TW201429488A - 具有較高碳水化合物抗原密度之疫苗及新穎皂素佐劑 - Google Patents
具有較高碳水化合物抗原密度之疫苗及新穎皂素佐劑 Download PDFInfo
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Abstract
本發明提供包含與作為載體蛋白之白喉毒素(DT)結合之碳水化合物抗原的疫苗,其中碳水化合物抗原分子與載體蛋白分子之數目比高於5:1。本文亦揭示一種新穎皂素佐劑及藉由投與有效量之本文所揭示之疫苗抑制癌細胞之方法。
Description
本申請案主張2013年1月4日申請之美國申請案第61/748,880號之權益,該美國申請案之全部揭示內容以引用之方式併入本文中。
癌症疫苗經設計藉由免疫系統強化身體天然保護自身之能力來治療癌症。其始終代表一種極具吸引力之治療方法,尤其鑒於在癌症治療中習知的手術、輻射及化學療法存在許多缺點。然而,由於癌症碳水化合物抗原之低免疫原性及許多合成疫苗主要誘發IgM及較低程度的IgG抗體,該癌症疫苗之有效性仍為低的。已探索不同的方法(諸如使用佐劑)以促進免疫識別及活化。
目前仍存在一種未滿足之需要,即開發一種具有改良免疫反應(尤其為IgG反應)之癌症疫苗及有效佐劑。本發明提供針對碳水化合物抗原之疫苗及佐劑以滿足此等及其他需要。
在一個實施例中,本發明揭示一種包含碳水化合物抗原或其免疫原性片段及類毒素蛋白之疫苗,其中碳水化合物抗原與類毒素蛋白之比率在5:1至39:1範圍內,其中該比率表示碳水化合物抗原與類毒素蛋白之分子數比。已發現碳水化合物抗原與類毒素蛋白之比率在5:1至39:1範圍內之疫苗的IgG產量相比於碳水化合物抗原與類毒素蛋白之比率等於或小於4:1之疫苗的IgG產量較高。
本發明之一個實施例提供經分離之式(I)化合物
或其醫藥學上可接受之鹽;其中R1係選自β-D-芹菜糖或β-D-木糖;
R2及R3係選自H、烷基或。
本發明之另一實施例提供醫藥組合物,其包含式(I)化合物
或其醫藥學上可接受之鹽,其中R1係選自β-D-芹菜糖或β-D-木糖;
R2及R3係選自H、烷基或,及醫藥學上可接受之載劑。
本發明之第三實施例提供新穎皂素佐劑OPT-821,其包含1857化合物V1A、1857化合物V1B、1857化合物V2A及1857化合物V2B。
本發明之第四實施例提供包含碳水化合物抗原或其免疫原性片段及OPT-821皂素佐劑之疫苗。在一個實施例中,疫苗進一步包含載體蛋白。已發現含有OPT-821皂素
佐劑之疫苗的IgG產量、抗體依賴性細胞介導的細胞毒性(ADCC)及/或補體依賴性細胞毒性(CDC)活性相比於不含OPT-821皂素佐劑之疫苗較高。
本發明亦係關於用於以下之方法:(i)抑制癌細胞,其包含向有需要之個體投與有效量之本文所述的疫苗,其中癌細胞受到抑制;及(ii)誘發免疫反應,其包含向有需要之個體投與有效量之本文所述的疫苗。
本發明亦揭示包含本文所述之疫苗及醫藥學上可接受之賦形劑或載劑之醫藥組合物。
含有此等術語之陳述應理解為不限制本文所述之主題或不限制以下專利申請專利範圍之涵義或範疇。此專利涵蓋之本發明的實施例藉由以下申請專利範圍而非此發明內容限定。此發明內容為本發明之各種態樣之高層次綜述且引入一些進一步描述於以下【實施方式】部分中之概念。此發明內容並不意欲確定所主張之主題之關鍵或基本特徵,亦不意欲孤立使用以確定所主張之主題的範疇。主題應參照整個說明書之適當部分、任一或所有圖式及各申請專利範圍來理解。
當閱讀以下附圖及【實施方式】時,本發明將變得更加清楚。
以下圖式詳細描述本發明之說明性實施例:圖1說明以下組合物第24天的抗Globo H IgG效價之柱狀圖:Globo H/KLH/OPT-821皂素、Globo H/DT/OPT-821皂素、Globo H/DT/C34及Globo H/KLH/C34。
圖1B為說明圖1A中之組合物歷經24天時期的抗Globo H IgG效價之線繪圖。
圖2為顯示歷經24天時期在小鼠中G2疫苗(Globo H/DT(8:1))、G3疫苗(Globo H/DT(8:1)/OPT-821)及G4疫苗(Globo H/DT(24:1)/OPT-821)之活體內ADCC及CDC活性之柱狀圖組合。圖2A說明ADCD原始資料,圖2B說明ADCD標準化資料,圖2C說明CDC原始資料且圖2D說明CDC標準化資料。
圖3A及圖3B為說明以下組合物歷經24天時期的總體IgM及IgG效價之線繪圖:G1(Globo H/KLH/OPT-821)、G2(Globo H/DT(3:1)/OPT-821)、G3及G4(Globo H/DT(8:1)/OPT-821)、G5(Globo H/DT(8:1)/C34)、G6(Globo H/KLH/C34)、G7(Globo H/DT(16:1)/OPT-821)及G8(PBS)。
圖4為顯示列於圖3中之組合物在第10天、第17天及第24天的IgM及IgG反應之柱狀圖組合:圖(A)至(C)說明列於圖3中之組合物分別在第10天、第17天及第24天之IgM反應。圖(D)至(F)說明列於圖3中之組合物分別在第10天、第17天及第24天之IgG反應。
圖5A至圖5C為OPT-821(包含化合物1989及1857)之質譜影像。
圖6為OPT-821之層析圖LC-UV影像。
圖7為OPT-821之層析圖LC-MS影像組合。
為了清晰及迅速理解本發明,本文定義某些術語。除非另外定義,否則本文所用之所有技術及科學術語均
具有熟習本發明所屬技術者通常所理解之相同含義。
如本文所用,「有效量」係指疫苗或醫藥組合物之劑量足以減輕癌症之症狀及徵候,該等症狀及徵候包括(但不限於)體重減輕、疼痛及腫瘤塊,其可在臨床上由可觸知的塊狀物或在放射學上經由不同的成像方法來偵測。
