TW202128219A - 醫藥組合物及其用途 - Google Patents
醫藥組合物及其用途 Download PDFInfo
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- TW202128219A TW202128219A TW109143765A TW109143765A TW202128219A TW 202128219 A TW202128219 A TW 202128219A TW 109143765 A TW109143765 A TW 109143765A TW 109143765 A TW109143765 A TW 109143765A TW 202128219 A TW202128219 A TW 202128219A
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Abstract
本發明提供了一種醫藥組合物,其包含:i)皰疹gE蛋白、所述蛋白的活性片段、所述蛋白的變體,或者其中至少兩種的混合物;ii)免疫刺激組合物,所述免疫刺激組合物包含皂苷和CpG寡聚去氧核苷酸,或者所述免疫刺激組合物由包含皂苷的佐劑和CpG寡聚去氧核苷酸組成。本發明提供了所述醫藥組合物在製備用於預防和/或治療水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病的藥物中的用途。本發明提供的醫藥組合物達到了出乎意料的技術效果,可介導更強的免疫應答。
Description
本發明屬於生物製藥領域。具體地,本發明涉及一種醫藥組合物,所述醫藥組合物包含皰疹gE蛋白和免疫刺激組合物。其中,所述免疫刺激組合物包含皂苷和CpG寡聚去氧核苷酸,或者所述免疫刺激組合物由包含皂苷的佐劑和CpG寡聚去氧核苷酸組成,其中所述CpG寡聚去氧核苷酸序列具有兩個或兩個以上拷貝的5’-TTCGTT-3’基序或5’-TCGTCGTCG-3’基序。本發明還涉及所述醫藥組合物用於預防帶狀皰疹、水痘或帶狀皰疹後神經痛的用途。
帶狀皰疹是由水痘-帶狀皰疹病毒(varicella-zoster virus,VZV)引起的病毒性皮膚病。VZV原發感染時通過呼吸道黏膜上皮進入局部淋巴結複製,感染病毒的淋巴細胞隨後經淋巴循環進入血液循環感染外週血單核白細胞,病毒隨血流播散至皮膚,臨床表現為水痘。水痘痊癒後,病毒潛伏在顱腦神經節複製,並沿外週神經移行至皮膚,臨床表現為帶狀皰疹。帶狀皰疹的最主要併發症是皰疹感染後神經痛(post-herpetic neuralgia,PHN),50歲以上人群中約20%會發生PHN,且隨著年齡增大,出現PHN的可能性越高,疼痛持續數月甚至數年。
接種帶狀皰疹疫苗是預防帶狀皰疹、減輕PHN等併發症的有效手段,目前,已上市的帶狀皰疹疫苗主要有默沙東的Zostavax與葛蘭素史克的Shingrix。其中,Zostavax於2006年上市,為減毒活疫苗;Shingrix於2017年10月上市,為重組帶狀皰疹疫苗。
發明人對現有技術進行了深入研究,發現佐劑對帶狀皰疹疫苗的治療作用起到重要作用。佐劑寡聚去氧核苷酸(CpG)是近年來發現的一類新型免疫刺激劑,其化學本質為含有胞嘧啶鳥嘌呤二核苷酸的寡去氧核苷酸,具有與天然CpG模式識別受體相似的免疫反應,能與細胞膜上的Toll樣受體結合,通過TLR9信號通路有效引發哺乳動物免疫反應。CpG引起的免疫反應以Th1型為主,可誘導Th2型免疫應答向Th1轉換,從而激發細胞免疫。通過啟動T細胞、B細胞、NK細胞等免疫活性細胞,產生大量的多種細胞因數,從而增強機體的特異性和非特異性免疫效應,是連接天然和獲得性免疫的重要紐帶。
皂苷為一類苷元為三萜或螺旋甾烷類化合物的糖苷,屬植物來源佐劑。目前常用的皂苷佐劑有QS系列,是從皂樹中提取得到的皂苷,該系列中最常用的是QS-21佐劑,但QS-21可誘導細胞溶血,有一定系統和局部的毒副作用。Alving等(ALVING CR, MATYAS G, BECK Z, et al. Revue Roumaine de Chimie, 2016, 61(8): 631-635.)研究發現,以ALF脂質體結合MPLA和QS-21作為佐劑對抗HIVgp140蛋白可有效增加血清中抗體滴度。
現有技術(WO2001051083A3)曾報導關於皂苷與CpG寡聚去氧核苷酸的免疫刺激組合物,其中CpG佐劑主要涉及CpG1826和CpG7909。然而,由於CpG寡聚去氧核苷酸具備結構多樣性,不同序列的CpG佐劑間的效果差異巨大。
因此,當前對免疫效果更強的佐劑以及藥物存在需求。
