TW202302622A - 三聚體穩定性hiv包膜蛋白突變 - Google Patents
三聚體穩定性hiv包膜蛋白突變 Download PDFInfo
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Abstract
提供了人類免疫缺陷病毒(HIV)包膜蛋白,其具有穩定該包膜蛋白的三聚體形式的特定突變。本文所述之HIV包膜蛋白具有提高的三聚體形成百分比和/或提高的三聚體產量。還提供了展示該等HIV包膜蛋白的粒子,編碼該等HIV包膜蛋白的核酸分子和載體,以及含有該等HIV包膜蛋白、粒子、核酸或載體的組成物。
Description
人類免疫缺陷病毒(HIV)影響全世界數百萬人,並且即使在廣泛的抗反轉錄病毒治療的時代,通過有效疫苗預防HIV仍然具有非常高的優先順序。HIV病毒不同毒株和演化支之間的抗原多樣性使得難以開發具有廣泛功效的疫苗。HIV-1係最常見和致病的病毒株,90%以上的HIV/AIDS病例來自HIV-1 M組感染。M組進一步細分為演化支或亞型,其中演化支C最大。有效疫苗理想地能夠引發強力的細胞反應和廣泛中和抗體兩者,該等廣泛中和抗體能夠中和來自不同演化支的HIV-1毒株。
HIV表面上的包膜蛋白刺突(Env)由糖蛋白gp120和gp41的異源二聚體的三聚體組成(圖1A)。前體蛋白gp160被弗林蛋白酶切割成gp120和gp41,gp120係刺突的頭部,並且包含CD4受體結合位點以及大的高變環(V1至V5),gp41係包膜蛋白刺突的膜錨定莖。與其他I類促融合蛋白一樣,gp41包含N端融合肽(FP)、C端跨膜(TM)結構域和細胞質結構域。HIV和靶細胞膜之間的膜融合需要包膜蛋白的一系列構象變化。HIV疫苗可以基於包膜蛋白進行開發。
然而,各種因素使得基於包膜蛋白開發HIV疫苗具有挑戰性,包括HIV-1的高遺傳變異性、包膜蛋白的緻密碳水化合物外殼、以及包膜蛋白刺突結構的相對動態和不穩定的性質。野生型包膜蛋白由於其功能而不穩定。因此,有時將穩定修飾引入到包膜結構中用於產生候選疫苗。包膜蛋白係中和抗體的靶標,並且高度糖基化,其藉由遮罩蛋白表位而降低免疫原性。所有已知的廣泛中和抗體(bNAb)確實適應該等聚糖。
對於疫苗開發,較佳的是使用可誘導bNAb的包膜蛋白。然而,大多數bNAb在其經歷任何構象變化之前僅識別天然包膜蛋白構象。因此,開發穩定的處於其天然樣緊密和封閉構象的包膜蛋白同時最小化非天然和(由此)非中和表位的呈遞,可以改進產生這種bNAb的效率。以前對生產HIV疫苗的做出的努力集中在開發包含三聚體HIV包膜蛋白gp140的融合前胞外結構域的疫苗。gp140不具有跨膜(TM)和細胞質結構域,但與gp120不同,它可以形成三聚體結構。此外,該等先前的努力主要集中在演化支A上。然而,已經誘導的中和抗體反應的廣度仍然有限。因此,如果穩定的天然包膜三聚體針對多個HIV演化支可用,也將是有益的。
二十多年來,已經嘗試開發穩定的處於其融合前三聚體構象的包膜蛋白,僅在產生能夠誘導廣泛中和抗體反應的包膜蛋白的可溶性穩定三聚體方面取得有限的成功。例如,已經將所謂的SOSIP突變(501C、605C和559P)引入包膜蛋白序列以改進可溶性gp140三聚體部分的形成(Sanders等人,
J. Virol. [病毒學雜誌] (2002) 76 (17): 8875-89)。所謂的SOSIP突變包括根據HIV-1分離株HXB2的gp160中的編號(這係本領域中使用的常規編號方案)的位置501和605處的半胱胺酸殘基和位置559處的脯胺酸殘基。在三維蛋白結構中彼此接近的位置501和605處的兩個半胱胺酸殘基的引入導致二硫橋。SOSIP突變體包膜蛋白,例如BG505_SOSIP和B41_SOSIP(來自具有SOSIP突變的HIV毒株BG505和B41(即9032-08.A1.4685)毒株的包膜蛋白),已經用於疫苗研究中,並且顯示誘導2級自體中和Ab(Sanders等人,
Science[科學] (2015), 349 (6224): 139-140)。
然而,即使所謂的SOSIP突變能夠穩定包膜蛋白的三聚體形式,此類SOSIP突變體的三聚體部分通常低於10%,仍然產生大量的單體和聚集體。即使是SOSIP突變體BG505_SOSIP(就其穩定三聚體形式的能力而言,它係一種很有前景的SOSIP突變體包膜)通常也只最多產生25%的三聚體形式(Julien等人,
Proc. Nat. Acad. Sci. [美國科學院院報] (2015), 112 (38), 11947-52)。此外,在該三聚體部分中,三聚體不是完全穩定的,因為它們在頂點呼吸。因此,除了SOSIP突變外,還設計了幾種另外的取代,諸如E64K、A316W和201C-433C,以穩定頂點並防止其呼吸(de Taeye等人,
Cell[細胞] (2015), 163 (7), 1702-15;Kwon等人, (2015)
Nat. Struct. Mol. Biol. [自然-結構與分子生物學] 22 (7) 522-31)。此外,已經報導了進一步的突變和策略以提高三聚化產量並優化融合前封閉HIV包膜三聚體的折疊和穩定性(WO 2018/050747;WO 2019/016062;Rutten等人, (2018)
Cell Reports[細胞報告] 23: 584-595;Rawi等人, (2020) Cell Reports [細胞報告] 33, 108432)。
因此,需要HIV包膜蛋白的穩定三聚體,其具有提高的三聚體形成百分比、提高的三聚體產量和/或提高的三聚體穩定性。較佳的是,HIV包膜蛋白的這種穩定三聚體也將展示與廣泛中和抗體(bNAb)的良好結合和與非廣泛中和Ab(非bNAb)的相對有限結合。本發明之目的係提供具有提高的三聚體百分比並且較佳的是也具有提高的三聚體產量的HIV Env蛋白。
本發明關於重組HIV包膜蛋白,該等蛋白與某些先前描述的HIV包膜三聚體相比具有提高的三聚體形成百分比和/或提高的三聚體產量。所得的穩定且良好折疊的HIV Env三聚體可用於免疫目的,例如,以改進在投與重組HIV Env三聚體時誘導廣泛中和抗體並且減少非中和抗體和弱中和抗體的誘導的機會。本發明還關於分離的核酸分子和編碼重組HIV包膜蛋白的載體,包含該等的細胞,以及重組HIV包膜蛋白、核酸分子、載體和/或細胞的組成物。
在一個一般方面,本發明關於重組人類免疫缺陷病毒(HIV)包膜(Env)蛋白,其包含位置650處的胺基酸色胺酸(Trp)、苯丙胺酸(Phe)、甲硫胺酸(Met)或白胺酸(Leu)中的一種,較佳的是Trp或Phe,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。在某些實施方式中,此類HIV Env蛋白進一步包含一或多個增加三聚體產量和/或穩定三聚體的突變,如本文所示。此類Env蛋白以前沒有描述過,並且位置650處的Trp、Phe、Met或Leu胺基酸導致三聚體產量增加。對於演化支B和演化支C衍生的Env蛋白,這與在該位置具有豐度最高的原始胺基酸(為麩醯胺酸,Gln,Q)的Env蛋白相比已經在本文中顯示。
在某些較佳的實施方式中,本發明之HIV Env蛋白包含位置650處的Trp。
在某些較佳的實施方式中,本發明之HIV Env蛋白包含位置650處的Phe。
在某些實施方式中,本發明之重組HIV包膜(Env)蛋白進一步包含所示位置處的以下胺基酸殘基中的一或多個:
(i) 位置651處的Phe、Leu、Met或Trp,較佳的是Phe;
(ii) 位置655處的Phe、Ile、Met或Trp,較佳的是Ile;
(iii) 位置535處的Asn或Gln,較佳的是Asn;
(iv) 位置589處的Val、Ile或Ala;
(v) 位置573處的Phe或Trp,較佳的是Phe;
(vi) 位置204處的Ile;
(vii) 位置647處的Phe、Met或Ile,較佳的是Phe;
(viii) 位置658處的Val、Ile、Phe、Met、Ala或Leu,較佳的是Val或Ile,更較佳的是Val;
(ix) 位置588處的Gln、Glu、Ile、Met、Val、Trp或Phe,較佳的是Gln或Glu;
(x) 位置64處的Lys或位置66處的Arg或位置64處的Lys和位置66處的Arg;
(xi) 位置316處的Trp;
(xii) 位置201和433兩者處的Cys;
(xiii) 位置556或558或位置556和558兩者處的Pro;
(xiv) 由具有7-10個胺基酸的環,較佳的是8個胺基酸的環,例如具有選自(SEQ ID NO: 9-14)中任一個的序列的環,替換胺基酸位置548-568處的環(HR1環);
(xv) 位置568處的Gly、或位置569處的Gly、或位置636處的Gly、或位置568和636兩者處的Gly、或位置569和636兩者處的Gly;
(xvi) 位置302處的Tyr、或位置519處的Arg、或位置520處的Arg、或位置302處的Tyr和位置519處的Arg、或位置302處的Tyr和位置520處的Arg、或位置302處的Tyr以及位置519和520兩者處的Arg;
(xvii) 該HIV Env蛋白的弗林蛋白酶切割序列中的突變,較佳的是位置508-511處由RRRRRR(SEQ ID NO: 6)進行的替換;
(xviii) 位置501和605處的Cys或位置559處的Pro,較佳的是位置501和605處的Cys和位置559處的Pro;
(xix) 位置108處的His;和/或
(xx) 位置538處的His,
其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。在某些實施方式中,本發明之HIV Env蛋白包含在選自由以上 (i) 至 (viii) 組成之群組的所示位置中的至少兩個位置處的所示胺基酸殘基。
在某些實施方式中,本發明之重組HIV Env蛋白包含位置108處的His、或位置538處的His、或位置108處的His和位置538處的His。
在某些實施方式中,本發明之重組HIV Env蛋白包含位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe,並且進一步包含 (a) 位置501和605處的Cys,或 (b) 位置559處的Pro,或較佳的是 (c) 位置501和605處的Cys和位置559處的Pro(所謂的「SOSIP」變體HIV Env蛋白),其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。在某些實施方式中,這與位置108處的His和/或位置538處的His組合。在某些實施方式中,這與以上 (i)-(viii) 中所述位置處的一或多個胺基酸組合。
在某些實施方式中,根據本發明重組HIV Env蛋白來自演化支C HIV。在某些實施方式中,根據本發明重組HIV Env蛋白來自演化支B HIV。在某些實施方式中,根據本發明重組HIV Env蛋白來自演化支A HIV。在某些實施方式中,根據本發明重組HIV Env蛋白來自演化支D、E、F、G、H、I、J、K或L HIV。在某些實施方式中,根據本發明的重組HIV Env蛋白來自演化支A、B、C、D、E、F、G、H、I、J、K或L中的兩個或更多個演化支中的HIV的循環重組形式(CRF)。
在某些實施方式中,本發明之重組HIV Env蛋白進一步包含HIV Env蛋白的弗林蛋白酶切割序列中的突變,如位置508-511處由RRRRRR(SEQ ID NO: 6)進行的替換。
在一個實施方式中,重組HIV Env蛋白係gp140蛋白。
在另一個實施方式中,重組HIV Env蛋白係gp160蛋白。
在某些實施方式中,重組HIV Env蛋白在細胞質區域被截短。在其某些實施方式中,截短在細胞質區域的7個胺基酸之後。
本發明還揭露了重組HIV Env蛋白,其包含與SEQ ID NO: 2、3、4、5、16中的任一個具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的胺基酸序列,並且其中位置650處的胺基酸係Trp、Phe、Met或Leu,較佳的是Trp或Phe。在該方面,當確定同一性%時,位置650不被考慮在內,並且其中編號係根據HIV-1分離株HXB2的gp160中的編號。同樣在這方面,確定同一性%時未考慮的所示位置處的胺基酸中的一或多個較佳的是選自本文在上述 (i)-(xx) 中指示為較佳的胺基酸。
在另一個一般方面,本發明關於三聚體複合物,其包含本文所述之任何重組HIV Env蛋白中的三種的非共價低聚物。
在另一個一般方面,本發明關於一種粒子,例如脂質體或奈米粒子,例如自組裝奈米粒子,在其表面上展示本發明之重組HIV Env蛋白或本發明之三聚體複合物。
在另一個方面,本發明關於編碼本發明之重組HIV Env蛋白的分離的核酸分子。
在另一個一般方面,本發明關於包含可操作地連接到啟動子的分離的核酸分子的載體。在一個實施方式中,該載體係病毒載體。在另一個實施方式中,該載體係表現載體。在一個較佳的實施方式中,該病毒載體係腺病毒載體。
另一個一般方面關於包含編碼本發明之重組HIV Env蛋白的分離的核酸分子或載體的宿主細胞。此類宿主細胞可以用於重組蛋白產生、重組蛋白表現或病毒顆粒(諸如重組腺病毒)產生。
另一個一般方面關於產生重組HIV Env蛋白之方法,該方法包括使包含編碼本發明之重組HIV Env蛋白的分離的核酸分子或載體的宿主細胞生長在適於產生該重組HIV Env蛋白的條件下。
又一個一般方面關於包含如本文所述之重組HIV Env蛋白、三聚體複合物、分離的核酸分子或載體以及藥學上可接受的載劑的組成物。
在另一個一般方面,本發明關於改善HIV Env蛋白的三聚體形成之方法,該方法包括藉由Trp、Phe、Met或Leu,較佳的是Trp或Phe取代親本HIV Env蛋白中位置650處的胺基酸殘基,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
在背景和整個說明書中引用或描述了各種出版物、文章和專利;該等參考文獻中的每一篇藉由引用以其全文併入本文。包括在本說明書中的對檔、法案、材料、裝置、製品等的討論係出於提供本發明的背景之目的。這種討論不承認任何或所有該等事項形成關於所揭露或要求保護的任何發明的先前技術的一部分。
除非另外定義,否則本文所用的所有技術和科學術語均具有與本發明所屬領域的普通技術者通常理解的相同含義。否則,本文所用的某些術語具有如說明書中闡述的含義。本文引用的所有專利、公開的專利申請和出版物如同完全列出一樣藉由引用併入本文。必須注意,除非上下文另外明確規定,否則如本文和所附申請專利範圍中所使用,單數形式「一個/一種(a/an)」和「該」包括複數指示物。
除非另有說明,否則任何數值(如本文所述之濃度或濃度範圍)應被理解為在所有情況下都被術語「約」修飾。因此,數值通常包括列舉值的 ± 10%。如本文所用,除非上下文另外明確指明,否則數值範圍的使用明確包括所有可能的子範圍、該範圍內的所有單個數值,包括值的此類範圍內的整數和分數。
在整個揭露內容中引用了胺基酸。有二十種天然存在的胺基酸以及許多非天然存在的胺基酸。每種已知的胺基酸(包括天然和非天然兩種胺基酸)均具有全名、單字母的縮寫代碼和三字母的縮寫代碼,所有該等都是熟悉該項技術者所熟知的。例如,用於二十種天然存在的胺基酸的三字母和單字母的縮寫代碼如下:丙胺酸(Ala;A)、精胺酸(Arg;R)、天冬胺酸(Asp;D)、天冬醯胺(Asn;N)、半胱胺酸(Cys;C)、甘胺酸(Gly;G)、麩胺酸(Glu;E)、麩醯胺酸(Gln;Q)、組胺酸(His;H)、異白胺酸(Ile;I)、白胺酸(Leu;L)、離胺酸(Lys;K)、甲硫胺酸(Met;M)、苯丙胺酸(Phe;F)、脯胺酸(Pro;P)、絲胺酸(Ser;S)、蘇胺酸(Thr;T)、色胺酸(Trp;W)、酪胺酸(Tyr;Y)以及纈胺酸(Val;V)。胺基酸可以藉由其全名、單字母的縮寫代碼或三字母的縮寫代碼來提及。
除非上下文有明確規定,否則如本文所用的HIV包膜蛋白的胺基酸序列中位置的編號根據HIV-1分離株HXB2的gp160中的編號,例如以下文獻中所述:Korber等人(Human Retroviruses and AIDS 1998: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences [人類反轉錄病毒和AIDS 1998:核酸和胺基酸序列的編譯和分析]. Korber等人編輯. 新墨西哥州洛斯阿拉莫斯的洛斯阿拉莫斯國家實驗室理論生物學和生物物理學小組(Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, N. Mex.)),該文獻藉由援引以其全文併入本文。根據HXB2的編號在HIV Env蛋白領域係常規的。HIV-1分離株HXB2的gp160具有SEQ ID NO: 1中所示的胺基酸序列。可以使用感興趣的HIV Env序列與此序列的比對來找到感興趣的序列中對應的胺基酸編號。
術語「百分比(%)序列同一性」或「同一性%」描述了兩個或更多個經比對的胺基酸序列與組成該等胺基酸序列的總長度的胺基酸殘基數相比而言一致的胺基酸的匹配(「命中」)數。換言之,使用比對,對於兩個或更多個序列,當將該等序列針對最大對應(如使用本領域已知的序列比較演算法測量的)進行比較和比對時,或者當手動比對和視覺檢查時,可以確定相同的胺基酸殘基的百分比(例如95%、97%或98%同一性)。被比較以確定序列同一性的序列由此可以相差胺基酸的一或多個取代、一或多個添加或一或多個缺失。用於比對蛋白序列的合適程式係熟悉該項技術者已知的。蛋白序列的百分比序列同一性可以例如用程式如CLUSTALW、Clustal Omega、FASTA或BLAST來確定,例如使用NCBI BLAST演算法(Altschul SF等人 (1997), Nucleic Acids Res. [核酸研究] 25: 3389-3402)。
HIV Env蛋白中的「對應位置」係指當比對至少兩個HIV Env序列時胺基酸殘基的位置。除非另有指示,否則按照本領域慣例,用於該等目的胺基酸位置編號係根據HIV-1分離株HXB2的gp160中的編號。
如本文所用的「根據本發明的突變」係親本HIV Env蛋白中位置650處的胺基酸被色胺酸(Trp)、苯丙胺酸(Phe)、甲硫胺酸(Met)或白胺酸(Leu)殘基取代。其中,較佳的是被Trp或Phe取代。如本文所用的另外的「穩定突變」係如本文在表1的條目 (i)-(xvi) 中任一項所述之突變,與親本分子相比,當藉由在所述親本分子中取代對應的胺基酸而引入突變時(參見例如WO 2019/016062),該突變增加HIV Env蛋白的三聚體百分比和/或三聚體產量(其可以例如根據AlphaLISA或粒徑排阻層析(SEC)測定法測量,例如本文所述之分析型SEC測定法,或例如WO 2019/016062中所述之SEC-MALS)。可視需要與根據本發明的突變組合的其他新的穩定突變係親本HIV Env蛋白中位置108處的胺基酸被組胺酸(His)殘基取代,或親本HIV Env蛋白中位置538處的胺基酸被組胺酸(His)殘基取代,或位置108和538兩者處的胺基酸被His殘基取代。由這樣的穩定突變得到的胺基酸典型在野生型HIV分離株的Env蛋白中很少發現(如果會有的話)。