術語「個體」可指患有癌症之脊椎動物或被認為需要癌症治療之脊椎動物。個體包括溫血動物,諸如哺乳動物,諸如靈長類動物且更佳為人類。非人類靈長類動物亦為個體。術語個體包括經馴養動物(諸如貓、狗等)、家畜(例如牛、馬、豬、綿羊、山羊等)及實驗動物(例如小鼠、兔、大鼠、沙鼠、天竺鼠等)。由此,本文中涵蓋獸醫用途及醫學調配物。
如本文所用,術語「烷基」係指直鏈或分支鏈單價烴,除非另外說明,否則其含有1至20個碳原子(例如C1至C8或C1至C4),可經取代或未經取代(本發明可包涵其他鏈長度,例如21至30個)。烷基之實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、異丁基及第三丁基。
術語「實質上純的」意謂實質上不含通常與呈自然狀態皂素締合的化合物且展現恆定且可重現的層析反應、溶離特徵及生物活性。術語「實質上純的」不意謂排除皂素與其他化合物之人造或合成混合物。
本文中之所有數字均可理解為由「約」修飾。
具有較高碳水化合物比率之疫苗
腫瘤相關之碳水化合物抗原通常展現不佳的免疫原性。已採用與載體蛋白結合之碳水化合物抗原以提高該
碳水化合物抗原之免疫原性。舉例而言,約700個Globo H分子與一個無毒匙孔螺血氰蛋白(KLH)蛋白質結合,平均約2至4個Globo H分子與白喉毒素(DT)結合,約8個Globo H分子與牛血清白蛋白(BSA)結合,且約6個Globo H分子與破傷風類毒素結合(美國專利第8,268,969號之表1)。
本發明提供一種包含碳水化合物抗原或其免疫原性片段及類毒素蛋白之疫苗,其中碳水化合物抗原與類毒素蛋白之比率在5:1至39:1範圍內,且該比率反映碳水化合物抗原或其免疫原性片段之分子數與類毒素蛋白分子數之比率。該疫苗比碳水化合物抗原分子數與類毒素蛋白分子數之比率等於或小於4:1之疫苗具有更佳的免疫原性。本發明亦包涵其他範圍,包括碳水化合物抗原或其免疫原性片段之分子數與類毒素蛋白分子數之比率為4:1、5:1、6:1、7:1、8:1、9:1、10:1、11:1、12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1、21:1、22:1、23:1、24:1、25:1、26:1、27:1、28:1、29:1、30:1、31:1、32:1、33:1、34:1、35:1、36:1、37:1、38:1或39:1。
在一個實施例中,類毒素蛋白為破傷風類毒素(TT)且碳水化合物-TT疫苗中碳水化合物抗原與TT之比率在7:1至12:1範圍內。
本發明提供一種包含碳水化合物抗原或其免疫原性片段及白喉毒素(DT)之疫苗,其中碳水化合物抗原與DT之比率在5:1至39:1範圍內,其中該比率反映碳水化合物抗原或其免疫原性片段之分子數與DT分子數之比率。在另一實施例中,碳水化合物-DT疫苗中碳水化合物抗原與DT之比
率在8:1至24:1範圍內。
碳水化合物抗原之實例包括(但不限於)Globo H、階段特異性胚胎抗原3(SSEA3)(亦稱為Gb5)、階段特異性胚胎抗原4(SSEA-4)、Gb-4、Gb-3、路易斯抗原(諸如sLex、Lex、sLea、Lea、Ley)、多醣抗原(諸如聚唾液酸(PSA)、sTn(c)、Tn(c)、Thomsen-Friedenreich抗原(TF(c)))、神經節苷脂(諸如GD1、GD2、GD3、海藻糖、GM1、GM1、GM2、GM3、GD1α及GM2)。其他碳水化合物抗原包括(但不限於):α-半乳糖、α-甘露糖-6-磷酸鹽、α-L-鼠李糖、α-GalNAc(Tn)、α-NeuAc-OCH2C6H4-對NHCOOCH2、Fucα1-2Galβ1-4GalNAcβ(H類型3)、NeuAcα2-8NeuAcα、(NeuAcα2-8)2聚唾液酸、NeuAca2-6Galb、NeuAcb2-6Gala(STn)、Gala1-3Galb1-4GlaNAcb(NeuAca2-8)3、GalNAcαa-3(Fucα1-2)Galβ(血型A)、Galα1-3(Fucα1-2)Galβ(血型B)、6Gal-HSO3-SiaLex、6GluNAc-HSO3-SiaLex及α2-6唾液酸化雙觸角N-聚糖。在一個實施例中,碳水化合物抗原為Globo H。「GloboH」為己醣(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1),其最初自人類乳癌細胞株MCF-7分離(Menard S、Tagliabue E、Canevari S、Fossati G、Colnaghi MI(1983)Generation of monoclonal antibodies reacting with normal and cancer cells of human breast.CancerRes,43,1295-300;及Bremer EG、Levery SB、Sonnino S、Ghidoni R、Canevari S、Kannagi R、Hakomori S.(1984)Characterization of a glycosphingolipid antigen defined by the monoclonal antibody MBr1 expressed in normal and neoplastic epithelial cells of human mammary gland.J BiolChem,259,14773-7)。Globo H在各種上皮細胞腫瘤(諸如結腸、卵巢、胃、胰臟、子宮內膜、肺、前列腺及乳房癌)中表現(Menard S等人,前述;Bremer EG等人,前述;Canevari S、Fossati G、Balsari A、Sonnino S、Colnagh iMI(1983))。GloboH為可市售的(例如Carbosynth,UK)且可藉由使用此項技術中熟知之方法連接醣苷至神經醯胺而合成。
