TWI486359B - 可用作誘發抗原專一性t細胞反應之免疫原性增強劑之融合蛋白 - Google Patents
可用作誘發抗原專一性t細胞反應之免疫原性增強劑之融合蛋白 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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Description
本發明大致係關於融合蛋白,詳言之則係關於可增強T細胞媒介免疫反應之融合蛋白。
分子生物學使吾人得以生產次單元疫苗,其中,次單元疫苗之免疫原為母蛋白或母複合物之一片段或次單元。最好能開發出一種穩定疫苗,其一方面可誘發T細胞致敏反應,一方面又具有足夠之靈活度,俾與一感染源多種品系之序列結合。
本發明之一態樣係關於一種融合蛋白,其包含:(a)一抗原呈現細胞(APC)結合部位或一CD91受體結合部位,其位於融合蛋白之N端;(b)一蛋白轉導部位,其位於APC結合部位或CD91受體結合部位之C端,蛋白轉導部位係由下列各項所組成之群組中選出:(i)一融合多胜肽,其包含一T細胞致敏信號轉導胜肽、一連結子及一移位胜肽,其中:(1)T細胞致敏信號轉導胜肽係位於融合多胜肽之N端;(2)連結子包含序列編號第15號,並連結T細胞致敏信號轉導胜肽與移位胜肽;且(3)移位胜肽就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列;(ii)一T細胞致敏信號轉導胜肽;及(iii)一移位胜肽,其就長度而言具有34-112個胺基酸殘基,且包含
一與序列編號第3、20或4號至少90%相同之胺基酸序列;及(c)一病原體的一抗原,其位於蛋白轉導部位之C端;其中:T細胞致敏信號轉導胜肽就長度而言具有28-53個胺基酸殘基,且包含一與序列編號第31號至少90%相同之胺基酸序列,其中Xaa8
為I或L;Xaa10
為V、F或A;Xaa11
為M或L;Xaa17
為L或I;且若蛋白轉導部位為移位胜肽(biii),則APC結合部位或CD91受體結合部位完全不含綠膿桿菌外毒素A(PE)結合部位I之胺基酸序列。
在本發明之一實施例中,APC結合部位或CD91受體結合部位係一多胜肽,且多胜肽包含一與下列各項所組成之群組中選出之序列至少90%相同之胺基酸序列:序列編號第5、9、6、7及8號。或者,APC結合部位係選自下列各項所組成之群組:受體相關蛋白-1(RAP1)部位III、α-2-大球蛋白受體相關蛋白(A2M)、HIV-Tat、熱休克蛋白(HSP)及綠膿桿菌外毒素A(PE)結合部位I。
在本發明之另一實施例中,融合蛋白完全不含綠膿桿菌外毒素A(PE)結合部位I之胺基酸序列。
在本發明之另一實施例中,融合蛋白尚包含一內質網(ER)滯留序列,其位於融合蛋白之C端。
在本發明之另一實施例中,內質網滯留序列包含胺基酸序列Lys-Asp-Glu-Leu(序列編號第14號)。ER滯留序列可包含一由下列各項所組成之群組中選出之序列:序列編號第14、16至19號。或者,ER滯留序列可由下列各項所組成之群組中選出之序列組成:序列編號第16至19號。
在本發明之另一實施例中,若抗原含有10個或多於10個抗原決定區,則融合蛋白之C端完全不含內質網滯留序列。
在本發明之另一實施例中,蛋白轉導部位為融合多胜肽(bi)。
在本發明之另一實施例中,蛋白轉導部位為T細胞致敏信號轉導胜肽(bii)。
在本發明之另一實施例中,融合蛋白於蛋白轉導部位與抗原之間尚包含另一連結子,此連結子包含序列編號第15號。
在本發明之另一實施例中,蛋白轉導部位為移位胜肽(biii)。
在本發明之另一實施例中,融合蛋白於APC結合部位或CD91受體結合部位與移位胜肽之間尚包含另一連結子,此連結子包含序列編號第15號。
在本發明之另一實施例中,蛋白轉導部位包含序列編號第30號。
在本發明之另一實施例中,APC結合部位包含一與下列各項所組成之群組中選出之序列至少95%相同之胺基酸序列:序列編號第5、9、6、7及8號。
在本發明之另一實施例中,APC結合部位或CD91受體結合部位係一多胜肽,且多胜肽包含一由下列各項所組成之群組中選出之胺基酸序列:序列編號第5、9、6、7及8號。
在本發明之另一實施例中,T細胞致敏信號轉導胜肽包含一與序列編號第1或2號至少90%相同之胺基酸序列。
在本發明之另一實施例中,T細胞致敏信號轉導胜肽包含一由下列各項所組成之群組中選出之胺基酸序列:序列編號第1及2號。
在本發明之另一實施例中,移位胜肽包含一由下列各項所組成之群組中選出之胺基酸序列:序列編號第3、20及4號。
在本發明之另一實施例中,移位胜肽就長度而言具有34-61個胺基酸殘基。
在本發明之另一實施例中,前述融合蛋白之蛋白轉導部位具有下列特色:(i)T細胞致敏信號轉導胜肽包含序列編號第1或2號之胺基酸序列;且(ii)移位胜肽包含一與序列編號第3號至少95%相同之胺基酸序列。
T細胞致敏信號轉導胜肽之特徵在於可誘發一抗體,此抗體可辨識出並結合於T細胞上CD28受體之K1
(X)2
E3
(X)4
(X)5
Y6
P7
P8
P9
Y10
胺基酸序列(序列編號第32號),其中(X)2
為I或L;(X)4
為V、F或A;且(X)5
為M或L。
本發明之另一態樣係關於一種融合蛋白,其係由下列各項所組成:(a)一抗原呈現細胞(APC)結合部位或一CD91受體結合部位,其位於
融合蛋白之N端;(b)一蛋白轉導部位,其位於APC結合部位或CD91受體結合部位之C端,蛋白轉導部位係由下列各項所組成之群組中選出:(i)一融合多胜肽,其包含一T細胞致敏信號轉導胜肽、一連結子及一移位胜肽,其中:(1)T細胞致敏信號轉導胜肽係位於融合多胜肽之N端;(2)連結子包含序列編號第15號,並連結T細胞致敏信號轉導胜肽與移位胜肽;且(3)移位胜肽就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列;(ii)一T細胞致敏信號轉導胜肽;及(iii)一移位胜肽,其就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列;及(c)一病原體的一抗原,其位於蛋白轉導部位之C端;其中:T細胞致敏信號轉導胜肽就長度而言具有28-53個胺基酸殘基,且包含一與序列編號第31號至少90%相同之胺基酸序列,其中Xaa8
為I或L;Xaa10
為V、F或A;Xaa11
為M或L;Xaa17
為L或I;且若蛋白轉導部位為移位胜肽(biii),則APC結合部位或CD91受體結合部位完全不含綠膿桿菌外毒素A(PE)結合部位I之胺基酸序列。
抗原呈現細胞(APC)可由下列各項所組成之群組中選出:樹狀細胞、巨噬細胞、B細胞及單核球。
在本發明之一實施例中,APC之細胞膜包含一CD91受體。
本發明之另一態樣係關於一種疫苗組合物,其包含:(a)一治療有效量之前述融合蛋白;及(b)一佐劑。
佐劑係一抗原傳送劑或一免疫增效劑。在本發明之一實施例中,疫苗組合物包含一抗原傳送劑但完全不含免疫增效劑。
本發明之又一態樣係關於一種用以誘發並增強一病原體抗原專一性T細胞反應之方法,方法包含下列步驟:對有需要之受治者施用一疫苗組合物,其中組合物包含一治療有效量之前述融合蛋白;及藉此誘發