在另一個方面,本發明提供了包含位置108處的組胺酸(His)的HIV Env蛋白,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。此類Env蛋白以前沒有描述過,並且位置108處的His胺基酸導致三聚體產量增加。對於演化支B和演化支C衍生的Env蛋白,這與在該位置具有豐度最高的原始胺基酸(為異白胺酸,Ile)的Env蛋白相比已經在本文中顯示。包含位置108處的組胺酸(His)的HIV Env蛋白可以視需要與位置650和/或538修飾或如本文所述之任何其他胺基酸修飾組合。在某些實施方式中,本發明之重組HIV Env蛋白包含位置108處的His並且進一步包含 (a) 位置501和605處的Cys,或 (b) 位置559處的Pro,或較佳的是 (c) 位置501和605處的Cys和位置559處的Pro,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
當提及HIV毒株(或來自它的Env蛋白)時,術語「天然」或「野生型」可互換使用,並且指自然界中存在的HIV毒株(或來自它的Env蛋白),例如,如感染HIV的患者中的。
本發明一般關於在包膜蛋白序列中的所示位置處包含穩定包膜蛋白的三聚體形式的某些胺基酸取代的重組HIV包膜(Env)蛋白。在HIV包膜蛋白的序列中引入本發明之所鑒定的胺基酸取代和視需要的一或多個另外的穩定突變可導致三聚體形成百分比增加和/或三聚體產量增加。這可以例如使用三聚體特異性抗體、粒徑排阻層析法和與結合到正確折疊的(穩定三聚體)Env蛋白的抗體的結合或替代性地結合到錯誤折疊的(非穩定或非三聚體)Env蛋白的抗體的結合來測量,並且增加的三聚體百分比和/或三聚體產量被認為指示穩定的、天然的、正確折疊的Env蛋白。
人類免疫缺陷病毒(HIV)係慢病毒屬(Lentivirinae)的成員,其係反轉錄病毒科(Retroviridae)的一部分。兩種HIV感染人類:HIV-1和HIV-2。HIV-1係最常見的HIV病毒毒株,並且已知比HIV-2更致病。如本文所使用,術語「人類免疫缺陷病毒」和「HIV」係指但不限於HIV-1和HIV-2。在較佳的實施方式中,HIV係指HIV-1。
HIV被分類為具有高度遺傳趨異的多個演化支。如本文所使用,術語「HIV演化支」或「HIV亞型」係指根據它們的遺傳相似性程度進行分類的相關人類免疫缺陷病毒。最大的一組HIV-1分離株被稱為M組(主要毒株),並且由至少從A至L的十二個演化支組成。
在一個一般方面,本發明關於重組HIV包膜(Env)蛋白。當有關於蛋白使用時,術語「重組」係指藉由重組技術或藉由體外化學合成產生的蛋白。根據本發明之實施方式,「重組」蛋白具有人工胺基酸序列,因為它含有在對應的天然存在的序列中未發現的至少一種序列元件(例如,胺基酸取代、缺失、添加,序列替換等)。較佳的是,「重組」蛋白係非天然存在的HIV包膜蛋白,其針對一或多種天然存在的HIV毒株誘導免疫反應或產生免疫。
術語「HIV包膜蛋白」、「HIV Env」和「HIV Env蛋白」係指蛋白或其片段或衍生物,其本質上在HIV病毒粒子的包膜上表現,並使HIV能夠靶向和附著於HIV感染細胞的質膜。在整個揭露中,術語「包膜」和「Env」可互換使用。該HIV
env基因編碼前體蛋白gp160,該前體蛋白gp160被蛋白水解性地切割成兩種成熟的包膜糖蛋白,即gp120和gp41。該切割反應由宿主細胞蛋白酶、弗林蛋白酶(或弗林蛋白酶樣蛋白酶)在反轉錄病毒包膜糖蛋白前體中高度保守的序列模體處介導。更具體地,gp160三聚化為 (gp160)
3,然後經歷切割成為兩個非共價締合的成熟糖蛋白gp120和gp41。病毒進入隨後由gp120/gp41異源二聚體的三聚體介導。Gp120係受體結合片段,並且結合到靶細胞上的CD4受體(和共受體)上,該靶細胞具有這樣的受體如,例如T-輔助細胞。非共價結合至gp120的Gp41係融合片段並且提供HIV進入細胞的第二步驟。Gp41最初埋在該病毒包膜內,但當gp120與CD4受體和共受體結合時,gp120改變其構象,從而導致gp41暴露,其中它可以幫助與宿主細胞融合。Gp140係gp160的胞外結構域。
根據本發明之實施方式,「HIV包膜(Env)蛋白」可為gp160或gp140蛋白,或其組合、融合物、截短物或衍生物。例如,「HIV包膜蛋白」可以包括與gp41蛋白非共價締合的gp120蛋白。「HIV包膜蛋白」還可為截短的HIV包膜蛋白,該截短的HIV包膜蛋白包括但不局限於包含在胞外結構域(即,延伸至細胞外空間的結構域)中C端截短、在gp41中截短物(如在gp41的胞外結構域的截短物,在gp41的跨膜結構域中截短物,或在gp41的細胞質結構域中截短物)的包膜蛋白。HIV包膜蛋白也可為gp140,對應於gp160胞外結構域,或gp140的延伸或截短形式。gp140蛋白的表現已描述於若干出版物中(例如Zhang等人,2001;Sanders等人,2002;Harris等人,2011),並且該蛋白也可以以不同的變體(例如基於不同的HIV毒株)從服務提供者訂購。根據本發明的gp140蛋白可以具有切割位點突變,使得gp120結構域和gp41結構域不被切割和共價連接,或者替代性地gp120結構域和gp41胞外結構域可被切割和共價連接,例如,藉由二硫橋(例如比如在SOSIP變體中)。「HIV包膜蛋白」還可為天然存在的HIV包膜蛋白的衍生物,該HIV包膜蛋白的衍生物具有例如在弗林蛋白酶切割位點中的序列突變、和/或所謂的SOSIP突變。根據本發明的HIV包膜蛋白也可以具有切割位點,使得gp120和gp41胞外結構域可以非共價連接。
在本發明之較佳的實施方式中,HIV Env蛋白係gp140蛋白或gp160蛋白,並且更較佳的是gp140蛋白。在其他較佳的實施方式中,Env蛋白被截短,例如,藉由與天然Env蛋白相比在細胞質區域的第7個殘基後的殘基的缺失。
根據本發明之實施方式,「HIV包膜蛋白」可為三聚體或單體,並且較佳的是為三聚體。該三聚體可為同源三聚體(例如,包含三種相同的多肽單元的三聚體)或異源三聚體(例如,包含不完全相同的三種多肽單元的三聚體)。較佳的是,該三聚體係同源三聚體。在切割的gp140或gp160的情況下,它係gp120-gp41二聚體的多肽單元的三聚體,並且在該等二聚體中所有三種都相同的情況下,這被認為是同源三聚體。在一些情況下,HIV包膜蛋白也可以六聚體的形式存在。
「HIV包膜蛋白」可為可溶性蛋白或膜結合蛋白。膜結合包膜蛋白典型包含跨膜結構域,例如在包含跨膜結構域(TM)的全長HIV包膜蛋白中。膜結合蛋白可以具有胞質結構域,但是不需要胞質結構域係膜結合的。可溶性包膜蛋白包含跨膜結構域的至少部分或完全缺失。例如,全長HIV包膜蛋白的C末端可以被截短以缺失跨膜結構域,從而產生可溶性蛋白(分別參見例如WO 2019/016062中的圖1A和1B對全長和截短的可溶性HIV Env蛋白的示意圖)。然而,相對於WO 2019/016062的圖1B所示的那些,具有較短截短和替代性截短位置的HIV包膜蛋白仍然可為可溶性的。可以在不同位置進行截短,並且非限制性實例係在胺基酸664、655、683等之後,該等都導致可溶性蛋白。與天然Env蛋白相比,根據本發明的膜結合Env蛋白可以包含完整或部分C端結構域(例如,藉由部分缺失C端細胞質結構域,例如在某些實施方式中,在細胞質區域的第7個殘基之後)。熟悉該項技術者清楚的是,細胞質區域中的缺失也可以來自細胞質結構域的第7個殘基以外的另一個殘基,例如在細胞質結構域的第1、2、3、4、5、6、8、9、10個或任何後面的殘基之後。
訊息肽在表現時典型存在於HIV Env蛋白的N末端,但被訊息肽酶切除,並且因此不存在於成熟蛋白中。訊息肽可以與其他訊息序列互換,並且訊息肽的兩個非限制性實例在本文提供於SEQ ID NO: 7和8中。
根據本發明之實施方式,HIV包膜蛋白例如gp160或gp140可以衍生自來自任何HIV演化支(或「亞型」)的HIV包膜蛋白序列,例如演化支A、演化支B、演化支C、演化支D、演化支E、演化支F、演化支G、演化支H等或其組合(例如,「循環重組形式」或衍生自不同亞型病毒之間的重組的CRF,例如BC、AE、AG、BE、BF、ADG等)。HIV包膜蛋白序列可為天然存在的序列、鑲嵌序列、共有序列、合成序列或其任何衍生物或片段。「鑲嵌序列」包含源自一或多個HIV演化支的至少三個HIV包膜序列的多個表位,並且可以藉由優化T細胞表位覆蓋的演算法來設計。鑲嵌HIV包膜蛋白序列的實例包括描述於例如Barouch等人,
Nat Med[自然方法] 2010, 16: 319-323;WO 2010/059732;和WO 2017/102929中的那些。如本文所用,「共有序列」係指基於同源蛋白的胺基酸序列比對的人工胺基酸序列,例如,如藉由同源蛋白的胺基酸序列的比對(例如,使用Clustal Omega)所確定的。它係基於來自例如至少1000個天然HIV分離株的Env的序列,在序列比對中每個位置處發現的最常見的胺基酸殘基的計算順序。「合成序列」係非天然存在的HIV包膜蛋白,其針對超過一種天然存在的HIV毒株誘導免疫反應或產生免疫。鑲嵌HIV包膜蛋白係合成HIV包膜蛋白的非限制性實例。在本發明之某些實施方式中,親本HIV Env蛋白係共有Env蛋白或合成Env蛋白。在親本Env蛋白中,引入突變以產生位置650處的胺基酸Trp、Phe、Met或Leu。在較佳的實施方式中,突變在HIV Env蛋白的位置650處產生Trp或Phe。視需要,這樣的HIV Env蛋白可以進一步具有在本文於表1所述之所示位置 (i) - (vii) 處的所示胺基酸中的至少一個。特別較佳的是以下Env蛋白,其具有位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe,進一步具有 (a) 在所示位置 (i)-(viii) 處的所示胺基酸殘基中的至少一個,較佳的是至少兩個,和/或 (b) 較佳的是具有另外的SOSIP(例如位置 (xviii) 處的所示胺基酸)和/或 (c) 弗林蛋白酶切割位點突變(例如位置 (xvii) 處的所示胺基酸),如下所述。
在本發明之某些實施方式中,HIV包膜蛋白(無論天然存在的序列、鑲嵌序列、共有序列、合成序列等)包含另外的序列突變,例如在弗林蛋白酶切割位點中,和/或所謂的SOSIP突變。
在本發明之一些實施方式中,本發明中HIV包膜蛋白具有進一步突變且為「SOSIP突變體HIV Env蛋白」。所謂的SOSIP突變係包括「SOS突變」(位置501和605處的Cys殘基,其導致在新產生的半胱胺酸殘基之間引入可能的二硫橋)和「IP突變」(位置559處的Pro殘基)的三聚體穩定突變。根據本發明之實施方式,SOSIP突變體Env蛋白包含至少一種突變,該突變選自由以下項組成之群組:位置501和605處的Cys;位置559處的Pro;並且較佳的是位置501和605處的Cys和位置559處的Pro。SOSIP突變體HIV Env蛋白可進一步包含其他序列突變,例如在弗林蛋白酶切割位點中。此外,在某些實施方式中,可以進一步添加突變,使得Env蛋白包含位置556或位置558或位置556和558處的Pro,據發現,其不僅可以充當SOSIP變體中位置559處的Pro的替代物,還可充當另外的突變,該等突變可進一步改進已經具有位置559處的Pro的SOSIP變體的三聚體形成。
在本發明之某些較佳的實施方式中,SOSIP突變體HIV Env蛋白包含位置501和605處的Cys和位置559處的Pro。
在某些實施方式中,本發明之HIV包膜蛋白進一步包含弗林蛋白酶切割位點中的突變。弗林蛋白酶切割序列中的突變可為胺基酸取代、缺失、插入或一個序列被另一個替換或連接子胺基酸序列進行的替換。較佳的是,在本發明中,使弗林蛋白酶切割位點突變可用於優化切割位點,使得弗林蛋白酶切割比野生型有所改進,例如藉由用RRRRRR(SEQ ID NO: 6)替換殘基508-511處的序列)[即用四個精胺酸殘基替換位置509-510處的典型胺基酸序列(例如EK)(即兩個替換和兩個添加),而在位置508和511處,大多數HIV Env蛋白中已經存在精胺酸殘基,因此該等典型地不需要被替換,但是由於文獻中最終結果常被稱為胺基酸序列RRRRRR,我們在本文保留了這一命名]。改進弗林蛋白酶切割的其他突變係已知的,並且也可以使用。替代性地,可以用連接子替換弗林蛋白酶切割位點,使得弗林蛋白酶切割不再是必要的,但是蛋白將採用天然樣構象(例如描述於(Sharma等人, 2015)和(Georgiev等人, 2015)中)。
在本發明之具體實施方式中,本發明之HIV包膜蛋白進一步包含所謂的SOSIP突變(較佳的是位置501和605處的Cys和位置559處的Pro)和弗林蛋白酶切割位點中的序列突變,較佳的是用RRRRRR(SEQ ID NO: 6)替換殘基508-511處的序列。在某些較佳的實施方式中,HIV Env包含所示SOSIP和弗林蛋白酶切割位點突變,並且此外進一步包含位置556或位置558、最較佳的是位置556和558兩者處的Pro殘基。
在本發明之某些實施方式中,HIV包膜蛋白的胺基酸序列係共有序列,如HIV包膜演化支C共有序列或HIV包膜演化支B共有序列。
可用於本發明的示例性HIV包膜蛋白包括HIV包膜演化支C共有序列(SEQ ID NO: 2)和HIV包膜演化支B共有序列(SEQ ID NO: 4)。該等HIV包膜演化支C和演化支B共有序列可以包含例如增強穩定性和/或三聚體形成的另外突變,例如如上所述之所謂的SOSIP突變和/或弗林蛋白酶切割位點中的序列突變,例如SEQ ID NO: 3所示的ConC_SOSIP序列和SEQ ID NO: 5所示的ConB_SOSIP序列中。
可用於本發明的較佳的HIV包膜蛋白序列(作為「背景」或「親本」分子,其中位置650突變成Trp、Phe、Met或Leu,較佳的是Trp或Phe)的其他非限制性實例包括合成的HIV Env蛋白,視需要具有如上所述之另外的SOSIP和/或弗林蛋白酶切割位點突變。其他非限制性實例係鑲嵌HIV包膜蛋白。
在某些實施方式中,親本分子係野生型HIV Env蛋白。這樣的親本分子可以視需要進一步具有如上所述之SOSIP和/或弗林蛋白酶切割位點突變。
導致位置650處的胺基酸被替換為胺基酸Trp、Phe、Met或Leu,視需要進一步被替換為表1中所述位置 (i)-(xvii) 處的所示胺基酸,和/或視需要進一步包括導致位置108和/或538處的胺基酸被替換為胺基酸His的突變的突變也可用於不存在SOSIP突變(例如在Env共有序列中或在來自野生型HIV分離株的Env蛋白中)的HIV Env蛋白,並且可能還改善其三聚化,因為本發明之突變獨立於SOSIP突變,具有不同的作用模式。實際上,例如,另外的穩定突變顯示在幾種不同的HIV Env蛋白骨架中起作用,如例如在WO 2019/016062中所述,包括在不存在SOS突變以及不存在IP突變的情況下改善HIV Env三聚化特性,以及在不存在任何SOSIP突變的情況下。因此,在某些實施方式中,根據本發明的HIV Env蛋白不含任何SOSIP突變。在另外其他實施方式中,還可以使用SOSIP突變的替代方案以進一步穩定三聚體。在某些替代性實施方式中,使用連接子代替「SOS」突變。在某些替代性實施方式中,用Pro殘基替換位置556和/或558中的一個或兩個,而不是「IP」突變。
根據本發明之實施方式的重組HIV包膜蛋白包含在HIV包膜蛋白的胺基酸序列中的特定位置處具有某一或多個胺基酸殘基的HIV包膜蛋白。具體地,顯示了可以使Env蛋白中的位置650突變成Trp、Phe、Met或Leu殘基以改進Env蛋白的三聚體形成,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。此外,在視需要的實施方式中,在表1中指出了包膜蛋白中的許多位置,以及在一或多個或每個所鑒定的位置處期望的特定胺基酸殘基,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。根據本發明的HIV Env蛋白具有位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe,並且視需要具有在如表1所提供的所示位置 (i)-(xx) 中的至少一個位置處的指定胺基酸殘基。
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表 1]
:根據某些實施方式的重組 HIV Env 蛋白的所示位置處另外的期望胺基酸
1根據HIV-1分離株HXB2的gp160中的編號
編號 | 位置 1 | 期望的胺基酸殘基 |
(i) | 651 | Phe、Leu、Met或Trp(較佳的是Phe) |
(ii) | 655 | Phe、Ile、Met或Trp(較佳的是Ile) |
(iii) | 535 | Asn或Gln(較佳的是Asn) |
(iv) | 589 | Val、Ile或Ala(較佳的是Val或Ile,最較佳的是Val) |
(v) | 573 | Phe或Trp(較佳的是Phe) |
(vi) | 204 | Ile |
(vii) | 647 | Phe、Met、或Ile(較佳的是Phe) |
(viii) | 658 | Val、Ile、Phe、Met、Ala、或Leu (較佳的是Val或Ile,最較佳的是Val) |
(ix) | 588 | Gln、Glu、Ile、Met、Val、Trp或Phe(較佳的是Gln或Glu) |
(x) | 64或66 | 位置64處的Lys;或位置66處的Arg; 或位置64處的Lys和位置66處的Arg |
(xi) | 316 | Trp |
(xii) | 201和433 | 兩個位置處的Cys |
(xiii) | 556或558或者556和558 | 任一個或兩個位置處的Pro |
(xiv) | 548-568(HR1環) | 由以下進行替換:具有7-10個胺基酸的較短且少柔性的環,較佳的是8個胺基酸的環,例如具有選自(SEQ ID NO: 9-14)中任一項所述之序列 |
(xv) | 568、569、636 | 該等位置中任一處的Gly,或位置568和636兩者處的Gly,或位置569和636兩者處的Gly |
(xvi) | 302、519、520 | 位置302處的Tyr、或位置519處的Arg、或位置520處的Arg;或位置302處的Tyr和位置519處的Arg;或位置302處的Tyr和位置520處的Arg;或位置302處的Tyr以及位置519和520兩者處的Arg |