針對現有技術的不足,發明人在進行了大量研究後,發現了免疫效果更強的免疫刺激組合物,以及包含所述免疫刺激組合物的醫藥組合物。本發明提供的醫藥組合物包含雙佐劑,並且其中皂苷和CpG寡聚去氧核苷酸之間表現出高效的協同作用,可以介導更強烈的免疫應答。本發明還提供了所述醫藥組合物用於預防和/或治療水痘、帶狀皰疹或帶狀皰疹後神經痛的用途。與現有技術相比,本申請的醫藥組合物表現出優異的免疫預防和治療作用。
本發明的目的是通過以下技術方案實現的:
一方面,本發明提供了一種醫藥組合物,其包含:
i)皰疹gE蛋白、所述蛋白的活性片段、所述蛋白的變體,或者其中至少兩種的混合物,
ii)免疫刺激組合物,所述免疫刺激組合物包含皂苷和CpG寡聚去氧核苷酸,或者所述免疫刺激組合物由包含皂苷的佐劑和CpG寡聚去氧核苷酸組成;其中,所述CpG寡聚去氧核苷酸序列具有兩個或兩個以上拷貝的5’-TTCGTT-3’基序或5’-TCGTCGTCG-3’基序。
根據本發明所述的醫藥組合物,其中所述CpG寡聚去氧核苷酸的序列選自以下中的任一種:CpG T1:TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)、CpG T2:TCG TTC GTT CGT TCG TTC GTT CGT T(SEQ ID NO: 3)和CpG T3:TCG TCG TCG TCG TCG TCG TCG(SEQ ID NO: 4);
優選地,所述CpG寡聚去氧核苷酸的序列為CpG T1:TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)。
根據本發明所述的醫藥組合物,其中,所述皂苷選自皂樹皂苷、人參皂苷、桔梗皂苷、黃芪皂苷、三七皂苷、甘草皂苷、合歡皮皂苷、麥冬皂苷、柴胡皂苷或竹節參皂苷中的一種或多種;優選地,所述皂苷為皂樹皂苷、人參皂苷、桔梗皂苷或黃芪甲苷,更優選地,所述皂樹皂苷為QS-7、QS-17、QS-18或QS-21,進一步優選地,所述皂樹皂苷為QS-21;所述人參皂苷可以為人參皂苷Rg1、人參皂苷Rg3、人參皂苷Rb1或人參皂苷Re;所述桔梗皂苷可以為桔梗皂苷D、桔梗皂苷D2或其兩者的混合物;所述黃芪皂苷可以為黃芪甲苷(黃芪皂苷IV)、黃芪皂苷I、黃芪皂苷II等單體或其中兩種或兩種以上皂苷單體的混合物;所述三七皂苷可以為三七皂苷R1;所述麥冬皂苷可以為麥冬皂苷D等;所述柴胡皂苷可以為柴胡皂苷a、柴胡皂苷d或其兩者的混合物;所述合歡皮皂苷可以為合歡皮總皂苷等;所述甘草皂苷可以為甘草總皂苷;所述竹節參皂苷可以為竹節參總皂苷。
根據本發明所述的醫藥組合物,其中,所述包含皂苷的佐劑為免疫刺激複合物佐劑(Iscom佐劑)。
根據本發明所述的醫藥組合物,其中,所述CpG寡聚去氧核苷酸包含硫代磷酸酯連接;優選地,所述CpG寡聚去氧核苷酸為硫代寡聚去氧核苷酸,更優選地為全硫代寡聚去氧核苷酸。
根據本發明所述的醫藥組合物,其中,所述CpG寡聚去氧核苷酸與所述皂苷的重量比為1~40: 0.1~2,優選為2~40: 0.1~2。
根據本發明所述的醫藥組合物,其中,所述CpG寡聚去氧核苷酸與所述皂苷的重量比為2: 1。
根據本發明所述的疫苗組合物,其還包含:iii)可藥用載體。
根據本發明所述的醫藥組合物,其中,所述皰疹gE蛋白包含如SEQ ID NO: 1所示的胺基酸序列或由其組成;優選地,所述皰疹gE蛋白的活性片段包含SEQ ID NO: 1中的第1位~第X位的連續胺基酸或由其組成,其中,X為507至518之間的整數。
根據本發明所述的醫藥組合物,其中,所述疫苗組合物的組分i)和ii)之間的重量比為1: 1.1~42,優選為1: 2.1~42。
根據本發明所述的醫藥組合物,其中,所述疫苗組合物的組分i)和ii)之間的重量比為1: 3。
另一方面,本發明提供了一種帶狀皰疹疫苗或水痘疫苗,其包含所述醫藥組合物。
再一方面,本發明提供了所述醫藥組合物在製備用於預防和/或治療水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病的藥物中的用途;優選地,所述水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病選自水痘、帶狀皰疹或帶狀皰疹後神經痛。
再一方面,本發明提供了所述醫藥組合物在製備用於在物件中產生針對水痘-帶狀皰疹病毒的體液免疫和/或細胞免疫應答的藥物中的用途。其中,所述藥物為帶狀皰疹疫苗或水痘疫苗,優選為帶狀皰疹疫苗。
再一方面,本發明提供了一種預防和/或治療水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病的方法,所述方法包括給予有需要的受試者預防和/或治療有效量的醫藥組合物;優選地,所述水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病選自水痘、帶狀皰疹或帶狀皰疹後神經痛。
再一方面,本發明提供了一種在物件中產生針對水痘-帶狀皰疹病毒的體液免疫和/或細胞免疫應答的藥物的方法,所述方法包括給予有需要的受試者有效量的醫藥組合物。