在鹼性條件下,亦即在超過或等於8、超過或等於9、超過或等於10、超過或等於11或超過或等於12之pH下,製造碳水化合物抗原與類毒素蛋白之比率大於或等於5:1之疫苗。可藉由此項技術中已知之方法,例如MALDI-TOF質譜分析來測定碳水化合物抗原與類毒素蛋白之比率。美國專利第8,268,969號;亦參見Morelle W,Faid V,Chirat F,Michalski JC.Methods Mol Biol.2009;534:5-21.doi:10.1007/978-1-59745-022-5_1.Analysis of N-and O-linked glycans from glycoproteins using MALDI-TOF mass spectrometry。
疫苗可進一步包含佐劑,其中該佐劑為諸如OPT-821之皂素,其在本文中描述或為α-半乳糖基-神經醯胺之合成類似物(α-GalCer或C1)。
術語「α-半乳糖基-神經醯胺」及「α-GalCer」係指刺激自然殺手T細胞來產生T輔助(TH)1及TH2細胞激素之醣脂,如美國專利第8,268,969號中所述,該美國專利之內容以全文引用之方式併入本文中。在一個實施例中,α-GalCer佐劑具有以下結構:
其中R為(CH2)24CH3、(CH2)7PhF、(CH2)10PhOPhF或(CH2)10PhF。
在一個實施例中,R為(CH2)10PhOPhF,稱為C34佐劑,具有以下結構:
新穎皂素佐劑
本發明提供可實質上純的OPT-821皂素。本發明包涵實質上純的OPT-821皂素以及生物活性片段。本發明亦可包涵不純形式之OPT-821皂素。經純化之OPT-821皂素當與本文所述之疫苗一起投與或與其他實質上純的皂素或非皂素佐劑混合時,展現增強之佐劑效應。
OPT-821皂素為天然存在的醣苷,藉由如例如美國專利第5,057,540號及美國專利第6,524,584號(其內容以全文引用之方式併入本文中)中所描述之高壓液相層析(HPLC)、低壓液體二氧化矽層析及親水性交互層析(HILIC)自奎拉雅屬皂樹(Quillajasaponaria Molina tree)之樹皮以高純度提取。高壓液相層析分析顯示OPT-821為結構相關之異構化合物的混合物。OPT-821皂素不同的純化異構化合物在本
文中揭示。
OPT-821皂素包含至少一種如下經分離之式I化合物:
其中R1為β-D-芹菜糖或β-D-木糖;及R2及R3獨立地為H、烷基、
(1989化合物之脂肪醯基部分),或
(1857化合物之脂肪醯基部分)。
OPT-821皂素亦可包含經分離之式I化合物,其中(i)R1為β-D-芹菜糖,R2為上文所描繪之1989化合物之脂肪醯基部分,及R3為H(1989化合物V1A);(ii)R1為β-D-芹菜糖,R2為H,及R3為上文所描繪之1989化合物之脂肪醯基部分(1989化合物V1B);(iii)R1為β-D-木糖,R2為上文所描繪之1989化合物之脂肪醯基部分,及R3為H(1989化合物V2A);或(iv)R1為β-D-木糖,R2為H,及R3為上文所描繪之1989化合物之脂肪醯基部分(1989化合物V2B)。總之,1989化合物V1A、1989化合物V1B、1989化合物V2A及1989化合物V2B稱為「1989化合物混合物」。
表1概述1989化合物之官能基及1989化合物混合物中之各1989化合物之莫耳%。
OPT-821皂素可包含經分離之式I化合物,其中:(i)R1為β-D-芹菜糖,R2為上文所描繪之1857化合物之脂肪醯基部分,及R3為H(1857化合物V1A);(ii)R1為β-D-芹菜糖,R2為H,及R3為上文所描繪之1857化合物之脂肪醯基部分(1857化合物V1B);(iii)R1為β-D-木糖,R2為上文所描繪之1857化合物之脂肪醯基部分,及R3為H(1857化合物V2A);或(iv)R1為β-D-木糖,R2為H,及R3為上文所描繪之1857化合物之脂肪醯基部分(1857化合物V2B)。總之,1857化合物V1A、1857化合物V1B、1857化合物V2A及1857化合物V2B稱為「1857化合物混合物」。
表2概述1857化合物之官能基及1857化合物混合物中之各1857化合物之莫耳%。
OPT-821皂素包含以下化合物中之一或多者:(i)
1857化合物V1A;(ii)1857化合物V1B;(iii)1857化合物V2A;(iii)1857化合物V2B;(iv)1989化合物V1A;(v)1989化合物V1B;(vi)1989化合物V2A;或(vii)1989化合物V2B。OPT-821皂素中之1857化合物混合物與1989化合物混合物之百分比在如下範圍內:(i)約1莫耳%至約15莫耳%之1857化合物混合物;及(ii)約85莫耳%至約99莫耳%之1989化合物混合物。
所有莫耳%均可以0.1%增量變化(例如約87%至約90%、約90.5%至約97%、約3.5%至約11%、約10%至約14%)。
1989化合物混合物可包含約60-70莫耳%之1989化合物V1A;約1-5莫耳%之1989化合物V1B;約30-40莫耳%之1989化合物V2A;及約0.1-3莫耳%之1989化合物V2B。所有莫耳%均可以0.1增量變化(例如65%、2.5%、35.6%)。
1857化合物混合物可包含約60-70莫耳%之1857化合物V1A;約1-5莫耳%之1857化合物V1B;約30-40莫耳%之1857化合物V2A;及約0.1-3莫耳%之1857化合物V2B。所有莫耳%均可以0.1增量變化(例如67%、1.5%、33.9%)。