並增強對病原體抗原具有專一性之T細胞反應。
本發明之再一態樣係關於一種殺死一疾病細胞之方法,其中疾病細胞可透過其細胞膜上之第I類主要組織相容性複合物(MHC)分子呈現一抗原,方法包含下列步驟:對有需要之受治者施用一疫苗組合物,其中組合物包含一治療有效量之前述融合蛋白;及藉此殺死可透過其細胞膜上之第I類MHC分子呈現一抗原之疾病細胞。
在本發明之一實施例中,疾病細胞為一癌症細胞。
本發明之再一態樣係關於一種用以預防及治療一病原體所引起之感染及/或減少感染所引起之症狀的方法,方法包含下列步驟:對有需要之受治者施用一疫苗組合物,其中組合物包含一如前述且達治療有效量之融合蛋白;及藉此預防及治療病原體所引起之感染及/或減少感染所引起之症狀。本發明亦關於將前述融合蛋白或疫苗組合物用於誘發並增強一病原體抗原專一性T細胞反應、或用於殺死一可透過其細胞膜上之第I類MHC分子呈現一抗原之疾病細胞,或用於預防及治療一病原體所引起之感染及/或減少感染所引起之症狀。
病原體可為下列各項所組成之群組中選出之至少一種:人類乳突病毒(HPV)、豬繁殖及呼吸症候群病毒(PRRSV)、人類免疫不全症病毒(HIV-1)、流行感冒病毒、登革熱病毒、C型肝炎病毒(HCV)、B型肝炎病毒(HBV)及豬環狀病毒2(PCV2)。
在本發明之一實施例中,前述融合蛋白係用於增強一有需要之受治者體內之抗原專一性胞毒T細胞反應。融合蛋白亦可用於增強一抗原專一性CD4+ T細胞反應,或用作一免疫原性增強劑,藉以在有需要之受治者體內誘發並增強一抗原專一性抗體力價反應(antibody titer responce)。
在參閱以下較佳實施例之說明及附圖後,當可清楚瞭解上述及其他實施態樣。熟習此項技術者可提出變化例與修正例而不脫離本案新穎概念之精神與範圍。
附圖顯示本發明一個以上之實施例,該等圖式之作用係與書面說明共同解釋本發明之原理。在可能情況下,所有圖式均以相同之參考標號標示同一實施例中相同或類似之元件。
第1圖為載體圖。
第2圖為照片,顯示融合蛋白RAP1-PE268-313
-E7-K3之SDS-PAGE分析結果。第1道:RAP1-PE268-313
-E7-K3(還原);第2道:分子標記;第3道:RAP1-PE268-313
-E7-K3(非還原)。
第3圖為載體圖。
第4圖為本發明一實施例RAP1-CD28convPEt-E7-K3蛋白之示意圖。
第5A圖繪示預防接種之時程。
第5B圖為照片,顯示融合蛋白之SDS-PAGE分析結果。1:RAP1-PE268-313
-E7-K3;2:PE407
-E7-K3;M:分子重量標記。第5C、5D圖分別繪示接種不同融合蛋白或安慰劑之動物組別之腫瘤大小曲線及無腫瘤小鼠百分比。
第6A圖為製備融合蛋白之流程圖,第6B圖則為融合蛋白SDS-PAGE分析結果之照片。第1、4道:分子重量標記;第2道:RAP1-CD28convPEt
-E7-K3(小鼠CD28conv,還原);第3道:RAP1-CD28convPEt
-E7-K3(小鼠CD28conv,未還原);第5道:RAP1-CD28convPEt
-E7-K3(人類CD28conv,還原);第6道:RAP1-CD28convPEt
-E7-K3(人類CD28conv,未還原)。
第7圖為T細胞致敏融合蛋白作用機構之示意圖。
第8圖為多物種之CD28序列比對圖。
第9A圖繪示預防接種之時程。
第9B、9C圖分別繪示接種不同融合蛋白或安慰劑之動物組別之腫瘤大小曲線及存活率。
第10圖係一含有RAP1之載體(RAP1-K3-pTac-2載體)之示意圖,載體可從一病原體製造出一含有質體之DNA***片段。
第11圖係含有各種病原體抗原之融合蛋白之構造示意圖。融合蛋白名稱分別為:1. PE268-313
-E7;2. CD28convPEt
-E7;3. CD28convPEt
-E718
;4. HCV核心;5. CD28convPEt
-HCV核心;6. CD28conv-HCV核心;7. HBx;8. CD28convPEt
-HBx;9. CD28conv-HBx;10. HBx終止;11. CD28convPEt-HBx終止;12. CD28conv-HBx終止;13. PCV2ORF2
;14. PE268-313
-PCV2ORF2
;15. CD28convPEt
-PCV2ORF2
;16. PE268-313
-DGD;17. CD28convPEt
-DGD;18.
PE268-313
-M12;19. CD28convPEt
-M12;20. PE268-313
-PQAB;21. CD28convPEt
-PQAB;22. PE268-313
-RSAB;23. CD28convPEt
-RSAB。
第12A至12F圖均為照片,顯示各種融合蛋白之SDS-PAGE分析結果。其中:第12A圖,1:PE407
-K3;2:PE407
-E7-K3;3:RAP1-CD28convPEt-E7-K3;4:RAP1-K3;M:分子重量標記。第12B圖,1:RAP1-CD28convPEt-E718
-K3;2:RAP1-K3;3:分子重量標記。第12C圖,1:RAP1-HCV120-K3;2:RAP1-CD28conv-HCV120-K3;3:RAP1-CD28convPEt-HCV120-K3;4:RAP1-K3。第12D圖,1:RAP1-HBx;2:RAP1-HBx-K3;3:RAP1-CD28conv-HBx;4:RAP1-CD28conv-HBx-K3;5:RAP1-CD28convPEt
-HBx;6:RAP1-CD28convPEt
-HBx-K3。第12E圖,1:RAP1-ORF2-K3;2:RAP1-PE268-313
-ORF2-K3;3:RAP1-CD28convPEt
-ORF2-K3;4:PE407
-ORF2-K3。第12F上圖,PE407
-PRRSV-K3,1:PE407
-DGD-K3;2:PE407
-PQAB-K3;3:PE407
-RSAB-K3;4:PE407
-M12-K3。第12F中間圖,RAP1-PE268-313
-PRRSV-K3,1:RAP1-PE268-313
-M12-K3;2:RAP1-PE268-313
-RSAB-K3;3:RAP1-PE268-313
-PQAB-K3;4:RAP1-PE268-313
-DGD-K3。第12F下圖,RAP1-CD28convPEt
-PRRSV-K3,1:RAP1-CD28convPEt
-PQAB-K3;2:RAP1-CD28convPEt
-RSAB-K3;3:RAP1-CD28convPEt
-DGD-K3;4:RAP1-CD28convPEt
-M12-K3。
第13圖繪示預防接種之時程。
第14A至14J圖繪示CD3+/CD8+脾細胞(第14A、14C、14D、14E、14F圖)及CD3+/CD4+脾細胞(第14B、14G、14H、14I、14J圖)以離體方式進行抗原專一性免疫反應分析後之IFNγ