本發明提供的免疫刺激組合物達到了出乎意料的技術效果,可介導更強的免疫應答。單獨使用CpG T1、CpG T2和CpGT3的免疫刺激作用弱於CpG1018、CpG7909和CpG1826等,但與QS21聯合應用後,所述免疫刺激組合物表現出出人意料的協同作用,免疫效果顯著增強。
CpG T1、CpG T2和CpGT3經初步實驗驗證,在帶狀皰疹抗原中的應用效果相當。其中CpG T1、CpG T2含有相同的基序5’-TTCGTT-3’,CpGT3經其他抗原(例如乙肝表面抗原、乙肝核心抗原等)實驗證明,免疫作用與CpG T1、CpG T2相當。
與現有技術相比,本發明提供的含有免疫刺激物的帶狀皰疹疫苗具有優越的免疫刺激作用,細胞免疫實驗證明該疫苗可誘導產生較強的皰疹gE蛋白特異性IFN-γ水準,蛋白免疫效果顯著優於單一佐劑。體液免疫實驗也證明該疫苗可產生較高的皰疹gE蛋白特異性IgG/IgG1/IgG2a抗體水準,且效果優於單一佐劑,顯著優於其他CPG佐劑和QS21的組合。
定義
本文使用的術語“CpG寡聚去氧核苷酸”或“CpG-ODN”是指短的單鏈合成DNA分子,其含有一個或更多個“CpG”單元,其中C表示胞嘧啶,G表示鳥嘌呤,p表示磷酸二酯鍵。特別地,所述CpG寡聚去氧核苷酸是非甲基化的。在一些實施方案中,所述CpG-ODN包含硫代磷酸酯連接或硫代磷酸酯骨架。也就是說,在一些實施方案中,所述CpG-ODN為硫代磷酸酯寡聚去氧核苷酸(即硫代寡聚去氧核苷酸)。優選地,所述CpG-ODN中所有核苷酸間連接均為硫代磷酸酯連接,即所述CpG-ODN為全硫代寡聚去氧核苷酸。在另一些實施方案中,所述CpG-ODN包含兩個或兩個以上拷貝的5’-TTCGTT-3’基序或5’-TCGTCGTCG-3’基序。特別地,所述CpG-ODN具有選自下列的序列:TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)、TCG TTC GTT CGT TCG TTC GTT CGT T(SEQ ID NO: 3)或TCG TCG TCG TCG TCG TCG TCG(SEQ ID NO: 4),優選地為TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)。
本文使用的“人參皂苷、桔梗皂苷、黃芪皂苷、三七皂苷、甘草皂苷、合歡皮皂苷、麥冬皂苷、柴胡皂苷或竹節參皂苷”是指是存在於對應植物中的活性成分,例如人參皂苷是一種固醇類化合物,主要存在於人參屬藥材中,是人參中的活性成分。在一些實施方案中,所述人參皂苷優選為人參皂苷Rg1、人參皂苷Rg3、人參皂苷Rb1、人參皂苷Re等單體或其中兩個或兩個以上皂苷單體的混合物;桔梗皂苷優選為桔梗皂苷D、桔梗皂苷D2或其兩者的混合物;黃芪皂苷優選為黃芪甲苷(黃芪皂苷IV)、黃芪皂苷I、黃芪皂苷II等單體或其中兩個或兩個以上皂苷單體的混合物;三七皂苷優選為三七皂苷R1等;麥冬皂苷優選為麥冬皂苷D等;柴胡皂苷優選為柴胡皂苷a、柴胡皂苷d或其兩者的混合物;合歡皮皂苷優選為合歡皮總皂苷等;甘草皂苷優選為甘草總皂苷等;竹節參皂苷優選為竹節參總皂苷等。
本文使用的“Iscom佐劑”為免疫刺激複合物佐劑,具體地為不包含抗原的Iscom基質(ISCOM MATRIX),是由磷脂、皂苷、膽固醇組成的籠狀結構的佐劑。
本文使用的“治療和/或預防有效量”或“有效量”是指足以顯示其對於所施用物件益處的劑量。施用的實際量,以及施用的速率和時間過程會取決於所治療者的自身情況和嚴重程度。治療的處方(例如對劑量的決定等)最終是全科醫生及其它醫生的責任並依賴其做決定,通常考慮所治療的疾病、患者個體的情況、遞送部位、施用方法以及對於醫生來說已知的其它因素。
本文所使用的術語“哺乳動物”是指人類,也可以是其它動物,如野生動物(如蒼鷺、鸛、鶴等),家畜(如鴨、鵝等)或實驗動物(如猩猩、猴子、大鼠、小鼠、兔子、豚鼠、土撥鼠、地松鼠等)。
在另一些實施方案中,本發明組合物還可包含另外的添加劑,如可藥用載體或添加劑,尤其是當它以藥物製劑形式存在時。
優選的藥物載體尤其是水,緩衝水溶液,優選等滲鹽溶液如PBS(磷酸鹽緩衝液)、葡萄糖、甘露醇、右旋葡萄糖、乳糖、澱粉、硬脂酸鎂、纖維素、碳酸鎂、0.3%甘油、透明質酸、乙醇或聚亞烷基二醇如聚丙二醇、甘油三酯等。所用藥物載體的類型尤其依賴于根據本發明的組合物是否配製為用於口服、鼻、皮內、皮下、肌內或靜脈施用。根據本發明的組合物可包含潤濕劑、乳化劑或緩衝液物質作為添加劑。
根據本發明的醫藥組合物、疫苗或者藥物製劑可通過任何適宜的途徑施用,例如可口服、鼻、皮內、皮下、肌內或靜脈內施用。
以下結合附圖通過具體實施方式的描述對本發明作進一步說明,但這並非是對本發明的限制,本領域技術人員根據本發明的基本思想,可以作出各種修改或改進,但是只要不脫離本發明的基本思想,均在本發明的範圍之內。