(xvii) | 508-511 | 弗林蛋白酶切割位點處的突變,較佳的是位置508-511處由RRRRRR(SEQ ID NO: 6)進行的替換 |
(xviii) | 501和605、或559、或501和506和559 | 位置501和605處的Cys或位置559處的Pro,較佳的是位置501和605處的Cys和位置559處的Pro |
(xix) | 108 | His |
(xx) | 538 | His |
其中在位置650處為Trp、Phe、Met或Leu,並且在一或多個其他所示位置引入視需要一或多個期望的胺基酸(或所示胺基酸)取代的HIV包膜蛋白的胺基酸序列被稱為「骨架HIV包膜序列」或「親本HIV包膜序列」。例如,如果SEQ ID NO: 3的ConC_SOSIP序列中的位置650突變為Trp、Phe、Met或Leu,則ConC_SOSIP序列被認為是「骨架」或「親本」序列。可以使用根據本發明之實施方式可以引入新的穩定突變(即,位置650處的胺基酸被Trp、Phe、Met或Leu取代)的任何HIV包膜蛋白作為「骨架」或「親本」序列,單獨或與其他突變組合,例如所謂的SOSIP突變和/或弗林蛋白酶切割位點中的突變。可以用作骨架的HIV Env蛋白的非限制性實例包括來自天然HIV分離株的HIV Env蛋白、合成的HIV Env蛋白或共有HIV Env蛋白。
根據本發明之某些實施方式,除了具有位置650處的Trp、Phe、Met或Leu外,HIV包膜蛋白還可以視需要具有在選自由表1中的位置 (i)-(xx) 組成之群組的所示位置中的至少一個位置處的所示胺基酸殘基。通常,已經看到,在所示位置 (i)-(xviii) 包含至少兩個、至少三個、至少四個、至少五個、至少六個、至少七個等取代的組合,較佳的是在所示位置 (i)-(viii) 包含至少兩個、至少三個等取代的組合的HIV Env蛋白與不具有或具有較少此類取代的骨架蛋白相比,具有改善的三聚化性質,參見例如WO 2019/016062。
根據本發明之某些實施方式,除了具有位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe之外,HIV包膜蛋白還可以視需要具有位置108處的His、或位置538處的His、或位置108和538兩者處的His。該等係據顯示獨立地導致如本文所示的改善性質的其他新突變。該等位置係彼此獨立的並且在某些實施方式中可以被組合以導致進一步的改善。此類分子(具有位置650處的Trp、Phe、Met或Leu和位置538和/或108處的His)可以視需要進一步具有在選自由表1中的位置 (i)-(xviii) 組成之群組的所示位置中的至少一個位置處的所示胺基酸殘基。
較佳的是,藉由胺基酸取代將位置650處的Trp、Phe、Met或Leu,和/或 (i) - (vii) 中的胺基酸中的至少一個引入重組HIV Env蛋白中。例如,重組HIV Env蛋白可以由以下HIV Env蛋白產生,該蛋白不含位置650處的Trp、Phe、Met或Leu,或包含以上 (i)-(xx) 中的胺基酸殘基中的零個或僅一個,使得所示胺基酸殘基中的全部或一或多個藉由胺基酸取代被引入重組HIV Env蛋白中。同樣,位置108和/或538處的His可以藉由胺基酸取代被引入重組HIV Env蛋白中。
鑒於本揭露,引入上述取代的HIV Env蛋白的胺基酸序列可為本領域已知的任何HIV Env蛋白,例如來自HIV演化支A、演化支B、演化支C等的天然存在的序列;鑲嵌序列;共有序列,例如演化支B或演化支C共有序列;合成序列;或其衍生物或片段。在本發明之某些實施方式中,HIV Env蛋白的胺基酸序列包含另外的突變,例如所謂的SOSIP突變和/或弗林蛋白酶切割位點中的突變。
在一個具體實施方式中,HIV Env骨架蛋白係包含至少一種突變的SOSIP突變體HIV Env蛋白,該突變選自由以下項組成之群組:位置501和605處的Cys;位置559處的Pro。在較佳的實施方式中,SOSIP突變體HIV Env蛋白包含位置501和605處的Cys和位置559處的Pro。根據該實施方式,重組HIV Env蛋白包含SOSIP突變體HIV Env蛋白的胺基酸序列和位置650處的在該位置產生Trp、Phe、Met或Leu的胺基酸取代,以及視需要在選自由表1中的條目 (i)-(xvi) 組成之群組的所示位置中的至少一個位置處由所示胺基酸殘基進行的一或多個另外的胺基酸取代。
SOSIP突變體HIV Env蛋白可進一步包含弗林蛋白酶切割位點中的突變,如位置608-511處由SEQ ID NO: 6進行的替換。
在一個具體實施方式中,HIV Env骨架蛋白係包含與SEQ ID NO: 2的胺基酸序列具有至少95%、96%、97%、98%、99%或100%同一性的胺基酸序列的HIV Env共有演化支C。在某些實施方式中,SEQ ID NO: 2的HIV共有演化支C序列進一步包含所謂的SOSIP突變,即位置501和605處的Cys和位置559處的Pro,並且在某些實施方式中進一步包含所謂的SOSIP突變和弗林蛋白酶切割位點中的突變,例如位置508-511處由SEQ ID NO: 6進行的替換。在一個具體實施方式中,HIV Env骨架蛋白包含SEQ ID NO: 3中所示的序列,或與其具有至少95%同一性的序列,其中與SEQ ID NO: 3相比,被SEQ ID NO: 6替換的位置501、559、605和508-511處的胺基酸沒有突變。
在另一個具體實施方式中,HIV Env骨架蛋白係包含與SEQ ID NO: 4的胺基酸序列具有至少95%、96%、97%、98%、99%或100%同一性的胺基酸序列的HIV Env共有演化支B。在某些實施方式中,SEQ ID NO: 4的HIV共有演化支B序列進一步包含所謂的SOSIP突變,即位置501和605處的Cys和位置559處的Pro,並且在某些實施方式中進一步包含所謂的SOSIP突變和弗林蛋白酶切割位點中的突變,例如位置508-511處由SEQ ID NO: 6進行的替換。在一個具體實施方式中,HIV Env骨架蛋白包含SEQ ID NO: 5中所示的序列,或與其具有至少95%同一性的序列,其中與SEQ ID NO: 5相比,被SEQ ID NO: 6替換的位置501、559、605和508-511處的胺基酸沒有突變。
在另一個具體實施方式中,HIV Env骨架蛋白係合成的HIV Env蛋白,其可以視需要具有如上所述之另外的SOSIP(501C、605C、559P)和/或弗林蛋白酶切割位點突變(508-511RRRRRR)。
在其他具體實施方式中,HIV Env骨架蛋白係來自野生型演化支A、演化支B或演化支C HIV病毒的HIV Env蛋白,視需要包含另外的突變以根據WO 2018/050747和WO 2019/016062中描述的方法修復和/或穩定序列。
在本發明之某些實施方式中,根據本發明的重組HIV Env蛋白(即,具有位置650處的Trp、Phe、Met或Leu,以及視需要具有在上表1中的位置 (i)-(viii) 處的一或多個所示胺基酸)可以進一步包含在選自由表1中的位置 (ix)-(xvi) 組成之群組的一或多個另外的所示位置處的所示胺基酸殘基(例如,經由取代)。胺基酸取代先前已描述於例如WO 2019/016062中。據發現該等胺基酸取代中的某些取代(例如 (ix))與突變 (i)-(viii)(的組合)非常好地組合,參見例如WO 2019/016062。然而,就本發明人所知,該等先前描述的突變未與本文所述之新取代(即位置650處的Trp、Phe、Met或Leu)組合描述。該等胺基酸突變與本發明之胺基酸取代組合可進一步增加三聚體產量和/或三聚體形成百分比。除了在位置650處被Trp、Phe、Met或Leu胺基酸殘基取代,以及視需要具有在如表1所述之所示位置中的一或多個位置處被所示胺基酸殘基進行的進一步取代和/或位置108和/或538處的His外,該等胺基酸取代還可以被引入本文所述之任何重組HIV Env蛋白中。本發明中鑒定的取代[位置650處的W、F、M或L;並且同樣對於位置538處的H和位置108處的H]據發明人所知,不存在於天然(組M,即總體)HIV Env序列中,未發現在以前報導的HIV Env蛋白序列中與表1的任何取代 (i)-(xx) 進行組合,並且以前沒有提出會導致提高的HIV Env蛋白三聚化、提高的三聚體產量和/或提高的三聚體穩定性。顯然,以前描述的突變沒有提供針對引入本發明之突變的任何建議,更不必說如例如藉由抗體PGT145結合測量的其對具有封閉頂點的三聚體形成的驚人效果。除了表1中點突變 (ix)-(xiii) 外,還可以由以下替換Env蛋白的HR1環(野生型序列中胺基酸殘基548-568,根據HXB2分離株的gp160的編號):具有7-10個胺基酸的較短且少柔性的環,較佳的是8個胺基酸的環,例如具有選自(SEQ ID NO: 9-14)中任一項所述之序列,參見,例如Kong等人(Nat Commun. [自然通訊] 2016年6月28日; 7: 12040. doi:10.1038/ncomms12040)描述了這樣的較短的環替換HR1環。這種進一步具有位置650處的Trp、Phe、Met或Leu胺基酸殘基,以及視需要在 (i)-(viii) 中的所示位置中的至少一個位置處的所示胺基酸殘基的Env變體也是本發明之實施方式。在本發明之某些實施方式中,可將 (ix)-(xiv) 中列出的突變添加到本發明之HIV Env蛋白中,即具有位置650處的Trp、Phe、Met或Leu。在另外的實施方式中,該等突變可以與突變組合成位置 (i) - (vii) 處的一或多個所示胺基酸。此外,可以進行組 (ix)-(xiv) 內的組合。
再次,那些實施方式中任一個可以在任何HIV Env蛋白中,例如,野生型分離株、共有Env、合成Env蛋白、SOSIP突變體Env蛋白等。
在某些實施方式中,HIV Env蛋白包含與SEQ ID NO: 2-5中的任一個具有至少95%同一性,例如至少96%、97%、98%、99%同一性或100%同一性的序列。為了測定同一性%,較佳的是不考慮位置650,另外較佳的是不考慮表1的位置 (i)-(xvi),還較佳的是不考慮位置108、501、538、559和605。據發現,位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe增加Env蛋白的三聚體百分比和三聚體產量。
根據本發明之實施方式,與在位置650處不具有Trp、Phe、Met或Leu而其他方面相同的HIV Env蛋白相比(較佳的是與在位置650處具有Gln而其他方面相同的HIV Env蛋白相比),重組HIV Env蛋白具有以下至少一者:(a) 提高的三聚體形成百分比,和 (b) 提高的三聚體產量。
如本文所用的「提高的三聚體形成百分比」係指當HIV包膜蛋白的骨架序列包含位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe時形成的三聚體百分比,與當HIV包膜序列的骨架序列包含位置650處的Gln殘基(Gln係在HIV-1 Env的大多數天然演化支C變體中存在於該位置的胺基酸)時形成的三聚體百分比相比更大。更一般地,「提高的三聚體形成百分比」係指當HIV包膜蛋白的骨架序列包含將位置650處的胺基酸取代為Trp、Phe、Met或Leu,較佳的是Trp或Phe,以及視需要包含表1所述之一或多個胺基酸取代時形成的三聚體百分比,與當HIV包膜序列的骨架序列不含此類胺基酸取代時形成的三聚體百分比相比更大。如本文所用的「提高的三聚體產量」係指當HIV包膜蛋白的骨架序列包含位置650處的Trp、Phe、Met或Leu,較佳的是Trp或Phe時獲得的包膜蛋白的三聚體形式的總量,與當HIV包膜序列的骨架序列包含位置650處的Gln殘基時獲得的包膜蛋白的三聚體形式的總量相比更大。更一般地,「提高的三聚體產量」係指當HIV包膜蛋白的骨架序列包含表1中所述之一或多個胺基酸取代時獲得的包膜蛋白的三聚體形式的總量,與當HIV包膜序列的骨架序列不含此類胺基酸取代時獲得的包膜蛋白的三聚體形式的總量相比更大。
可以藉由使用與HIV Env蛋白的三聚體形式特異性結合的抗體的抗體結合測定來測量三聚體形成。可用於檢測三聚體形式的三聚體特異性抗體的實例包括但不限於單株抗體(mAb)PGT145、PGDM1400、PG16和PGT151。較佳的是,三聚體特異性抗體係mAb PGT145。鑒於本揭露,可以使用本領域中已知的任何抗體結合測定來測量本發明之重組HIV Env蛋白的三聚體形成百分比,例如ELISA、AlphaLISA等。
在具體實施方式中,藉由AlphaLISA來測量三聚體形成。AlphaLISA係基於珠的迫近測定,其中藉由供體珠的高能輻射產生的單線態氧分子轉移到相對於供體珠在大約200 nm距離內的受體珠。單線態氧分子轉移到受體珠引發了一連串的化學反應,產生化學發光信號,它然後可以被檢測到(Eglen等人.
Curr. Chem. Genomics[當前化學基因組學], 2008, 25 (1): 2-10)。例如,用Flag-His標籤標記的重組HIV包膜蛋白可以用三聚體特異性mAb、同與三聚體特異性mAb結合的抗體軛合的供體珠粒、鎳軛合的供體珠粒、與抗His抗體軛合的受體珠粒、以及與抗Flag抗體軛合的受體珠粒進行孵育。可以藉由測量從一對與和三聚體特異性mAb結合的抗體軛合的供體珠和與抗His抗體軛合的受體珠產生的化學發光信號來確定形成的三聚體的量。可以藉由測量由一對鎳軛合的供體珠粒和抗Flag軛合的受體珠粒生成的化學發光信號來測定表現的HIV包膜蛋白的總量。例如,可以如WO 2019/016062的實例3中詳細描述的藉由AlphaLISA測定來測量三聚體的量和表現的總包膜蛋白。可以藉由將形成的三聚體的量除以表現的包膜蛋白的總量來計算三聚體形成百分比。在某些實施方式中,三聚體形成藉由與廣泛中和HIV Env結合抗體PGT145、PGDM1400或兩者結合來測量,並且在相同條件下(例如在AlphaLISA測定中)與不具有本發明突變的親本分子的這種結合進行比較(該等抗體中的每一種對於熟悉該項技術者而言係可獲得的,如其先前已經描述的(參見例如Lee等人, 2017, Immunity [免疫] 46: 690-702,包括補充資訊)並且可以從各種來源諸如NIH AIDS試劑項目,或從創新生物實驗室(Creative Biolabs)獲得,或者可基於其已知序列以重組方式產生;本文所述之其他有用的抗體也是先前技術已知的,並且可以藉由類似方法獲得)。在某些實施方式中,與HIV Env親本蛋白相比,本發明之HIV Env蛋白與抗體PGT145和/或PGDM1400的結合增加,並且在某些實施方式中,與HIV Env親本蛋白相比,本發明之HIV Env蛋白與非廣泛中和抗體17b的結合大約相同或較佳的是減少。
也可以使用能夠將三聚體形式與其他形式的HIV包膜蛋白(例如單體形式)分離的層析技術來測定形成的三聚體的量和表現的包膜蛋白的總量。可使用的此類技術的實例包括但不限於粒徑排阻層析法(SEC),例如分析型SEC或SEC多角度光散射(SEC-MALS)。根據某些實施方式,使用SEC-MALS或(分析型)SEC測定三聚體形成百分比。根據某些實施方式,使用SEC-MALS或(分析型)SEC測定三聚體產量。
本發明在某些實施方式中還提供了用於改善HIV Env蛋白的三聚體形成之方法,該方法包括用Trp、Phe、Met或Leu,較佳的是用Trp或Phe取代親本HIV Env蛋白的位置650處的殘基(通常為Gln)。例如,這可以通過使用標準的分子生物學技術來實現。
核酸、載體和細胞
在另一個一般方面,本發明提供了編碼根據本發明的重組HIV Env蛋白的核酸分子和包含該核酸分子的載體。本發明之核酸分子可以呈RNA形式或呈藉由選殖而獲得或以合成方式而產生的DNA形式。DNA可為雙股的或單股的。DNA可以例如包含cDNA、基因組DNA或其組合。該等核酸分子和載體可以用於產生重組蛋白、在宿主細胞中表現蛋白或產生病毒顆粒。
在某些實施方式中,對編碼根據本發明的蛋白的核酸分子進行密碼子優化,以在哺乳動物細胞(較佳的是,人類細胞)或昆蟲細胞中表現。密碼子優化的方法係已知的並且先前已經描述(例如針對哺乳動物細胞的WO 96/09378)。與野生型序列相比,如果至少一個非較佳密碼子被更較佳的密碼子置換,則認為序列係密碼子優化的。在本文,非較佳密碼子係在生物體中不如另一個編碼相同胺基酸的密碼子經常地使用的密碼子,並且更較佳的密碼子係在生物體中比非較佳密碼子更經常地使用的密碼子。對於特定生物體的密碼子使用的頻率可見於密碼子頻率表,如在http://www.kazusa.or.jp/codon中。較佳的是多於一個非較佳密碼子,較佳的是最多的或所有非較佳密碼子,被更較佳的密碼子置換。較佳的是,在生物體中最經常使用的密碼子用於密碼子優化的序列。被較佳的密碼子置換一般導致更高表現。
熟悉該項技術者將理解,由於遺傳密碼的簡併性,許多不同的多核苷酸和核酸分子可以編碼相同的蛋白。還應當理解,技術者可以使用常規技術製造不影響由核酸分子編碼的蛋白序列的核苷酸取代,以反映有待表現蛋白的任何特定宿主生物體的密碼子使用。因此,除非另外說明,否則「編碼胺基酸序列的核苷酸序列」包括彼此呈簡併形式且編碼相同胺基酸序列的所有核苷酸序列。編碼蛋白和RNA的核苷酸序列可以包括或可以不包括內含子。
核酸序列可以使用常規分子生物學技術選殖,或藉由DNA合成從頭產生,這可以藉由在DNA和/或RNA合成和/或分子選殖領域具有業務的服務公司使用常規程式進行。
編碼本發明之重組HIV Env蛋白的核酸也可為例如呈mRNA的形式。這樣的mRNA可直接用於例如在細胞培養中產生Env蛋白,但也可以經由疫苗接種,例如藉由在藥物遞送媒介物諸如脂質體或脂質奈米粒子中投與mRNA。核酸或mRNA也可以呈自擴增RNA或自複製RNA的形式,例如基於正義RNA病毒諸如甲病毒的自複製機制。這樣的自複製RNA(或repRNA或RNA複製子)可以呈表現甲病毒非結構蛋白基因的RNA分子的形式,使得它可以指導其自身在細胞中的複製擴增,而不產生子代病毒。例如,repRNA可以包含5’和3’甲病毒複製識別序列、甲病毒非結構蛋白的編碼序列、編碼抗原(諸如本發明之HIV Env蛋白)的異源基因,和表現抗原的工具,以及聚腺苷酸化區。此類repRNA在宿主內的廣泛組織中誘導暫態的高水平抗原表現,並且能夠在分裂和非分裂細胞中起作用。repRNA可以作為DNA分子遞送至細胞,repRNA從該細胞發射,包裝在病毒複製子顆粒(VRP)中,或作為裸的修飾或未修飾的RNA分子。在某些實施方式中,mRNA可為核苷修飾的,例如mRNA或複製RNA可以包含修飾的核鹼基,諸如US 2011/0300205中所述之那些。repRNA的非限制性實例可見於WO 2019/023566。在非限制性實施方式中,mRNA疫苗和自擴增RNA疫苗可以例如包括如(Pardi等人, 2018, Nature Reviews Drug Discovery [自然綜述:藥物發現] 17: 261-279)和(Zhang等人, 2019, Front. Immunol. [免疫學前沿] 10: 594)中所述之疫苗形式和變型。