+細胞數,該等脾細胞係來自表5之動物組,且該等動物組已分別接種安慰劑或含有PCV2(第14A、14B圖,其PCV2抗原為ORF2)或PRRSV抗原(第14C至14J圖,其PRRSV抗原分別為DGD、M12、PQAB、RSAB、DGD、M12、PQAB及RSAB)之融合蛋白。圖中:無抗原激發;:有抗原激發。
本節將透過以下範例詳細說明本發明之內容,唯該等範例僅供例示之用,熟習此項技術者當可輕易思及多種修改及變化之方式。以下
將詳述本發明之多種實施例。請參閱圖式,圖中相同標號均代表相同元件。在本說明書及後附之申請專利範圍中,除非上下文另外載明,否則「一」及「該」亦可解釋為複數。此外,在本說明書及後附之申請專利範圍中,除非上下文另外載明,否則「中」及「內」均包括「位於其中」及「位於其上」。再者,說明書中可能附有標題及小標題以方便閱讀,但該等標題並不影響本發明之範圍。以下將詳細定義本說明書所用之若干術語。
定義
本說明書所使用之術語在本發明範圍內及各術語之特定上下文中大致具有其相關領域中之通常涵義。本說明書中用以描述本發明之特定用語將在下文中或在本說明書之他處加以說明,以利業界人士瞭解本發明之相關敘述。為便於閱讀,某些術語可能會以斜體及/或引號等格式加以凸顯,但使用這些凸顯格式並不影響術語之範圍與意義。同一術語在相同上下文中之範圍與意義皆相同,此與是否採用凸顯格式無關。此外。同一件事之表達方式不止一種。因此,本文所討論之術語或可用替代用語及同義詞取代,且一術語是否在本文中經詳細說明或討論並無任何特別意義。本文提供某些術語之同義詞,但使用某一或多個同義詞並不表示排除其他同義詞。本說明書所提供之範例(包括此處所討論之術語範例)僅供說明之用,而非用於侷限本發明或任何例示術語之範圍與意義。同樣,本發明並不限於本說明書所列舉之各種實施例。
除非另有定義,否則本文中所有技術與科學術語之意涵均與熟習本發明相關技術者所普遍瞭解者相同。若有相互衝突之處,則以本說明書及其所提供之定義為解釋依據。
在本文中,「左右」、「約」或「大約」均指一已知數值或範圍之20%以內,較佳者為10%以內,更佳者則為5%以內。本文所列之數量為約略值,亦即即使未明白寫出「左右」、「約」或「大約」等詞,仍帶有該等用詞之涵義。
「抗原呈現細胞(APC)或輔助細胞」一詞係指一細胞可透過其表面上之主要組織相容性複合物(MHC)與外來抗原複合,進而呈現外來抗原,使T細胞得以經由T細胞受體(TCR)辨識出MHC與抗原之複合物。此種細胞可處理抗原,並對T細胞呈現抗原。專業抗原呈現細胞主要包
括以下幾類:樹狀細胞(DC)、巨噬細胞、單核球及若干B細胞。
「抗原呈現細胞(APC)結合部位」一詞係指一可結合至一抗原呈現細胞(APC)之部位。此APC結合部位可為一多胜肽,其中多胜肽包含一與下列各項所組成之群組中選出之序列至少90%相同之胺基酸序列:序列編號第5、6、7、8及9號。APC結合部位係一配位子,其可辨識出並結合於APC上之受體。
分化群91(CD91)係一可於細胞膜中形成受體且參與受體媒介胞吞作用之蛋白。
「蛋白轉導部位」一詞係指一多胜肽或一融合多胜肽,其可致敏T細胞並因而增強抗原專一性T細胞反應,及/或將一抗原導向抗原呈現之第I類主要組織相容性複合物(MHC-I)通道(亦即一胞毒T細胞通道)(亦即以該通道為目標)。
「致敏T細胞」一詞大致係指將CD8+及CD4+ T細胞敏化,藉以增強由抗原攻毒所引起之CD8+(CTL)及CD4+ T細胞反應,其中抗原專一性細胞媒介免疫反應之量測方式係將一抗原所誘發製造之抗原專一性誘發γ
-干擾素量化。例如,一抗原在無致敏信號(亦即無蛋白轉導部位)之情況下,或許僅能誘發微弱之細胞媒介免疫反應,甚至無法誘發此反應;亦即CD8+及CD4+ T細胞僅製造出少量抗原專一性γ
-干擾素,甚至未製造出此干擾素。但在致敏信號(蛋白轉導部位)存在之情況下,抗原或許能誘發並增強細胞媒介免疫反應。因此,致敏信號(蛋白轉導部位)之作用在於敏化宿主體內之CD4+及CD8+ T細胞;當宿主日後接受抗原攻毒時,由於CD4+及CD8+ T細胞業已敏化,抗原將可誘發並增強抗原專一性細胞媒介免疫反應。
一蛋白轉導部位可為一胜肽及/或多胜肽,並由下列各項所組成之群組中選出:(i)一融合多胜肽,其包含一T細胞致敏信號轉導胜肽、一連結子及一移位胜肽,其中:(1)T細胞致敏信號轉導胜肽係位於融合多胜肽之N端;(2)連結子包含序列編號第15號,且連結T細胞致敏信號轉導胜肽與移位胜肽;且
,3)移位胜肽就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列;(ii)一T細胞致敏信號轉導胜肽;及(iii)一移位胜肽,其就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列。
一蛋白轉導部位可為一「融合多胜肽」,其中融合多胜肽包含一T細胞致敏信號轉導胜肽、一連結子及一移位胜肽。例如,融合多胜肽可為多胜肽「CD28convPEt
」。
「CD28conv」一詞係指一CD28守恆區,其為一「T細胞致敏信號轉導胜肽」。「CD28conv」係一可誘發CD28致效劑抗體之抗原決定區。
「PEt
」一詞係指一就長度而言具有34-112個胺基酸殘基之移位胜肽。
「CD28conv」與「PEt
」之間存在一連結子。融合多胜肽「CD28convPEt
」之方位或排列方式至關重要,因為「CD28conv」(或T細胞致敏信號轉導胜肽)必須位於PEt
(或移位胜肽)之上游,亦即,PEt
必須位於「CD28conv」之C端,方能增強T細胞反應。「CD28convPEt
」可提高對CD28conv具有專一性之IgG力價(又稱為CD28專一性致效劑抗體),且其所能提高之幅度遠大於方位與之相反之融合胜肽PEt
CD28conv所能提高之幅度。CD28專一性致效劑抗體兼可敏化CD4+及CD8+ T細胞。方位正確之融合多胜肽CD28convPEt
於CD28conv與PEt
部位之間具有一連結子(RXRXKR)。此連結子含有一對抗原呈現細胞(APC)具有專一性之蛋白酶(細胞自溶酵素L)切割位置Lys-Arg(KR)。因此,融合蛋白RAP1-CD28convPEt
-抗原-K3經消化後將形成兩片段:RAP1-CD28conv及PEt
-抗原-K3。RAP1-CD28conv片段可於溶體中進一步被消化,使CD28conv之抗原決定區透過MHC II通道而對APC細胞之表面呈現,從而誘發一體液免疫反應並製造出CD28致效劑抗體。是以,CD28致效劑抗體乃由B細胞產出。此CD28致效劑抗體可結合至T細胞表面上之CD28,並將T細胞(CD4+及CD8+ T細胞)預先活化。
一「T細胞致敏信號轉導胜肽」就長度而言具有28-53個胺基
酸殘基,且包含一與序列編號第31號至少90%相同之胺基酸序列,其中Xaa8
為I或L;Xaa10
為V、F或A;Xaa11
為M或L;Xaa17
為L或I。
T細胞致敏信號轉導胜肽包含關鍵區K1
(I/L)2
E3
(V/F/A)4
(M/L)5
Y6
P7
P8
P9
Y10
(序列編號第32號),其中(X)2
為I或L;(X)4
為V、F或A;(X)5