以下參照具體的實施例來說明本發明。本領域技術人員能夠理解,這些實施例僅用於說明本發明,其不以任何方式限制本發明的範圍。
下述實施例中的實驗方法,如無特殊說明,均為常規方法。下述實施例中所用的原料、試劑材料等,如無特殊說明,均為市售購買產品。
實施例1 重組帶狀皰疹疫苗組合物的製備方法
1.1 製備皰疹gE蛋白:胺基酸序列如SEQ ID NO: 1所示。
參考文獻Thomsson E, Persson L等在《Journal of Virological Methods》2011,第175卷,第1期,第53-59頁中的報導,具體步驟如下:
根據目的蛋白序列對其核酸序列進行優化,使其密碼子符合哺乳動物表達系統,並對目的基因進行合成;將合成的目的基因通過酶切連接的方式與pcDNA3.1(+)質體連接,轉化Top 10感受態,挑取陽性單克隆,對陽性單克隆進行測序驗證;大量擴增單克隆菌體,用無內毒素質體抽提試劑盒進行大量抽提符合細胞轉染的質體;通過暫態轉染方式用質體轉染CHO懸浮細胞,CHO細胞活力低於70%或發酵時間大於7天時,在4℃下以5000 rpm離心30 min收集發酵液上清。將發酵液在4℃層析櫃中透析至含50 mM Tris-HCl、500 mM NaCl、20 mM咪唑的溶液中,透析比例1:100,每4 h透析一次,共透析3次;通過鎳柱對收集的樣品進行純化,對收集目的蛋白峰樣品進行SDS-PAGE檢測,合併較純的純化液,用含20 mM磷酸鹽、150 mM NaCl的溶液在4℃層析櫃中透析24 h,透析比例1:100,每8h換液一次;將樣品過0.22 µm無菌濾膜,4℃冰箱中保存備用。
1.2 製備CPG寡聚去氧核苷酸原料:
寡聚去氧核苷酸是合成製備的寡聚去氧核苷酸序列片段,其含有一個或多個CpG基序,本實施例使用CPG序列見表1:
表1 CPG寡聚去氧核苷酸的具體序列
CPG寡聚去氧核苷酸 | 序列 |
CpG T1 | TCGTTCGTTCGTTCGTTCGTT(SEQ ID NO: 2) |
CpG T2 | TCG TTC GTT CGT TCG TTC GTT CGT T(SEQ ID NO: 3) |
CpG T3 | TCG TCG TCG TCG TCG TCG TCG(SEQ ID NO: 4) |
CpG 1018 | TGACTGTGAACGTTCGAGATGA(SEQ ID NO: 5) |
CpG 7909 | TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID NO: 6) |
具體製備方法:使用常規固相亞磷醯胺三酯法化學合成方法製備,由3’端開始,1)脫保護基:先用三氯乙酸脫去連接在CpG上的核苷酸的保護基團DMT(二甲氧基三苯甲基),獲得游離的5’羥基,以供下一步縮合反應使用;2)活化:將亞磷醯胺保護的核苷酸單體與四氮唑活化劑混合並進入合成柱,形成亞磷醯胺四唑活性中間體,此中間體與CpG上已脫保護基的核苷酸發生縮合反應;3)連接:亞磷醯胺四唑活性中間體遇到CpG上已脫保護基的核苷酸時,將與其5’羥基發生親和反應,縮合並脫去四唑,此時寡核苷酸鏈向前延長一個堿基;4)氧化:縮合反應時核苷酸單體是通過亞磷酯鍵與連在CpG上的寡核苷酸連接,而亞磷酯鍵不穩定,易被酸或堿水解,此時使用硫代試劑將亞磷醯胺氧化為硫磷雙鍵的磷酸三酯,從而得到穩定的寡核苷酸;5)封閉:縮合反應後為了防止連在CpG上的未參與反應的5’羥基在隨後的循環反應中被延伸,常通過乙醯化來封閉此端羥基;經過以上五個步驟後,一個去氧核苷酸就連到CpG的核苷酸上;重複以上的脫保護基、活化、連接、氧化、封閉過程即可得到一個DNA片段粗品;最後對其進行切割、脫保護基、純化、定量等合成後處理即可。
實施例2 CPG寡聚去氧核苷酸的篩選實驗
2.1 實驗動物:
C57BL/6(N)小鼠,雌性,5週齡,42隻,購於上海斯萊克實驗動物有限責任公司。
2.2 試劑材料:
使用PBS溶液(購自Hyclone公司)將實施例1中獲得皰疹gE原液分別稀釋至50μg/mL,使用PBS溶液將實施例1中獲得的CpG分別稀釋至100μg/mL。
2.3 實驗分組:
見表2,每隻小鼠每次注射量為100μL/隻,對照組注射PBS溶液100μL/隻。
表2 實驗動物分組及每組注射量
組別 | 數量(隻) | 組分μg/隻 | |||||
皰疹gE蛋白 | CpG T1 | CpG T2 | CpG T3 | CpG7909 | CpG1018 | ||
對照 | 6 | ||||||
抗原 | 6 | 5 | |||||
T1 | 6 | 5 | 10 | ||||
T2 | 6 | 5 | 10 | ||||
T3 | 6 | 5 | 10 | ||||
