TWI752988B - 免疫性/治療性聚醣組合物及其用途 - Google Patents
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Abstract
本發明涵蓋包括Globo系列抗原(SSEA-4、Globo H或SSEA-3)醣共軛物和治療佐劑(OBI-821或OBI-834)的免疫性/治療性組合物,及其製備方法,以及使用其來治療諸如癌症的增生性疾病的方法。治療性共軛物包括與載體連接的抗原。具體而言,該治療性接合物包括SSEA-4、Globo H或SSEA-3部分和經由連接子連接的KLH部分次單元。該治療性組合物被部分構想充當癌症疫苗(單價、二價或三價疫苗)用於通過免疫系統增強身體的自然保護能力而免於受損或異常細胞(例如癌症細胞)引起的危害。例示性免疫反應可以下列為特徵:疾病嚴重性的降低,包括但不限於疾病的預防、疾病發作的延遲、症狀嚴重性的降低、發病率的降低及死亡的延遲。
Description
本申請案主張於2016年7月27日提出申請的第62/367,528號美國專利臨時申請案的優先權。前述申請案之全部內容以引用方式併入本文中。
本發明係關於用於癌症免疫治療的組合物和方法,具體而言是能夠引起抗癌免疫反應的免疫性/治療性醣共軛物。
惡性腫瘤細胞中有許多表面碳水化合物的表現。例如,已證實Globo H(Fucα1→2 Galβ1→3 GalNAcβ1→3 Galα1→4 Galβ1→4 Glc)在多種上皮癌上過度表現,且與乳癌和小細胞肺癌的腫瘤侵襲性和不良預後有關。先前的研究顯示,在乳癌細胞和乳癌幹細胞上觀察到Globo H和階段特異性胚胎抗原3(SSEA-3,也稱為Gb5)(Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1)(WW Chang等人,「Globo H和SSEA-3在乳癌幹細胞的表現及岩藻醣轉移酶1和2在Globo H合成中的參與(Expression of Globo H and SSEA-3 in breast cancer stem cells and the involvement of fucosyl transferases 1 and 2 in Globo H synthesis.)」,PNAS, 105(33): 11667-11672, 2008)。SSEA-4(階段特異性胚胎抗原4)(一種六醣(Neu5Acα2→ 3Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1))常被用作多能人類胚胎幹細胞的細胞表面標記物,而且已被用於分離間質幹細胞和富集神經先驅細胞(Kannagi R等人,EMBO J, 2:2355-2361, 1983)。先前的研究顯示,階段特異性胚胎抗原4(SSEA-4)可以作為多形性神經膠質母細胞瘤和其他癌症的潛在治療標靶(WW Chang等人,PNAS, 111(7): 2482-2487, 2014)。此等研究結果支持了Globo系列抗原(Globo H、SSEA-3及SSEA-4)是癌細胞的獨特標靶,可以使治療劑有效標靶癌細胞。
因此,本發明概括而言涵蓋包括Globo系列抗原(SSEA-4、Globo H及SSEA-3)的治療性及/或預防性組合物、以及免疫治療劑、疫苗、劑型、套組及製備方法、以及其療法。
在一具體實施例中,本發明包含經分離的治療性共軛物,該治療性接合物包含經由對-硝基苯連接子、4-(4-N-馬來醯亞胺甲基)環己烷-1-羧基醯肼(MMCCH)連接子、或4-(N-馬來醯亞胺甲基)-環己烷-1-羧酸酯(MCCa)連接子共價連接到鑰孔蟲戚血藍蛋白(KLH)或白喉毒素交叉反應性物質197(DT-CRM 197)部分次單元的Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分。