根據本發明之實施方式,編碼該重組HIV包膜蛋白的核酸可操作地連接至啟動子,這意味著該核酸在啟動子的控制下。該啟動子可為同源啟動子(即,來源於與載體相同的遺傳來源)或異源啟動子(即,來源於不同載體或遺傳來源)。適合的啟動子的非限制性實例包括人巨細胞病毒立即早期(hCMV IE,或簡稱「CMV」)啟動子和勞斯肉瘤病毒(RSV)啟動子。較佳的是,該啟動子位於表現盒內的核酸的上游。
根據本發明的核酸可以結合到載體中。在某些實施方式中,載體包括DNA和/或RNA。根據本發明之實施方式,載體可為表現載體。表現載體包括但不限於用於重組蛋白表現的載體和用於將核酸遞送至受試者中用於在該受試者的組織中表現的載體,諸如病毒載體。適合與本發明一起使用的病毒載體的實例包括但不限於腺病毒載體、腺相關病毒載體、痘病毒載體、改良安卡拉痘苗(MVA)載體、腸道病毒載體、委內瑞拉馬腦炎病毒載體、塞姆利基森林病毒載體、菸草鑲嵌病毒載體、慢病毒載體、甲病毒載體等。載體也可為非病毒載體。非病毒載體的實例包括但不限於質體、細菌人工染色體、酵母人工染色體、噬菌體等。
在本發明之某些實施方式中,該載體係腺病毒載體,例如重組腺病毒載體。重組腺病毒載體可以例如來源於人腺病毒(HAdV或AdHu)或者猿猴腺病毒諸如黑猩猩或大猩猩腺病毒(ChAd、AdCh或SAdV)或恒河猴腺病毒(rhAd)。較佳的是,腺病毒載體係重組人腺病毒載體,例如重組人腺病毒血清型26,或重組人腺病毒血清型5、4、35、7、48等中的任一種。在其他實施方式中,腺病毒載體係rhAd載體,例如rhAd51、rhAd52或rhAd53。在其他實施方式中,重組腺病毒基於黑猩猩腺病毒,諸如ChAdOx 1(參見例如WO 2012/172277)或ChAdOx 2(參見例如WO 2018/215766)或BZ28(參見例如WO 2019/086466)。在其他實施方式中,重組腺病毒基於大猩猩腺病毒,諸如BLY6(參見例如WO 2019/086456)或BZ1(參見例如WO 2019/086466)。
重組腺病毒載體的製備在本領域係熟知的。例如,在例如WO 2007/104792和Abbink等人, (2007)
Virol.[病毒學] 81 (9): 4654-63中描述了重組腺病毒26載體的製備。腺病毒26的示例性基因組序列發現於GenBank登錄號EF 153474和WO 2007/104792的SEQ ID NO: 1中。US 2015/0291935中提供了rhAd51、rhAd52和rhAd53的示例性基因組序列。
根據本發明之實施方式,本文所述之任何重組HIV Env蛋白可由本文所述之任何載體表現和/或編碼。鑒於遺傳密碼的簡併性,技術者將充分意識到可以根據本領域完全常規的方法來設計編碼同一種蛋白的幾個核酸序列。編碼本發明之重組HIV Env蛋白的核酸可以視需要是密碼子優化的,以確保在宿主細胞(例如,細菌或哺乳動物細胞)中適當表現。密碼子優化係廣泛應用於本領域的技術。
本發明還提供了包含本文所述之任何核酸分子和載體的細胞,較佳的是分離的細胞。例如,該等細胞可以用於產生重組蛋白,或用於產生病毒顆粒。
因此,本發明之實施方式還涉及製造重組HIV Env蛋白之方法。該方法包括用表現載體轉染宿主細胞,該表現載體包含可操作地連接至啟動子的編碼根據本發明實施方式的重組HIV Env蛋白的核酸;在適合於表現該重組HIV Env蛋白的條件下培養該轉染的細胞,並視需要純化或分離在該細胞中表現的重組HIV Env蛋白。重組HIV Env蛋白可以藉由本領域已知的任何方法從細胞中分離或收集,包括親和層析法、粒徑排阻層析法等。鑒於本揭露內容,用於重組蛋白表現的技術係熟悉該項技術者熟知的。也可以研究表現的重組HIV Env蛋白而不需要純化或分離該表現的蛋白,例如藉由分析用編碼該重組HIV Env蛋白的表現載體轉染並在適合於表現該HIV Env蛋白的條件下生長的細胞的上清液。
在較佳的實施方式中,將表現的重組HIV Env蛋白在允許締合該蛋白以形成穩定的三聚體複合物的條件下純化。例如,可以在33°C-39°C(例如37°C)和2%-12% CO
2(例如8% CO
2)下培養用與啟動子(例如,CMV啟動子)可操作地連接的編碼該重組HIV Env蛋白的表現載體轉染的哺乳動物細胞。表現也可以在替代性表現系統諸如昆蟲細胞或酵母細胞(都是本領域中常規的)中進行。然後可以例如藉由凝集素親和層析從細胞培養物中分離表現的HIV Env蛋白,其結合糖蛋白。結合到柱上的HIV Env蛋白可以用哌喃甘露糖苷洗脫。可以按需要使從柱上洗脫的HIV Env蛋白經受進一步的純化步驟,例如粒徑排阻層析,以去除任何殘留的污染物,例如細胞污染物,還有Env聚集物,gp140單體和gp120單體。也可以使用替代性純化方法,非限制性實例包括抗體親和層析、用非bNAb進行的陰性選擇、抗標籤純化或其他層析如離子交換層析等以及本領域已知的其他方法來分離表現的HIV Env蛋白。
鑒於本揭露,可以藉由本領域已知的任何方法製備編碼本發明之重組HIV Env蛋白的核酸分子和表現載體。例如,可以使用熟悉該項技術者熟知的基因工程技術和分子生物學技術,例如定點誘變、聚合酶鏈反應(PCR)等,藉由將編碼所示位置處的一或多個胺基酸取代的突變引入骨架HIV包膜序列中來製備編碼重組HIV Env蛋白的核酸。然後還可以使用標準分子生物學技術將核酸分子引入或「選殖」到表現載體中。然後可以在宿主細胞中從表現載體表現該重組HIV包膜蛋白,並且鑒於本揭露,藉由本領域已知的任何方法從細胞培養物中純化表現的蛋白。
三聚體複合物
在另一個一般方面,本發明關於三聚體複合物,其包含根據本發明的重組HIV Env蛋白中的三種的非共價低聚物。該三聚體複合物可以包含本文所述之任何重組HIV Env蛋白。較佳的是,該三聚體複合物包含根據本發明的重組HIV Env蛋白的三種一致的單體(或一致的異源二聚體,如果gp140被切割的話)。該三聚體複合物可以與其他形式(例如單體形式)的HIV包膜蛋白分離,或該三聚體複合物可與其他形式(例如單體形式)的HIV包膜蛋白一起存在。
組成物和方法
在另一個一般方面,本發明關於包含重組HIV Env蛋白、三聚體複合物、分離的核酸、載體或宿主細胞以及藥學上可接受的載劑的組成物。該組成物可以包含本文所述之任何重組HIV Env蛋白、三聚體複合物、分離的核酸分子、載體或宿主細胞。
載劑可以包括一或多種藥學上可接受的賦形劑,諸如黏合劑、崩散劑、膨潤劑、助懸劑、乳化劑、潤濕劑、潤滑劑、調味劑、甜味劑、防腐劑、染料、增溶劑以及塗層。該載劑或其他材料的確切性質可以取決於投與途徑,例如肌內、皮內、皮下、口服、靜脈內、皮膚、黏膜內(例如,腸)、鼻內或腹膜內途徑。對於液體可注射製劑(例如,懸浮液和溶液),適合的載劑和添加劑包括水、乙二醇、油、醇、防腐劑、著色劑等。對於固體口服製劑(例如散劑、膠囊、囊片、軟膠囊和片劑),適合的載劑和添加劑包括澱粉、糖、稀釋劑、製粒劑、潤滑劑、黏合劑、崩散劑等。對於鼻噴霧劑/吸入劑混合物,該水性溶液/懸浮液可以包含作為適合的載劑和添加劑的水、乙二醇、油、軟化劑、穩定劑、潤濕劑、防腐劑、芳香劑、調味劑等。
本發明之組成物可以配製成適於向受試者投與以便於投與並改善功效的任何物質,包括但不限於口服(腸內)投與和腸胃外注射。腸胃外注射包括靜脈內注射或輸注、皮下注射、皮內注射和肌內注射。本發明之組成物還可以配製用於其他投與途徑,包括經黏膜、眼、直腸、長效植入、舌下投與、舌下、從口腔黏膜繞過門脈循環、吸入或鼻內。
本發明之實施方式還涉及製備該組成物之方法。根據本發明之實施方式,生產組成物的方法包括將本發明之重組HIV Env蛋白、三聚體複合物、分離的核酸、載體或宿主細胞與一或多種藥學上可接受的載劑混合。熟悉該項技術者將熟悉用於製備此類組成物的常規技術。
HIV抗原(例如,衍生自HIV
gag、
pol和/或
env基因產物的蛋白或其片段)和表現該HIV抗原的載體(例如病毒載體)已經用於免疫原性組成物和疫苗中,用於針對HIV感染對受試者進行疫苗接種或在受試者中產生針對HIV感染的免疫反應。如本文所用,「受試者」意指將投與或已經投與根據本發明實施方式的免疫原性組成物的任何動物,較佳的是哺乳動物,最較佳的是人。如本文所用的術語「哺乳動物」涵蓋任何哺乳動物。哺乳動物的實例包括但不限於小鼠、大鼠、兔、豚鼠、猴、人等,較佳的是人。本發明之重組HIV Env蛋白還可以用作抗原,以在有需要的受試者中誘導針對人類免疫缺陷病毒(HIV)的免疫反應。免疫反應可以針對一或多種HIV演化支,諸如演化支A、演化支B、演化支C等。組成物可以包含表現重組HIV Env蛋白的載體,或者組成物可包含根據本發明實施方式的分離的重組HIV Env蛋白。
例如,可以將包含重組HIV蛋白或其三聚體複合物的組成物給予有需要的受試者以在受試者中誘導針對HIV感染的免疫反應。也可以將包含編碼本發明之重組HIV Env蛋白的載體(如腺病毒載體)的組成物投與有需要的受試者以在受試者中誘導針對HIV感染的免疫反應,其中該載體表現該重組HIV Env蛋白。本文所述之方法還包括將本發明之組成物與較佳的是由一或多種載體(例如腺病毒載體或MVA載體)表現的一或多種另外的HIV抗原(例如,源自HIV
gag、
pol和/或
env基因產物的蛋白或其片段)組合投與,包括引發和加強免疫反應的方法。
在某些實施方式中,該HIV Env蛋白可以展示在粒子如脂質體、病毒樣粒子(VLP)、奈米粒子、病毒體或外來體上,視需要與內源和/或外源性佐劑組合。當與其自身的可溶性或單體Env蛋白相比時,這樣的粒子典型在體內展示增強的抗原呈遞功效。
可以製備展示HIV Env蛋白的VLP的實例,例如藉由與自組裝病毒蛋白如HIV Gag核或其他反轉錄病毒Gag蛋白共表現該HIV Env蛋白。VLP類似病毒,但不具有感染性,因為它們不含病毒遺傳物質。病毒結構蛋白(諸如包膜或殼體)的表現可以導致VLP的自組裝。VLP係熟悉該項技術者所熟知的,並且它們在疫苗中用途例如描述於(Kushnir等人, 2012)中。
在某些較佳的實施方式中,該顆粒係脂質體。脂質體係具有至少一個脂質雙層的球形囊泡。HIV Env三聚體蛋白可以例如藉由靜電相互作用(例如藉由向HIV Env三聚體的C端添加His-標籤)和併入到脂質體中衍生化脂質的頭部基團中二價螯合原子(如Ni
2+或Co
2+)而非共價偶合到該等脂質體上。在某些非限制性和示例性實施方式中,該脂質體包含1,2-二硬脂醯基-sn-甘油基-3-磷酸膽鹼(DSPC)、膽固醇和1,2-二油醯基-sn-甘油基-3-[(N-(5-胺基-1-羧戊基)亞胺基二乙酸)琥珀醯基]的鎳或鈷鹽(DGS-NTA(Ni
2+)或DGS-NTA(Co
2+)),莫耳比為60 : 36 : 4。在較佳的實施方式中,HIV Env三聚體蛋白共價偶合到脂質體表面,例如經由整合在脂質體表面的馬來醯亞胺官能基。在其某些非限制性示例性實施方式中,該脂質體包含DSPC、膽固醇和1,2-二棕櫚醯基-
sn-甘油基-3-磷酸乙醇胺-N-[4-(對馬來醯亞胺基甲基)環己烷-甲醯胺]脂質,莫耳比為54 : 30 : 16。HIV Env蛋白可以與其偶合,例如經由HIV Env蛋白中添加的C端半胱胺酸。共價偶合的變體更穩定,引起高抗原特異性IgG滴度,並且掩蔽了在抗原性上較不相關的Env三聚體「底部」的表位。用於製備與脂質體偶合的HIV Env三聚體和表徵它們的方法係已知的,並且已經在(Bale等人, 2017)中描述,該文獻藉由援引併入本文。本發明還提供了融合到和/或展示在脂質體上的本發明之HIV Env蛋白。
在某些實施方式中,本發明之HIV Env蛋白與自組裝粒子融合或展示在奈米粒子上。抗原奈米粒子係呈遞多個拷貝的抗原(例如本發明之HIV Env蛋白)的多肽的組裝,其導致多結合位點(親合力)並且可以提供改進的抗原穩定性和免疫原性。製備自組裝蛋白奈米粒子及其用於疫苗中之用途係熟悉該項技術者熟知的,參見例如(Zhao等人, 2014),(López-Sagaseta等人, 2016)。作為非限制性實例,自組裝奈米粒子可以基於鐵蛋白、細菌鐵蛋白或DPS。在表面上展示蛋白的DPS奈米粒子例如描述於WO 2011/082087中。這種粒子上的三聚體HIV-1抗原的說明已經例如在(He等人, 2016)中描述過。其他自組裝蛋白奈米粒子及其製備例如揭露於藉由援引併入本文的WO 2014/124301和US 2016/0122392中。本發明還提供了融合到和/或展示在自組裝奈米粒子上的本發明之HIV Env蛋白。本發明還提供了包含根據本發明的VLP、脂質體或自組裝奈米粒子的組成物。
在某些實施方式中,佐劑被包括在本發明之組成物中或與本發明之組成物共同投與。佐劑的使用係視需要的,並且當組成物用於疫苗接種的目的時,可以進一步增強免疫反應。適於共同投與或包含在根據本發明的組成物中的佐劑較佳的是應當是在人體中潛在安全、良好耐受和有效的佐劑。此類佐劑係技術者所熟知的,並且非限制性實例包括QS-21、Detox-PC、MPL-SE、MoGM-CSF、TiterMax-G、CRL- 1005、GERBU、TERamide、PSC97B、Adjumer、PG-026、GSK-I、GcMAF、B-alethine、MPC-026、Adjuvax、CpG ODN、Betafectin、鋁鹽諸如磷酸鋁(例如AdjuPhos)或氫氧化鋁以及MF59。
本文還揭露了包含與SEQ ID NO: 2或SEQ ID NO: 4(分別代表HIV包膜共有演化支C和共有演化支B序列)的胺基酸序列具有至少95%、96%、97%、98%、99%或100%同一性的胺基酸序列的重組HIV包膜蛋白。包含與SEQ ID NO: 2或SEQ ID NO: 4的胺基酸序列具有至少95%、96%、97%、98%、99%或100%同一性的胺基酸序列的重組HIV包膜蛋白可以視需要另外包含所謂的SOSIP突變和/或弗林蛋白酶切割位點中的突變,例如在SEQ ID NO: 3所示的那些序列或進一步包含位置558和/或位置556處的Pro的SEQ ID NO: 3以及SEQ ID NO: 5或進一步包含位置558和/或位置556處的Pro的SEQ ID NO: 5中。當確定該等序列的同一性%時,較佳的是不考慮突變的弗林蛋白酶切割位點處和位置501、605、559、556和558處的胺基酸。此類蛋白以高水平表現並且具有高水平的穩定性和三聚體形成。在某些實施方式中,此類HIV Env蛋白可以用作骨架蛋白,其中可以使T538突變為H以獲得本發明之分子。本發明也揭露了編碼該等序列的分離的核酸分子,包含與啟動子可操作地連接的該等序列的載體,以及包含該蛋白、分離的核酸分子或載體的組成物。
實例
實例 1 : HIV 包膜在位置 650 處突變為 Trp 、 Phe 、 Met 或 Leu 增加三聚體產量。
將包含SOSIP突變(位置501和605處的半胱胺酸殘基和位置559處的脯胺酸殘基)以及藉由用6個精胺酸殘基替換殘基508-511處的弗林蛋白酶位點而優化的弗林蛋白酶切割位點的HIV演化支C和演化支B包膜(Env)蛋白共有序列用作骨架序列,用於研究位置650處的突變對HIV Env蛋白的三聚體形成的影響。此外,C端在殘基664處被截短,產生編碼可溶性HIV gp140蛋白的序列。另外,在演化支C變體(ConC_SOSIP)中使位置295處的Val突變為Asn(V295N),以產生存在於大多數HIV毒株中並且可以改進與在一些實驗中使用的某些抗體的結合的N-連接的糖基化位點。上述所有取代/修飾位置均相對於HIV-1分離株HXB2的gp160中的編號。骨架演化支C和演化支B HIV gp140序列(分別稱為「ConC_SOSIP」和「ConB_SOSIP」)如(SEQ ID NO: 3和5)所示。特別地,在該等骨架分子中位置650處的Gln殘基被Trp殘基替換(Q650W突變,也稱為「本發明之突變」之一)。此外,在ConC_SOSIP骨架中位置650處的Gln殘基也被Phe(Q650F)、Met(Q650M)、Ile(Q650I)或Leu(Q650L)殘基替換,其中Q650F、Q650M和Q650L也稱為「本發明之突變」。類似地,在ConC_SOSIP和ConB_SOSIP骨架中位置108處的Ile殘基被His殘基替換(I108H突變)。類似地,在ConC_SOSIP和ConB_SOSIP骨架中位置538處的Ile殘基被His殘基替換(T538H突變)。所得的重組HIV Env蛋白作為可溶性gp140蛋白表現。根據已知的方法進行實驗,例如如WO 2018/050747中所述。
AlphaLISA
測定
AlphaLISA®(珀金埃爾默公司(Perkin-Elmer))係基於珠的鄰近測定,其中將藉由供體珠的高能輻射產生的單線態氧分子轉移到大約200 nm的距離內的受體珠粒上。它係靈敏的高通量篩選測定,不需要洗滌步驟。一系列級聯的化學反應產生化學發光信號(Eglen等人. Curr Chem Genomics [當代化學基因組學], 2008)。對於AlphaLISA測定,構建體配備有分選酶A-Flag-His標籤(SEQ ID NO: 15)。HIV構建體在Expi293F細胞中表現,將該等細胞在96孔板(200 µl/孔)中培養3天。將粗上清液在AlphaLISA®緩衝液(PBS + 0.05% Tween-20 + 0.5 mg/mL BSA)中稀釋120倍,但基於17b的測定除外,其中將上清液稀釋12倍。隨後將10 µl該等稀釋液轉移至半區96孔板中並與40 µl受體珠、供體珠和mAb的混合物混合。使用前將珠充分混合。在室溫、非振盪下孵育2小時後,用Neo(伯騰公司(BioTek))測量信號。將供體珠與ProtA(目錄號:AS102M,珀金埃爾默公司)軛合,後者可以結合到mAb。將受體珠與抗His抗體(目錄號:AL112R,珀金埃爾默公司)軛合以檢測蛋白的His標籤。對於總蛋白水平的定量,使用與鎳軛合的供體珠(目錄號:AS101M,珀金埃爾默公司)連同攜帶抗Flag抗體(目錄號:AL112R,珀金埃爾默公司)的受體珠的組合。對於17b與sCD4-His的組合,使用ProtA供體珠和抗Flag受體珠的組合。從針對不同Env蛋白測得的AlphaLISA計數中減去模擬轉染(無Env)的平均信號。作為參考,分別將親本ConC_SOSIP或ConB_SOSIP Env質體用於演化支C和演化支B Env突變體。
用於分析的單株抗體(mAb)係本領域熟知的(參見例如WO 2018/050747),並且在表2中連同它們的一些特徵示出。
[表2]:實驗用HIV Env抗體
mAb | 廣泛中和 | 表位 | 三聚體特異性 |
PGT145 | 是 | 頂點 | 是 |
VRC026 | 是 | 頂點 | 是 |
PGDM1400 | 是 | 頂點 | 是 |
PG16 | 是 | 頂點 | 是 |
PG9 | 是 | 頂點 | 否 |
35O22 | 是 | gp120-gp41介面 | 否 |
PGT128 | 是 | V3基部 | 否 |