在另一實施例中,實質上純的OPT-821係自奎拉雅屬皂樹粗提取物純化,其中該OPT-821之特徵為當在具有5μm粒度、100Å孔隙、4.6mm ID×25cm L之對稱性C18管柱的逆相HPLC上使用包含A:B為95%:5%至75%:25%之移動相的溶離程式分析11分鐘時,單個主峰佔層析圖中除溶劑峰
外所有峰之總面積的90%或更多,其中移動相A為含有0.1%三氟乙酸之蒸餾水且移動相B為含有0.1%三氟乙酸之乙腈,流動速率為1ml/min。
在一個實施例中,醫藥組合物包含式(I)化合物
其中,R1為β-D-芹菜糖或β-D-木糖;及R2及R3獨立地為H、烷基、或
(1857化合物之脂肪醯基部分),及醫藥學上可接受之載劑。
疫苗可包含碳水化合物抗原或其免疫原性片段及OPT-821皂素。在另一實施例中,疫苗包含選自Globo H、SSEA-3、SSEA-4、Gb-4或其混合物之碳水化合物抗原、DT
及OPT-821皂素。在又一實施例中,疫苗包含碳水化合物抗原或其免疫原性片段;載體蛋白及OPT-821皂素。載體蛋白之非限制性實例包括類毒素蛋白及非類毒素蛋白(諸如KLH)。
類毒素蛋白
與碳水化合物抗原結合之類毒素蛋白可為白喉毒素(DT)或破傷風類毒素(TT)。
毒素可例如藉由用甲醛、戊二醛、UDP-二醛、過氧化物、氧處理或藉由突變(例如使用重組方法)而失去活性。Relyveld等人,Methods in Enzymology,93:24,1983。Woodrow及Levine編,New Generation Vaccines,Marcel Dekker,Inc.,New York,1989。Genth等人,Inf.and Immun.,68(3):1094-1101,2000。具有降低之毒性的突變型白喉毒素亦可使用重組方法產生。美國專利第5,085,862號;第5,221,618號;第5,244,657號;第5,332,583號;第5,358,868號;及第5,433,945號。
DT為白喉毒素交叉反應性物質(DT-CRM)或白喉類毒素。DT-CRM係指突變型白喉毒素,例如藉由突變或藉由化學改變,使得其不再具有足夠的ADP-核糖基。DT-CRM之非限制性實例包括DT-CRM 30、DT-CRM 45、DT-CRM 176、DT-CRM 197及DT-CRM 228。白喉類毒素為經甲醛失活之白喉毒素。DT可市售或可藉由此項技術中已知之方法製備,諸如重組DNA技術,如美國專利第5,614,382號中所描述,其內容以全文引用的方式併入本文中。
本文所述之疫苗的碳水化合物抗原可藉由美國
專利第8,268,969號中所描述之合成方法經由對硝基苯基連接子與載體蛋白共價鍵結,該美國專利之內容以全文引用之方式併入本文中。
本發明之疫苗可誘發以下一或多個活性:相比於IgM效價更高的IgG效價、更高的補體依賴性細胞毒性(CDC)活性及/或更高的抗體依賴性細胞介導的細胞毒性(ADCC)活性。在另一實施例中,疫苗誘發以下一或多個細胞:自然殺手細胞、CD4+ T淋巴細胞或CD8+ T淋巴細胞。其他可量測之免疫參數,包括(但不限於)T輔助細胞活化。
本發明亦提供包含本文所述之疫苗及醫藥學上可接受之媒劑、賦形劑或載劑之醫藥組合物。合適之媒劑為例如水、生理食鹽水、右旋糖、甘油、乙醇或其類似物及其組合。另外,媒劑可含有其他賦形劑,諸如濕潤劑或乳化劑、pH緩衝劑或佐劑。醫藥學上可接受之載劑可含有用於例如穩定化或提高或降低本發明之醫藥組合物之吸收或清除速率的生理學上可接受之化合物。生理學上可接受之化合物可包括例如碳水化合物(諸如葡萄糖、蔗糖或聚葡萄糖)、抗氧化劑(諸如抗壞血酸或麩胱甘肽)、螯合劑、低分子量蛋白質、清潔劑、脂質體載劑或其他穩定劑及/或緩衝劑。賦形劑可為非離子界面活性劑、聚乙烯吡咯啶酮、人類血清白蛋白、氫氧化鋁、具有麻醉作用之藥劑及各種未經修飾及衍生化之環糊精。更佳地,非離子界面活性劑可包括聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60及聚山梨醇酯80。較佳之聚乙烯吡咯啶酮可為Plasdone C15(醫藥級之聚乙烯吡咯啶酮)。具有麻醉作用之藥劑較佳為苄醇。其他生理學上可接受之化合
物包括濕潤劑、乳化劑、分散劑或防腐劑。參見例如Remington's Pharmaceutical Science第21版,Mack出版公司,Easton,Pa.(「Remington's」)。本發明之醫藥組合物亦可包括輔助物質,諸如藥理學藥劑、細胞激素或其他生物反應調節劑。包含該賦形劑或載劑之醫藥組合物藉由熟知之習知方法調配。
疫苗可調配用於以下投與途徑:肌肉內、皮內、口服、經皮、經鼻、經頰、經直腸、經陰道、藉由吸入或藉由皮下投與。其他投與模式可為適用的,只要可誘發令人滿意的免疫原性即可。
本發明之醫藥組合物可經製備成可注射劑,呈液體溶液或懸浮液形式,或呈適合於在注射之前溶解或懸浮於液體媒劑中之固體形式。醫藥組合物亦可以固體形式製備,乳化或將活性成分囊封於用於持續遞送之脂質體媒劑或其他微粒載劑中。舉例而言,醫藥組合物可呈以下形式:油乳液、油包水乳液、水包油包水乳液、位點特異性乳液、長期滯留乳液、乳化膠、微乳液、奈米乳液、脂質體、微粒、微球體、奈米球、奈米粒子及各種天然或合成聚合物,諸如不可再吸收之不透性聚合物(諸如乙烯乙酸乙烯酯共聚物及Hytrel®共聚物)、可膨脹聚合物(諸如水凝膠)或可再吸收性聚合物(諸如膠原蛋白)及某些聚合酸或聚酯(諸如用於製造可再吸收性縫合線者),其允許疫苗持續釋放。
本發明化合物之醫藥學上可接受之鹽及其生理學功能衍生物包括源自適當鹼(諸如鹼金屬(例如鈉、鉀)、鹼土金屬(例如鈣、鎂)、銨及NX4 +(其中X為C1-C4烷基))