7909 | 6 | 5 | 10 | ||||
1018 | 6 | 5 | 10 |
2.4 動物免疫:
所有組別每2週進行1次肌肉注射,接種部位為右側後大腿,連續給藥2次,即分別于第0週和第2週注射給藥,第4週將所有小鼠處死。
2.5 檢測步驟:
小鼠免疫後第7天取脾,按常規方法製備脾淋巴細胞,具體如下:無菌操作取脾臟:用無菌鑷子及剪刀剪取脾臟,放於70 μm細胞濾網中,置於含有2 mL預冷處理的2% FBS(購自GIBCO公司)-PBS的平皿中;用研磨棒研磨脾臟,脾臟細胞通過篩目進入平皿中,得到細胞懸液,用巴氏吸管將懸液放入經40 μm細胞濾網過濾(購自BD公司)的50mL無菌離心管;500×g,4℃離心5分鐘;棄去上清,加入2 mL 1×破紅劑(購自BD公司)重懸細胞,4℃避光靜置5分鐘,以破碎紅細胞;加入10 mL 2% FBS-PBS終止破紅反應;500×g,4℃離心5分鐘;棄去上清,加入5 mL 2% FBS-PBS重懸細胞備用。
使用刺激物gE特異性肽庫刺激脾細胞;按照試劑盒說明書,使用ELISPOT試劑盒(BD公司)檢測gE抗原特異性IFN-γ分泌水準;使用ImmunoSPOT Series 3酶聯斑點分析儀讀取ELISPOT試劑盒測出的斑點數(具體操作步驟參考中國專利CN104043120B的實施例7)。其中gE特異性肽庫序列見SEQ ID NO: 7~21。
表3 gE特異性肽庫
gE特異性肽庫 | 序列 |
SEQ ID NO: 7 | SVLRYDDFHIDEDKL |
SEQ ID NO: 8 | YDDFHIDEDKLDTNS |
SEQ ID NO: 9 | HIDEDKLDTNSVYEP |
SEQ ID NO: 10 | DKLDTNSVYEPYYHS |
SEQ ID NO: 11 | TNSVYEPYYHSDHAE |
SEQ ID NO: 12 | YEPYYHSDHAESSWV |
SEQ ID NO: 13 | YHSDHAESSWVNRGE |
SEQ ID NO: 14 | HAESSWVNRGESSRK |
SEQ ID NO: 15 | SWVNRGESSRKAYDH |
SEQ ID NO: 16 | RGESSRKAYDHNSPY |
SEQ ID NO: 17 | SRKAYDHNSPYIWPR |
SEQ ID NO: 18 | YDHNSPYIWPRNDYD |
SEQ ID NO: 19 | SPYIWPRNDYDGFLE |
SEQ ID NO: 20 | WPRNDYDGFLENAHE |
SEQ ID NO: 21 | DYDGFLENAHEHHGV |
2.6 評價指標:
若對照孔斑點數≤5 SCF,樣品孔斑點數≥10 SCF,判定為陽性;若5 SFC<對照孔斑點數≤10 SCF,樣品孔斑點數/對照孔斑點數≥2,判定為陽性;若對照孔斑點數>10 SFC,樣品孔斑點數/對照孔斑點數≥3,判定為陽性。
2.7 實驗結果:
ELISPOT斑點結果見圖1,結果顯示:採用不同CPG佐劑的疫苗組合物免疫效果相近,其中CpG7909的效果最好,略高於CpG T1~T3;CpG1018與CpG T1~T3的免疫效果相當;本發明提供的三個序列中,CpGT1的效果最優,高於CpGT2和CpGT3。因此,後續實驗主要以CpGT1和CpG7909為主要對比。
實施例3 不同劑量的免疫刺激組合物對重組帶狀皰疹疫苗組合物的藥效影響
3.1 實驗動物及模型建立:
C57BL/6(N)小鼠,雌性,5週齡,72隻,購於上海斯萊克實驗動物有限責任公司。
3.2 試劑材料:
1)皰疹gE蛋白、CpG T1、CpG 7909均由實施例1制得;
2)QS-21(CAS.NO.A010-023,購自BRENNTAG公司);
3)使用PBS溶液(購自Hyclone公司)將皰疹gE原液稀釋至50μg/mL,使用PBS溶液將QS-21分別稀釋至5 μg/mL、50 μg/mL、100 μg/mL,使用PBS溶液將CpG T1溶解並分別稀釋至50 μg/mL、100 μg/mL、2 mg/mL,使用PBS溶液將CPG7909溶解並稀釋至100 μg/mL,供下一步使用。
3.3 實驗分組:
見表4,每次注射量為100 μL/隻。其中對照組注射PBS溶液100 μL/隻。
3.4 實驗步驟:同實施例2.5。
3.5 實驗結果:
ELISPOT斑點結果見圖2,結果顯示,CpG T1與QS21的劑量變化對疫苗組合物的治療效果有顯著性影響,其中,皰疹gE蛋白與免疫刺激組合物(CpG T1+ QS-21)高於1:2.1的疫苗組合物誘導產生皰疹gE蛋白特異性IFN-γ的水準顯著高於CPG7909組,例如表4的劑量5-劑量9的免疫刺激組合物。但由於種屬差異性,佐劑劑量進一步增加誘導效果並無顯著性增加,推測原因為小鼠無法準確反映佐劑的免疫強度。