PGT151 | 是 | gp120-gp41介面 | 是 |
F105 | 否 | CD4bs | 否 |
447-52d | 否 | V3冠 | 否 |
B6 | 否 | CD4bs | 否 |
14e | 否 | V3冠 | 否 |
17b | 否 | CCR5bs | 否 |
17b + CD4 | NA | CD4bs & CCR5bs | 否 |
定量 | NA | 標籤 | 否 |
廣泛中和抗體(bNAb)結合來自許多HIV毒株的Env的天然融合前構象。非bNAb結合錯誤折疊的非天然Env或高度可變的暴露環。還藉由測量可溶性HIV gp140 Env蛋白變體與已知結合該HIV包膜蛋白的共受體結合位點的抗體(mAb 17b)的結合來測試蛋白折疊,該HIV包膜蛋白僅在結合CD4後暴露(數據未顯示)。具體地,可溶性受體CD4(sCD4)與mAb 17組合使用以評價CD4誘導的構象變化。在沒有預先的CD4結合到該包膜蛋白的情況下,mAb 17b與HIV gp140 Env蛋白變體的結合係部分解折疊的或預先觸發的包膜蛋白(即,在不存在CD4結合時採取「開放」構象的不穩定Env)的指示。
通常,如果在該等實驗中與親本Env分子相比,一或多種bNAb的結合增加並且一或多種非bNAb的結合不增加或甚至減少,則它因此是HIV Env變體的積極屬性。
分析型 SEC在96孔形式的細胞培養物中表現了HIV Env變體。超高效液相層析系統(Vanquish,賽默飛世爾科技公司(Thermo Scientific))和與Optilab µT-rEX折射率檢測器(懷雅特公司(Wyatt))耦合的µDAWN TREOS儀器(懷雅特公司)與線上Nanostar DLS讀數器(懷雅特公司)組合用於進行分析型粒徑排阻層析(分析型SEC)實驗。將澄清的粗細胞培養物上清液以0.3 mL/min施加到TSK-凝膠UP-SW3000 4.6 x 150 mm柱上,該柱具有在流動緩衝液(150 mM磷酸鈉、50 mM氯化鈉,pH 7.0)中平衡的相應保護柱(東曹生命科學(Tosoh Bioscience))。當分析上清液樣本時,µMALS檢測器係離線的,並且使用Chromeleon 7.2.8.0套裝軟體分析分析型SEC數據。從HIV Env轉染的細胞的上清液的信號中減去未轉染細胞的上清液的信號。
篩選所產生的重組HIV Env蛋白變體的三聚體形成以檢查Q650W突變相對於骨架序列是否提高三聚體形成百分比和/或提高三聚體產量。將分析型SEC(圖1A,圖2A)用於測定三聚體產量。將評價一組廣泛中和HIV抗體(bNAb)和非bNAb與重組HIV Env蛋白的結合的AlphaLISA測定用於驗證相對三聚體產量和確定HIV Env蛋白的構象特徵(圖1B,圖2B)。
在分析型SEC中,據顯示,突變Q650W增加ConC_SOSIP和ConB_SOSIP兩者的三聚體產量(圖1A和圖2A)。此外,與不具有突變的親本分子相比,突變Q650W在AlphaLISA中增加了bNAb抗體結合。證實了三聚體特異性頂點定向廣泛中和抗體(bNAb)PGT145、VRC026和PGDM1400的增加,表明ConC_SOSIP的三聚體產量和/或三聚體折疊的改善(圖1B)。對ConB_SOSIP進行了相同的觀察,但VRC026除外,其不與該HIV Env結合,無論是否穩定(圖2B)。在AlphaLISA中,Q650W減少了ConC_SOSIP和ConB_SOSIP的非bNAb 17b的結合(圖1B和圖2B),這係期望的特徵並表明Env三聚體的封閉天然融合前構象。在CD4存在下與mAb 17b的結合增加證明該bNAb 17b的表位仍然是完整的。
在位置650處,除了色胺酸(W)外還測試了一些其他胺基酸取代。苯丙胺酸(F)顯著增加了三聚體產量,並且甲硫胺酸(M)和白胺酸(L)也增加了三聚體,而在令人驚訝的對比中,異白胺酸(I)減少三聚體形成,如在用編碼相應HIV Env ConC_SOSIP變體的質體轉染後使用對Expi293F細胞培養物上清液的分析型SEC所示(圖3)。
還顯示,突變T538H與不具有該突變的親本分子相比增加了ConC_SOSIP和ConB-SOSIP的三聚體產量(圖4A和圖5A),以及AlphaLISA中的bNAb結合。對於T538H突變,證實了三聚體特異性頂點定向廣泛中和抗體(bNAb)PGT145、VRC026和PGDM1400的增加,表明ConC_SOSIP的三聚體產量和/或三聚體折疊的改善(圖4B);對ConB_SOSIP進行了相同的觀察,但VRC026除外,其不與該HIV Env結合,無論是否有T538H穩定(圖5B)。在AlphaLISA中,T538H減少了ConC_SOSIP和ConB_SOSIP的非bNAb 17b的結合(圖4B和圖5B)。
還顯示,突變I108H與不具有該突變的親本分子相比增加了ConC_SOSIP和ConB-SOSIP的三聚體產量(圖6A和圖7A),以及AlphaLISA中的bNAb結合。對於I108H突變,證實了三聚體特異性頂點定向廣泛中和抗體(bNAb)PGT145、VRC026和PGDM1400的增加,表明ConC_SOSIP的三聚體產量和/或三聚體折疊的改善(圖6B);對ConB_SOSIP進行了相同的觀察,但VRC026除外,其不與該HIV Env結合,無論是否有I108H穩定(圖7B)。在AlphaLISA中,I108H強烈減少了ConC_SOSIP和ConB_SOSIP的非bNAb 17b的結合(圖6B和圖7B)。
還顯示,突變I108H、T538H和Q650W的組合與僅含I108H的ConB_SOSIP相比增加了ConB_SOSIP的三聚體產量(圖8A)和AlphaLISA中的bNAb結合。對於ConB_SOSIP_I108H_T538H_Q650W,證實了三聚體特異性頂點定向廣泛中和抗體(bNAb)PGT145和PGDM1400的增加,表明與ConB_SOSIP_I108H相比三聚體產量和/或三聚體折疊得到改善(圖8B)。與ConB_SOSIP_I108H相比,對於ConB_SOSIP_I108H_T538H_Q650W觀察到藉由AlphaLISA測得的非bNAb的相同減少(圖8B)。
位置650W、650F、650M或650L,較佳的是650W或650F的突變也在來自其他演化支的HIV Env蛋白中、在天然HIV Env序列中、在不含SOSIP突變中的一種或全部的HIV Env蛋白中、在具有表1的條目 (i)-(xvi) 中所示的突變中的一或多種的HIV Env蛋白中、在具有T538H和/或I108H突變的HIV Env蛋白中進行,並且基於本申請和對HIV Env蛋白的知識,似乎650W、650F、650M和650L突變中的每一種,較佳的是650W或650F也在大多數或全部該等背景中起作用以增加三聚體形成和/或三聚體產量。
本文所示的數據證明,本發明之分子,即在位置650處具有Trp、Phe、Met或Leu,較佳的是Trp或Leu的HIV Env蛋白與在該位置處具有天然存在的胺基酸的HIV Env蛋白相比,具有驚人增加的三聚體形成和/或三聚體產量。所得的在位置650處具有Trp的Env三聚體具有增加的處於封閉天然融合前構象的傾向。
具有增加的三聚體形成百分比的HIV包膜蛋白從製造的角度來說係有利的,如用於疫苗,因為將需要更少純化和除去製劑中存在的不希望的非天然構象的包膜蛋白。另外,增加的總三聚體表現產量對於製造疫苗產品係有利的。主要處於封閉天然融合前構象的HIV包膜蛋白也是疫苗接種所需的,因為據信它們在實際感染過程中在結構上更接近Env蛋白,因此對處於這種構象的Env蛋白產生的免疫反應係非常有益的。
應理解的是,本文所述之實例和實施方式僅用於說明的目的,並且可以在不脫離其廣泛的發明構思的情況下對上述實施方式進行改變。因此,應理解的是,本發明不限於所揭露的具體實施方式,而是旨在覆蓋如由所附請求項限定的本發明之精神和範圍內的修改。
序列表
SEQ ID NO: 1HIV-1分離株HXB2的gp160(訊息序列以斜體表示;位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)
SEQ ID NO: 2HIV Env示例性共有演化支C(僅共有序列,不包括任何訊息序列、跨膜結構域(664係最後一個胺基酸)、SOSIP突變和/或弗林蛋白酶切割位點突變;位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)
SEQ ID NO: 3ConC_SOSIP(成熟演化支C共有序列,其具有SOSIP突變和弗林蛋白酶切割位點以及C端截短,和在C端的分選酶A-Flag-His標籤(加底線);位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)(HIV150606)
SEQ ID NO: 4HIV Env示例性共有演化支B(僅共有序列,不包括任何訊息序列、跨膜結構域(664係最後一個胺基酸)、SOSIP突變和/或弗林蛋白酶切割位點突變;位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)
SEQ ID NO: 5ConB_SOSIP(成熟演化支C共有序列,其具有SOSIP突變和弗林蛋白酶切割位點以及C端截短,和在C端的分選酶A-Flag-His標籤(加底線);位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)(HIV150599)
SEQ ID NO: 6(弗林蛋白酶切割位點突變體序列)
RRRRRR
SEQ ID NO: 7(訊息序列的實例(例如用於ConC_SOSIP))
MRVRGILRNWQQWWIWGILGFWMLMICNVVG(注解:最後的VG可為成熟蛋白的開始或訊息序列的結束)
SEQ ID NO: 8(訊息序列的實例(例如用於ConB_SOSIP)
MRVKGIRKNYQHLWRWGTMLLGMLMICSA
SEQ ID NO: 9(可替換HR1環的8胺基酸序列的實例)
NPDWLPDM
SEQ ID NO: 10(可替換HR1環的8胺基酸序列的實例)
GSGSGSGS
SEQ ID NO: 11(可替換HR1環的8胺基酸序列的實例)
DDVHPDWD
SEQ ID NO: 12(可替換HR1環的8胺基酸序列的實例)
RDTFALMM
SEQ ID NO: 13(可替換HR1環的8胺基酸序列的實例)
DEEKVMDF
SEQ ID NO: 14(可替換HR1環的8胺基酸序列的實例)
DEDPHWDP
SEQ ID NO: 15(分選酶A-Flag-His標籤)
SEQ ID NO: 16(示例性全長ConC_SOSIP(包括訊息序列,以斜體表示);位置108處的Ile、位置538處的Thr和位置650處的Gln加底線和粗體)
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無
當結合附圖閱讀時,將更好地理解前述概述以及本發明之以下詳述。應理解的是本發明不限於附圖中示出的準確實施方式。
[圖1A和圖1B]顯示突變Q650W增加了ConC_SOSIP的三聚體產量。A) 用編碼HIV Env ConC-SOSIP及其Q650W變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConC_SOSIP及其Q650W變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖2A和圖2B]顯示突變Q650W增加了ConB_SOSIP的三聚體產量。A) 用編碼HIV Env ConB-SOSIP及其Q650W變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConB_SOSIP及其Q650W變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖3]顯示在使用Expi293F細胞培養物上清液的分析型SEC中,突變Q650F、Q650M和Q650L增加了ConC_SOSIP的三聚體產量,而突變Q650I減少了ConC_SOSIP中的三聚體形成。
[圖4A和圖4B]顯示突變T538H增加了ConC_SOSIP的三聚體產量。A) 用編碼HIV Env ConC-SOSIP及其T538H變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConC_SOSIP及其T538H變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖5A和圖5B]顯示突變T538H增加了ConB_SOSIP的三聚體產量。A) 用編碼HIV Env ConB-SOSIP及其T538H變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConB_SOSIP及其T538H變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖6A和圖6B]顯示突變I108H增加了ConC_SOSIP的三聚體產量。A) 用編碼HIV Env ConC-SOSIP及其I108H變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConC_SOSIP及其I108H變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖7A和圖7B]顯示突變I108H增加了ConB_SOSIP的三聚體產量。A) 用編碼HIV Env ConB-SOSIP及其I108H變體的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConB_SOSIP及其I108H變體的AlphaLISA結合。所有測量均一式三份地進行。
[圖8A和圖8B]顯示與僅包含I108H突變的ConcB_SOSIP相比,突變I108H、T538H和Q650W增加了三聚體產量。A) 用編碼包含I108H、T538H和Q650W突變的HIV Env ConB-SOSIP和僅包含I108H突變的HIV Env ConB-SOSIP的質體轉染後對Expi293F細胞培養物上清液的分析型SEC。B) 具有HIV Env特異性bNAb和非bNAb的細胞培養物上清液與ConB_SOSIP_I108H_T538H_Q650W和ConB_SOSIP_I108H變體的AlphaLISA結合。所有測量均一式三份地進行。
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<![CDATA[<110> 荷蘭商傑森疫苗防護公司(Janssen Vaccines & Prevention B.V.)]]> Rutten, Lucy Langedijk, Johannes P.M. Juraszek, Jarek <![CDATA[<120> 三聚體穩定性HIV包膜蛋白突變]]> <![CDATA[<130> CRU6054]]> <![CDATA[<150> EP21158800.9]]> <![CDATA[<151> 2021-02-23]]> <![CDATA[<160> 16 ]]> <![CDATA[<170> PatentIn版本3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 856]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類免疫缺陷病毒]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> HIV-1分離株HXB2的gp160]]> <![CDATA[<400> 1]]> Met Arg Val Lys Glu Lys Tyr Gln His Leu Trp Arg Trp Gly Trp Arg 1 5 10 15 Trp Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Thr Glu 20 25 30 Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala 35 40 45 Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu 50 55 60 Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn 65 70 75 80 Pro Gln Glu Val Val Leu Val Asn Val Thr Glu Asn Phe Asn Met Trp 85 90 95 Lys Asn Asp Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp 100 105 110 Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Ser 115 120 125 Leu Lys Cys Thr Asp Leu Lys Asn Asp Thr Asn Thr Asn Ser Ser Ser 130 135 140 Gly Arg Met Ile Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe Asn 145 150 155 160 Ile Ser Thr Ser Ile Arg Gly Lys Val Gln Lys Glu Tyr Ala Phe Phe 165 170 175 Tyr Lys Leu Asp Ile Ile Pro Ile Asp Asn Asp Thr Thr Ser Tyr Lys 180 185 190 Leu Thr Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Val 195 200 205 Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala 210 215 220 Ile Leu Lys Cys Asn Asn Lys Thr Phe Asn Gly Thr Gly Pro Cys Thr 225 230 235 240 Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser 245 250 255 Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val Ile 260 265 270 Arg Ser Val Asn Phe Thr Asp Asn Ala Lys Thr Ile