之鹽。胺基之醫藥學上可接受之鹽包括以下各酸之鹽:有機羧酸,諸如酒石酸、脂族、環脂族、芳族、雜環、羧酸及磺酸類別之有機酸,諸如甲酸、葡糖醛酸、蘋果酸、順丁烯二酸、反丁烯二酸、丙酮酸、天冬胺酸、麩胺酸、苯甲酸、鄰胺基苯甲酸、甲磺酸、水楊酸、羥基苯甲酸、苯乙酸、杏仁酸、恩波酸(雙羥萘酸)、甲烷磺酸、乙烷磺酸、苯磺酸、泛酸、甲苯磺酸、2-羥基乙烷磺酸、對胺基苯磺酸、硬脂酸、褐藻酸、羥基丁酸、環己基胺基磺酸、半乳糖二酸及半乳糖醛酸及其類似物、乳糖酸、反丁烯二酸及丁二酸;有機磺酸,諸如甲烷磺酸、乙烷磺酸、羥乙磺酸、次苄基磺酸及對甲苯磺酸;及無機酸,諸如鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、硫酸、胺磺酸及磷酸及其類似物。具有羥基之化合物的醫藥學上可接受之鹽由該化合物之陰離子組合合適之陽離子(諸如Na+、NH4 +或NX4 +(其中X為例如C1-C4烷基)、Ca++、Li+、Mg++或K+及鋅)或由一級、二級及三級胺、環胺、N,N'-二苯甲基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺(N-甲基還原葡糖胺)及普魯卡因(procaine)及其類似物製成之有機鹽組成。所有此等鹽均可藉由習知方法自對應的化合物製備,例如藉由使適當酸或鹼與呈游離形式之化合物反應。
誘發免疫反應/抑制癌細胞之方法
本發明之另一態樣係關於誘發免疫反應之方法,其包含向有需要之個體投與有效量之本文所述之疫苗。免疫反應包括(但不限於)NK細胞反應、ADCC及CDC活性及IgM及IgG產生。
在又一態樣中,本發明提供抑制癌細胞之方法,其包含向有需要之個體投與有效量之本文所述之疫苗。在一個實施例中,癌症係選自乳癌、肺癌、食道癌、直腸癌、膽管癌、肝癌、頰癌、胃癌、結腸癌、鼻咽癌、腎臟/腎癌、腦腫瘤、前列腺癌、卵巢癌、子宮頸癌、子宮內膜癌、胰臟癌、睾丸癌、膀胱癌、頭頸癌、口腔癌、神經內分泌癌、腎上腺癌、甲狀腺癌、骨癌、皮膚癌(例如基底細胞癌、鱗狀細胞癌或黑素瘤)。在另一實施例中,癌症為表現Globo H之癌症。表現Globo H之癌症的非限制性實例包括乳癌、肺癌、胃癌、結腸癌、胰臟癌、前列腺癌、卵巢癌及子宮內膜癌。由疫苗所產生之抗體(諸如抗Globo H抗體)固有地抑制表現Globo H之癌症。
在某些實施例中,有效量之疫苗用於誘發所需的免疫效應,諸如在個體中針對特異性碳水化合物抗原(例如Globo H)刺激IgG產生。疫苗或醫藥組合物之有效量或劑量可視碳水化合物抗原之量、所用佐劑之類型、投與模式及待治療個體之年齡、體格及病狀而變化。誘發免疫原性所需要的疫苗或醫藥組合物之確切量將由醫師確定。
疫苗可以具有或不具有一或多個按特定時間間隔投與加強劑量之單獨劑量(stat dose),以達成在數月至數年間長期免疫保護性效應。投與頻率可視多種因素中之任一者而變化,例如症狀嚴重程度、所需之免疫保護程度、醫藥組合物是否用於預防或治癒目的等。舉例而言,在一個實施例中,根據本發明之醫藥組合物每月一次、每月兩次、每月三次、每隔一週(qow)、每週一次(qw)、每週兩次(biw)、每
週三次(tiw)、每週四次、每週五次、每週六次、每隔一天(qod)、每天(qd)、一天兩次(qid)或一天三次(tid)投與。疫苗亦可與其他習知療法同時或依序投與,諸如化學療法、靶把療法或用於癌症治療之靶把腫瘤相關的碳水化合物抗原之抗體。
本發明進一步藉由以下實例說明,該等實例出於論證而非限制之目的提供。根據本發明,熟習此項技術者應瞭解,在不背離本發明之精神及範疇的情況下可對所揭示之特定實施例作出許多改變且仍獲得相同或類似結果。
實例1:製備具有較高碳水化合物/毒素蛋白比率之疫苗及提取OPT-821
Globo H與KLH或DT結合,此結合根據此項技術中已知之方法,例如如美國專利第6,544,952號或第8,268,969號中所描述,該等專利之內容以全文引用的方式併入本文中。所得疫苗包含Globo H:DT(Globo H與DT之分子比率=2-4:1)。
產生糖結合物之一般程序
糖結合物如下製造:
將BSA、DT-CRM197及破傷風類毒素(Adimmune,台灣)溶解於100mM磷酸鹽緩衝液pH 7.2中(約5mg/ml),且向溶液中添加30至40當量之Globo H半酯35。在室溫下
輕輕攪拌混合物24h。隨後用去離子水稀釋該混合物且針對去離子水之5次改變進行透析。隨後將溶液凍乾成白色粉末。所獲得之Globo H-蛋白質結合物可藉由MALDI-TOF分析表徵以測定碳水化合物結合率。41(GH-BSA)之MALDI-TOF實驗值為76029,42(GH-DT-CRM197)實驗值為62138,43(GH-TT)實驗值為162902,44(GH-BaMV)未測定。MALDI-TOF MS分析糖結合物。糖結合物及主要載體蛋白可用ddH2O復原(約1μg/μl)。基質(芥子酸)用1:1乙腈及去離子水新鮮製備,使最終基質濃度為10mg/ml,包括0.1% TFA。輕輕裝載及混合基質溶液與糖結合物,隨後空氣乾燥板。在量測之前使用牛血清白蛋白進行必不可少的校準。各糖結合物及主要蛋白質樣品在線性正模式下偵測。平均分子量允許計算結合在載體蛋白上之碳水化合物分子之平均數目。
碳水化合物抗原分子:毒素蛋白分子之比率超過5:1之疫苗根據以下步驟製造:
(a)將10ml-25ml Globo H(可購自OBI Pharma,台灣)及對硝基苯酯連接子(可購自OBI Pharma,台灣)溶解於25μl DMF(可購自Sigma-Aldrich,美國)中。
(b)用2.5ml磷酸鹽緩衝液(亦即pH>8之鹼性緩衝液)溶解25mg DT。
