagtggtag cgtaggctat 180 gcggactcta tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatta acagtctgag agctgaggac acggccttat attactgtgc aaaagcattc 300 tggttcgggg agttatcggg ttacggtatg gacgtctggg gccaagggac cctggtcacc 360 gtctcctca 369 <![CDATA[<210> 33]]> <![CDATA[<211> ]]>330 <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 33]]> caggctgtgg tgactcagcc tccctccgcg tccgggtttc ctggacagtc agtcaccatc 60 tcctgcactg gaaccagcag tgacgttggt agttataact atgtctcctg gtaccaacag 120 cacccaggca aagcccccaa actcataatt tatgcggtca ctaggcggcc ctcaggggtc 180 cctgagcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240 caggctgagg atgaggctga ttattactgc acctcatatg caggcaacaa caaggatgtc 300 ttcggaactg ggaccaaggt caccgtccta 330 <![CDATA[<210> 34]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 34]]> caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cagctttaac atctatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaaac tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240 atggaactga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaccactt 300 tggggggaat tttactatga tatctggggc caagggaccc tggtcaccgt ctcctca 357 <![CDATA[<210> 35]]> <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 35]]> caggctgtgg tgactcagtc tccaggcacc ctgtccttgt ctccagggga aagagccacc 60 ctctcttgca gggccagtca gagtgttagc agcgggtact cagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca aaagggccgc tggcatccca 180 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag ctgtttgcta cctcacctcc gcccttcggc 300 caagggacac gactggagat taaa 324 <![CDATA[<210> 36]]> <![CDATA[<211> 399]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 36]]> caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt aattatgtta tggagtgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgttgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagatcagag 300 tgggagtctt cctatggttc ggggaattat tatacagatt acttctacta ctacgctatg 360 gacgtctggg gcccagggac cctggtcacc gtctcctca 399 <![CDATA[<210> 37]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 37]]> caggctgtgg tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca ggtctaatca gagcctcctg cgtggtatta gatacaacta tttggattgg 120 tacctgcaga aaccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180 tccggggtcc ctgacaggtt cagtggcagt ggatcagcca cagattttac actgaaaatc 240 agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300 accaccttcg gccaagggac acgactggag attaaa 336 <![CDATA[<210> 38]]> <![CDATA[<211> 387]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 38]]> caggtgcagc tggaggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60 acctgttcct tctctgggtt ctcactcacc actactggag tgactgtggg ctggatccgt 120 cagcccccag gaaaggcctt ggagtggctt gcactcattt attgggatga tgataagcgc 180 tacagcccat ctctgaagag caggctcacc atcaccaagg acacctccaa aaaccaggtg 240 gtccttacca tgaccaacat ggaccctgtg gacactgcca catattactg tgcgcactcc 300 accggctact atgatagtag tggctatcga ggggcccttg atgcttttgc tgtctggggc 360 caagggaccc tggtcaccgt ctcctca 387 <![CDATA[<210> 39]]> <![CDATA[<211> 339]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 39]]> cagattgtgg tgactcagtt tccagactcc ccggctgtgt ctttgggcga gagggccacc 60 atcaactgca agtccagcca gagtgtttta taccactcca acaataaaaa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aacctgctca tttactgggc atctgcccga 180 caatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300 ccgtacactt ttggccaggg gaccaagctg gagatcaaa 339 <![CDATA[<210> 40]]> <![CDATA[<211> 381]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 40]]> caggtgcagc tggtgcagtc gggcccagga ctggtgaagc cttcggacac cctgtccctc 60 acctgcagtg tctcaagtga cgccctccgc agcaggagtt attactgggg ctgggtccgc 120 cagccccccg ggaagggatt ggagtggatt gggactgtct cttatagtgg gggcacctac 180 tacaacccgt ccctccagag tcgagtcacc gtgtcggtgg acacgtccaa gaaccacttc 240 tccctgaggt tgaactctgt gaccgccgca gacgcggctg tttattactg tgcgagatct 300 tatttctatg atggcagtgg ttactactac ctgagctact ttgactcctg gggccaggga 360 accctggtca ccgtctcctc a 381 <![CDATA[<210> 41]]> <![CDATA[<211> 327]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 41]]> caggctgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60 acctgtgctt ccagcactgg agcagtcacc agtggtcact atccaaactg gttccagcag 120 aaacctggac aaccacccag ggccctgatt tatagcacag acaacaagca ctcctggacc 180 cctgcccggt tctcaggctc cctcctaggg gtcaaggctg ccctgacact gtcagatgta 240 cagcctgagg acgaggctga ctattactgc ctgctccatt ttggtggtgt cgtggtcttc 300 ggcggaggga ccaagctgac cgtccta 327 <![CDATA[<210> 42]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 42]]> caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgttcaa cgtctggatt caccttcagg atgtatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggccgtt atttttaacg atggagttaa gaaatattat 180 ggagacgccg tgaagggccg attcaccgtc tccagagaca attccaggaa caccctgtat 240 ctggaaatga aaagcctgag agtcgacgac acggctgcct actactgtgc gagagacggg 300 attcctgacc ccgaacgcgg tgactacggg ggcttggact actggggcca gggaaccctg 360 gtcaccgtct cctca 375 <![CDATA[<210> 43]]> <![CDATA[<211> 322]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 43]]> cagactgtgg tgactcagtc tccatcctcc ctgtctgcat ctgtaggaga cacagtcacc 60 atcacttgcc gggcaagtca gagcattacc agttatttaa actggtatca gcagaaacca 120 ggaaaagccc caaagctcct catctatgct acatccagtt tgcaaagtgg gctcccctca 180 aggttcagtg gcagtggcta tgggacagaa ttcactctca ccatcagtgg tctgcaacct 240 gaagattttg caacatacta ctgtcaacag agttacagtt ttcctcgaac gttcggccaa 300 gggaccaagg tggaaatgga ta 322 <![CDATA[<210> 44]]> <![CDATA[<211> 372]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 44]]> caggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcaa cctctggatt catctttgat gattatgcca tgtactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggaaa catagcctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ttggaaatga acagtctgag agctgaggac acggccttgt attactgtgt aaaagatctt 300 tacgggtacg atattttgac tggtaatgga tatgattact ggggccaggg aaccctggtc 360 accgtctcct ca 372 <![CDATA[<210> 45]]> <![CDATA[<211> 337]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 45]]> caggctgtgg tgactcagtc ttcactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca ggtctagtca gagcctcctg caaagtaatg gatacaacta tttggattgg 120 tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180 tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240 agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactcct 300 ccgacgttcg gccaagggac caaggtggaa atcaaaa 337 <![CDATA[<210> 46]]> <![CDATA[<211> 390]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 46]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 ccctgcaagg cttctggaga caccctcagt tactacggaa tcacttgggt gcgacgggcc 120 cctggacaag ggcttgagtg gatgggacag atcatccctt tctttgctac aacaatctcc 180 gcacagaagt tccagggcag actcaccatg accgcggaag aatccacgag cactggctac 240 atggagcgca cattttacat ggacttgagt agccttagac ctgaggacac ggccgtatac 300 tactgtgcgg ggggctacta tggttcgggg agttcgggcg actacggttt ggacgtctgg 360 ggccaaggga ccctggtcac cgtctcctca 390 <![CDATA[<210> 47]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 47]]> caggctgtgg tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtaaactg gtaccagcag 120 cttccaggaa cagcccccaa actcctcatc tatggtaaca acaatcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240 caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggttcg 300 ggagtcttcg gaactgggac cgaggtcacc gtccta 336 <![CDATA[<210> 48]]> <![CDATA[<211> 384]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 48]]> caggtgcagc tggtgcagtc gggcccagga ctggtgaagc cttcggagac cctgtccctg 60 acgtgcgctg tttctggtga ctccatcggc agtagaagtt tctactgggg ctggatccgc 120 cagcccccag ggaaggggct ggagtggatt ggaagtatct attataatgg gaccacctac 180 tacaagccgt ccctcaagag tcgagtcacc atatccctag acacgtccaa gaaccagttc 240 tccctgaggc tgagctctct gaccgccaca gacacgggtg tctattactg tgcgcgggcg 300 ccaacctact gtagtccttc cagctgcgca gttcactggt acttcaatct ctggggccgt 360 ggcaccctgg tcaccgtctc ctca 384 <![CDATA[<210> 49]]> <![CDATA[<211> 354]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 49]]> caggtgcagc tggtgcagtc tggagctgag ctgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta catatttacc aaatatggta tcagttggct gcgacaggcc 120 cctggacaag ggcttgagtg ggtgggatgg atcagcgctt acaatgaaaa cacaaactat 180 gcagagaagt tccagggcag agtcaccttg accacagatg catccacgag cacggcctac 240 atggagctga ggaacctgag atctgacgac acggccgtat acttctgtgc gagagaagtc 300 tggttcgcgg agtatattta ctggggccag ggaaccctgg tcaccgtctc ctca 354 <![CDATA[<210> 50]]> <![CDATA[<211> 300]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 50]]> caggctgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60 acctgttctg ccaacagtgg agcagtcacc agtgattact atccaaactg gttccagcag 120 aaacctggac aagcacccag ggcactgatt tatagtgcaa gcaacaaatt ctcctggacg 180 cctgcccggt tctcaggctc cctccttggg ggcaaagctg ccctgacact gtcaggtgcg 240 cagcctgagg acgaggctga gtattactgc ctggtctact ctggtgatgg tgtggttttc 300 <![CDATA[<210> 51]]> <![CDATA[<211> 331]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 51]]> cagtctgtgg tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60 tcctgcactg gaaccagcag tgacgttggt gcttataact atgtctcctg gtaccaacaa 120 cacccaggca aagcccccaa actcgtgatt tatgatgtcg ctaatcggcc ctcagggatt 180 tctgaccgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240 caggctgagg acgaggctga ttattactgc ggctcatata ccagcgacgt ctcgccggtt 300 ttcagcgggg ggaccaagct gaccgtcctc a 331 <![CDATA[<210> 52]]> <![CDATA[<211> 399]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成寡核苷酸]]> <![CDATA[<400> 52]]> caggtgcagc tggtgcagtc tgggtctgag ttgaagaagc ctggggcctc agtgaagctt 60 tcctgcaagg cttctggata caccttcaca agtcatccta tgaattgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacacca agactgggaa cctaacttat 180 gcccagggct tcacaggacg gtttgtcttc tccttggaca cctctgtcag gacggcgtat 240 ctgcagatca gcggcctaaa ggctgaggac actgccattt attactgtgc gagagatgag 300 tatagtggct acgattcggt aggggtgttc cgtggttctt ttgacgactt ctacggtatg 360 gacgtctggg gccaagggac cctggtcacc gtctcctca 399 <![CDATA[<210> 53]]> <![CDATA[<211> 126]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 53]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Thr Tyr Lys Gly Tyr Thr Gln Tyr Ala Gln Asn Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Thr Asp Thr Pro Ala Thr Thr Val Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Leu Ser Glu Thr Gly Tyr Phe Tyr Tyr Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 54]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 54]]> Gln Ala Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Asp 20 25 30 Tyr Asn Val His Trp Tyr Gln Leu Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Thr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Ala Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 55]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 55]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Ser Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met 35 40 45 Gly Trp Ile Asp Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Asp Phe 50 55 60 Ala Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Thr Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Tyr Tyr Val Asp Leu Trp Gly Ser Tyr Arg Gln Asp Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly His 115 <![CDATA[<210> 56]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 56]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Gly Ser Ser Asn Ile Gly Ser Asn 20 25 30 Pro