為M或L。
以下範例使用對小鼠具有專一性之T細胞致敏信號轉導胜肽(TDIYFCKIEFMYPPPYLDNEKSNGTIIH,序列編號第31號,其中X8
為I,X10
為F,X11
為M)。
第7圖係以融合蛋白RAP1-CD28convPEt
-E7-K3為例,並透過示意圖說明T細胞致敏融合蛋白之作用機構。RAP1-CD28convPEt
-E7-K3自N端至C端依序包含:(1)全長RAP1之部位III,位於N端;(2)CD28conv;(3)一連結子;(4)一來自綠膿桿菌外毒素A之改質移位胜肽;(5)一全長第16型HPV E7蛋白;及(6)作為ER滯留信號之三段KDEL,位於C端。HPV16 E7蛋白經處理後可進入已接種融合蛋白之受治者其細胞內之抗原決定區。相較於僅含有抗體之傳統疫苗,RAP1-CD28convPEt
-E7-K3可誘發較佳之胞毒T細胞(CTL)反應。RAP1-CD28convPEt
-E7-K3蛋白之功用在於改善APC(例如樹狀細胞)之攝取效率,促進HPV16 E7抗原之處理,俾將其導向蛋白酶體通道,使其可透過MHC I複合物呈現。疫苗RAP1-CD28convPEt
-E7-K3可誘發對HPV16 E7蛋白具有專一性之CTL免疫反應,其作用機構如第7圖所示:(a)疫苗結合至APC(例如樹狀細胞)之表面受體(CD91),並經由胞吞作用而內部化;(b1)細胞自溶酵素L蛋白酶於移位胜肽PEt
前之位置進行消化,致使RAP1-CD28convPEt
-E7-K3產生蛋白質水解;或(b2)RAP1-CD28convPEt
-E7-K3循環至E.R.後,因弗林蛋白酶於移位胜肽PEt
前之位置發揮作用而產生蛋白質水解;(b3)在此同時,RAP1-CD28conv由胞溶體蛋白酶消化,致使CD28conv之抗原決定區透過MHC II而對細胞表面呈現,從而誘發CD28致效劑抗體之製造,使T細胞預先活化;(c)最重要之步驟乃PEt
-E7-K3之透膜移位,亦即在移位胜肽(PEt
)之作用下,使PEt
-E7-K3從溶體進入細胞質室;(d)PEt
-E7-K3經蛋白酶體通道消化後,便透過MHC I複合物呈現E7之抗原決定區,並誘發對E7具有專一性之細胞媒介免疫反應。
第8圖繪示不同物種之CD28守恆區序列比對及其一致序
列。一致序列中加畫底線之序列(KIEVMYPPPY;序列編號第32號,其中X2
為I,X4
為V,X5
為M)乃CD28致效劑抗體辨識與結合之關鍵區。此關鍵區可以K1
(I/L)2
E3
(V/F/A)4
(M/L)5
Y6
P7
P8
P9
Y10
表示,其中僅第四個胺基酸殘基具有物種專一性:亦即人類、大鼠、豬、綿羊、狗及馬為V;小鼠為F;火雞為V。關鍵區序列可用K1
(X)2
E3
(X)4
(X)5
Y6
P7
P8
P9
Y10
(序列編號第32號)表示,其中(X)2
為I或L;(X)4
為V、F或A;(X)5
為M或L。
PEt
可包含一與序列編號第3或20號至少90%相同之胺基酸序列。例如,PEt
之胺基酸序列可為PE之a.a.280-a.a.313(序列編號第3號)、a.a.268-a.a.313(序列編號第20號)、a.a.253-a.a.313或a.a.253-a.a.364(序列編號第4號)。換言之,PEt
之胺基酸序列可含有PE部位II(a.a.253至a.a.364;序列編號第4號)之任一區,只要胺基酸序列包含a.a.280-a.a.313(序列編號第3號)此一必要片段即可。
抗原可為一病原體蛋白、多胜肽或胜肽,其可導致由病原體所引發之疾病,或可於病原體所感染之宿主體內誘發一免疫反應;或為與腫瘤相關之抗原(TAA),其為一專門表現於腫瘤細胞內之多胜肽。所述抗原可選自病原體或癌症細胞,其包括但不限於人類乳突病毒(HPV)、PRRSV、HIV-1、流行感冒病毒、登革熱病毒、C型肝炎病毒(HCV)、B型肝炎病毒(HBV)、豬環狀病毒2(PCV2)、非小細胞肺癌、乳癌、黑色素瘤、淋巴瘤、結腸癌、肝細胞癌,及上列各項之任一組合。例如,在此選用HPV E7蛋白(E7)、HCV核心蛋白(HCV核心)、HBV X蛋白(HBx)作為開發疫苗之抗原。所述抗原可為兩種以上之抗原(可選自一或多種病原體蛋白)融合而成之融合抗原。例如,可將PRRSV ORF6與ORF5片段融合為融合抗原,或將PRRSV與PCV2病原體之抗原蛋白加以融合。
內質網滯留序列之作用在於協助抗原移位(亦即從一胞吞室移至ER),並將其留在內腔中。內質網滯留序列包含序列Lys Asp Glu Leu(KDEL)或RDEL。一ER序列可包含(或實質上由下列各項組成、或由下列各項組成):序列KKDLRDELKDEL(序列編號第16號)、KKDELRDELKDEL(序列編號第17號),KKDELRVELKDEL(序列編號第18號)。
分子重量為39kDa(千道爾頓)之受體相關蛋白(RAP1)係一ER駐留蛋白,且為低密度脂蛋白受體相關蛋白之分子伴侶(molecular
chaperone)。RAP1對CD91具有高結合親和度(Kd~3nM),且係由三個功能類似之部位構成。
發明人發現,本發明之融合蛋白可誘發並增強T細胞媒介免疫反應。以RAP1-CD28convPEt
-E7-K3為例,RAP1-CD28convPEt
-E7-K3疫苗之策略主要在於激發特定T細胞之製造與活化,其中特定T細胞係指可辨識出遭HPV16感染且已表現出目標抗原E7之細胞者。藉由傳送抗原至樹狀細胞,即可製造出對抗原具有專一性之CD8+ T細胞及CD4+ T細胞。第1型輔助CD4+ T細胞尤能有效激發並增強胞毒CD8+ T細胞之免疫反應。結合適應性免疫系統之以上兩種技術,吾人便能以具有專一性之方式,於身體多個位置殺死遭HPV16感染之細胞或與HPV16相關之腫瘤細胞而不致對正常組織造成顯著傷害。
「受治者」一詞係指人類或非人類之動物。
「治療」一詞係指對已罹患癌症、或已遭受感染、或已出現疾病症狀、或具有罹病傾向並且有需要之受治者施用一有效量之融合蛋白,藉以治癒、減輕、解除、改善、緩解或預防疾病、或其症狀、或罹患疾病之傾向。一健康照護專業人士可根據任何適當診斷方法之結果判別出此種受治者。
「有效量」一詞係指一活性化合物對受治者產生治療效果所需之劑量。熟習此項技術者應知,有效量會隨施用途徑、賦形劑之使用以及是否併用其他治療手段而有所變化。
縮寫:CD 28即分化群28。
範例
以下所述僅為根據本發明實施例所提供之例示用設備、器材、方法與相關結果,不應視為本發明之限制。請注意,各範例之標題或子標題僅為方便閱讀之用,亦不應視為本發明之限制。此外,只要本發明係據其本身實施,不論係基於任何特定學說或實行方案,均不受在此所敘及之特定學說之限制,且與所述學說正確與否無涉。
範例1
表現載體之建構
第1圖繪示融合蛋白RAP1-PE268-313
-E7-K3之表現載體,其中
融合蛋白包含RAP1部位3(序列編號第5號)、移位最小基本胜肽(PE268-313
;序列編號第20號)、抗原E7及內質網滯留序列(K3,或一KDEL信號;序列編號第16、17、18或19號)。移位最小基本胜肽(PE268-313