(c)在室溫下將步驟(a)中之混合物添加至步驟(g)中之混合物中隔夜。所得混合物具有8至9.2之間的pH。
結果:如藉由MALDI-TOF MS測定,10ml Globo H產生包含Globo H:DT(8:1)之疫苗且25Globo H產生包含Globo H:DT(24:1)之疫苗。
製備OPT-821皂素
OPT-821皂素根據以下步驟自奎拉雅屬皂樹提取物提取:
(a)藉由大粒子C18逆相層析法預先過濾奎拉雅屬皂樹提取物,隨後藉由基於二氧化矽之製備型正相層析法來純化。此舉產生粗OPT-821。
(b)再次藉由大粒子C18逆相層析法預先過濾步驟(a)中之粗OPT-821,隨後進行逆相製備型HPLC。OPT-821物質依序藉由去鹽及凍乾製程製成。
自奎拉雅屬皂樹之樹皮提取之經純化的OPT-821皂素藉由質譜分析。圖5A中1989.01處之質量峰、圖5B中1989.12處之質量峰及1989.13處之質量峰說明存在分子量為約1989之化合物。分子量為約1989之化合物的莫耳比為:圖5A中為89.8%,圖5B中為96.8%,及圖5C中為87.0%。類似地,圖5A中1856.97處之質量峰、圖5B中1856.02峰處之質量峰及1857.09處之質量峰說明存在分子量為約1857之化合物。分子量為約1857之化合物的莫耳比為:圖5A中為10.2%,圖5B中為3.2%,及圖5C中為13%。
經純化之OPT-821皂素進一步藉由層析法分析。圖6為層析圖LC-UV影像(管柱:PolyLCPolyHYDROXYETHYL A 200 * 4.6mm 5μm,300A)。第一峰說明存在1989 V1(A及B)化合物及1857化合物V1(A及B)化合物(約65.94%),且第二峰說明存在1989 V2(A及B)化合物及1857 V2(A及B)化合物(約34.06%)。圖7為層析圖LC-MS影像(管柱:Waters Symmetry ODS
150*2.1mm)。上部圖中之峰1說明存在1989化合物V1B及V2B(約2.2%),而峰4說明存在1989化合物V1A及V2A(約97.8%)。下部圖中之峰2說明存在1857化合物V1 B及1857化合物V2 B(約1.9%)且峰3說明存在1857化合物V1A及1857化合物V2A。
實例2:具有較高碳水化合物/毒素蛋白質比率的疫苗之免疫原性及OPT-281皂素之佐劑功效
使用CL57B/6小鼠進行實例1中之Globo H/DT(8:1)疫苗的活體內免疫原性及OPT-821皂素之佐劑功效的評估。
約八週大的CL57B/6小鼠隨機分成以下四個研究組:
在第一次注射之前或第0天及在各注射之後三天(亦即在第10天、第17天及第24天),經眶後或面靜脈不用抗凝血劑收集血液樣品。血液樣品經離心以分離血清與血細胞。收集血清且儲存在-20℃下,其稍後藉由ELISA分析。將來自各小鼠之血清連續稀釋以用於抗Globo H IgG分析。將Globo H-神經醯胺塗佈在分析板上隔夜,隨後用1×阻斷緩衝液(Sigma)阻斷30分鐘且用PBST洗滌。經稀釋之血清樣品添加至分析板,在室溫(RT)下培育1小時且洗滌。將山羊
抗小鼠IgG-AP二次抗體(Southern Biotech)添加至樣品中且在RT下培育45分鐘。再次洗滌板,隨後添加色素原受質且在37℃下培育20分鐘。藉由添加停止溶液終止反應。藉由板讀取器(Molecular Device)在405nm波長下定量光學密度。Mann-Whitney t測試用於統計學分析。圖1A及圖1B顯示所測試之疫苗的定量抗Globo H IgG效價。
結果:來自Globo H/DT(比率為8:1)免疫之小鼠的IgG效價顯著高於具有C34佐劑之Globo H/KLH的IgG效價(P<0.01)。來自Globo H/DT(比率為8:1)免疫之小鼠的IgG效價高於具有OPT-821皂素佐劑之Globo H/KLH的IgG效價。(參見圖1(A))。不管所使用之載體蛋白的類型,OPT-821皂素相比於C34佐劑引起統計學上顯著更高的IgG效價(P<0.05,參見圖1A及圖1B)。
實例3:使用ADCC及CDC分析進行具有較高碳水化合物/毒素蛋白比率的疫苗之免疫原性及OPT-281皂素之佐劑功效的評估
用表3中之疫苗免疫四組路易斯大鼠。
用列於表3中之疫苗在第0天、第7天、第14天及第21天經皮下免疫大鼠。在第一次注射之前(亦即第0天)及在第10天、第17天及第24天收集周邊血液單核細胞
(PBMC)及血漿。
使用此項技術中已知之鈣黃綠素AM釋放法進行ADCC及CDC分析。程序描述如下:
用鈣黃綠素AM標記標靶細胞
MCF-7乳癌細胞(標靶細胞)在補充有2mM L-麩醯胺酸、1mM丙酮酸鈉及0.01mg/mL胰島素、10%胎牛血清之最低必需培養基中培養。將標靶細胞添加至96孔板(5×103個細胞/孔),且在潮濕的5% CO2氛圍中在37℃下培育隔夜。丟棄培養基且各孔用PBS洗滌一次。將100L 20M鈣黃綠素-AM溶液添加至各孔中(每孔2nmol)且在潮濕的5% CO2氛圍中在37℃下培育2小時。乾燥上清液且各孔用PBS洗滌三次。
用樣品血漿培育標靶細胞
樣品血漿經熱失活且將50L 1/5X熱失活之樣品血漿添加至各孔中,除了「完全釋放」及「背景」對照組。在添加50L PBMC或血清之後最終稀釋倍數將為1/10X。板在37℃下(避光)培育30分鐘。
用PBMC或補體培育標靶細胞
在培育之後,在ADCC分析中將50微升PBMC(2×106個細胞/mL)(針對E:T比率為20:1)添加至各孔中,且在CDC分析中將50微升1/10X稀釋之血清添加至各孔中,除了「完全釋放」及「背景」對照組。反應混合物在潮濕之5% CO2氛圍中在37℃下培育4小時。在培育時間之最後15分鐘,將含有2% Triton溶液之不含酚紅的MEM(50微升)添加至「完全釋放」對照組中,且將不含酚紅的MEM(50微升)添加至「背景」對照組中。板在100g下離心5分鐘,且隨後將80