Ile Val Gln Leu 275 280 285 Asn Thr Ser Val Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg 290 295 300 Lys Arg Ile Arg Ile Gln Arg Gly Pro Gly Arg Ala Phe Val Thr Ile 305 310 315 320 Gly Lys Ile Gly Asn Met Arg Gln Ala His Cys Asn Ile Ser Arg Ala 325 330 335 Lys Trp Asn Asn Thr Leu Lys Gln Ile Ala Ser Lys Leu Arg Glu Gln 340 345 350 Phe Gly Asn Asn Lys Thr Ile Ile Phe Lys Gln Ser Ser Gly Gly Asp 355 360 365 Pro Glu Ile Val Thr His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr 370 375 380 Cys Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Phe Asn Ser Thr Trp 385 390 395 400 Ser Thr Glu Gly Ser Asn Asn Thr Glu Gly Ser Asp Thr Ile Thr Leu 405 410 415 Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Lys Val Gly Lys 420 425 430 Ala Met Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser Asn 435 440 445 Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Ser Asn Asn Glu 450 455 460 Ser Glu Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg 465 470 475 480 Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val 485 490 495 Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala 500 505 510 Val Gly Ile Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser 515 520 525 Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg Gln Leu 530 535 540 Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu 545 550 555 560 Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu 565 570 575 Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln Leu 580 585 590 Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val 595 600 605 Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp Asn 610 615 620 His Thr Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser 625 630 635 640 Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn 645 650 655 Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp 660 665 670 Phe Asn Ile Thr Asn Trp Leu Trp Tyr Ile Lys Leu Phe Ile Met Ile 675 680 685 Val Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser Ile 690 695 700 Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr His 705 710 715 720 Leu Pro Thr Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu Glu 725 730 735 Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly Ser 740 745 750 Leu Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr 755 760 765 His Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu Leu 770 775 780 Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu 785 790 795 800 Gln Tyr Trp Ser Gln Glu Leu Lys Asn Ser Ala Val Ser Leu Leu Asn 805 810 815 Ala Thr Ala Ile Ala Val Ala Glu Gly Thr Asp Arg Val Ile Glu Val 820 825 830 Val Gln Gly Ala Cys Arg Ala Ile Arg His Ile Pro Arg Arg Ile Arg 835 840 845 Gln Gly Leu Glu Arg Ile Leu Leu 850 855 <![CDATA[<210> 2]]> <![CDATA[<211> 615]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> HIV Env共有演化支C]]> <![CDATA[<400> 2]]> Asn Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala 1 5 10 15 Lys Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys Glu 20 25 30 Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn 35 40 45 Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp 50 55 60 Lys Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp 65 70 75 80 Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr 85 90 95 Leu Asn Cys Thr Asn Val Asn Val Thr Asn Thr Asn Asn Asn Asn Met 100 105 110 Lys Glu Glu Met Lys Asn Cys Ser Phe Asn Thr Thr Thr Glu Ile Arg 115 120 125 Asp Lys Lys Gln Lys Glu Tyr Ala Leu Phe Tyr Arg Leu Asp Ile Val 130 135 140 Pro Leu Asn Glu Asn Ser Ser Glu Tyr Arg Leu Ile Asn Cys Asn Thr 145 150 155 160 Ser Thr Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro 165 170 175 Ile His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn 180 185 190 Lys Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln 195 200 205 Cys Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn 210 215 220 Gly Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr 225 230 235 240 Asp Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Ser Val Glu Ile 245 250 255 Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly 260 265 270 Pro Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg 275 280 285 Gln Ala His Cys Asn Ile Ser Glu Ala Lys Trp Asn Lys Thr Leu Gln 290 295 300 Arg Val Lys Lys Lys Leu Lys Glu His Phe Pro Asn Lys Thr Ile Lys 305 310 315 320 Phe Ala Pro Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe 325 330 335 Asn Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Lys Leu Phe Asn 340 345 350 Ser Thr Tyr Asn Asn Thr Thr Ser Asn Ser Thr Ile Thr Leu Pro Cys 355 360 365 Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Met 370 375 380 Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Lys Ser Asn Ile Thr 385 390 395 400 Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asn Asn Asn Asn Thr Glu 405 410 415 Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu 420 425 430 Leu Tyr Lys Tyr Lys Val Val Glu Ile Lys Pro Leu Gly Ile Ala Pro 435 440 445 Thr Lys Ala Lys Arg Arg Val Val Glu Arg Glu Lys Arg Arg Ala Val 450 455 460 Gly Ile Gly Ala Val Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser Thr 465 470 475 480 Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu 485 490 495 Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Ile Glu Ala 500 505 510 Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln 515 520 525 Ala Arg Val Leu Ala Ile Glu Arg Tyr Leu Lys Asp Gln Gln Leu Leu 530 535 540 Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val Pro 545 550 555 560 Trp Asn Ser Ser Trp Ser Asn Lys Ser Gln Glu Asp Ile Trp Asp Asn 565 570 575 Met Thr Trp Met Gln Trp Asp Arg Glu Ile Ser Asn Tyr Thr Asp Thr 580 585 590 Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu 595 600 605 Lys Asp Leu Leu Ala Leu Asp 610 615 <![CDATA[<210> 3]]> <![CDATA[<211> 677]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ConC_SOSIP序列]]> <![CDATA[<400> 3]]> Asn Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala 1 5 10 15 Lys Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys Glu 20 25 30 Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn 35 40 45 Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp 50 55 60 Lys Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp 65 70 75 80 Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr 85 90 95 Leu Asn Cys Thr Asn Val Asn Val Thr Asn Thr Asn Asn Asn Asn Met 100 105 110 Lys Glu Glu Met Lys Asn Cys Ser Phe Asn Thr Thr Thr Glu Ile Arg 115 120 125 Asp Lys Lys Gln Lys Glu Tyr Ala Leu Phe Tyr Arg Leu Asp Ile Val 130 135 140 Pro Leu Asn Glu Asn Ser Ser Glu Tyr Arg Leu Ile Asn Cys Asn Thr 145 150 155 160 Ser Thr Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro 165 170 175 Ile His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn 180 185 190 Lys Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln 195 200 205 Cys Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn 210 215 220 Gly Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr 225 230 235 240 Asp Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Ser Val Glu Ile 245 250 255 Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly 260 265 270 Pro Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg 275 280 285 Gln Ala His Cys Asn Ile Ser Glu Ala Lys Trp Asn Lys Thr Leu Gln 290 295 300 Arg Val Lys Lys Lys Leu Lys Glu His Phe Pro Asn Lys Thr Ile Lys 305 310 315 320 Phe Ala Pro Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe 325 330 335 Asn Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Lys Leu Phe Asn 340 345 350 Ser Thr Tyr Asn Asn Thr Thr Ser Asn Ser Thr Ile Thr Leu Pro Cys 355 360 365 Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Met 370 375 380 Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Lys Ser Asn Ile Thr 385 390 395 400 Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asn Asn Asn Asn Thr Glu 405 410 415 Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu 420 425 430 Leu Tyr Lys Tyr Lys Val Val Glu Ile Lys Pro Leu Gly Ile Ala Pro 435 440 445 Thr Lys Cys Lys Arg Arg Val Val Glu Arg Arg Arg Arg Arg Arg Ala 450 455 460 Val Gly Ile Gly Ala Val Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser 465 470 475 480 Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu 485 490 495 Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Pro Glu 500 505 510 Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu 515 520 525 Gln Ala Arg Val Leu Ala Ile Glu Arg Tyr Leu Lys Asp Gln Gln Leu 530 535 540 Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Cys Thr Ala Val 545 550 555 560 Pro Trp Asn Ser Ser Trp Ser Asn Lys Ser Gln Glu Asp Ile Trp Asp 565 570 575 Asn Met Thr Trp Met Gln Trp Asp Arg Glu Ile Ser Asn Tyr Thr Asp 580 585 590 Thr Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn 595 600 605 Glu Lys Asp Leu Leu Ala Leu Asp Ala Ala Ala Leu Pro Glu Thr Gly 610 615 620 Gly Gly Ser Asp Tyr Lys Asp Asp Asp Asp Lys Pro Gly Gly Gly Gly 625 630 635 640 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 645 650 655 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His 660 665 670 His His His His His 675 <![CDATA[<210> 4]]> <![CDATA[<211> 630]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> HIV Env共有演化支B]]> <![CDATA[<400> 4]]> Ala Glu Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys 1 5 10 15 Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp 20 25 30 Thr Glu Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp 35 40 45 Pro Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn Phe Asn 50 55 60 Met Trp Lys Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser 65 70 75 80 Leu Trp Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys 85 90 95 Val Thr Leu Asn Cys Thr Asp Leu Asn Asn Asn Thr Thr Asn Asn Asn 100 105 110 Ser Ser Ser Glu Lys Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe 115 120 125 Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Gln Lys Glu Tyr Ala Leu 130 135 140 Phe Tyr Lys Leu Asp Val Val Pro Ile Asp Asn Asn Asn Thr Ser Tyr 145 150 155 160 Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys 165 170 175 Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe 180 185 190 Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys 195 200 205 Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val 210 215 220 Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val 225 230 235 240 Ile Arg Ser Glu Asn Phe Thr Asp Asn Ala Lys Thr Ile Ile Val Gln 245 250 255 Leu Asn Glu Ser Val Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr 260 265 270 Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Gly 275 280 285 Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Thr 290 295 300 Lys Trp Asn Asn Thr Leu Lys Gln Ile Val Lys Lys Leu Arg Glu Gln 305 310 315 320 Phe Gly Asn Lys Thr Ile Val Phe Asn Gln Ser Ser Gly Gly Asp Pro 325 330 335 Glu Ile Val Met His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys 340 345 350 Asn Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Asn Gly Thr Trp 355 360 365 Asn Asn Thr Thr Gly Asn Asp Thr Ile Thr Leu Pro Cys Arg Ile Lys 370 375 380 Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro 385 390 395 400 Pro Ile Arg Gly Gln Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu 405 410 415 Leu Thr Arg Asp Gly Gly Asn Asn Asn Asn Asn Thr Thr Glu Thr Phe 420 425 430 Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr 435 440 445 Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys 450 455 460 Cys Lys Arg Arg Val Val Gln Arg Arg Arg Arg Arg Arg Ala Val Gly 465 470 475 480 Ile Gly Ala Met Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser Thr Met 485 490 495 Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu Ser 500 505 510 Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Pro Glu Ala Gln 515 520 525 Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala 530 535 540 Arg Val Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly 545 550 555 560 Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Cys Thr Ala Val Pro Trp 565 570 575 Asn Thr Ser Trp Ser Asn Lys Ser Leu Asp Glu Ile Trp Asp Asn Met 580 585 590 Thr Trp Met Gln Trp Glu Arg Glu Ile Asp Asn Tyr Thr Gly Leu Ile 595 600 605 Tyr Thr Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln 610 615 620 Glu Leu Leu Glu Leu Asp 625 630 <![CDATA[<210> 5]]> <![CDATA[<211> 691]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ConB_SOSIP序列]]> <![CDATA[<400> 5]]> Ala Glu Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys 1 5 10 15 Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp 20 25 30 Thr Glu Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp 35 40 45 Pro Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn Phe Asn 50 55 60 Met Trp Lys Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser 65 70 75 80 Leu Trp Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys 85 90 95 Val Thr Leu Asn Cys Thr Asp Leu Asn Asn Asn Thr Thr Asn Asn Asn 100 105 110 Ser Ser Ser Glu Lys Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe 115 120 125 Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Gln Lys Glu Tyr Ala Leu 130 135 140 Phe Tyr Lys Leu Asp Val Val Pro Ile Asp Asn Asn Asn Thr Ser Tyr 145 150 155 160 Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys 165 170 175 Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe 180 185 190 Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys 195 200 205 Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val 210 215 220 Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val 225 230 235 240 Ile Arg Ser Glu Asn Phe Thr Asp Asn Ala Lys Thr Ile Ile Val Gln 245 250 255 Leu Asn Glu Ser Val Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr 260 265 270 Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Gly 275 280 285 Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Thr 290 295 300 Lys Trp Asn Asn Thr Leu Lys Gln Ile Val Lys Lys Leu Arg Glu Gln 305 310 315 320 Phe Gly Asn Lys Thr Ile Val Phe Asn Gln Ser Ser Gly Gly Asp Pro 325 330 335 Glu Ile Val Met His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys 340 345 350 Asn Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Asn Gly Thr Trp 355 360 365 Asn Asn Thr Thr Gly Asn Asp Thr Ile Thr Leu Pro Cys Arg Ile Lys 370 375 380 Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro 385 390 395 400 Pro Ile Arg Gly Gln Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu 405 410 415 Leu Thr Arg Asp Gly Gly Asn Asn Asn Asn Asn Thr Thr Glu Thr Phe 420 425 430 Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr 435 440 445 Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys 450 455 460 Cys Lys Arg Arg Val Val Gln Arg Arg Arg Arg Arg Arg Ala Val Gly 465 470 475 480 Ile Gly Ala Met Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser Thr Met 485 490 495 Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu Ser 500 505 510 Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Pro Glu Ala Gln 515 520 525 Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala 530 535 540 Arg Val Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly 545 550 555 560 Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Cys Thr Ala Val Pro Trp 565 570 575 Asn Thr Ser Trp Ser Asn Lys Ser Leu Asp Glu Ile Trp Asp Asn Met 580 585 590 Thr Trp Met Gln Trp Glu Arg Glu Ile Asp Asn Tyr Thr Gly Leu Ile 595 600 605 Tyr Thr Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln 610 615 620 Glu Leu Leu Glu Leu Asp Ala Ala Ala Leu Pro Glu Thr Gly Gly Gly 625 630 635 640 Ser Asp Tyr Lys Asp Asp Asp Asp Lys Pro Gly Gly Gly Gly Ser Gly 645 650 655 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 660 665 670 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His His His 675 680 685 His His His 690 <![CDATA[<210> 6]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 弗林蛋白酶切割位點突變體序列]]> <![CDATA[<400> 6]]> Arg Arg Arg Arg Arg Arg 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 31]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 訊息序列]]> <![CDATA[<400> 7]]> Met Arg Val Arg Gly Ile Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp 1 5 10 15 Gly Ile Leu Gly Phe Trp Met Leu Met Ile Cys Asn Val Val Gly 20 25 30 <![CDATA[<210> 8]]> <![CDATA[<211> 29]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 訊息序列]]> <![CDATA[<400> 8]]> Met Arg Val Lys Gly Ile Arg Lys Asn Tyr Gln His Leu Trp Arg Trp 1 5 10 15 Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala 20 25 <![CDATA[<210> 