Val Asn Trp Tyr Gln Met Val Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Leu Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Asn Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Asp Ser Leu 85 90 95 Ser Gly Arg Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <![CDATA[<210> 57]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 57]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Thr Tyr Asn Gly Asp Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Thr Glu Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Phe Glu Phe Pro Gly Asp Cys Ser Gly Gly Ser Cys Tyr 100 105 110 Ser Arg Phe Ile Tyr Gln His Asn Asp Met Asp Val Trp Gly His Gly 115 120 125 Thr Leu Val Thr Val Ser Ser Ala Ser 130 135 <![CDATA[<210> 58]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 58]]> Gln Ala Val Val Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn His 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Tyr Lys Arg Pro Ser Val Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Ala Ser Ala Thr Leu Gly Ile Ile Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 59]]> <![CDATA[<211> 127]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 59]]> Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Asp 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Ser Ser Asp Ala Leu Arg Ser Arg 20 25 30 Ser Tyr Tyr Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Thr Val Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Gln Ser Arg Val Thr Val Ser Val Asp Thr Ser Lys Asn His Phe 65 70 75 80 Ser Leu Arg Leu Asn Ser Val Thr Ala Ala Asp Ala Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ser Tyr Phe Tyr Asp Gly Ser Gly Tyr Tyr Tyr Leu Ser 100 105 110 Tyr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 60]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 60]]> Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly 20 25 30 His Tyr Pro Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Arg Ala 35 40 45 Leu Ile Tyr Ser Thr Asp Asn Lys His Ser Trp Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Val Lys Ala Ala Leu Thr Leu Ser Asp Val 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Leu His Phe Gly Gly 85 90 95 Val Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 61]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 61]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asp Tyr Val Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 62]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人]]>工序列 <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 62]]> Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Pro Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Ala Thr Ser Thr Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Gly Ile 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <![CDATA[<210> 63]]> <![CDATA[<211> 126]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 63]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Ser Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ser Ile Pro Val Phe Ala Thr Val Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Pro Tyr Cys Ser Ser Met Asn Cys Tyr Thr Thr Phe Tyr Tyr 100 105 110 Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 64]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 64]]> Gln Ala Val Val Thr Gln Pro Ala Ser Val Phe Gly Phe Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Phe Gly Thr Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Gln Ala Pro Lys Leu 35 40 45 Met Ile Phe Asp Val Ser Asn 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 Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Ser Tyr Tyr Cys Ser Ser Tyr Thr Ser Gly 85 90 95 Ser Thr Leu Tyr Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 65]]> <![CDATA[<211> 127]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 65]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Ser Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met 35 40 45 Gly Trp Ile Asp Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Asp Phe 50 55 60 Ala Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Thr Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Tyr Tyr Val Asp Leu Trp Gly Ser Tyr Arg Gln Asp Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly His Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 66]]> <![CDATA[<211> 11]]>1 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 66]]> Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Gly Val Thr Ile Ser Cys Ser Gly Gly Ser Ser Asn Ile Gly Ser Asn 20 25 30 Pro Val Asn Trp Tyr Gln Met Val Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Leu Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Asn Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Asp Ser Leu 85 90 95 Ser Gly Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 67]]> <![CDATA[<211> 123]]> <![CDATA[<21]]>2> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成肽]]> <br/> <br/><![CDATA[<400> 67]]> <br/> <br/><![CDATA[Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ile Leu Ser Lys Leu 20 25 30 Ser Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Gly Ser Glu Arg Glu Asp Gly Glu Thr Val Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ile Ser Leu Thr Glu Asp Thr Ser Ile Glu Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Ser Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Gly Gly Phe Trp Ser Met Ile Gly Gly Asn Gly Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 68]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 68]]> Gln Ala Val Val Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Asn 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Glu Arg Leu Ile 35 40 45 Tyr Gly Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95 Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 69]]> <![CDATA[<211> 126]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 69]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Phe Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Ala Ile Thr Tyr Pro Gly Gly Gly Ser Pro Ser Tyr Ala Pro Gln Phe 50 55 60 Gln Gly Arg Leu Thr Met Thr Asp Asp Thr Ser Ala Thr Thr Val Tyr 65 70 75 80 Met Asp Leu Ser Asp Leu Thr Ser Lys Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala His Arg Ser Ile Gly Thr Thr Pro Leu Asp Ser Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Phe Lys 115 120 125 <![CDATA[<210> 70]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 70]]> Gln Val Gln Leu Val Gln Ser Gly Gly Arg Val Val Gln Ala Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asn Asp Gly Ser Lys Glu Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gly Ile Pro Asp Pro Glu Arg Gly Asp Tyr Gly Gly Leu 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 71]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 71]]> Gln Thr Val Val Thr Gln Phe Pro Ser Ser Pro Phe Ala Ser Val Gly 1 5 10 15 Asp Gly Val Thr Ile Thr Cys Arg Ala Arg Gln Ser Ile Ser Ser Tyr 20 25 30 Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Phe Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 72]]> <![CDATA[<211> 127]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 72]]> Gln Val Gln Leu Val Gln Ser Gly Ala Gln Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Pro Ser Gly Gly Thr Phe Asn Asn Asn 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Val Pro Asn Phe Gly Thr Pro Thr Tyr Gly Gln Asp Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Phe 65 70 75 80 Leu Glu Leu Thr Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Arg Thr Ala Val Thr Pro Met Gln Leu Gly Leu Gln Phe 100 105 110 Tyr Phe Asp Phe Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 73]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 73]]> Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Ser Ala Asn Ser Gly Ala Val Thr Ser Asp 20 25 30 Tyr Tyr Pro Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala 35 40 45 Leu Ile Tyr Ser Ala Ser Asn Lys Phe Ser Trp Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Val Tyr Ser Gly Asp 85 90 95 Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 100 105 <![CDATA[<210> 74]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 74]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Ser Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Met 35 40 45 Gly Arg Ile Asn Pro Asn Thr Gly Val Ser Thr Ser Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Thr Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Asn Asp Ser Ser Gly Tyr Tyr Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 75]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 75]]> Gln Ile Val Val Thr Gln Ser Pro Ser Ser Leu Phe Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 <![CDATA[<210> 76]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 76]]> Gln Val Gln Leu Val Gln Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Ile Ser 20 25 30 Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Glu Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Ser Met Thr Lys Gly Gly Ala Ile Tyr Gly Gln Ala Tyr 100 105 110 Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val 115 120 <![CDATA[<210> 77]]> <![CDATA[<211> 80]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 77]]> Pro Ser Pro Ala Leu Glu Pro Asp Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 10 15 Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Ile Ile 20 25 30 Tyr Asp Val Thr Asp Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Ala 35 40 45 Ser Lys Ser Ala Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala 50 55 60 Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr 65 70 75 80 <![CDATA[<210> 78]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 78]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Gly Phe Glu Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Arg Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Asp Gln Val Tyr Tyr Arg Ser Gly Ser Tyr Ser Gly Tyr Val 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val 115 120 <![CDATA[<210> 79]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 79]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Arg Thr Phe Ser Ser Tyr 20 25 30 Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Leu Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gln Leu Tyr Tyr Asn Asp Gly Ser Gly Tyr Ile Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Ala Leu Val 115 120 <![CDATA[<210> 80]]> <![CDATA[<211> 130]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 80]]> Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Thr 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Ser Phe Ile Ser Ser 20 25 30 Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Trp Ile Val Val Ala Ser Ala Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Arg Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Glu His Arg Ser Pro Cys Ser Gly Gly Asp Ser Cys Tyr Ser 100 105 110 Leu Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser 130 <![CDATA[<210> 81]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 81]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Pro Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Val Ser Asn Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Thr Ser Ser Gly Arg Thr Phe Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Gly Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Pro Phe Gly Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 