儘管表4中的劑量1、2、4與對照CPG7909組的免疫刺激效果相當,但是使用的佐劑劑量低於同等CPG7909組,因此也具有出乎意料的技術效果。
表4 實驗動物分組
組別 | 數量(隻) | 組分(μg/隻小鼠) | |||||
皰疹gE蛋白 | CpG T1 | QS21 | CPG7909 | ||||
對照 | 6 | ||||||
抗原 | 6 | 5 | |||||
劑量1 | 6 | 5 | 5 | 0.5 | |||
劑量2 | 6 | 5 | 5 | 5 | |||
劑量3 | 6 | 5 | 5 | 10 | |||
劑量4 | 6 | 5 | 10 | 0.5 | |||
劑量5 | 6 | 5 | 10 | 5 | |||
劑量6 | 6 | 5 | 10 | 10 | |||
劑量7 | 6 | 5 | 200 | 0.5 | |||
劑量8 | 6 | 5 | 200 | 5 | |||
劑量9 | 6 | 5 | 200 | 10 | |||
CPG7909 | 6 | 5 | 5 | 10 | |||
實施例4 重組帶狀皰疹疫苗組合物的細胞免疫藥效驗證
4.1 實驗動物:
C57BL/6(N)小鼠,雌性,5週齡,48隻,購於上海斯萊克實驗動物有限責任公司。
4.2 試劑材料:
使用PBS溶液(購自Hyclone公司)將實施例1中獲得皰疹gE原液分別稀釋至50 μg/mL和1 0μg/mL,使用PBS溶液將QS-21(購自BRENNTAG公司,CAS.NO.A010-023)分別稀釋至50 μg/mL和10 μg/mL,使用PBS溶液將實施例1中獲得的CpG分別稀釋至10 0μg/mL和20 μg/mL。
4.3 實驗分組:見表5,每隻小鼠每次注射量為100 μL/隻,其中A組為陰性對照,注射PBS溶液100 μL/隻。
表5 實驗動物分組及每組注射量
組別 | 數量(隻) | 組分μg/隻 | |||
皰疹gE蛋白 | CpG T1 | CpG7909 | QS-21 | ||
A | 6 | ||||
B | 6 | 5 | |||
C | 6 | 5 | 10 | ||
D | 6 | 5 | 5 | ||
E | 6 | 5 | 10 | 5 | |
F | 6 | 5 | 10 | 5 | |
G | 6 | 1 | 2 | 1 | |
H | 6 | 1 | 2 | 1 |
4.4 動物免疫:所有組別每2週進行1次肌肉注射,接種部位為右側後大腿,連續給藥2次,即分別于第0週和第2週注射給藥,第4週將所有小鼠處死。
4.5 檢測步驟:同實施例2.5。
4.6 評價指標:同實施例2.6。
4.7 實驗結果:各組小鼠脾細胞分泌gE特異性IFN-γ的T淋巴細胞斑點數水準如圖3所示,gE特異性IFN-γ陽轉率結果如表6所示。結果表明:免疫高劑量的E、F組對應的脾細胞分泌gE特異性IFN-γ的T淋巴細胞斑點數水準(>4000SFC/106
脾細胞)均顯著高於低劑量的G、H組;其中,E組、G組(CpGT1+QS-21)對應的脾細胞分泌gE特異性IFN-γ的T淋巴細胞斑點數水準高於同劑量的F組、H組(CpG7909+QS-21),E-H組IFN-γ的轉陽率均為100%。
表6 脾細胞分泌的gE特異性IFN-γ的轉陽率
組別 | A | B | C | D | E | F | G | H |
轉陽數量/隻 | 1/6 | 0/6 | 4/6 | 5/6 | 6/6 | 6/6 | 6/6 | 6/6 |
轉陽率/% | 16.7 | 0 | 66.7 | 83.3 | 100 | 100 | 100 | 100 |
實施例5 重組帶狀皰疹疫苗組合物的體液免疫藥效驗證
5.1 實驗動物:
C57BL/6(N)小鼠,雌性,5週齡,48隻,購於上海斯萊克實驗動物有限責任公司。
5.2 試劑材料:同實施例3.2。
5.3 實驗分組:同實施例3.3。
5.4 動物免疫:所有組別每2週進行1次肌肉注射,接種部位為右側後大腿,連續給藥2次,即分別于第0週和第2週注射給藥。
5.5 檢測步驟:免疫後第28天進行採血,分離血清(全血置於37℃恒溫培養箱放置40 min,12000 rpm、4℃離心10 min;吸取上清,凍存於-20℃備用),按照試劑盒說明書,使用ELISA試劑盒(上海科華)檢測產生的皰疹gE蛋白特異性抗體陽轉率。檢測設空白對照、陰性對照和待測樣品,每種兩個平行孔,其中陰性對照為陰性小鼠血清;除空白對照外,各孔分別加入陰性對照或待測樣品,再加入酶結合物,混勻封板後37℃孵育30分鐘;使用洗滌液洗滌各孔,每孔加入顯色劑A液和顯色劑B液,混勻封板後37℃孵育15分鐘;每孔加入終止液混勻;使用酶標儀讀取450nm波長處的各孔OD值。
5.6 實驗結果:ELISA檢測小鼠血清中抗原特異性IgG抗體及亞型水準如圖4所示,其中,A圖:各組小鼠血清的IgG水準;B圖:各組小鼠血清的IgG1水準;C圖:各組小鼠血清的IgG2a水準;D圖:各組小鼠血清的IgG2a與IgG1的比值。