;序列編號第20號)係取自PE(序列編號第10號)多胜肽序列中a.a.268至a.a.313之區域。
此表現載體係利用第10圖所示之質體RAP1-K3建構而成。質體RAP1-K3(第10圖)含有RAP-1部位3與K3之融合基因,其製造方法如下:以聚合酶連鎖反應法(PCR)合成一可編碼NdeI
RAP1-(EcoRI,XhoI
)-K3XhoI
之DNA片段,然後利用康黴素抗藥基因將其綁入質體pUC18骨幹中,形成質體RAP1-K3(第10圖)。製造表現載體RAP1-PE268-313
-E7-K3(第1圖)時,則係將一可編碼PE268-313
-E7之DNA片段***質體RAP1-K3(第10圖)中。運用類似之方法,吾人利用PCR製造出可編碼各種融合胜肽之DNA片段(第11圖),並將其分別***質體RAP1-K3(第10圖)中以形成各種融合蛋白之表現載體(第12A至12F圖)。第3圖所示為融合蛋白RAP1-CD28convPEt
-E7-K3(第3圖)之表現載體。
CD28convPEt
片段含有細胞自溶酵素L及弗林蛋白酶之切割位置。第4圖為融合蛋白RAP1-CD28convPEt
-E7-K3之胺基酸序列圖,藉此顯示CD28convPEt
片段之重要性。圖中兩箭頭分別代表細胞自溶酵素L及弗林蛋白酶之切割位置。兩切割位置不僅可做為連接CD28conv與PEt
-E7之連結子,亦使吾人得以切開融合蛋白,以便將PEt
-E7-K3片段從溶體釋放至細胞質中。E7可以來自各種病原體之其他任何所需抗原取代,並與CD28convPEt
融合,之後再將其融合產物***第10圖之質體中,以形成第11圖所示各種融合蛋白之表現載體。
PE268-313
之序列為:pletftrhrqqrgweqleqcgypvqrlvalylaarlswnqvdqvir(序列編號第20號)。CD28convPEt
之完整序列如下:tdiyfckiefmypppyldneksngtiihrarykrg
weqleqcgypvqrlvalylaarlswnqvdqvirgs(序列編號第30號),其中畫底線之序列代表一含有細胞自溶酵素L與弗林蛋白酶切割位置之連結子序列。
範例2
蛋白表現
帶有蛋白表現載體之大腸桿菌(E.coli)BL21細胞係於37℃之溫度下,以內含25μg/ml康黴素之Luria Bertani培養液培養。當培養物到達早期對數生長期(A600=0.1至0.4)時,加入異丙基-β-D-硫代半乳糖苷(IPTG),使其最終濃度為0.5至2mM以達誘發之目的。以IPTG誘發4小時後,收集細胞並以音波振動干擾之。將含有過表現蛋白之包涵體分離出來,於8M尿素/TN緩衝液(8M尿素、50mM三羥甲基氨基甲烷(Tris)、50mM NaCl,pH 8.0)中溶解。
融合蛋白RAP1-PE268-313
-E7-K3之再摺疊係於4℃之溫度下,以50倍體積之TNZ緩衝液(50mM Tris、50mM NaCl及0.01mM ZnCl2
,pH 8.0)進行隔夜透析。再摺疊後之蛋白分別於還原(包含二硫蘇糖醇;+DTT)及非還原(不含二硫蘇糖醇;-DTT)條件下接受SDS-PAGE分析(第2圖)。分析結果顯示,大部分之再摺疊蛋白於非還原條件下為單體,意即RAP1融合蛋白可輕易再摺疊且未聚集成一體(第2圖)。
第6A圖為一流程圖,顯示融合蛋白RAP1-CD28PEt
-E7-K3(其含有小鼠之CD28conv或人類之CD28conv)先行表現再從大腸桿菌包涵體中萃取而出之過程。SDS-PAGE分析結果顯示,融合蛋白已充分再摺疊(第6B圖)。
第11圖係一清單,羅列以類似方法表現之各種融合蛋白:(1)RAP1-PE268-313
-E7-K3;(2)RAP1-CD28convPEt
-E7-K3;(3)RAP1-CD28PEt
-E718
-K3;(4)RAP1-HCV核心-K3;(5)RAP1-CD28conv-HCV核心-K3;(6)RAP1-CD28convPEt
-HCV核心-K3;(7)RAP1-HBx;(8)RAP1-HBx-K3;(9)RAP1-CD28conv-HBx;(10)RAP1-CD28conv-HBx-K3;(11)RAP1-CD28convPEt
-HBx;(12)RAP1-CD28convPEt
-HBx-K3;(13)RAP1-PCV2ORF2
-K3;(14)RAP1-PE268-313
-PCV2ORF2
-K3;(15)RAP1-CD28convPEt
-PCV2ORF2
-K3;(16)RAP1-PE268-313
-DGD-K3;(17)RAP1-PE268-313
-M12-K3;(18)RAP1-PE268-313
-PQAB-K3;(19)RAP1-PE268-313
-RSAB-K3;(20)RAP1-CD28convPEt
-DGD-K3;(21)RAP1-CD28convPEt
-M12-K3;(22)RAP1-CD28convPEt
-PQAB-K3;(23)RAP1-CD28convPEt
-RSAB-K3。上列融合蛋白均依前述方法再摺疊。SDS-PAGE分析結果顯示,該等融合蛋白均已充分再摺疊,故可用於製備疫
苗(第12A至12F圖)。
範例3
RAP1-PE268-313
-E7-K3可抑制第16型人類乳突病毒(HPV)E7蛋白所引發之腫瘤生長
融合蛋白PE407
-E7-K3及RAP1-PE268-313
-E7-K3以前述方式使其表現,並透過SDS-PAGE檢查蛋白再摺疊之狀況(第5B圖)。小鼠係以皮下注射之方式,以2 x 103
個TC-01細胞(其為帶有第16型HPV E7基因之小鼠肺部上皮細胞株)攻毒,藉以誘發第16型HPV上皮癌。以TC-01細胞攻毒十二天後,小鼠以每周一次、連續3周之頻率,經皮下注射分別接種安慰劑(磷酸鹽緩衝溶液+磷酸鋁)或PE407
-E7-K3(200μg/劑)或RAP1-PE268-313
-E7-K3(200μg/劑)(均以AS04C(GlaxoSmithKline)為佐劑)(第5A圖及表3)。AS04C係一胞毒T淋巴球增強佐劑,包含MPL(單磷酯脂質A,一免疫增效劑)及磷酸鋁(一有助於抗原傳送之蛋白質吸收劑)。「K3」一詞代表胺基酸序列KDELKDELKDEL(序列編號第19號)。各組之腫瘤大小及無腫瘤動物數均加以記錄(第5C至5D圖)。疫苗PE407
-E7-K3及RAP1-PE268-313
-E7-K3以AS04C為佐劑時,均對腫瘤生長具有顯著之抑制效果,但接種RAP1-PE268-313
-E7-K3之小鼠組,其無腫瘤小鼠之比例較高。此一結果顯示,就抑制腫瘤生長而言,疫苗RAP1-PE268-313
-E7-K3與PE407
-E7-K3一樣有效,或前者更為有效,且前者更能提高無腫瘤動物之比例。
範例4
RAP1-CD28convPEt
-E7-K3可抑制第16型人類乳突病毒(HPV)E7蛋白所引發之腫瘤生長並提高存活率
此範例係檢視融合蛋白PE467
-E7-K3及RAP1-CD28convPEt
-E7-K3在使用及不使用免疫增效劑之情況下對腫瘤大小及存活率之影響。小鼠經皮下注射之方式,以較高劑量(3x104