82]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 82]]> Gln Ala Val Val Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ala Ile Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Gly Asn Trp Gln Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 83]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 83]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Val Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asn Ser Gly Ser Val Gly Tyr Ala Asp Ser Met 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Ala Phe Trp Phe Gly Glu Leu Ser Gly Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 84]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 84]]> Gln Ala Val Val Thr Gln Pro Pro Ser Ala Ser Gly Phe Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Ala Val Thr Arg Arg Pro Ser Gly Val Pro Glu Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Thr Ser Tyr Ala Gly Asn 85 90 95 Asn Lys Asp Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 <![CDATA[<210> 85]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 85]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Asn Ile Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Leu Trp Gly Glu Phe Tyr Tyr Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 86]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 86]]> Gln Ala Val Val Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly 20 25 30 Tyr Ser Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Lys Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Leu Phe Ala Thr Ser Pro 85 90 95 Pro Pro Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <![CDATA[<210> 87]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 87]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Val Met Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Glu Trp Glu Ser Ser Tyr Gly Ser Gly Asn Tyr Tyr Thr 100 105 110 Asp Tyr Phe Tyr Tyr Tyr Ala Met Asp Val Trp Gly Pro Gly Thr Leu 115 120 125 Val Thr Val Ser Ser 130 <![CDATA[<210> 88]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 88]]> Gln Ala Val Val Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Asn Gln Ser Leu Leu Arg Gly 20 25 30 Ile Arg Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Ala Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Thr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 89]]> <![CDATA[<211> 129]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 89]]> Gln Val Gln Leu Glu Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Thr Thr Thr 20 25 30 Gly Val Thr Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Ser Thr Gly Tyr Tyr Asp Ser Ser Gly Tyr Arg Gly Ala 100 105 110 Leu Asp Ala Phe Ala Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120 125 Ser <![CDATA[<210> 90]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 90]]> Gln Ile Val Val Thr Gln Phe Pro Asp Ser Pro Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr His 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Asn Leu Leu Ile Tyr Trp Ala Ser Ala Arg Gln Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys <![CDATA[<210> 91]]> <![CDATA[<211]]>> 127]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成肽]]> <br/> <br/><![CDATA[<400> 91]]> <br/> <br/><![CDATA[Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Asp 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Ser Ser Asp Ala Leu Arg Ser Arg 20 25 30 Ser Tyr Tyr Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Thr Val Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Gln Ser Arg Val Thr Val Ser Val Asp Thr Ser Lys Asn His Phe 65 70 75 80 Ser Leu Arg Leu Asn Ser Val Thr Ala Ala Asp Ala Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ser Tyr Phe Tyr Asp Gly Ser Gly Tyr Tyr Tyr Leu Ser 100 105 110 Tyr Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 92]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 92]]> Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly 20 25 30 His Tyr Pro Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Arg Ala 35 40 45 Leu Ile Tyr Ser Thr Asp Asn Lys His Ser Trp Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Val Lys Ala Ala Leu Thr Leu Ser Asp Val 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Leu His Phe Gly Gly 85 90 95 Val Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 93]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 93]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Thr Ser Gly Phe Thr Phe Arg Met Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Phe Asn Asp Gly Val Lys Lys Tyr Tyr Gly Asp Ala Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Lys Ser Leu Arg Val Asp Asp Thr Ala Ala Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Pro Asp Pro Glu Arg Gly Asp Tyr Gly Gly Leu 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 94]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 94]]> Gln Thr Val Val Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Thr Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu Gln Ser Gly Leu Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Phe Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Met Asp 100 105 <![CDATA[<210> 95]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 95]]> Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Ile Phe Asp Asp Tyr 20 25 30 Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Asn Ile Ala Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Leu Tyr Gly Tyr Asp Ile Leu Thr Gly Asn Gly Tyr Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 96]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 96]]> Gln Ala Val Val Thr Gln Ser Ser Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Gln Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 97]]> <![CDATA[<211> 130]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 97]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Pro Cys Lys Ala Ser Gly Asp Thr Leu Ser Tyr Tyr 20 25 30 Gly Ile Thr Trp Val Arg Arg Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gln Ile Ile Pro Phe Phe Ala Thr Thr Ile Ser Ala Gln Lys Phe 50 55 60 Gln Gly Arg Leu Thr Met Thr Ala Glu Glu Ser Thr Ser Thr Gly Tyr 65 70 75 80 Met Glu Arg Thr Phe Tyr Met Asp Leu Ser Ser Leu Arg Pro Glu Asp 85 90 95 Thr Ala Val Tyr Tyr Cys Ala Gly Gly Tyr Tyr Gly Ser Gly Ser Ser 100 105 110 Gly Asp Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser 130 <![CDATA[<210> 98]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 98]]> Gln Ala Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Ser Gly Val Phe Gly Thr Gly Thr Glu Val Thr Val Leu 100 105 110 <![CDATA[<210> 99]]> <![CDATA[<211> 128]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 99]]> Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Ile Gly Ser Arg 20 25 30 Ser Phe Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Asn Gly Thr Thr Tyr Tyr Lys Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Arg Leu Ser Ser Leu Thr Ala Thr Asp Thr Gly Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Thr Tyr Cys Ser Pro Ser Ser Cys Ala Val His 100 105 110 Trp Tyr Phe Asn Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 100]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 100]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Lys Tyr 20 25 30 Gly Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Glu Asn Thr Asn Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Thr Asp Ala Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Asn Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Val Trp Phe Ala Glu Tyr Ile Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 101]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 101]]> Gln Ser Val Val 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 Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Val Ile Tyr Asp Val Ala Asn Arg Pro Ser Gly Ile Ser Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Thr Ser Asp 85 90 95 Val Ser Pro Val Phe Ser Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 102]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 102]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Pro Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Lys Thr Gly Asn Leu Thr Tyr Ala Gln Gly Phe 50 55 60 Thr Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Arg Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Gly Leu Lys Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Asp Glu Tyr Ser Gly Tyr Asp Ser Val Gly Val Phe Arg Gly 100 105 110 Ser Phe Asp Asp Phe Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Leu 115 120 125 Val Thr Val Ser Ser 130 <![CDATA[<210> 103]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 103]]> Gly Tyr Ser Phe Thr Ser Tyr Gly 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 104]]> Ile Ser Thr Tyr Lys Gly Tyr Thr 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 105]]> Ala Arg Val Leu Ser Glu Thr Gly Tyr Phe Tyr Tyr Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val <![CDATA[<210> 106]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 106]]> Gly Tyr Ser Phe Thr Ser Tyr Ser 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 107]]> Ile Asp Thr Asn Thr Gly Asn Pro 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 108]]> Ala Thr Tyr Tyr Val Asp Leu Trp Gly Ser Tyr Arg Gln Asp Tyr Tyr 1 5 10 15 Gly Met Asp Val 20 <![CDATA[<210> 109]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 109]]> Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 110]]> Ile Ser Thr Tyr Asn Gly Asp Thr 1 5 <![CDATA[<210> 111]]> <![CDATA[<211> 28]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 111]]> Ala Arg Asp Phe Glu Phe Pro Gly Asp Cys Ser Gly Gly Ser Cys Tyr 1 5 10 15 Ser Arg Phe Ile Tyr Gln His Asn Asp Met Asp Val 20 25 <![CDATA[<210> 112]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 112]]> Ser Asp Ala Leu Arg Ser Arg Ser Tyr Tyr 1 5 10 <![CDATA[<210> 113]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 113]]> Val Ser Tyr Ser Gly Gly Thr 1 5 <![CDATA[<210> 114]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 114]]> Ala Arg Ser Tyr Phe Tyr Asp Gly Ser Gly Tyr Tyr Tyr Leu Ser Tyr 1 5 10 15 Phe Asp Ser <![CDATA[<210> 115]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 115]]> Gly Phe Thr Phe Ser Asn Tyr Ala 1 5 <![CDATA[<210> 116]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 116]]> Ile Trp Tyr Asp Gly Ser Asn Lys 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 117]]> Ala Arg Gly Asp Tyr Val Leu Asp Tyr 1 5 <![CDATA[<210> 118]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人]]>工序列 <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 118]]> Gly Gly Thr Ser Ser Thr Tyr Ala 1 5 <![CDATA[<210> 119]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 119]]> Ser Ile Pro Val Phe Ala Thr Val 1 5 <![CDATA[<210> 120]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 120]]> Ala Ser Pro Tyr Cys Ser Ser Met Asn Cys Tyr Thr Thr Phe Tyr Tyr 1 5 10 15 Phe Asp Phe <![CDATA[<210> 121]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220]]>>]]> <br/><![CDATA[<223> 合成肽]]> <br/> <br/><![CDATA[<400> 121]]> <br/> <br/><![CDATA[Gly Tyr Ser Phe Thr Ser Tyr Ser 1 5 <![CDATA[<210> 122]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 122]]> Ile Asp Thr Asn Thr Gly Asn Pro 1 5 <![CDATA[<210> 123]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 123]]> Ala Thr Tyr Tyr Val Asp Leu Trp Gly Ser Tyr Arg Gln Asp Tyr Tyr 1 5 10 15 Gly Met Asp Val 20 <![CDATA[<210> 