微升上清液轉移至96孔黑色板。在485nm激發及538nm發射波長下量測螢光。
圖2A至圖2D顯示G2、G3及G4疫苗之活體內ADCC及CDC活性。
結果:如圖2B及圖2D中所說明,在第24天G3疫苗(具有OPT-821皂素佐劑)之ADCC及CDC活性比G2疫苗(不具有皂素佐劑)之ADCC及CDC活性高。如圖2B及圖2D中所說明,在第24天G4疫苗(Globo H/DT比率為24:1)之ADCD及CDC活性比G3疫苗(Golbo H/DT比率為8:1)之ADCD及CDC活性高。此等結果顯示OPT-821皂素佐劑及碳水化合物抗原/毒素蛋白比率超過5:1之疫苗增強且誘發更長久的ADCC及CDC反應。
實例4:具有較高碳水化合物/毒素蛋白比率的疫苗之免疫反應及OPT-821皂素之佐劑功效
使用CL57B/6小鼠或Balb/c小鼠進行實例1中之Globo H/DT(8:1)及Globo H/DT(16:1)疫苗及OPT-821皂素佐劑的活體內評估。
約八週大的CL57B/6小鼠隨機分成以下8個研究組:
在第一次注射之前或第0天,在第10天、第17天及第24天經後眶或面靜脈不用抗凝血劑收集血液樣品。血液樣品經離心以分離血清與血細胞。收集血清且儲存在-20℃下,其稍後藉由ELISA分析。將來自各小鼠之血清連續稀釋以用於抗Globo H IgG及IgM分析。圖3A、圖3B及圖4顯示所測試之疫苗的定量抗Globo H IgM及抗Globo H IgG效價。
結果:具有OPT-821皂素佐劑之疫苗相比於具有C34佐劑之疫苗誘發統計學上顯著更多的抗Globo H IgM及抗Globo H IgG(參見圖3A、圖3B及圖4)。以下為統計學顯著差異:●在第17天G3疫苗(OPT-821皂素)之IgM效價顯著高於G5疫苗(C34)之IgM效價(p=0.02);●在第17天G1疫苗(OPT-821皂素)之IgM效價顯著高於G6疫苗(C34)之IgM效價(p=0.03),●在第24天G3疫苗(OPT-821皂素)之IgM效價顯著高於G5疫苗(C34)之IgM效價(p=0.03),●在第17天G3疫苗(OPT-821皂素)之IgG效價顯著高於G5疫苗(C34)之IgG效價(p=0.001),●在第17天G1疫苗(OPT-821皂素)之IgG效價顯著高於G6疫苗(C34)之IgG效價(p=0.003),●在第24天G3疫苗(OPT-821皂素)之IgG效價顯著高於G5疫苗(C34)之IgG效價(p=0.003),及
●在第24天G1疫苗(OPT-821皂素)之IgG效價顯著高於G6疫苗(C34)之IgG效價(p=0.004)。
此等結果說明OPT-821皂素佐劑相比於C34佐劑顯著增強IgM及IgG反應。
在第17天及第24天Globo H/KLH/OPT 821皂素(G1)相比於Globo H/DT(3:1)/OPT-821皂素(G2)誘發顯著更高的IgM及IgG效價。不受特定理論約束,G1因具有較高的碳水化合物密度(每個KLH載體蛋白約700個Glob H單元),會引起較強的免疫反應,而G2具有較低的碳水化合物密度(每個DT載體蛋白3個Globo H單元),會引起較弱的免疫反應。以下統計學顯著差異:●在第17天G1疫苗(KLH)之IgM效價顯著高於G2疫苗(DT)之IgM效價(p=0.003),●在第24天G1疫苗(KLH)之IgM效價顯著高於G2疫苗(DT)之IgM效價(p=0.03),●在第24天G1疫苗(KLH)之IgG效價顯著高於G2疫苗(DT)之IgG效價(p=0.004)。
在第17天及第24天Globo H/DT(Globo H與DT之分子比率為8:1)/OPT-821皂素(G3及G4)及Globo H/DT(Globo H與DT之分子比率為16:1)/OPT-821皂素(G7)之IgM及IgG效價與Globo H/KLH/OPT-821皂素(G1)之IgM及IgG效價可相當(參見圖4)。儘管相比GH-KLH(Globo H與DT之分子比率為700:1)具有較低的碳水化合物密度,但GH-DT(Globo H與DT之分子比率為8:1)展現與GH-KLH可相當的免疫原性。
具有較高Globo H/DT比率(Globo H與DT之分子比率為8:1或16:1)的疫苗相比於具有較低Globo H/DT比率(3:1)的疫苗誘發更高且持續時間更長的IgM及IgG效價。注意以下統計學顯著差異:●在第17天G3疫苗(Globo H與DT之分子比率為8:1比率)之IgM效價顯著高於G2疫苗(3:1比率)之IgM效價(p=0.02),●在第17天G7疫苗(Globo H與DT之分子比率為16:1比率)之IgM效價顯著高於G2疫苗(3:1比率)之IgM效價(p=0.006),●在第17天G3疫苗(Globo H與DT之分子比率為8:1比率)之IgG效價顯著高於G2疫苗(3:1比率)之IgG效價(p=0.01),●在第17天G7疫苗(Globo H與DT之分子比率為16:1比率)之IgG效價顯著高於G2疫苗(Globo H與DT之分子比率為3:1比率)之IgG效價(p=0.03),●在第24天G3疫苗(Globo H與DT之分子比率為8:1比率)之IgG效價顯著高於G2疫苗(3:1比率)之IgG效價(p=0.01),●在第24天G7疫苗(Globo H與DT之分子比率為16:1比率)之IgG效價顯著高於G2疫苗(Globo H與DT之分子比率為3:1比率)之IgG效價(p=0.01),在第17天及第25天Globo H/DT(Globo H與DT之分子比率為8:1)/OPT-821皂素(G3)及Globo H/DT(16:1)/OPT-821皂素(G7)之IgG效價顯著高於Globo H/DT(Globo H與DT