)之TC-01細胞攻毒。攻毒七天後,小鼠以每周一次、連續3周之方式,經皮下注射分別接種安慰劑、PE407
-E7-K3(100μg/劑)或RAP1-CD28convPEt
-E7-K3(100μg/劑)(搭配免疫增效劑GPI-0100或蛋白質吸收劑磷酸鋁)(第9A圖及表4)。GPI-0100係一Th1/CTL激發佐劑(免疫增效劑)。各組之腫瘤大小及存活率均加以記錄(第9B至9C圖)。當與佐劑GPI-0100搭配使用時,
PE407
-E7-K3及RAP1-CD28convPEt
-E7-K3均可抑制腫瘤生長。且吾人意外發現,RAP1-CD28convPEt
-E7-K3抑制腫瘤生長之效果與佐劑無關。當與蛋白質吸收劑磷酸鋁搭配使用而未與佐劑GPI-0100搭配使用時,RAP1-CD28convPEt
-E7-K3仍可有效抑制腫瘤生長,且其效力與搭配免疫增效劑GPI-0100使用時相同(請見第9B圖之空心三角形與實心三角形)。
至於PE407
-E7-K3抑制腫瘤生長之效力則視佐劑而定。PE407
-E7-K3與蛋白質吸收劑磷酸鋁搭配使用時,其效力低於與免疫增效劑GPI-0100搭配使用之效力(請見第9B圖之實心正方形與空心圓形)。
就存活率而言,施用RAP1-CD28convPEt
-E7-K3並以免疫增效劑GPI-0100或蛋白質吸收劑磷酸鋁為佐劑之小鼠,其存活率高於接種PE407
-E7-K3並以GPI-0100或磷酸鋁為佐劑之組別(第9C圖)。此一結果顯示,RAP1-CD28convPEt
-E7-K3即使未搭配免疫增效劑GPI-0100,仍可誘發Th1/CTL免疫反應。實驗結果亦顯示,若從提高動物存活率之觀點觀之,融合蛋白RAP1-CD28convPEt
-E7-K3係優於PE407
-E7-K3之疫苗。
範例5
免疫原性分析
本範例測試多種疫苗之免疫原性。簡言之,小鼠先區分為下列各組:HPV16 E7、HPV 18 E7、HCV核心、HBV HBx、PCV2 ORF2及PRRSV(表5),各組再劃分為數個次組,各次組依每周一次、連續3周之頻率,以皮下注射之方式接種安慰劑或針對一病原體的一或多種抗原而設計之疫苗(第13圖)。PRRSV疫苗除外,其他所有疫苗均由單一融合蛋白及吸收劑磷酸鋁構成,其中單一融合蛋白含有一病原體之至少一種抗體。抗原或為一病原體的一全長蛋白,或為一含有病原體的一抗原之至少一抗原決定區之非全長蛋白,或為兩種以上抗原之融合胜肽,其中各抗原係從一病原體之不同蛋白中選出。
接種時程、疫苗種類及劑量如表5及第13圖所示。簡言之,小鼠係以每周一次、連續3周之頻率,接種第13A圖所示之疫苗。所有小鼠均在最一次接種7天後犧牲,並取其脾臟。脾細胞經分離後,於6孔培養板中培養(2x107
個細胞/2ml/孔),其中病原體各重組抗原之濃度為10μg/ml。脾細胞係在37℃及1μg/ml GolgiPlug(BD Pharmingen,San Diego,
CA)存在之條件下被激發,為時16小時。
激發過後之脾細胞以FACScan緩衝液清洗,細胞表面標記CD8a、CD4及CD3則以藻紅素共軛單株大鼠抗小鼠CD8a抗體、AF700共軛單株大鼠抗小鼠CD4抗體及AF647共軛單株大鼠抗小鼠CD3抗體染色。接著再以Cytofix/Cytoperm套組浸透並固定細胞,其操作方式悉依製造商(BD Pharmingen)之指示。細胞內之IFN-γ係以AF488共軛單株大鼠抗小鼠IFN-γ染色,以便量測免疫反應及細胞介素之含量。另以Gallios流動式細胞量測儀及Kaluza分析軟體(Beckman Coulter)進行流動式細胞量測分析。
本範例測試下列PRRSV疫苗之免疫原性:PE407
-PRRSV-K3、RAP1-PE268-313
-PRRSV-K3及RAP1-CD28convPEt
-PRRSV-K3疫苗。各疫苗均含有四種不同融合蛋白之混合物,且各融合蛋白均含有不同抗原,該等抗原係從下列各項所組成之群組中選出:DGD、M12、PQAB及RSAB(表5)。小鼠之接種及脾細胞之激發均以類似前述之方式操作。簡言之,所有小鼠均在最後一次接種7天後犧牲,並取其脾臟。脾細胞經分離後,於6孔培養板中培養(2x107
個細胞/2ml/孔),其中DGD、M12、PQAB及RSAB重組抗原之濃度均為10μg/ml。脾細胞係在37℃及1μg/ml GolgiPlug(BD Pharmingen,San Diego,CA)存在之條件下被激發,為時16小時。
「DGD」(序列編號第26號)之胺基酸序列如下:RHHFTPSERQLCLSSIQTAFNQGAGTCILSDSGRISYTVEFSLPTHHTVRLIRVTAPPSA LDQVIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAANADVVSLTCPVAAGECAGPADSGDALLERNYPTGAEELGDGGDV RHHFTPSERQLCLSSIQTAFNQGAGTCILSDSGRISYTVEFSLPTHHTVRLIRVTAPPSA
。DGD代表PRRSV ORF7 a.a.64-a.a.123(粗體)、連結子(加畫底線)及ORF7 a.a.64-a.a.123(粗體)之融合抗原。
「M12」一詞代表PRRSV ORF1b a.a.1046-a.a.1210之一抗原,其胺基酸序列(序列編號第27號)如下:NNKECTVAQALGNGDKFRATDKRVVDSLRAICADLEGSSSPLPKVAHNLGFYFSPDLTQFAKLPIELAPHWPVVSTQNNEKWPDRLVASLRPLDKYSRA
CIGAGYMVGPSVFLGTPGVVSYYLTKFVKGEAQVLPETVFSTGRIEVDCREYLDDREREVAASLPH。
「PQAB」(序列編號第28號)之胺基酸序列如下:GSSLDDFCYDSTAPQKVLLAFSITYASNDSSSHLQLIYNLTLCELNGTDWLANKFDWA
。PQAB代表PRRSV美洲株ORF6 a.a.2-a.a.26及ORF5 a.a.31-a.a.63(加畫底線)之融合抗原。
RSAB之胺基酸序列為MGSLDDFCNDSTAAQKLVLAFSITYTPIFVAGGSSSTYQYIYNLTICELNGTDWLSNHFDWA
(序列編號第29號)。「RSAB」一詞代表PRRSV歐洲株ORF6 a.a.2-28及ORF5 a.a.31-64(加畫底線)之融合抗原。
範例6
融合蛋白RAP1-CD28convPEt
-E7-K3之RAP1部位3的片段以A2M最小(序列編號第6號)、HIV-Tat最小(序列編號第7號)或HSPs最小(序列編號第8號)取代,藉以分別製造出融合蛋白A2M-CD28convPEt
-E7-K3、Tat-CD28convPEt
-E7-K3及HSP-CD28convPEt
-E7-K3疫苗。在此以類似前述之方法檢測該等疫苗能否增強TC-1腫瘤抑制活性及細胞媒介免疫反應。表1列出各融合蛋白之成分序列編號,表2則列出受測之融合蛋白(測試其對動物T細胞媒介免疫反應之影響)及其抗原序列。
表4
a.