124]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 124]]> Gly Tyr Ile Leu Ser Lys Leu Ser 1 5 <![CDATA[<210> 125]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 125]]> Ser Glu Arg Glu Asp Gly Glu Thr 1 5 <![CDATA[<210> 126]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 126]]> Ala Thr Gly Gly Phe Trp Ser Met Ile Gly Gly Asn Gly Val Asp Tyr 1 5 10 15 <![CDATA[<210> 127]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 127]]> Gly Tyr Thr Phe Thr Ser Tyr Phe 1 5 <![CDATA[<210> 128]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 128]]> Thr Tyr Pro Gly Gly Gly Ser Pro 1 5 <![CDATA[<210> 129]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 129]]> Ala Arg Gly Ala His Arg Ser Ile Gly Thr Thr Pro Leu Asp Ser 1 5 10 15 <![CDATA[<210> 130]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 130]]> Gly Phe Thr Phe Ser Met Tyr Gly 1 5 <![CDATA[<210> 131]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 131]]> Ile Trp Asn Asp Gly Ser Lys Glu 1 5 <![CDATA[<210> 132]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 132]]> Ala Arg Asp Gly Ile Pro Asp Pro Glu Arg Gly Asp Tyr Gly Gly Leu 1 5 10 15 Asp Tyr <![CDATA[<210> 133]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 133]]> Gly Gly Thr Phe Asn Asn Asn Gly 1 5 <![CDATA[<210> 134]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 134]]> Ile Val Pro Asn Phe Gly Thr Pro 1 5 <![CDATA[<210> 135]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 135]]> Ala Arg Gly Arg Thr Ala Val Thr Pro Met Gln Leu Gly Leu Gln Phe 1 5 10 15 Tyr Phe Asp Phe 20 <![CDATA[<210> 136]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 136]]> Gly Tyr Thr Phe Thr Asp Asn Ser 1 5 <![CDATA[<210> 137]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 137]]> Ile Asn Pro Asn Thr Gly Val Ser 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 138]]> Ala Arg Glu Glu Asn Asp Ser Ser Gly Tyr Tyr Leu 1 5 10 <![CDATA[<210> 139]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 139]]> Gly Phe Ser Leu Ser Ile Ser Gly Val Gly 1 5 10 <![CDATA[<210> 140]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 140]]> Ile Tyr Trp Asp Asp Asp Lys 1 5 <![CDATA[<210> 141]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 141]]> Ala His Ser Met Thr Lys Gly Gly Ala Ile Tyr Gly Gln Ala Tyr Phe 1 5 10 15 Glu Tyr <![CDATA[<210> 142]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 142]]> Gly Tyr Thr Leu Thr Glu Leu Ser 1 5 <![CDATA[<210> 143]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 1]]>43 Phe Glu Pro Glu Asp Gly Glu Thr 1 5 <![CDATA[<210> 144]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 144]]> Thr Thr Asp Gln Val Tyr Tyr Arg Ser Gly Ser Tyr Ser Gly Tyr Val 1 5 10 15 Asp Tyr <![CDATA[<210> 145]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 145]]> Gly Arg Thr Phe Ser Ser Tyr Val 1 5 <![CDATA[<210> 146]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 146]]> Ile Ile Pro Leu Phe Gly Thr Ala 1 5 <![CDATA[<210> 147]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 147]]> Ala Arg Gly Ala Gln Leu Tyr Tyr Asn Asp Gly Ser Gly Tyr Ile Phe 1 5 10 15 Asp Tyr <![CDATA[<210> 148]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 148]]> Gly Phe Ser Phe Ile Ser Ser Ala 1 5 <![CDATA[<210> 149]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 149]]> Ile Val Val Ala Ser Ala Asn Thr 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 150]]> Ala Ala Glu His Arg Ser Pro Cys Ser Gly Gly Asp Ser Cys Tyr Ser 1 5 10 15 Leu Tyr Tyr Gly Met Asp Val 20 <![CDATA[<210> 151]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 151]]> Gly Phe Thr Val Ser Asn Tyr Gly 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> ]]>152 Ile Ser Thr Ser Ser Gly Arg Thr 1 5 <![CDATA[<210> 153]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 153]]> Ala Lys Gly Pro Phe Gly Gly Asp Phe Asp Tyr 1 5 10 <![CDATA[<210> 154]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 154]]> Gly Phe Thr Phe Asp Val Tyr Ala 1 5 <![CDATA[<210> 155]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 155]]> Ile Ser Trp Asn Ser Gly Ser Val 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 156]]> Ala Lys Ala Phe Trp Phe Gly Glu Leu Ser Gly Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> 157]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 157]]> Gly Tyr Ser Phe Asn Ile Tyr Gly 1 5 <![CDATA[<210> 158]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 158]]> Ile Ser Ala Tyr Asn Gly Asn Thr 1 5 <![CDATA[<210> 159]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 159]]> Ala Arg Pro Leu Trp Gly Glu Phe Tyr Tyr Asp Ile 1 5 10 <![CDATA[<210> 160]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 160]]> Gly Phe Thr Phe Ser Asn Tyr Val 1 5 <![CDATA[<210> 161]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 161]]> Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 26]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 162]]> Ala Arg Ser Glu Trp Glu Ser Ser Tyr Gly Ser Gly Asn Tyr Tyr Thr 1 5 10 15 Asp Tyr Phe Tyr Tyr Tyr Ala Met Asp Val 20 25 <![CDATA[<210> 163]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 163]]> Gly Phe Ser Leu Thr Thr Thr Gly Val Thr 1 5 10 <![CDATA[<210> 164]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 164]]> Ile Tyr Trp Asp Asp Asp Lys 1 5 <![CDATA[<210> 165]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]>序列 <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 165]]> Ala His Ser Thr Gly Tyr Tyr Asp Ser Ser Gly Tyr Arg Gly Ala Leu 1 5 10 15 Asp Ala Phe Ala Val 20 <![CDATA[<210> 166]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 166]]> Ser Asp Ala Leu Arg Ser Arg Ser Tyr Tyr 1 5 10 <![CDATA[<210> 167]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 167]]> Val Ser Tyr Ser Gly Gly Thr 1 5 <![CDATA[<210> 168]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 168]]> Ala Arg Ser Tyr Phe Tyr Asp Gly Ser Gly Tyr Tyr Tyr Leu Ser Tyr 1 5 10 15 Phe Asp Ser <![CDATA[<210> 169]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 169]]> Gly Phe Thr Phe Arg Met Tyr Gly 1 5 <![CDATA[<210> 170]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 170]]> Ile Phe Asn Asp Gly Val Lys Lys 1 5 <![CDATA[<210> 171]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 171]]> Ala Arg Asp Gly Ile Pro Asp Pro Glu Arg Gly Asp Tyr Gly Gly Leu 1 5 10 15 Asp Tyr <![CDATA[<210> 172]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 172]]> Gly Phe Ile Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 173]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 173]]> Ile Ser Trp Asn Ser Gly Asn Ile 1 5 <![CDATA[<210> 174]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 174]]> Val Lys Asp Leu Tyr Gly Tyr Asp Ile Leu Thr Gly Asn Gly Tyr Asp 1 5 10 15 Tyr <![CDATA[<210> 175]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 175]]> Gly Asp Thr Leu Ser Tyr Tyr Gly 1 5 <![CDATA[<210> 176]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 176]]> Ile Ile Pro Phe Phe Ala Thr Thr 1 5 <![CDATA[<210> 177]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 177]]> Thr Ala Val Tyr Tyr Cys Ala Gly Gly Tyr Tyr Gly Ser Gly Ser Ser 1 5 10 15 Gly Asp Tyr Gly Leu Asp Val 20 <![CDATA[<210> 178]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 178]]> Gly Asp Ser Ile Gly Ser Arg Ser Phe Tyr 1 5 10 <![CDATA[<210> 179]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 179]]> Ile Tyr Tyr Asn Gly Thr Thr 1 5 <![CDATA[<210> 180]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 180]]> Ala Arg Ala Pro Thr Tyr Cys Ser Pro Ser Ser Cys Ala Val His Trp 1 5 10 15 Tyr Phe Asn Leu 20 <![CDATA[<210> 181]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 181]]> Gly Tyr Ile Phe Thr Lys Tyr Gly 1 5 <![CDATA[<210> 182]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 182]]> Ile Ser Ala Tyr Asn Glu Asn Thr 1 5 <![CDATA[<210> 183]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 183]]> Ala Arg Glu Val Trp Phe Ala Glu Tyr Ile Tyr 1 5 10 <![CDATA[<210> 184]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 184]]> Gly Tyr Thr Phe Thr Ser His Pro 1 5 <![CDATA[<210> 185]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 185]]> Ile Asn Thr Lys Thr Gly Asn Leu 1 5 <![CDATA[<210> 186]]> <![CDATA[<211> 26]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 186]]> Ala Arg Asp Glu Tyr Ser Gly Tyr Asp Ser Val Gly Val Phe Arg Gly 1 5 10 15 Ser Phe Asp Asp Phe Tyr Gly Met Asp Val 20 25 <![CDATA[<210> 187]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 187]]> Ser Ser Asn Ile Gly Ala Asp Tyr Asn 1 5 <![CDATA[<210> 188]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 188]]> Gly Asn Thr 1 <![CDATA[<210> 189]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 189]]> Gln Ser Tyr Asp Ser Ser Leu Ser Ala Ser Val 1 5 10 <![CDATA[<210> ]]> 190 <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 190]]> Ser Ser Asn Ile Gly Ser Asn Pro 1 5 <![CDATA[<210> 191]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 191]]> Thr Asn Asn 1 <![CDATA[<210> 192]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 192]]> Ala Val Trp Asp Asp Ser Leu Ser Gly Arg Trp Val 1 5 10 <![CDATA[<210> 193]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 193]]> Ser Ser Asn Ile Gly Asn His Tyr 1 5 <![CDATA[<210> 194]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]>肽 <![CDATA[<400> 194]]> Asp Asn Tyr 1 <![CDATA[<210> 195]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 195]]> Gly Thr Trp Asp Ser Ser Leu Ser Ala Val Val 1 5 10 <![CDATA[<210> 196]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 196]]> Thr Gly Ala Val Thr Ser Gly His Tyr 1 5 <![CDATA[<210> 197]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 197]]> Ser Thr Asp 1 <![CDATA[<210> 198]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 198]]> Leu Leu His Phe Gly Gly Val Val Val 1 5 <![CDATA[<210> 199]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 199]]> Gln Ser Ile Pro Ser Tyr 1 5 <![CDATA[<210> 200]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 200]]> Ala Thr Ser 1 <![CDATA[<210> 201]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 201]]> Gln Gln Ser Tyr Asn Thr Gly Ile Phe Thr 1 5 10 <![CDATA[<210> 202]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 202]]> Ser Ser Asp Phe Gly Thr Tyr Asn Tyr 1 5 <![CDATA[<210> 203]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 203]]> Asp Val Ser 1 <![CDATA[<210> 204]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 204]]> Ser Ser Tyr Thr Ser Gly Ser Thr Leu Tyr Gly Gly Gly 1 5 10 <![CDATA[<210> 205]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 205]]> Ser Ser Asn Ile Gly Ser Asn Pro 1 5 <![CDATA[<210> 206]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 206]]> Thr Asn Asn 1 <![CDATA[<210> 207]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 207]]> Ala Val Trp Asp Asp Ser Leu Ser Gly Arg Trp Val 1 5 10 <![CDATA[<210> 208]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 208]]> Gln Asp Ile Arg Asn Asn 1 5 <![CDATA[<210> 209]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 209]]> Gly Thr Ser 1 <![CDATA[<210> 210]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 210]]> Leu Gln His Asn Ser Tyr Pro Pro Thr 1 5 <![CDATA[<210> 211]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 211]]> Gln Ser Ile Ser Ser Tyr 1 5 <![CDATA[<210> 212]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 212]]> Ala