結果表明:含有本發明所述免疫刺激物的E組免疫效果顯著優於單獨的CpG組(C組)和QS-21組(D組)和雙佐劑對照(F組),且對應的IgG和IgG2a抗體水準與兩組均存在顯著差異,即在QS-21中加入CpG可提高相應的體液免疫水準。
實施例6 不同皂苷對重組帶狀皰疹疫苗組合物的藥效影響
6.1 實驗動物及模型建立:
C57BL/6(N)小鼠,雌性,5週齡,48隻,購於上海斯萊克實驗動物有限責任公司。
6.2 試劑材料:
1)皰疹gE蛋白、CpG T1、CpG 7909均由實施例1制得;
2)QS-21(CAS.NO.A010-023,購自BRENNTAG公司);人參皂苷Rg1(CAS: 22427-39-0,購自南京春秋生物工程有限公司)、黃芪甲苷(CAS: 84687-43-4,購自南京春秋生物工程有限公司)、桔梗皂苷D(CAS: 58479-68-8,購自湖北雲鎂科技有限公司),Iscom佐劑(購自上海熹垣生物科技有限公司)
3)使用PBS溶液(購自Hyclone公司)將皰疹gE原液稀釋至50 μg/mL,使用PBS溶液將各皂苷分別稀釋至50 μg/mL,使用PBS溶液將CpG T1和CpG 7909分別溶解並稀釋至100 μg/mL,供下一步使用。
6.3 實驗分組:
見表7,每次注射量為100 μL/隻。其中對照組注射PBS溶液100 μL/隻。
6.4 實驗步驟:同實施例2.5。
6.5 實驗結果:
ELISPOT斑點結果見圖5,結果顯示,CpG T1與各皂苷聯合應用後均產生了高效的協同作用,誘導產生gE特異性IFN-γ水準顯著高於其他CpG和皂苷的組合物,其中,QS-21的效果最佳。
表7 實驗動物分組
組別 | 數量(隻) | 組分(μg/隻小鼠) | |||||||
gE | CpG T1 | QS- 21 | 人參皂苷Rg1 | 桔梗皂苷D | 黃芪甲苷 | Iscom佐劑 | CpG 7909 | ||
對照 | 6 | ||||||||
抗原 | 6 | 5 | |||||||
QS-21 | 6 | 5 | 10 | 5 | |||||
人參皂苷Rg1 | 6 | 5 | 10 | 5 | |||||
桔梗皂苷D | 6 | 5 | 10 | 5 | |||||
黃芪甲苷 | 6 | 5 | 10 | 5 | |||||
Iscom佐劑 | 6 | 5 | 10 | 5 | |||||
7909 | 6 | 5 | 5 | 10 |
綜上所述,本發明提供的帶狀皰疹疫苗具有優越的免疫刺激作用,細胞免疫實驗證明該疫苗可誘導產生較強的皰疹gE蛋白特異性IFN-γ水準,蛋白免疫效果顯著優於單一佐劑。
儘管以上已經對本發明作了詳細描述,但是本領域技術人員理解,在不偏離本發明的精神和範圍的前提下可以對本發明進行各種修改和改變。本發明的權利範圍並不限於上文所作的詳細描述,所述修改和改變應歸屬於申請專利範圍。
無
以下,結合附圖來詳細說明本發明的實施方案,其中:
圖1顯示了不同的CPG寡聚去氧核苷酸對皰疹gE抗原特異性IFN-γ分泌水準的影響;
圖2顯示了不同的免疫刺激組合物劑量對皰疹gE抗原特異性IFN-γ分泌水準的影響;
圖3顯示了根據本發明的帶狀皰疹疫苗對皰疹gE抗原特異性IFN-γ分泌水準的影響;
圖4顯示了根據本發明的帶狀皰疹疫苗對小鼠血清中抗原特異性IgG抗體及其亞型水準的影響;
其中,A圖:各組小鼠血清的IgG水準;B圖:各組小鼠血清的IgG1水準;C圖:各組小鼠血清的IgG2a水準;D圖:各組小鼠血清的IgG2a與IgG1的比值;
圖5顯示了不同皂苷對皰疹gE抗原特異性IFN-γ分泌水準的影響。
無
Claims (20)
- 一種醫藥組合物,其包含: i)皰疹gE蛋白、所述蛋白的活性片段、所述蛋白的變體,或者其中至少兩種的混合物, ii)免疫刺激組合物,所述免疫刺激組合物包含皂苷和CpG寡聚去氧核苷酸,或者所述免疫刺激組合物由包含皂苷的佐劑和CpG寡聚去氧核苷酸組成;其中,所述CpG寡聚去氧核苷酸序列具有兩個或兩個以上拷貝的5’-TTCGTT-3’基序或5’-TCGTCGTCG-3’基序。
- 如請求項1所述的醫藥組合物,其中,所述CpG寡聚去氧核苷酸的序列選自以下中的任一種:CpG T1:TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)、CpG T2:TCG TTC GTT CGT TCG TTC GTT CGT T(SEQ ID NO: 3)和CpG T3:TCG TCG TCG TCG TCG TCG TCG(SEQ ID NO: 4); 優選地,所述CpG寡聚去氧核苷酸的序列為CpG T1:TCG TTC GTT CGT TCG TTC GTT(SEQ ID NO: 2)。