之分子比率為3:1)/OPT-821皂素(G2)之IgG效價(P<0.05)。
本說明書中所引用之所有公開案、專利及專利申請案均以引用的方式併入本文中,就如同各個別公開案或專利申請案特定地且個別地指示以引用的方式併入一般。
本發明不限於本文所揭示之實施例的範疇,該等實施例預期作為本發明之個別態樣的單個說明,而非限制本發明之範疇。根據前述描述及教示,對於熟習此項技術者而言除本文所述外,本發明之模型及方法的各種修改亦將變得顯而易見,且同樣地意欲屬於本發明之範疇。在不背離本發明之真實範疇及精神的情況下,可實踐該等修改或其他實施例。
Claims (37)
- 一種疫苗,其包含(a)碳水化合物抗原或其免疫原性片段;及(b)類毒素蛋白,其中碳水化合物抗原與類毒素蛋白之比率在5:1至39:1範圍內。
- 如請求項1之疫苗,其中該類毒素蛋白為白喉毒素(DT)。
- 如請求項2之疫苗,其中碳水化合物抗原與DT之比率在8:1至24:1範圍內。
- 如請求項1之疫苗,其中該類毒素蛋白為破傷風類毒素(TT)。
- 如請求項4之疫苗,其中碳水化合物抗原與TT之比率在7:1至12:1範圍內。
- 如請求項1之疫苗,其中該碳水化合物抗原係選自Globo H、SSEA-3、SSEA-4或Gb-4。
- 如請求項6之疫苗,其中該碳水化合物抗原為Globo H。
- 如請求項2之疫苗,其中該DT為白喉毒素交叉反應性物質或白喉類毒素。
- 如請求項8之疫苗,其中該白喉毒素交叉反應性物質係選自CRM30、CRM45、CRM 176、CRM 197或CRM 228。
- 如請求項1之疫苗,其進一步包含皂素佐劑。
- 如請求項10之疫苗,其中該皂素佐劑為OPT-821皂素。
- 如請求項1之疫苗,其進一步包含α-半乳糖基-神經醯胺(α-GalCer)佐劑。
- 如請求項12之疫苗,其中該α-GalCer佐劑具有以下結構:
- 一種醫藥組合物,其包含(a)碳水化合物抗原或其免疫原性片段;(b)類毒素蛋白;及(c)醫藥學上可接受之載劑,其中碳水化合物抗原與DT之比率在5:1至39:1範圍內。
- 如請求項14之醫藥組合物,其中該類毒素蛋白為白喉毒素(DT)。
- 一種經分離之式(I)化合物,
- 如請求項16之經分離之化合物,其中R1為β-D-芹菜糖, R2為且R3為H。
- 如請求項16之經分離之化合物,其中R1為β-D-芹菜糖, R2為H且R3為。
- 如請求項16之經分離之化合物,其中R1為β-D-木糖,R2 為且R3為H。
- 如請求項16之經分離之化合物,其中R1為β-D-木糖,R2 為H且R3為。
- 一種醫藥組合物,其包含式(I)化合物
- 一種OPT-821皂素,其包含以下經分離之化合物中之一或多者:1857化合物V1A;1857化合物V1B;1857化合物V2A;及1857化合物V2B。
- 如請求項22之OPT-821皂素,其進一步包含以下經分離之化合物中之一或多者:1989化合物V1A;1989化合物V1B;1989化合物V2A;及1989化合物V2B。
- 一種OPT-821皂素,其包含:約1至約15莫耳%之1857化合物混合物;及約85至約99莫耳%之1989化合物混合物。
- 如請求項24之OPT-821皂素,其中該1857化合物混合物包含:約60-70莫耳%之1857化合物V1A; 約1-5莫耳%之1857化合物V1B;約30-40莫耳%之1857化合物V2A;及約0.1-3莫耳%之1857化合物V2B。
- 如請求項24之OPT-821皂素,其中該1989化合物混合物包含:約60-70莫耳%之1989化合物V1A;約1-5莫耳%之1989化合物V1B;約30-40莫耳%之1989化合物V2A;及約0.1-3莫耳%之1989化合物V2B。
- 一種疫苗,其包含:(a)碳水化合物抗原或其免疫原性片段;及(b)OPT-821皂素。
- 如請求項27之疫苗,其中該碳水化合物抗原或其免疫原性片段係選自Globo H、SSEA-3、SSEA-4、Gb-4或其混合物。
- 如請求項27之疫苗,其進一步包含載體蛋白。
- 如請求項29之疫苗,其中該載體蛋白為失活之白喉毒素(DT)。
- 如請求項30之疫苗,其中該DT為白喉毒素交叉反應性物質或白喉類毒素。
- 如請求項31之疫苗,其中該白喉毒素交叉反應性物質係選自CRM30、CRM45、CRM 176、CRM 197或CRM 228。
- 如請求項29之疫苗,其中該載體蛋白為KLH。
- 一種醫藥組合物,其包含(a)如請求項1或27之疫苗;及 (b)醫藥學上可接受之載劑。
- 一種用於抑制癌細胞之方法,其包含向有需要之個體投與有效量之如請求項1或27之疫苗,其中該等癌細胞受到抑制。
- 如請求項35之方法,其中該癌症為表現Globo H之癌症。
- 如請求項36之方法,其中該表現Glolo H之癌症為乳癌、肺癌、胃癌、結腸癌、胰臟癌、前列腺癌、卵巢癌及子宮內膜癌。
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CN107427564A (zh) * | 2014-09-15 | 2017-12-01 | 台湾浩鼎生技股份有限公司 | 免疫原性/治疗性糖缀合物组合物及其用途 |
TWI697333B (zh) * | 2016-04-22 | 2020-07-01 | 台灣浩鼎生技股份有限公司 | 經由Globo系列抗原之免疫活化或免疫調節之癌症免疫療法 |
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