Thr Ser 1 <![CDATA[<210> 213]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 213]]> Gln Gln Ser Tyr Ser Phe Pro Arg Thr 1 5 <![CDATA[<210> 214]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 214]]> Ser Gly Ala Val Thr Ser Asp Tyr Tyr 1 5 <![CDATA[<210> 215]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 215]]> Ser Ala Ser 1 <![CDATA[<210> 216]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 216]]> Leu Val Tyr Ser Gly Asp Gly Val Val 1 5 <![CDATA[<210> 217]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 217]]> Gln Ser Ile Ser Thr Tyr 1 5 <![CDATA[<210> 218]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 218]]> Ala Ala Ser 1 <![CDATA[<210> 219]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 219]]> Gln Gln Ser Tyr Arg Thr Pro Trp Thr 1 5 <![CDATA[<210> 220]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 220]]> Asp Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 <![CDATA[<210> 221]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 221]]> Asp Val Thr 1 <![CDATA[<210> 222]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 222]]> Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <![CDATA[<210> 223]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 223]]> Gln Ser Val Ala Ile Tyr 1 5 <![CDATA[<210> 224]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 224]]> Asp Ala Ser 1 <![CDATA[<210> 225]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 225]]> Gln Gln Arg Gly Asn Trp Gln Tyr Thr 1 5 <![CDATA[<210> 226]]> <![CDATA[<211> 9]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 226]]> Ser Ser Asp Val Gly Ser Tyr Asn Tyr 1 5 <![CDATA[<210> 227]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 227]]> Ala Val Thr 1 <![CDATA[<210> 228]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 228]]> Thr Ser Tyr Ala Gly Asn Asn Lys Asp Val 1 5 10 <![CDATA[<210> 229]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 229]]> Gln Ser Val Ser Ser Gly Tyr 1 5 <![CDATA[<210> 230]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 230]]> Gly Ala Ser 1 <![CDATA[<210> 231]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 231]]> Gln Leu Phe Ala Thr Ser Pro Pro Pro 1 5 <![CDATA[<210> 232]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 232]]> Gln Ser Leu Leu Arg Gly Ile Arg Tyr Asn Tyr 1 5 10 <![CDATA[<210> 233]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 233]]> Leu Gly Ser 1 <![CDATA[<210> 234]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 234]]> Met Gln Ala Leu Gln Thr Pro Thr Thr 1 5 <![CDATA[<210> 235]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 235]]> Gln Ser Val Leu Tyr His Ser Asn Asn Lys Asn Tyr 1 5 10 <![CDATA[<210> 236]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 236]]> Trp Ala Ser 1 <![CDATA[<210> 237]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 237]]> Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr 1 5 <![CDATA[<210> 238]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 238]]> Thr Gly Ala Val Thr Ser Gly His Tyr 1 5 <![CDATA[<210> 239]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 239]]> Ser Thr Asp 1 <![CDATA[<210> 240]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 240]]> Leu Leu His Phe Gly Gly Val Val Val 1 5 <![CDATA[<210> 241]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 241]]> Gln Ser Ile Thr Ser Tyr 1 5 <![CDATA[<210> 242]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 242]]> Ala Thr Ser 1 <![CDATA[<210> 243]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 243]]> Gln Gln Ser Tyr Ser Phe Pro Arg Thr 1 5 <![CDATA[<210> 244]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 244]]> Gln Ser Leu Leu Gln Ser Asn Gly Tyr Asn Tyr 1 5 10 <![CDATA[<210> 245]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 245]]> Leu Gly Ser 1 <![CDATA[<210> 246]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 246]]> Met Gln Ala Leu Gln Thr Pro Pro Thr 1 5 <![CDATA[<210> 247]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 247]]> Ser Ser Asn Ile Gly Ala Gly Tyr Asp 1 5 <![CDATA[<210> 248]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 248]]> Gly Asn Asn 1 <![CDATA[<210> 249]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 249]]> Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Gly Val 1 5 10 <![CDATA[<210> 250]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 250]]> Ser Ser Asp Val Gly Ala Tyr Asn Tyr 1 5 <![CDATA[<210> 251]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 251]]> Asp Val Ala 1 <![CDATA[<210> 252]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成肽]]> <![CDATA[<400> 252]]> Gly Ser Tyr Thr Ser Asp Val Ser Pro Val 1 5 10 <![CDATA[<210> 253]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 253]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tctagtcaac 60 agaccgggct acagccccat ggtactggag atggagctac tgtcagtcac tttggagcca 120 acgctatcgc ttgattacat cacgtgcgaa tacaaaaccg tcatcccgtc tccgtacgtg 180 aaatgctgcg gtacagcaga gtgcaaggac aaaaacctac ctgactacag ctgtaaggtc 240 ttcaccggcg tctacccatt tatgtggggc ggcgcctact gcttctgcga cgctgaaaac 300 acgcaattga gcgaagcaca tgtggagaag tccgaatcat gcaaaacaga atttgcatca 360 gcatacaggg ctcataccgc atccgcatca gctaagctcc gcgtccttta ccaaggaaat 420 aacatcactg taactgccta tgcaaacggc gaccatgccg tcacagttaa ggacgccaaa 480 ttcattgtgg ggccaatgtc ttcagcctgg acaccttttg acaacaaaat cgtggtgtac 540 aaaggtgacg tttacaacat ggactacccg ccctttggcg caggaagacc aggacaattt 600 ggcgatatcc aaagtcgcac gcctgagagc aaagacgtct atgctaacac acaactggta 660 ctgcagagac cggctgcggg tacggtacac gtgccatact ctcaggcacc atctggcttt 720 aagtattggt taaaagaacg aggggcgtcg ctacagcaca cagcaccatt tggctgccaa 780 atagcaacaa acccggtaag agcgatgaac tgcgccgtag ggaacatgcc catctccatc 840 gacataccgg atgcggcctt cactagggtc gtcgacgcgc cctctttaac ggacatgtca 900 tgcgaggtac cagcctgcac ccattcctca gactttgggg gcgtcgccat tattaaatat 960 gcagtcagca agaaaggcaa gtgtgcggtg cattcgatga ccaacgccgt cactatccgg 1020 gaagctgaga tagaagttga agggaattct cagctgcaaa tctctttctc gacggccttg 1080 gccagcgccg aattccgcgt acaagtctgt tctacacaag tacactgtgc agccgagtgc 1140 caccctccga aggaccacat agtcaactac ccggcgtcac ataccaccct cggggtccag 1200 gacatttccg ctacggcgat gtcatgggtg cagaagatca cgggaggtgt gggactggtt 1260 gtcgctgttg cagcactgat tctaatcgtg gtgctatgcg tgtcgttcag caggcac 1317 <![CDATA[<210> 254]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 254]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tctagtcaat 60 agacctggct acagccccat ggtattggag atggaactac tgtcagtcac tttggagcca 120 acactatcgc ttgattacat cacgtgcgag tacaaaaccg tcatcccgtc tccgtacgtg 180 aagtgctgcg gtacagcaga gtgcaaggac aaaaacctac ctgactacag ctgtaaggtc 240 ttcaccggcg tctacccatt tatgtggggc ggcgcctact gcttctgcga cgctgaaaac 300 acgcagttga gcgaagcaca tgtggagaag tccgaatcat gcaaaacaga atttgcatca 360 gcatacaggg ctcataccgc atctgcatca gctaagctcc gcgtccttta ccaaggaaat 420 aacatcactg taactgccta tgcaaacggc gaccatgccg tcacagttaa ggacgccaaa 480 ttcattgtgg ggccaatgtc ttcagcctgg acacctttcg acaacaaaat tgtggtgtac 540 aaaggtgacg tctataacat ggactacccg ccctttggcg caggaagacc aggacaattt 600 ggcgatatcc aaagtcgcac acctgagagt aaagacgtct atgctaatac acaactggta 660 ctgcagagac cggctgcggg tacggtacac gtgccatact ctcaggcacc atctggcttt 720 aagtattggc taaaagaacg cggggcgtca ctgcagcaca cagcaccatt tggctgccaa 780 atagcaacaa acccggtaag agcggtgaac tgcgccgtag ggaacatgcc catctccatc 840 gacataccgg aagcggcctt cactagggtc gtcgacgcgc cctctttaac ggacatgtcg 900 tgcgaggtac tagcctgcac ccattcctca gactttgggg gcgtcgccat tattaaatat 960 gcagccagca agaaaggcaa gtgtgcggtg cattcgatga ctaacgccgt cactattcgg 1020 gaagctgaga tagaagttga agggaattct cagctgcaaa tctctttctc gacggcctta 1080 gccagcgccg aattccgcgt acaagtctgt tctacacaag tacactgtgc agctgagtgc 1140 caccccccga aggaccacat agtcaactac ccggcgtcac ataccaccct cggggtccag 1200 gacatctccg ctacggcgat gtcatgggtg cagaagatca cgggaggtgt gggactggtt 1260 gttgctgttg ccgcactgat tctaatcgtg gtgctatgcg tgtcgttcag caggcac 1317 <![CDATA[<210> 255]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 255]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tctagtcaat 60 agacctggct acagccccat ggtattggag atggaactac tgtcagtcac tttggagcca 120 acactatcgc ttgattacat cacgtgcgag tacaaaaccg tcatcccgtc tccgtacgtg 180 aagtgctgcg gtacagcaga gtgcaaggac aaaaacctac ctgactacag ctgtaaggtc 240 ttcaccggcg tctacccatt tatgtggggc ggcgcctact gcttctgcga cgctgaaaac 300 acgcagttga gcgaagcaca cgtggagaag tccgaatcat gcaaaacaga atttgcatca 360 gcatacaggg ctcataccgc atctgcatca gctaagctcc gcgtccttta ccaaggaaat 420 aacatcactg taactgccta tgcaaacggc gaccatgccg tcacagttaa ggacgccaaa 480 ttcattgtgg ggccaatgtc ttcagcctgg acacctttcg acaacaaaat tgtggtgtac 540 aaaggtgacg tctataacat ggactacccg ccctttggcg caggaagacc aggacaattt 600 ggcgatatcc aaagtcgcac acctgagagt aaagacgtct atgctaatac acaactggta 660 ctgcagagac cggctgtggg tacggtacac gtgccatact ctcaggcacc atctggcttt 720 aagtattggc taaaagaacg cggggcgtcg ctgcagcaca cagcaccatt tggctgccaa 780 atagcaacaa acccggtaag agcggtgaac tgcgccgtag ggaacatgcc catctccatc 840 gacataccgg aagcggcctt cactagggtc gtcgacgcgc cctctttaac ggacatgtcg 900 tgcgaggtac cagcctgcac ccattcctca gactttgggg gcgtcgccat tattaaatat 960 gcagccagca agaaaggcaa gtgtgcggtg cattcgatga ctaacgccgt cactattcgg 1020 gaagctgaga tagaagttga agggaattct cagctgcaaa tctctttctc gacggcctta 1080 gccagcgccg aattccgcgt acaagtctgt tctacacaag tacactgtgc agccgagtgc 1140 caccccccga aggaccacat agtcaactac ccggcgtcac ataccaccct cggggtccag 1200 gacatctccg ctacggcgat gtcatgggtg cagaagatca cgggaggtgt gggactggtt 1260 gttgctgttg ccgcactgat tctaatcgtg gtgctatgcg tgtcgttcag caggcac 1317 <![CDATA[<210> 256]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 256]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tctagtcaac 60 agaccgggct acagccccat ggtactggag atggagcttc tgtcagtcac tttggagcca 120 acgctatcgc ttgattacat cacgtgcgag tataaaaccg tcatcccgtc tccgtacgtg 180 aaatgctgcg gtacagcaga gtgcaaggac aagagcctac ctgattacag ctgtaaggtc 240 ttcaccggcg tctacccatt catgtggggc ggcgcctact gcttctgcga cactgaaaat 300 acgcaattga gcgaagcaca tgtggagaag tccgaatcat gcaaaacaga atttgcatca 360 gcatataggg ctcataccgc atccgcatca gctaagctcc gcgtccttta ccaaggaaat 420 aatgttactg tatctgctta tgcaaacggc gatcatgccg tcacagttaa ggacgctaaa 480 ttcattgtgg ggccaatgtc ttcagcctgg acaccttttg acaataaaat cgtggtgtac 540 aaaggcgacg tctacaacat ggactacccg cccttcggcg caggaagacc aggacaattt 600 ggcgacatcc aaagtcgcac gcctgagagc gaagacgtct atgctaacac acaactggta 660 ctgcagagac cgtccgcggg tacggtgcac gtgccgtact ctcaggcacc atctggcttc 720 aagtattggc taaaagaacg aggggcgtcg ctgcagcaca cagcaccatt tggctgtcaa 780 atagcaacaa acccggtaag agcgatgaac tgcgccgtag ggaacatgcc tatctccatc 840 gacataccgg acgcggcctt cactagggtc gtcgacgcgc catctttaac ggacatgtcg 900 tgtgaggtac cagcctgcac ccactcctca gactttgggg gcgtagccat cattaaatat 960 gcagccagca agaaaggcaa gtgtgcggtg cattcgatga ctaacgccgt cactattcgg 1020 gaagctgaaa tagaagtaga agggaactct cagttgcaaa tctctttttc gacggcccta 1080 gccagcgccg aattccgcgt acaagtctgt tctacacaag tacactgtgc agccgagtgc 1140 catccaccga aagaccatat agtcaattac ccggcgtcac acaccaccct cggggtccaa 1200 gacatttccg ttacggcgat gtcatgggtg cagaagatca cgggaggtgt gggactggtt 1260 gtcgctgttg cagcactgat cctaatcgtg gtgctatgcg tgtcgtttag caggcac 1317 <![CDATA[<210> 257]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 257]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tctagtcaac 60 agaccgggct acagccccat