每劑含有PE407
-DGD-K3(12μg)、PE407
-M12-K3(6μg)、PE407
-PQAB-K3(6μg)及PE407
-RSAB-K3(6μg)之混合物。
b.
每劑含有RAP1-PE268-313
-DGD-K3(12μg)、RAP1-PE268-313
-M12-K3(6μg)、RAP1-PE268-313
-PQAB-K3(6μg)及RAP1-PE268-313
-RSAB-K3(6μg)之混合物。
c.
每劑含有RAP1-CD28convPEt
-DGD-K3(12μg)、RAP1-CD28convPEt-M12-K3(6μg)、RAP1-CD28convPEt
-PQAB-K3(6μg)及RAP1-CD28convPEt
-RSAB-K3(6μg)之混合物。
本範例之免疫原性評估係量測脾細胞中CD3+/CD4+/IFNγ+及CD3+/CD8+/IFNγ+T細胞數,藉以評估由各疫苗所誘發之抗原專一性細胞媒介免疫反應。結果顯示,疫苗RAP1-CD28convPEt
-抗原-K3可誘發強烈T細胞反應。如表7所示,由CD28convPEt
-E718
-K3所誘發之CD3+/CD4+/IFNγ+T細胞數為RAP1-K3所誘發之細胞數之約50倍,由CD28convPEt
-E718
-K3所誘發之CD3+/CD8+/IFNγ+ T細胞數則為RAP1-K3所誘發之細胞數之9倍以上。
就誘發T細胞媒介免疫原性而言,疫苗RAP1-CD28convPEt
-抗原-K3之效果優於PE407
-抗原-K3。舉例而言,如表6所示,由CD28convPEt
-E716
-K3所誘發之CD3+/CD4+/IFNγ+ T細胞數及CD3+/CD8+/IFNγ+ T細胞數分別為PE407
-E716
-K3所誘發之T細胞數之約5倍與7倍。此一結果顯示,疫苗RAP1-CD28convPEt
-E7-K3之細胞媒介免疫原性高於PE407
-E7-K3。表6至表9顯示CD3+/CD4+脾細胞及CD3+/CD8+脾細胞以離體(ex vivo)方式進行抗原專一性免疫反應分析之結果,該等脾細胞係來自表5之動物組,且該等動物組已分別接種安慰劑或含有E716
、E718
、HCV核心或HBx抗原之融合蛋白。
一融合蛋白若包含RAP1部位III、致敏信號CD28conv(但不含移位胜肽PEt
)、抗原及ER滯留信號,且所選用之抗原包含10或多於10個抗原決定區,便足以誘發強烈之抗原專一性T細胞媒介免疫反應。如表8所示,當疫苗RAP1-CD28conv-HCV核心-K3誘發T細胞反應時,CD3+/CD4+/IFNγ+及CD3+/CD8+/IFNγ+ T細胞數分別為安慰劑組之20倍及7.6倍。抗原HCV核心含有11個眾所周知之MHC I抗原決定區。
吾人意外發現,ER滯留信號並非本發明融合蛋白誘發強烈細胞媒介免疫原性之必要條件。換言之,即使ER滯留序列不存在,本發明之融合蛋白仍可誘發強烈T細胞反應。如表9所示,由RAP1-CD28convPEt
-HBx(其不含ER滯留信號K3)所誘發之CD3+/CD4+/IFNγ+及CD3+/CD8+/IFNγ+ T細胞數分別為安慰劑組之7倍及74倍。
相較之下,美國專利第7378100B2及7335361號則顯示ER滯留信號K3乃PE相關融合蛋白(PE407
-抗原-K3)誘發T細胞反應所不可或缺
之要件。
吾人發現,一包含RAP1部位III、移位胜肽PE218-313
(但不含致敏信號CD28conv)、抗原及一ER滯留信號之融合蛋白係優於一不含RAP1部位III之PE相關融合蛋白。如第15C至15J圖所示,疫苗RAP1-PE268-313
-PRRSV-K3所誘發之CD3+/CD4+/1FNγ+及CD3+/CD8+/IFNγ+ T細胞數係大於疫苗PE407
-PRRSV-K3所誘發之T細胞數。
以上為本發明之實施範例,其作用僅在於說明,並未窮盡本發明之所有可能型態,且本發明之實施亦不限於所述型態。依據以上教示可實現本發明之多種修改及變化。以上實施例與範例之選用及敘述,純為闡述本發明之原理與該等原理之應用,俾便精於此技術之人士利用本發明及各種實施例或依實際需要而以不同方式修改實現本發明之技術。熟習此技術之人士可在不違本案精神之情況下,輕易想見多種替代實施例。因此,本發明之範圍應取決於後附申請專利範圍,而非由上述實施範例加以界定。
<110> 生控基因疫苗股份有限公司
<120> 可用作誘發抗原專一性T細胞反應之免疫原性增強劑之融合蛋白
<140> TW 102144580
<141> 2013-12-05
<150> US/61733879
<151> 2012-12-05
<160> 32
<170> PatentIn version 3.5
<210> 1
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> hCD28核心
<400> 1
<210> 2
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> hCD28最大
<400> 2
<210> 3
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> PEt核心
<400> 3
<210> 4
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> PEt最大
<400> 4
<210> 5
<211> 104
<212> PRT
<213> 人工序列
<220>
<223> RAP1最小
<400> 5
<210> 6
<211> 153
<212> PRT
<213> 人工序列
<220>
<223> A2M最小
<400> 6
<210> 7
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> HIV-Tat最小
<400> 7
<210> 8
<211> 641
<212> PRT
<213> 人工序列
<220>
<223> HSPs最小
<400> 8
<210> 9
<211> 252
<212> PRT
<213> 綠膿桿菌
<400> 9
<210> 10
<211> 613
<212> PRT
<213> 綠膿桿菌
<400> 10
<210> 11
<211> 323
<212> PRT
<213> 人類
<400> 11
<210> 12
<211> 357
<212> PRT
<213> 人類
<400> 12
<210> 13
<211> 101
<212> PRT
<213> 人類免疫不全症病毒
<400> 13
<210> 14
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 內質網(ER)滯留序列
<400> 14
<210> 15
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CD28-PEt之連接子
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa可為任一種天然胺基酸
<400> 15
<210> 16
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 內質網(ER)滯留序列
<400> 16
<210> 17
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 內質網(ER)滯留序列
<400> 17
<210> 18
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 內質網(ER)滯留序列
<400> 18
<210> 19