9]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 9]]> Asn Pro Asp Trp Leu Pro Asp Met 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 10]]> Gly Ser Gly Ser Gly Ser Gly Ser 1 5 <![CDATA[<210> 11]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 11]]> Asp Asp Val His Pro Asp Trp Asp 1 5 <![CDATA[<210> 12]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 12]]> Arg Asp Thr Phe Ala Leu Met Met 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 13]]> Asp Glu Glu Lys Val Met Asp Phe 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 可以替換HR1環的8胺基酸序列的實例]]> <![CDATA[<400> 14]]> Asp Glu Asp Pro His Trp Asp Pro 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 61]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 分選酶A-Flag-His標籤]]> <![CDATA[<400> 15]]> Ala Ala Ala Leu Pro Glu Thr Gly Gly Gly Ser Asp Tyr Lys Asp Asp 1 5 10 15 Asp Asp Lys Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45 Gly Ser Gly Gly Gly Gly Ser His His His His His His 50 55 60 <![CDATA[<210> 16]]> <![CDATA[<211> 844]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 全長ConC_SOSIP]]> <![CDATA[<400> 16]]> Met Arg Val Arg Gly Ile Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp 1 5 10 15 Gly Ile Leu Gly Phe Trp Met Leu Met Ile Cys Asn Val Val Gly Asn 20 25 30 Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Lys 35 40 45 Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys Glu Val 50 55 60 His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro 65 70 75 80 Gln Glu Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys 85 90 95 Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp 100 105 110 Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu 115 120 125 Asn Cys Thr Asn Val Asn Val Thr Asn Thr Asn Asn Asn Asn Met Lys 130 135 140 Glu Glu Met Lys Asn Cys Ser Phe Asn Thr Thr Thr Glu Ile Arg Asp 145 150 155 160 Lys Lys Gln Lys Glu Tyr Ala Leu Phe Tyr Arg Leu Asp Ile Val Pro 165 170 175 Leu Asn Glu Asn Ser Ser Glu Tyr Arg Leu Ile Asn Cys Asn Thr Ser 180 185 190 Thr Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile 195 200 205 His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys 210 215 220 Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys 225 230 235 240 Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly 245 250 255 Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asp 260 265 270 Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Ser Val Glu Ile Asn 275 280 285 Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro 290 295 300 Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln 305 310 315 320 Ala His Cys Asn Ile Ser Glu Ala Lys Trp Asn Lys Thr Leu Gln Arg 325 330 335 Val Lys Lys Lys Leu Lys Glu His Phe Pro Asn Lys Thr Ile Lys Phe 340 345 350 Ala Pro Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn 355 360 365 Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Lys Leu Phe Asn Ser 370 375 380 Thr Tyr Asn Asn Thr Thr Ser Asn Ser Thr Ile Thr Leu Pro Cys Arg 385 390 395 400 Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Met Tyr 405 410 415 Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Lys Ser Asn Ile Thr Gly 420 425 430 Leu Leu Leu Thr Arg Asp Gly Gly Asn Asn Asn Asn Asn Thr Glu Thr 435 440 445 Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu 450 455 460 Tyr Lys Tyr Lys Val Val Glu Ile Lys Pro Leu Gly Ile Ala Pro Thr 465 470 475 480 Lys Cys Lys Arg Arg Val Val Glu Arg Glu Lys Arg Ala Val Gly Ile 485 490 495 Gly Ala Val Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser Thr Met Gly 500 505 510 Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu Ser Gly 515 520 525 Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Pro Glu Ala Gln Gln 530 535 540 His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg 545 550 555 560 Val Leu Ala Ile Glu Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile 565 570 575 Trp Gly Cys Ser Gly Lys Leu Ile Cys Cys Thr Ala Val Pro Trp Asn 580 585 590 Ser Ser Trp Ser Asn Lys Ser Gln Glu Asp Ile Trp Asp Asn Met Thr 595 600 605 Trp Met Gln Trp Asp Arg Glu Ile Ser Asn Tyr Thr Asp Thr Ile Tyr 610 615 620 Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Lys Asp 625 630 635 640 Leu Leu Ala Leu Asp Ser Trp Asn Asn Leu Trp Asn Trp Phe Asp Ile 645 650 655 Thr Asn Trp Leu Trp Tyr Ile Lys Ile Phe Ile Met Ile Val Gly Gly 660 665 670 Leu Ile Gly Leu Arg Ile Ile Phe Ala Val Leu Ser Ile Val Asn Arg 675 680 685 Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr Leu Thr Pro Asn 690 695 700 Pro Arg Gly Pro Asp Arg Leu Gly Arg Ile Glu Glu Glu Gly Gly Glu 705 710 715 720 Gln Asp Arg Asp Arg Ser Ile Arg Leu Val Ser Gly Phe Leu Ala Leu 725 730 735 Ala Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr His Arg Leu 740 745 750 Arg Asp Phe Ile Leu Ile Ala Ala Arg Ala Val Glu Leu Leu Gly Arg 755 760 765 Ser Ser Leu Arg Gly Leu Gln Arg Gly Trp Glu Ala Leu Lys Tyr Leu 770 775 780 Gly Ser Leu Val Gln Tyr Trp Gly Leu Glu Leu Lys Lys Ser Ala Ile 785 790 795 800 Ser Leu Leu Asp Thr Ile Ala Ile Ala Val Ala Glu Gly Thr Asp Arg 805 810 815 Ile Ile Glu Leu Ile Gln Arg Ile Cys Arg Ala Ile Arg Asn Ile Pro 820 825 830 Arg Arg Ile Arg Gln Gly Phe Glu Ala Ala Leu Leu 835 840
Claims (20)
- 一種重組人類免疫缺陷病毒(HIV)包膜(Env)蛋白,其包含位置650處的胺基酸色胺酸(Trp)、苯丙胺酸(Phe)、甲硫胺酸(Met)或白胺酸(Leu)中的一種, 其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
- 如請求項1所述之重組HIV Env蛋白,其進一步包含所示位置處的以下胺基酸殘基中的一或多個: (i) 位置651處的Phe、Leu、Met或Trp,較佳的是Phe; (ii) 位置655處的Phe、Ile、Met或Trp,較佳的是Ile; (iii) 位置535處的Asn或Gln,較佳的是Asn; (iv) 位置589處的Val、Ile或Ala,較佳的是Val或Ile,更較佳的是Val; (v) 位置573處的Phe或Trp,較佳的是Phe; (vi) 位置204處的Ile; (vii) 位置647處的Phe、Met或Ile,較佳的是Phe; (viii) 位置658處的Val、Ile、Phe、Met、Ala或Leu,較佳的是Val或Ile,更較佳的是Val; (ix) 位置588處的Gln、Glu、Ile、Met、Val、Trp或Phe,較佳的是Gln或Glu; (x) 位置64處的Lys或位置66處的Arg或位置64處的Lys和位置66處的Arg; (xi) 位置316處的Trp; (xii) 位置201和433兩者處的Cys; (xiii) 位置556或558或位置556和558兩者處的Pro; (xiv) 由具有7-10個胺基酸的環,較佳的是8個胺基酸的環,例如具有選自(SEQ ID NO: 9-14)中任一個的序列的環,替換胺基酸位置548-568處的環(HR1環); (xv) 位置568處的Gly、或位置569處的Gly、或位置636處的Gly、或位置568和636兩者處的Gly、或位置569和636兩者處的Gly; (xvi) 位置302處的Tyr、或位置519處的Arg、或位置520處的Arg、或位置302處的Tyr和位置519處的Arg、或位置302處的Tyr和位置520處的Arg、或位置302處的Tyr以及位置519和520兩者處的Arg; (xvii) 該HIV Env蛋白的弗林蛋白酶切割序列中的突變,較佳的是位置508-511處由RRRRRR(SEQ ID NO: 6)進行的替換; (xviii) 位置501和605處的Cys或位置559處的Pro,較佳的是位置501和605處的Cys和位置559處的Pro; (xix) 位置108處的His;和/或 (xx) 位置538處的His, 其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
- 如請求項1或2所述之重組HIV Env蛋白,其包含位置650處的Trp。
- 如請求項1或2所述之重組HIV Env蛋白,其包含位置650處的Phe。
- 如請求項1-4中任一項所述之重組HIV Env蛋白,其包含位置108處的His。
- 如請求項1-5中任一項所述之重組HIV Env蛋白,其包含位置538處的His。
- 如請求項1-6中任一項所述之重組HIV Env蛋白,其包含位置501和605處的Cys或位置559處的Pro,較佳的是位置501和605處的Cys和位置559處的Pro。
- 如請求項1-7中任一項所述之重組HIV Env蛋白,其包含位置501和605處的Cys和位置559處的Pro。
- 如請求項1-8中任一項所述之重組HIV Env蛋白,其係gp140或gp160蛋白,或在細胞質區域中具有截短的Env蛋白。
- 如請求項1-9中任一項所述之重組HIV Env蛋白,其係演化支A HIV、演化支B HIV或演化支C HIV的Env蛋白。
- 一種三聚體複合物,其包含三種相同的如請求項1-10中任一項所述之重組HIV Env蛋白的非共價低聚物。
- 一種粒子,較佳的是脂質體或奈米粒子,在其表面上展示如請求項1至10中任一項所述之重組HIV Env蛋白或如請求項11所述之三聚體複合物。
- 一種分離的核酸分子,其編碼如請求項1至10中任一項所述之重組HIV Env蛋白。
- 一種載體,其包含可操作地連接至啟動子的如請求項13所述之分離的核酸分子。
- 如請求項14所述之載體,其係腺病毒載體。
- 一種宿主細胞,其包含如請求項13所述之分離的核酸分子或如請求項14或15所述之載體。
- 一種生產重組HIV Env蛋白之方法,該方法包括使如請求項16所述之宿主細胞在適於產生該重組HIV Env蛋白的條件下生長。
- 一種組成物,其包含如請求項1至10中任一項所述之重組HIV Env蛋白、如請求項11所述之三聚體複合物、如請求項12所述之粒子、如請求項13所述之分離的核酸分子或如請求項14或15所述之載體,以及藥學上可接受的載劑。
- 一種改善HIV Env蛋白的三聚體形成之方法,該方法包括藉由Trp、Phe、Met或Leu之一,較佳的是藉由Trp或Phe取代親本HIV Env蛋白中位置650處的胺基酸殘基,其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
- 一種重組人類免疫缺陷病毒(HIV)包膜(Env)蛋白,其包含位置108處的組胺酸(His),其中位置的編號係根據HIV-1分離株HXB2的gp160中的編號。
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US5786464C1 (en) | 1994-09-19 | 2012-04-24 | Gen Hospital Corp | Overexpression of mammalian and viral proteins |
WO2005034842A2 (en) * | 2003-05-19 | 2005-04-21 | Progenics Pharmaceuticals, Inc. | Peptides useful as hiv fusion inhibitors |
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US20110300205A1 (en) | 2009-07-06 | 2011-12-08 | Novartis Ag | Self replicating rna molecules and uses thereof |
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US9630994B2 (en) | 2014-11-03 | 2017-04-25 | University Of Washington | Polypeptides for use in self-assembling protein nanostructures |
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