ggtattggag atggagcttc tgtctgtcac cttggaacca 120 acgctatcgc ttgattacat cacgtgcgag tataaaaccg ttatcccgtc tccgtacgtg 180 aaatgctgcg gtacagcaga gtgtaaggac aagagcctac ctgattacag ctgtaaggtc 240 ttcaccggcg tctacccatt catgtggggc ggcgcctact gcttctgcga caccgaaaat 300 acgcaattga gcgaagcaca tgtggagaag tccgaatcat gcaaaacaga atttgcatca 360 gcatacaggg ctcataccgc atccgcatca gctaagctcc gcgtccttta ccaaggaaat 420 aatatcactg tggctgctta tgcaaacggc gaccatgccg tcacagttaa ggacgctaaa 480 ttcatagtgg ggccaatgtc ttcagcctgg acacctttcg acaataaaat cgtggtgtac 540 aaaggcgacg tctacaacat ggactacccg cccttcggcg caggaagacc aggacaattt 600 ggcgacatcc aaagtcgcac gcctgagagc gaagacgtct atgctaatac acaactggta 660 ctgcagagac cgtccgcggg tacggtgcac gtgccgtact ctcaggcacc atctggcttc 720 aagtattggc taaaagaacg aggggcgtcg ctgcagcaca cagcaccatt tggctgtcaa 780 atagcaacaa acccggtaag agcgatgaac tgcgccgtag ggaacatgcc tatctccatc 840 gacataccgg acgcggcctt taccagggtc gtcgacgcgc catctttaac ggacatgtcg 900 tgtgaggtat cagcctgcac ccattcctca gactttgggg gcgtagccat cattaaatat 960 gcagccagta agaaaggcaa gtgtgcagtg cactcgatga ctaacgccgt cactattcgg 1020 gaagctgaaa tagaagtaga agggaactct cagttgcaaa tctctttttc gacggcccta 1080 gccagcgccg aatttcgcgt acaagtctgt tctacacaag tacactgtgc agccgagtgc 1140 catccaccga aagaccatat agtcaattac ccggcgtcac acaccaccct cggggtccaa 1200 gacatttccg ctacggcgat gtcatgggtg cagaagatca cgggaggtgt gggactggtt 1260 gtcgctgttg cagcactgat cctaatcgtg gtgctatgcg tgtcgtttag caggcac 1317 <![CDATA[<210> 258]]> <![CDATA[<211> 1317]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 258]]> tacgaacacg taacagtgat cccgaacacg gtgggagtac cgtataagac tcttgtcaac 60 agaccgggtt acagccccat ggtattggag atggagctac aatcggtcac cttggaacca 120 acactgtcac ttgactacat cacgtgcgag tacaaaactg tcatcccctc cccgtacgtg 180 aagtgctgtg gtacagcaga gtgcaaggac aagagcctac cagactacag ctgcaaggtc 240 tttactggag tctacccatt tatgtggggc ggcgcctact gcttttgcga cgccgaaaat 300 acgcaattga gcgaggcaca tgtagagaaa tctgaatctt gcaaaacaga gtttgcatcg 360 gcctacagag cccacaccgc atcggcgtcg gcgaagctcc gcgtccttta ccaaggaaac 420 aacattactg tagctgccta cgctaacggc gaccatgccg tcacagtaaa ggacgccaag 480 tttgtcgtgg gaccaatgtc ctccgcctgg acaccttttg acaacaaaat cgtggtgtac 540 aaaggcgacg tctacaacat ggactaccca ccttttggcg caggaagacc aggacaattt 600 ggtgacattc aaagtcgtac accggaaagt aaagacgttt atgccaacac tcagttggta 660 ctacagaggc cagcagcagg cacggtacat gtaccatact ctcaggcacc atctggcttc 720 aagtattggc tgaaggaacg aggagcatcg ctacagcaca cggcaccgtt cggttgccag 780 attgcgacaa acccggtaag agctgtaaat tgcgctgtgg ggaacatacc aatttccatc 840 gacataccgg atgcggcctt tactagggtt gtcgatgcac cctctgtaac ggacatgtca 900 tgcgaagtac cagcctgcac tcactcctcc gactttgggg gcgtcgccat catcaaatat 960 acagctagca agaaaggtaa atgtgcagta cattcgatga ccaacgccgt taccattcga 1020 gaagccgacg tagaagtaga ggggaattcc cagctgcaaa tatccttctc aacagccttg 1080 gcaagcgccg agtttcgcgt gcaagtgtgc tccacacaag tacactgcgc agccgcatgc 1140 caccctccaa aggaccacat agtcaattac ccagcatcac acaccaccct tggggtccag 1200 gatatatcca caacggcaat gtcttgggtg cagaagatta cgggaggagt aggattaatt 1260 gttgctgttg ctgccttaat tttaattgtg gtgctatgcg tgtcgtttag caggcac 1317 <![CDATA[<210> 259]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 259]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Gln Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Ser Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Ala Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Ile Thr Val 130 135 140 Ala Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Val Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Lys Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ala Ala Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Val Asn Cys Ala 260 265 270 Val Gly Asn Ile Pro Ile Ser Ile Asp Ile Pro Asp Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Val Thr Asp Met Ser Cys Glu Val Pro 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Thr Ala Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Asp Val Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Ala Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Thr Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Ile Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 260]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 260]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Leu Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Asn Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Ala Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Ile Thr Val 130 135 140 Thr Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Ile Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Lys Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ala Ala Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Met Asn Cys Ala 260 265 270 Val Gly Asn Met Pro Ile Ser Ile Asp Ile Pro Asp Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Leu Thr Asp Met Ser Cys Glu Val Pro 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Ala Val Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Glu Ile Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Glu Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Ala Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Val Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 261]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 261]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Leu Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Asn Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Ala Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Ile Thr Val 130 135 140 Thr Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Ile Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Lys Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ala Ala Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Val Asn Cys Ala 260 265 270 Val Gly Asn Met Pro Ile Ser Ile Asp Ile Pro Glu Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Leu Thr Asp Met Ser Cys Glu Val Leu 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Ala Ala Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Glu Ile Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Glu Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Ala Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Val Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 262]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 262]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Leu Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Asn Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Ala Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Ile Thr Val 130 135 140 Thr Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Ile Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Lys Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ala Val Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Val Asn Cys Ala 260 265 270 Val Gly Asn Met Pro Ile Ser Ile Asp Ile Pro Glu Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Leu Thr Asp Met Ser Cys Glu Val Pro 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Ala Ala Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Glu Ile Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Glu Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Ala Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Val Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 263]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 263]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Leu Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Ser Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Thr Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Ile Thr Val 130 135 140 Ala Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Ile Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Glu Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ser Ala Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Met Asn Cys Ala 260 265 270 Val Gly Asn Met Pro Ile Ser Ile Asp Ile Pro Asp Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Leu Thr Asp Met Ser Cys Glu Val Ser 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Ala Ala Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Glu Ile Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Glu Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Ala Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Val Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 264]]> <![CDATA[<211> 439]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 264]]> Tyr Glu His Val Thr Val Ile Pro Asn Thr Val Gly Val Pro Tyr Lys 1 5 10 15 Thr Leu Val Asn Arg Pro Gly Tyr Ser Pro Met Val Leu Glu Met Glu 20 25 30 Leu Leu Ser Val Thr Leu Glu Pro Thr Leu Ser Leu Asp Tyr Ile Thr 35 40 45 Cys Glu Tyr Lys Thr Val Ile Pro Ser Pro Tyr Val Lys Cys Cys Gly 50 55 60 Thr Ala Glu Cys Lys Asp Lys Ser Leu Pro Asp Tyr Ser Cys Lys Val 65 70 75 80 Phe Thr Gly Val Tyr Pro Phe Met Trp Gly Gly Ala Tyr Cys Phe Cys 85 90 95 Asp Thr Glu Asn Thr Gln Leu Ser Glu Ala His Val Glu Lys Ser Glu 100 105 110 Ser Cys Lys Thr Glu Phe Ala Ser Ala Tyr Arg Ala His Thr Ala Ser 115 120 125 Ala Ser Ala Lys Leu Arg Val Leu Tyr Gln Gly Asn Asn Val Thr Val 130 135 140 Ser Ala Tyr Ala Asn Gly Asp His Ala Val Thr Val Lys Asp Ala Lys 145 150 155 160 Phe Ile Val Gly Pro Met Ser Ser Ala Trp Thr Pro Phe Asp Asn Lys 165 170 175 Ile Val Val Tyr Lys Gly Asp Val Tyr Asn Met Asp Tyr Pro Pro Phe 180 185 190 Gly Ala Gly Arg Pro Gly Gln Phe Gly Asp Ile Gln Ser Arg Thr Pro 195 200 205 Glu Ser Glu Asp Val Tyr Ala Asn Thr Gln Leu Val Leu Gln Arg Pro 210 215 220 Ser Ala Gly Thr Val His Val Pro Tyr Ser Gln Ala Pro Ser Gly Phe 225 230 235 240 Lys Tyr Trp Leu Lys Glu Arg Gly Ala Ser Leu Gln His Thr Ala Pro 245 250 255 Phe Gly Cys Gln Ile Ala Thr Asn Pro Val Arg Ala Met Asn Cys Ala 260 265 270 Val Gly Asn Met Pro Ile Ser Ile Asp Ile Pro Asp Ala Ala Phe Thr 275 280 285 Arg Val Val Asp Ala Pro Ser Leu Thr Asp Met Ser Cys Glu Val Pro 290 295 300 Ala Cys Thr His Ser Ser Asp Phe Gly Gly Val Ala Ile Ile Lys Tyr 305 310 315 320 Ala Ala Ser Lys Lys Gly Lys Cys Ala Val His Ser Met Thr Asn Ala 325 330 335 Val Thr Ile Arg Glu Ala Glu Ile Glu Val Glu Gly Asn Ser Gln Leu 340 345 350 Gln Ile Ser Phe Ser Thr Ala Leu Ala Ser Ala Glu Phe Arg Val Gln 355 360 365 Val Cys Ser Thr Gln Val His Cys Ala Ala Glu Cys His Pro Pro Lys 370 375 380 Asp His Ile Val Asn Tyr Pro Ala Ser His Thr Thr Leu Gly Val Gln 385 390 395 400 Asp Ile Ser Val Thr Ala Met Ser Trp Val Gln Lys Ile Thr Gly Gly 405 410 415 Val Gly Leu Val Val Ala Val Ala Ala Leu Ile Leu Ile Val Val Leu 420 425 430 Cys Val Ser Phe Ser Arg His 435 <![CDATA[<210> 265]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 265]]> agtattaagg acaacttcaa tgtctataaa gccataagac cgtacctagc tcactgtccc 60 gactgtggag aagggcactc gtgccatagt cccgtagcgc tagaacgcat cagaaacgaa 120 gcgacagacg ggacgctgaa aatccaggtt tccttgcaaa tcggaataaa gacggatgat 180 agccatgatt ggaccaagct gcgttacatg gacaatcata tgccagcaga cgcagagagg 240 gccaggctat ttgtaagaac gtcagcaccg tgcacgatta ctggaacaat gggacacttc 300 atcctggccc gatgtccgaa aggagaaact ctgacggtgg gattcactga cggtaggaag 360 atcagtcact catgtacgca cccatttcac cacgaccctc ctgtgatagg ccgggaaaaa 420 tttcattccc gaccgcagca cggtagagaa ctaccttgca gcacgtacgc gcagagcacc 480 gctgcaactg ccgaggagat agaggtacat atgcccccag acaccccaga tcgcacattg 540 atgtcacaac agtccggtaa tgtaaagatc acagtcaata