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 內質網(ER)滯留序列
<400> 19
<210> 20
<211> 46
<212> PRT
<213> 綠膿桿菌
<400> 20
<210> 21
<211> 98
<212> PRT
<213> 人類乳突病毒第16型
<400> 21
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<211> 105
<212> PRT
<213> 人類乳突病毒第18型
<400> 22
<210> 23
<211> 190
<212> PRT
<213> C型肝炎病毒
<400> 23
<210> 24
<211> 154
<212> PRT
<213> B型肝炎病毒
<400> 24
<210> 25
<211> 192
<212> PRT
<213> 豬環狀病毒
<400> 25
<210> 26
<211> 220
<212> PRT
<213> 豬繁殖及呼吸症候群病毒
<400> 26
<210> 27
<211> 165
<212> PRT
<213> 豬繁殖及呼吸症候群病毒
<400> 27
<210> 28
<211> 58
<212> PRT
<213> 豬繁殖及呼吸症候群病毒
<400> 28
<210> 29
<211> 62
<212> PRT
<213> 豬繁殖及呼吸症候群病毒
<400> 29
<210> 30
<211> 68
<212> PRT
<213> 人工序列
<220>
<223> CD28-PEt
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (10)..(11)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (32)..(32)
<223> Xaa可為任一種天然胺基酸
<400> 30
<210> 31
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> CD28一致序列
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (10)..(11)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可為任一種天然胺基酸
<400> 31
<210> 32
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD28關鍵區
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa可為任一種天然胺基酸
<220>
<221> misc_feature
<222> (4)..(5)
<223> Xaa可為任一種天然胺基酸
<400> 32
Claims (20)
- 一種融合蛋白,包含:(a)一抗原呈現細胞(APC)結合部位或一CD91受體結合部位,其位於融合蛋白之N端;(b)一蛋白轉導部位,其位於APC結合部位或CD91受體結合部位之C端,蛋白轉導部位係由下列各項所組成之群組中選出:(i)一融合多胜肽,其包含一T細胞致敏信號轉導胜肽、一連結子及一移位胜肽,其中:(1)T細胞致敏信號轉導胜肽係位於融合多胜肽之N端;(2)連結子包含序列編號第15號,並連結T細胞致敏信號轉導胜肽與移位胜肽;且(3)移位胜肽就長度而言具有34-112個胺基酸殘基,且包含一與序列編號第3、20或4號至少90%相同之胺基酸序列;(ii)一T細胞致敏信號轉導胜肽;及(iii)一移位胜肽,其就長度而言具有34-46個胺基酸殘基,且包含一與序列編號第3或20號至少90%相同之胺基酸序列;及(c)一病原體的一抗原,其位於蛋白轉導部位之C端;其中:T細胞致敏信號轉導胜肽就長度而言具有28-53個胺基酸殘基,且包含序列編號第31號之胺基酸序列,其中Xaa8 為I或L;Xaa10 為V、F或A;Xaa11 為M或L;Xaa17 為L或I;且若蛋白轉導部位為移位胜肽(biii),則APC結合部位或CD91受體結合部位完全不含綠膿桿菌外毒素A(PE)結合部位I之胺基酸序列。
- 如申請專利範圍第1項之融合蛋白,其中APC結合部位或CD91受體結合部位為一多胜肽,多胜肽包含一與下列各項所組成之群組中選出之序列至少90%相同之胺基酸序列:序列編號第5、9、6、7及8號。
- 如申請專利範圍第1項之融合蛋白,尚包含一內質網滯留序列,其位於融合蛋白之C端。
- 如申請專利範圍第3項之融合蛋白,其中內質網滯留序列包含胺基酸序列Lys-Asp-Glu-Leu(序列編號第14號)。
- 如申請專利範圍第1項之融合蛋白,其中若抗原含有10個或多於10個抗原決定區,則融合蛋白之C端完全不含內質網滯留序列。
- 如申請專利範圍第1項之融合蛋白,其中蛋白轉導部位為融合多胜肽(bi)。
- 如申請專利範圍第1項之融合蛋白,其中蛋白轉導部位為T細胞致敏信號轉導胜肽(bii)。
- 如申請專利範圍第7項之融合蛋白,尚包含另一連結子,其位於蛋白轉導部位與抗原之間,且包含序列編號第15號。
- 如申請專利範圍第1項之融合蛋白,其中蛋白轉導部位為移位胜肽(biii)。
- 如申請專利範圍第9項之融合蛋白,尚包含另一連結子,其位於APC結合部位或CD91受體結合部位與移位胜肽之間,且包含序列編號第15號。
- 如申請專利範圍第1項之融合蛋白,其中蛋白轉導部位包含序列編號第30號。
- 一種疫苗組合物,包含:(a)一如申請專利範圍第1項且達治療有效量之融合蛋白;及(b)一佐劑。
- 如申請專利範圍第1項之融合蛋白,其中APC結合部位或CD91受體結合部位為一多胜肽,多胜肽包含一由下列各項所組成之群組中選出之胺基酸序列:序列編號第5、9、6、7及8號。
- 如申請專利範圍第1項之融合蛋白,其中T細胞致敏信號轉導胜肽包含一由下列各項所組成之群組中選出之胺基酸序列:序列編號第1及2號。
- 如申請專利範圍第1項之融合蛋白,其中移位胜肽包含序列編號第3號。
- 如申請專利範圍第1項之融合蛋白,其中病原體可為下列各項所組成之群組中選出之至少一種:人類乳突病毒(HPV)、豬繁殖及呼吸症候群病毒(PRRSV)、人類免疫不全症病毒(HIV-1)、流行感冒病毒、登革熱病毒、C型肝炎病毒(HCV)、B型肝炎病毒(HBV)及豬環狀病毒2(PCV2)。
- 一種如申請專利範圍第1項之融合蛋白的應用,在用於製備一種誘發並增強對病原體抗原具有專一性之T細胞反應的藥物。
- 一種如申請專利範圍第1項之融合蛋白的應用,在用於製備一種殺死一疾病細胞的藥物,其中疾病細胞可透過其細胞膜上之第I類主要組織相容 性複合物(MHC)分子呈現一抗原。
- 如申請專利範圍第18項的應用,其中疾病細胞為一癌症細胞。
- 一種如申請專利範圍第1項之融合蛋白的應用,在用於製備一種預防及治療一病原體所引起之感染及/或減少感染所引起之症狀的藥物。
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WO2021138582A1 (en) * | 2019-12-31 | 2021-07-08 | The Johns Hopkins University | Fusion proteins and methods of use thereof |
AU2021268885A1 (en) * | 2020-05-06 | 2022-10-27 | Navicure Biopharmaceuticals Limited | Fusion proteins for immunotherapy against cancer and infectious diseases |
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