- 如請求項1或2所述的醫藥組合物,其中,所述皂苷選自皂樹皂苷、人參皂苷、桔梗皂苷、黃芪皂苷、三七皂苷、甘草皂苷、合歡皮皂苷、麥冬皂苷、柴胡皂苷或竹節參皂苷的一種或多種。
- 如請求項3所述的醫藥組合物,其中,所述皂樹皂苷為QS-7、QS-17、QS-18或QS-21,優選地,所述皂苷為QS-21;所述人參皂苷為人參皂苷Rg1、人參皂苷Rg3、人參皂苷Rb1或人參皂苷Re;所述桔梗皂苷為桔梗皂苷D、桔梗皂苷D2或其兩者的混合物;所述黃芪皂苷為黃芪甲苷、黃芪皂苷I、黃芪皂苷II或其中兩種或兩種以上皂苷單體的混合物;所述三七皂苷為三七皂苷R1;所述麥冬皂苷為麥冬皂苷D;所述柴胡皂苷為柴胡皂苷a、柴胡皂苷d或其兩者的混合物;所述合歡皮皂苷為合歡皮總皂苷;所述甘草皂苷為甘草總皂苷;所述竹節參皂苷為竹節參總皂苷。
- 如請求項1至4中任一項所述的醫藥組合物,其中,所述包含皂苷的佐劑為Iscom佐劑。
- 如請求項1至5中任一項所述的醫藥組合物,其中所述CpG寡聚去氧核苷酸包含硫代磷酸酯連接。
- 如請求項1至6中任一項所述的醫藥組合物,其中所述CpG寡聚去氧核苷酸為硫代寡聚去氧核苷酸。
- 如請求項1至7中任一項所述的醫藥組合物,其中所述CpG寡聚去氧核苷酸為全硫代寡聚去氧核苷酸。
- 如請求項1至8中任一項所述的醫藥組合物,其中CpG寡聚去氧核苷酸與皂苷的重量比為1~40:0.1~2,優選為2~40:0.1~2。
- 如請求項1至9中任一項所述的醫藥組合物,其中CpG寡聚去氧核苷酸與皂苷的重量比為2:1。
- 如請求項1至10中任一項所述的醫藥組合物,其中,所述醫藥組合物還含有: iii)可藥用載體。
- 如請求項1至11中任一項所述的醫藥組合物,其中,所述皰疹gE蛋白包含如SEQ ID NO: 1所示的胺基酸序列或由其組成。
- 如請求項1至12中任一項所述的醫藥組合物,其中,所述皰疹gE蛋白的活性片段包含SEQ ID NO: 1中的第1位~第X位的連續胺基酸或由其組成,其中,X為507至518之間的整數。
- 如請求項1至13中任一項所述的醫藥組合物,其中,所述組分i)和ii)之間的重量比為1: 1.1~42,優選為1: 2.1~42。
- 如請求項1至14中任一項所述的醫藥組合物,其中,所述組分i)和ii)之間的重量比為1: 3。
- 一種帶狀皰疹疫苗或水痘疫苗,其包含如請求項1至15中任一項所述的醫藥組合物。
- 一種如請求項1至15中任一項所述的醫藥組合物在製備用於預防和/或治療水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病的藥物中的用途。
- 如請求項17所述的用途,其中,所述水痘-帶狀皰疹病毒感染和/或水痘-帶狀皰疹病毒介導的疾病選自水痘、帶狀皰疹、帶狀皰疹後神經痛。
- 一種如請求項1至15中任一項所述的醫藥組合物在製備用於在物件中產生針對水痘-帶狀皰疹病毒的體液免疫和/或細胞免疫應答的藥物中的用途。
- 如請求項19所述的用途,其中,所述藥物為帶狀皰疹疫苗或水痘疫苗。
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WO2021115410A1 (zh) * | 2019-12-13 | 2021-06-17 | 南京远大赛威信生物医药有限公司 | 免疫刺激组合物及其用途 |
CN116327912A (zh) * | 2021-12-23 | 2023-06-27 | 上海泽润生物科技有限公司 | 带状疱疹疫苗组合物 |
CN114891072B (zh) * | 2022-03-11 | 2023-07-04 | 上海博唯生物科技有限公司 | 预防和/或治疗疱疹病毒的截短的疫苗抗原肽及其制备方法和应用 |
CN117653724A (zh) * | 2022-09-07 | 2024-03-08 | 远大赛威信生命科学(南京)有限公司 | 一种用于预防乙型肝炎病毒感染的药物组合物及其应用 |
CN116159134A (zh) * | 2023-01-31 | 2023-05-26 | 四川大学 | 七叶皂苷和/或其盐化合物作为佐剂在疫苗中的应用 |
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CN112972670B (zh) | 2023-12-19 |
WO2021115409A1 (zh) | 2021-06-17 |
TW202128217A (zh) | 2021-08-01 |
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EP4074335A1 (en) | 2022-10-19 |
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