gtcagacggt gcggtacaag 600 tgtaattgcg gtgactcaaa tgaaggacta accactacag acaaagtgat taataactgc 660 aaggttgatc aatgccatgc cgcggtcacc aatcacaaaa aatggcagta taattcccct 720 ctggtcccgc gtaatgctga actcggggac cgaaaaggaa aagttcacat tccgtttcct 780 ctggcaaatg tgacatgcag ggtgcctaag gcaaggaacc ccaccgtgac gtacggaaaa 840 aaccaagtca tcatgctgct gtatcctgac cacccaacgc tcctgtccta ccggaatatg 900 ggagaagaac caaactatca agaagagtgg gtgacgcata agaaggagat caggttaacc 960 gtgccgactg aagggctcga ggtcacgtgg ggcaacaacg agccgtacaa gtattggccg 1020 cagttatcca caaacggtac agcccacggc cacccgcatg agataatttt gtattattat 1080 gagctgtacc ctactatgac tgtggtagtt gtgtcagtgg cctcgttcgt actcctgtcg 1140 atggtgggtg tggcagtggg gatgtgcatg tgtgcacgac gcagatgcat tacaccgtac 1200 gaactgacac caggagctac cgtccctttc ctgcttagcc taatatgctg cattagaaca 1260 gctaaagcg 1269 <![CDATA[<210> 266]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 266]]> agtactaagg acaattttaa tgtctataaa gctacaagac catatctagc tcattgtcct 60 gactgcggag aagggcattc gtgccacagc cctatcgcat tggagcgcat cagaaatgaa 120 gcaacggacg gaacgctgaa aatccaggtc tctttgcaga tcgggataaa gacagatgac 180 agccacgatt ggaccaagct gcgctatatg gatagccata cgccagcgga cgcggagcga 240 gccggattgc ttgtaaggac ttcagcaccg tgcacgatca ccgggaccat gggacacttt 300 attctcgccc gatgcccgaa aggagagacg ctgacagtgg gatttacgga cagcagaaag 360 atcagccaca catgcacaca cccgttccat catgaaccac ctgtgatagg tagggagagg 420 ttccactctc gaccacaaca tggtaaagag ttaccttgca gcacgtacgt gcagagcacc 480 gctgccactg ccgaggagat agaggtgcat atgcccccag atactcctga ccgcacgctg 540 atgacgcagc agtctggcaa cgtgaagatc acagttaatg ggcagacggt gcggtacaag 600 tgcaactgcg gcggctcaaa cgagggactg acaaccacag acaaagtgat caataactgc 660 aaaattgatc agtgccatgc tgcagtcact aatcacaaga agtggcaata caactcccct 720 ttagtcccgc gtaacgctga actcggggac cgtaaaggaa agattcacat cccattccca 780 ttggcaaacg tgacttgcag agtgccaaaa gcaagaaacc ccacagtaac gtacggaaaa 840 aaccaagtca ccatgctgct gtatcctgac catccgacac tcttgtctta tcgtaacatg 900 ggacaggaac caaattacca cgaggagtgg gtgacacaca agaaggaggt taccttgacc 960 gtgcctactg agggtctgga ggtcacttgg ggcaacaacg aaccatacaa gtactggccg 1020 cagatgtcta cgaacggtac tgctcatggt cacccacatg agataatctt gtactattat 1080 gagctgtacc ccactatgac tgtaatcatt gtgtcggtgg cctcgttcgt gcttctgtcg 1140 atggtgggca cagcagtggg gatgtgtgtg tgcgcacggc gcagatgcat tacaccatat 1200 gaattaacac caggagccac cgttcccttt ctgctcagcc tgctatgttg cgtcagaacg 1260 accaaggcg 1269 <![CDATA[<210> 267]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 267]]> agcaccaagg acaacttcaa tgtctataaa gccacaagac catacttagc tcactgtccc 60 gactgtggag aagggcactc gtgccatagt cccgtagcac tagaacgcat cagaaatgaa 120 gcgacagacg ggacgctgaa aatccaggtc tccttgcaaa tcggaataaa gacggatgac 180 agccacgatt ggaccaagct gcgttatatg gacaaccaca tgccagcaga cgcagagagg 240 gcggggctat ttgtaagaac atcagcaccg tgtacgatta ctggaacaat gggacacttc 300 atcctggccc gatgtccaaa aggggaaact ctgacggtgg gattcactga cagtaggaag 360 attagtcact catgtacgca cccatttcac cacgaccctc ctgtgatagg tcgggaaaaa 420 ttccattccc gaccgcagca cggtaaagag ctaccttgca gcacgtacgt gcagagcacc 480 gccgcaacta ccgaggagat agaggtacac atgcccccag acacccctga tcgcacatta 540 atgtcacaac agtccggcaa cgtaaagatc acagtcaatg gccagacggt gcggtacaag 600 tgtaattgcg gtggctcaaa tgaaggacta acaactacag acaaagtgat taataactgc 660 aaggttgatc aatgtcatgc cgcggtcacc aatcacaaaa agtggcagta taactcccct 720 ctggtcccgc gtaatgctga acttggggac cgaaaaggaa aaattcacat cccgtttccg 780 ctggcaaatg taacatgcag ggtgcctaaa gcaaggaacc ccaccgtgac gtacgggaaa 840 aaccaagtca tcatgctact gtatcctgac cacccaacac tcctgtccta ccggaatatg 900 ggagaagaac caaactatca agaagagtgg gtgatgcata agaaggaagt cgtgctaacc 960 gtgccgactg aagggctcga ggtcacgtgg ggcaacaacg agccgtataa gtattggccg 1020 cagttatcta caaacggtac agcccatggc cacccgcatg agataattct gtattattat 1080 gagctgtacc ccactatgac tgtagtagtt gtgtcagtgg ccacgttcat actcctgtcg 1140 atggtgggta tggcagcggg gatgtgcatg tgtgcacgac gcagatgcat cacaccgtat 1200 gaactgacac caggagctac cgtccctttc ctgcttagcc taatatgctg catcagaaca 1260 gctaaagcg 1269 <![CDATA[<210> 268]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 268]]> agcaccaagg acaacttcaa tgtctataaa gccacaagac catacttagc tcactgtccc 60 gactgtggag aagggcactc gtgccatagt cccgtagcac tagaacgcat cagaaatgaa 120 gcgacagacg ggacgctgaa aatccaggtc tccttgcaaa tcggaataaa gacggacgac 180 agccacgatt ggaccaagct gcgttatatg gacaaccaca tgccagcaga cgcagagagg 240 gcggggctat ttgtaagaac atcagcaccg tgtacgatta ctggaacaat gggacacttc 300 atcctggccc gatgtccaaa aggggaaact ctgacggtgg gattcactga cagtaggaag 360 attagtcatt catgtacgca cccatttcac cacgaccctc ctgtgatagg tcgggaaaaa 420 ttccattccc gaccgcagca cggtaaagag ctaccttgca gcacgtacgt gcagagcacc 480 gccgcaacta ccgaggagat agaggtacac atgcccccag acacccctga tcgcacatta 540 atgtcacaac agtccggcaa cgtaaagatc acagtcaatg gccagacggt gcggtacaag 600 tgtaattgcg gtggctcaaa tgaaggacta acaactacag acaaagtgat taataactgc 660 aaggttgatc aatgtcatgc cgcggtcacc aatcacaaaa agtggcagta taactcccct 720 ctggtcccgc gtaatgctga acttggggac cgaaaaggaa aaattcacat cccgtttccg 780 ctggcaaatg taacatgcag ggtgcctaaa gcaaggaacc ccaccgtgac gtacgggaaa 840 aaccaagtca tcatgctact gtatcctgac cacccaacac tcctgtccta ccggaatatg 900 ggagaagaac caaactatca agaagagtgg gtgatgcata agaaggaagt cgtgctaacc 960 gtgccgactg aagggctcga ggtcacgtgg ggcaacaacg agccgtataa gtattggccg 1020 cagttatcta caaacggtac agcccatggc cacccgcatg agataattct gtattattat 1080 gagctgtacc ctactatgac tgtagtagtt gtgtcagtgg ccacgttcat actcctgtcg 1140 atggtgggta tggcagtggg gatgtgcatg tgtgcacgac gcagatgcat cacaccgtat 1200 gaactgacac caggagctac cgtccctttc ctgcttagcc taatatgctg catcagaaca 1260 gctaaagcg 1269 <![CDATA[<210> 269]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 269]]> agcaccaagg acaacttcaa tgtctataaa gccacaagac catacctagc tcactgtccc 60 gactgtggag aagggcactc gtgccatagt cccgtagcac tagaacgcat cagaaatgaa 120 gcgacagacg ggacgctgaa aatccaggtc tccttgcaaa ttggaatagg gacggatgat 180 agccatgatt ggaccaagct gcgttacatg gacaatcaca taccagcaga cgcagggagg 240 gccgggctat ttgtaagaac atcagcacca tgcacgatta ctggaacaat gggacacttc 300 atcctggccc gatgtccgaa aggagaaact ctgacggtgg gattcactga cagtaggaag 360 attagtcact catgtacgca cccatttcac cacgaccctc ctgtgatagg ccgggaaaaa 420 ttccattccc gaccgcagca cggtaaagag ctaccttgca gcacgtacgt gcagagcaac 480 gccgcaactg ccgaggagat agaggtacac atgcccccag acacccctga tcgcacattg 540 ctgtcacaac agtccggcaa cgtaaagatc acagtcaata gtcagacggt gcggtataag 600 tgtaattgcg gtggctcaaa tgaaggacta ataactacag ataaagtgat taataactgc 660 aaggttgatc aatgtcatgc cgcggtcacc aatcacaaaa agtggcagta taactcccct 720 ctggtcccgc gtaacgctga actcggggac cgaaaaggaa aaattcacat cccgtttccg 780 ctggcaaatg taacatgcat ggtgcctaaa gcaaggaacc ccaccgtgac gtacgggaaa 840 aaccaagtca tcatgctact gtatcctgac cacccaacac tcctgtccta ccggagtatg 900 ggagaagaac caaactatca agaagagtgg gtgacgcaca agaaggaggt cgtgctaacc 960 gtgccgactg aagggctcga ggttacgtgg ggcaacaacg agccgtataa gtattggccg 1020 cagttatctg caaacggtac agcccacggc cacccgcatg agataatctt gtactattat 1080 gagctgtacc ctactatgac tgtagtagtt gtgtcagtgg cctcgttcat actcctgtcg 1140 atggtgggta tggcagtggg gatgtgcatg tgtgcacgac gcagatgcat cacaccatac 1200 gaactgacac caggagctac cgtccctttc ctgcttagcc taatatgctg catcagaaca 1260 gctaaagcg 1269 <![CDATA[<210> 270]]> <![CDATA[<211> 1269]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 270]]> agtattaagg accacttcaa tgtctataaa gccacaagac cgtacctagc tcactgtccc 60 gactgtggag aagggcactc gtgccatagt cccgtagcgc tagaacgcat cagaaacgaa 120 gcgacagacg ggacgttgaa aatccaggtt tccttgcaaa tcggaataaa gacggatgat 180 agccatgatt ggaccaagct gcgttatatg gacaatcaca tgccagcaga cgcagagcgg 240 gccgggctat ttgtaagaac gtcagcaccg tgcacgatta ctggaacaat gggacacttc 300 attctggccc gatgtccgaa aggagaaact ctgacggcgg ggttcactga cggtaggaag 360 atcagtcact catgtacgca cccatttcac catgaccctc ctgtgatagg ccgggaaaaa 420 ttccattccc gaccgcagca cggtagggaa ctaccttgca gcacgtacgc gcagagcacc 480 gctgcaactg ccgaggagat agaggtacac atgcccccag acaccccaga tcgcacatta 540 atgtcacaac agtccggcaa tgtaaagatc acagtcaata gtcagacggt gcggtacaag 600 tgcaattgtg gtgactcaag tgaaggatta accactacag ataaagtgat taataactgc 660 aaggtcgatc aatgccatgc cgcggtcacc aatcacaaaa aatggcagta taattcccct 720 ctggtcccgc gtaatgctga attcggggac cggaaaggaa aagttcacat tccatttcct 780 ctggcaaatg tgacatgcag ggtgcctaaa gcaagaaacc ccaccgtgac gtacggaaaa 840 aaccaagtca tcatgttgct gtatcctgac cacccaacgc tcctgtccta caggaatatg 900 ggagaagaac caaactatca agaagagtgg gtgacgcata agaaggagat caggttaacc 960 gtgccgactg aggggctcga ggtcacgtgg ggtaacaatg agccgtacaa gtattggccg 1020 cagttatcca caaacggtac agcccacggc cacccgcatg agataattct gtattattat 1080 gagctgtacc caactatgac tgcggtagtt ttgtcagtgg cctcgttcat actcctgtcg 1140 atggtgggtg tggcagtggg gatgtgcatg tgtgcacgac gcagatgcat tacaccgtac 1200 gaactgacac caggagctac cgtccctttc ctgcttagcc taatatgctg cattagaaca 1260 gctaaagcg 1269 <![CDATA[<210> 271]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 271]]> Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Ile 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Lys Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Ser His Thr Pro Ala Asp Ala Glu Arg 65 70 75 80 Ala Gly Leu Leu Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Ser Arg Lys Ile Ser His Thr Cys Thr His Pro 115 120 125 Phe His His Glu Pro Pro Val Ile Gly Arg Glu Arg Phe His Ser Arg 130 135 140 Pro Gln His Gly Lys Glu Leu Pro Cys Ser Thr Tyr Val Gln Ser Thr 145 150 155 160 Ala Ala Thr Ala Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Met Thr Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Gly Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Gly Ser Asn Glu 195 200 205 Gly Leu Thr Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Ile Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Ile His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Arg Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Thr Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Asn Met Gly Gln Glu Pro 290 295 300 Asn Tyr His Glu Glu Trp Val Thr His Lys Lys Glu Val Thr Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Met Ser Thr Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Ile Ile Val Ser Val Ala Ser Phe Val Leu Leu Ser Met Val Gly Thr 370 375 380 Ala Val Gly Met Cys Val Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Leu Cys 405 410 415 Cys Val Arg Thr Thr Lys Ala 420 <![CDATA[<210> 272]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 272]]> Ser Ile Lys Asp His Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Lys Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Met Pro Ala Asp Ala Glu Arg 65 70 75 80 Ala Gly Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Ala Gly Phe Thr Asp Gly Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Arg Glu Leu Pro Cys Ser Thr Tyr Ala Gln Ser Thr 145 150 155 160 Ala Ala Thr Ala Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Met Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Ser Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Asp Ser Ser Glu 195 200 205 Gly Leu Thr Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Phe Gly Asp Arg Lys Gly Lys Val His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Arg Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Asn Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Thr His Lys Lys Glu Ile Arg Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Thr Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Ala 355 360 365 Val Val Leu Ser Val Ala Ser Phe Ile Leu Leu Ser Met Val Gly Val 370 375 380 Ala Val Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420 <![CDATA[<210> 273]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 273]]> Ser Ile Lys Asp Asn Phe Asn Val Tyr Lys Ala Ile Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Lys Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Met Pro Ala Asp Ala Glu Arg 65 70 75 80 Ala Arg Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Gly Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Arg Glu Leu Pro Cys Ser Thr Tyr Ala Gln Ser Thr 145 150 155 160 Ala Ala Thr Ala Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Met Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Ser Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Asp Ser Asn Glu 195 200 205 Gly Leu Thr Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Val His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Arg Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Asn Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Thr His Lys Lys Glu Ile Arg Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Thr Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Val Val Val Ser Val Ala Ser Phe Val Leu Leu Ser Met Val Gly Val 370 375 380 Ala Val Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420 <![CDATA[<210> 274]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 274]]> Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Gly Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Ile Pro Ala Asp Ala Gly Arg 65 70 75 80 Ala Gly Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Ser Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Lys Glu Leu Pro Cys Ser Thr Tyr Val Gln Ser Asn 145 150 155 160 Ala Ala Thr Ala Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Leu Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Ser Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Gly Ser Asn Glu 195 200 205 Gly Leu Ile Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Ile His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Met Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Ser Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Thr His Lys Lys Glu Val Val Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Ala Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Val Val Val Ser Val Ala Ser Phe Ile Leu Leu Ser Met Val Gly Met 370 375 380 Ala Val Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420 <![CDATA[<210> 275]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 275]]> Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Lys Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Met Pro Ala Asp Ala Glu Arg 65 70 75 80 Ala Gly Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Ser Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Lys Glu Leu Pro Cys Ser Thr Tyr Val Gln Ser Thr 145 150 155 160 Ala Ala Thr Thr Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Met Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Gly Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Gly Ser Asn Glu 195 200 205 Gly Leu Thr Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Ile His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Arg Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Asn Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Met His Lys Lys Glu Val Val Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Thr Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Val Val Val Ser Val Ala Thr Phe Ile Leu Leu Ser Met Val Gly Met 370 375 380 Ala Val Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420 <![CDATA[<210> 276]]> <![CDATA[<211> 423]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 屈公病毒]]> <![CDATA[<400> 276]]> Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu 1 5 10 15 Ala His Cys Pro Asp Cys Gly Glu Gly His Ser Cys His Ser Pro Val 20 25 30 Ala Leu Glu Arg Ile Arg Asn Glu Ala Thr Asp Gly Thr Leu Lys Ile 35 40 45 Gln Val Ser Leu Gln Ile Gly Ile Lys Thr Asp Asp Ser His Asp Trp 50 55 60 Thr Lys Leu Arg Tyr Met Asp Asn His Met Pro Ala Asp Ala Glu Arg 65 70 75 80 Ala Gly Leu Phe Val Arg Thr Ser Ala Pro Cys Thr Ile Thr Gly Thr 85 90 95 Met Gly His Phe Ile Leu Ala Arg Cys Pro Lys Gly Glu Thr Leu Thr 100 105 110 Val Gly Phe Thr Asp Ser Arg Lys Ile Ser His Ser Cys Thr His Pro 115 120 125 Phe His His Asp Pro Pro Val Ile Gly Arg Glu Lys Phe His Ser Arg 130 135 140 Pro Gln His Gly Lys Glu Leu Pro Cys Ser Thr Tyr Val Gln Ser Thr 145 150 155 160 Ala Ala Thr Thr Glu Glu Ile Glu Val His Met Pro Pro Asp Thr Pro 165 170 175 Asp Arg Thr Leu Met Ser Gln Gln Ser Gly Asn Val Lys Ile Thr Val 180 185 190 Asn Gly Gln Thr Val Arg Tyr Lys Cys Asn Cys Gly Gly Ser Asn Glu 195 200 205 Gly Leu Thr Thr Thr Asp Lys Val Ile Asn Asn Cys Lys Val Asp Gln 210 215 220 Cys His Ala Ala Val Thr Asn His Lys Lys Trp Gln Tyr Asn Ser Pro 225 230 235 240 Leu Val Pro Arg Asn Ala Glu Leu Gly Asp Arg Lys Gly Lys Ile His 245 250 255 Ile Pro Phe Pro Leu Ala Asn Val Thr Cys Arg Val Pro Lys Ala Arg 260 265 270 Asn Pro Thr Val Thr Tyr Gly Lys Asn Gln Val Ile Met Leu Leu Tyr 275 280 285 Pro Asp His Pro Thr Leu Leu Ser Tyr Arg Asn Met Gly Glu Glu Pro 290 295 300 Asn Tyr Gln Glu Glu Trp Val Met His Lys Lys Glu Val Val Leu Thr 305 310 315 320 Val Pro Thr Glu Gly Leu Glu Val Thr Trp Gly Asn Asn Glu Pro Tyr 325 330 335 Lys Tyr Trp Pro Gln Leu Ser Thr Asn Gly Thr Ala His Gly His Pro 340 345 350 His Glu Ile Ile Leu Tyr Tyr Tyr Glu Leu Tyr Pro Thr Met Thr Val 355 360 365 Val Val Val Ser Val Ala Thr Phe Ile Leu Leu Ser Met Val Gly Met 370 375 380 Ala Ala Gly Met Cys Met Cys Ala Arg Arg Arg Cys Ile Thr Pro Tyr 385 390 395 400 Glu Leu Thr Pro Gly Ala Thr Val Pro Phe Leu Leu Ser Leu Ile Cys 405 410 415 Cys Ile Arg Thr Ala Lys Ala 420
Claims (25)
- 一種分離及/或重組之單株抗體或其抗原結合片段,其中該抗體或抗體片段包含選自以下之純系成對之重鏈及輕鏈CDR序列: i) 胺基酸序列分別為SEQ ID NO: 124、125及126之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 208、209及210之CDRL1、CDRL2及CDRL3; ii) 胺基酸序列分別為SEQ ID NO: 106、107及108之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 190、191及192之CDRL1、CDRL2及CDRL3; iii) 胺基酸序列分別為SEQ ID NO: 109、110及111之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 193、194及195之CDRL1、CDRL2及CDRL3; iv) 胺基酸序列分別為SEQ ID NO: 112、113及114之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 196、197及198之CDRL1、CDRL2及CDRL3; v) 胺基酸序列分別為SEQ ID NO: 115、116及117之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 199、200及201之CDRL1、CDRL2及CDRL3; vi) 胺基酸序列分別為SEQ ID NO: 118、119及120之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 202、203及204之CDRL1、CDRL2及CDRL3; vii) 胺基酸序列分別為SEQ ID NO: 121、122及123之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 205、206及207之CDRL1、CDRL2及CDRL3; viii) 胺基酸序列分別為SEQ ID NO: 130、131及132之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 211、212及213之CDRL1、CDRL2及CDRL3; ix) 胺基酸序列分別為SEQ ID NO: 133、134及135之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 214、215及216之CDRL1、CDRL2及CDRL3; x) 胺基酸序列分別為SEQ ID NO: 136、137及138之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 217、218及219之CDRL1、CDRL2及CDRL3; xi) 胺基酸序列分別為SEQ ID NO: 139、140及141之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 220、221及222之CDRL1、CDRL2及CDRL3; xii) 胺基酸序列分別為SEQ ID NO: 151、152及153之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 223、224及225之CDRL1、CDRL2及CDRL3; xiii) 胺基酸序列分別為SEQ ID NO: 154、155及156之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 226、227及228之CDRL1、CDRL2及CDRL3; xiv) 胺基酸序列分別為SEQ ID NO: 157、158及159之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 229、230及231之CDRL1、CDRL2及CDRL3; xv) 胺基酸序列分別為SEQ ID NO: 160、161及162之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 232、233及234之CDRL1、CDRL2及CDRL3; xvi) 胺基酸序列分別為SEQ ID NO: 163、164及165之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 235、236及237之CDRL1、CDRL2及CDRL3; xvii) 胺基酸序列分別為SEQ ID NO: 166、167及168之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 238、239及240之CDRL1、CDRL2及CDRL3; xviii)胺基酸序列分別為SEQ ID NO: 169、170及171之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 241、242及243之CDRL1、CDRL2及CDRL3; xix) 胺基酸序列分別為SEQ ID NO: 172、173及174之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 244、245及246之CDRL1、CDRL2及CDRL3; xx) 胺基酸序列分別為SEQ ID NO: 175、176及177之CDRH1、CDRH2及CDRH3,及胺基酸序列分別為SEQ ID NO: 247、248及249之CDRL1、CDRL2及CDRL3。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段係由如表1之純系成對序列之輕鏈及重鏈可變區序列編碼。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段係由與表1之純系成對序列具有至少70%、80%或90%一致性的輕鏈及重鏈可變區序列編碼。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段係由與表1之純系成對序列具有至少95%一致性的輕鏈及重鏈可變區序列編碼。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段包含如表2之純系成對序列之輕鏈及重鏈可變區序列。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段包含與表2之純系成對序列具有95%一致性的輕鏈及重鏈可變區序列。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體片段為重組ScFv(單鏈可變片段)抗體、Fab片段、F(ab') 2片段或Fv片段。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體為嵌合抗體,或為靶向除糖蛋白以外的屈公病毒抗原之雙特異性抗體。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體為IgG。
- 如請求項1之分離及/或重組之單株抗體,其中該抗體或抗體片段進一步包含細胞穿透肽及/或為胞內抗體。
- 如請求項1之分離及/或重組之單株抗體,其包含選自由以下組成之群的重鏈及輕鏈可變序列對:SEQ ID NO:67/68、55/56、57/58、59/60、61/62、63/64、65/66、70/71、72/73、74/75、76/77、81/82、83/84、85/86、87/88、89/90、91/92、93/94、95/96及97/98。
- 一種融合瘤,其編碼如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段。
- 一種偵測個體之屈公病毒(Chikungunya virus)感染之活體外( ex vivo)方法,其包含: (a) 使來自該個體之樣品與請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段接觸;及 (b) 藉由該抗體或抗體片段與該樣品中屈公病毒糖蛋白E2之結合,偵測該樣品中之E2。
- 如請求項13之方法,其中該樣品為體液。
- 如請求項13之方法,其進一步包含再次進行步驟(a)及(b)且測定E2含量相較於該第一次分析之變化。
- 一種如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段於製備醫藥品之用途,其中該醫藥品係用於治療感染屈公病毒之個體或降低有感染屈公病毒風險之個體之感染可能性。
- 如請求項16之用途,其中該分離及/或重組之單株抗體或抗體片段係在感染之前投與。
- 如請求項16之用途,其中該分離及/或重組之單株抗體或抗體片段係在感染之後投與。
- 如請求項16之用途,其中該分離及/或重組之單株抗體或抗體片段被投與,或編碼該抗體或抗體片段之RNA或DNA序列或載體被基因遞送。
- 一種醫藥組合物,其包含如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段。
- 一種細胞株,其產生如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段。
- 一種產生如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段的方法,其中該方法包含下列步驟: (a) 培養產生該分離及/或重組之單株抗體或抗體片段的細胞株;及 (b) 純化該產生之分離及/或重組之單株抗體或抗體片段。
- 如請求項22之方法,其中該方法包含調配該分離及/或重組之單株抗體或抗體片段為醫藥組合物之步驟。
- 一種套組,其包含如請求項1至11中任一項之分離及/或重組之單株抗體或抗體片段。
- 如請求項24之套組,其中該套組包含包裝材料。
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US11286295B2 (en) | 2016-10-20 | 2022-03-29 | Sanofi | Anti-CHIKV monoclonal antibodies directed against the E2 structural protein |
KR102029394B1 (ko) * | 2017-11-14 | 2019-10-07 | 재단법인 바이오나노헬스가드연구단 | 치쿤구니아 바이러스 감염 진단용 단일클론항체, 이를 생산하는 하이브리도마 및 이를 이용한 치쿤구니아 바이러스 감염 진단 방법 |
EP3735270A1 (en) | 2018-01-05 | 2020-11-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
EP3735589A2 (en) * | 2018-01-05 | 2020-11-11 | Vanderbilt University | Antibody-mediated neutralization of chikungunya virus |
JP6906207B2 (ja) * | 2018-02-09 | 2021-07-21 | 国立大学法人大阪大学 | チクングニアウイルス検出用免疫クロマト分析装置 |
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WO2019236875A1 (en) * | 2018-06-06 | 2019-12-12 | Albert Einstein College Of Medicine, Inc. | Antibodies or antibody-fragments thereof targeting alphaviruses, and compositions and methods comprising same |
WO2021042021A1 (en) * | 2019-08-31 | 2021-03-04 | Vanderbilt University | Human antibodies to alphaviruses |
KR102202082B1 (ko) * | 2019-09-25 | 2021-01-11 | 충북대학교 산학협력단 | 치쿤군야 바이러스의 외피단백질 도메인 ⅱ에 대해 특이적으로 결합하는 단일클론항체, 이를 생산하는 하이브리도마 세포주 및 이의 용도 |
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