在另一說明性的具體實施例中,本發明包含具有以下一般結構的經分離的免疫性/治療性共軛物:其中n獨立為約1至約3000的整數,m獨立為約1至約20的整數。在某些具體實施例中,當m大於1時,KLH部分可以聚集形成多聚體結構。在某些具體實施例中,聚集是共價鍵。在某些其它具體實施例中,聚集不是共價鍵(例如,聚集是藉由氫鍵或疏水相互作用形成)。在某些具體實施例中,單體KLH部分(即其中m = 1)可以包括約1至約150個SSEA-4部分。在某些具體實施例中,二聚體KLH部分(即其中m = 2)可以包括約1至約300個SSEA-4部分。在某些具體實施例中,三聚體KLH部分(即其中m = 3)可以包括約1至約450個SSEA-4部分。在某些具體實施例中,四聚體KLH部分(即其中m = 4)可以包括約1至約600個SSEA-4部分。在某些具體實施例中,五聚體KLH部分(即其中m = 5)可以包括約1至約750個SSEA-4部分。在某些具體實施例中,六聚體KLH部分(即其中m = 6)可以包括約1至約900個SSEA-4部分。在某些具體實施例中,二十聚體KLH部分(即其中m = 20)可以包括約1至約3000個SSEA-4部分。
在一具體實施例中,SSEA-4部分包含(Neu5Acα2→ 3Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1)。在另外的具體實施例中,KLH部分次單元是KLH-1或KLH-2部分或其組合。本文中使用的用語「KLH」是指KLH-1、KLH-2、及/或其組合。
在另一個說明性具體實施例中,本發明包含具有以下一般結構的分離免疫性/治療性共軛物:其中n獨立為約1至約3000的整數,m獨立為約1至約20的整數。在某些具體實施例中,當m大於1時,KLH部分可以聚集形成多聚體結構。在某些具體實施例中,聚集是共價鍵。在某些其它具體實施例中,聚集不是共價鍵(例如,聚集是藉由氫鍵或疏水相互作用形成)。在某些具體實施例中,單體KLH部分(即其中m = 1)可以包括約1至約150個SSEA-3部分。在某些具體實施例中,二聚體KLH部分(即其中m = 2)可以包括約1至約300個SSEA-3部分。在某些具體實施例中,三聚體KLH部分(即其中m = 3)可以包括約1至約450個SSEA-3部分。在某些具體實施例中,四聚體KLH部分(即其中m = 4)可以包括約1至約600個SSEA-3部分。在某些具體實施例中,五聚體KLH部分(即其中m = 5)可以包括約1至約750個SSEA-3部分。在某些具體實施例中,六聚體KLH部分(即其中m = 6)可以包括約1至約900個SSEA-3部分。在某些具體實施例中,二十聚體KLH部分(即其中m = 20)可以包括約1至約3000個SSEA-3部分。
在一具體實施例中,SSEA-3部分包含(Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1)。在另外的具體實施例中,KLH部分次單元是KLH-1或KLH-2部分或其組合。本文中使用的「KLH」乙詞是指KLH-1、KLH-2、及/或其組合。
在另一個說明性具體實施例中,本發明包含具有以下一般結構的分離免疫性/治療性共軛物:其中n獨立為約1至約3000的整數,m獨立為約1至約20的整數。在某些具體實施例中,當m大於1時,KLH部分可以聚集形成多聚體結構。在某些具體實施例中,聚集是共價鍵。在某些其它具體實施例中,聚集不是共價鍵(例如,聚集是藉由氫鍵或疏水相互作用形成)。在某些具體實施例中,單體KLH部分(即其中m = 1)可以包括約1至約150個Globo H部分。在某些具體實施例中,二聚體KLH部分(即其中m = 2)可以包括約1至約300個Globo H部分。在某些具體實施例中,三聚體KLH部分(即其中m = 3)可以包括約1至約450個Globo H部分。在某些具體實施例中,四聚體KLH部分(即其中m = 4)可以包括約1至約600個Globo H部分。在某些具體實施例中,五聚體KLH部分(即其中m = 5)可以包括約1至約750個Globo H部分。在某些具體實施例中,六聚體KLH部分(即其中m = 6)可以包括約1至約900個Globo H部分。在某些具體實施例中,二十聚體KLH部分(即其中m = 20)可以包括約1至約3000個Globo H部分。
在一具體實施例中,Globo H部分包含(Fucα1→2 Galβ1→3 GalNAcβ1→3 Galα1→4 Galβ1→4 Glc)。在另外的具體實施例中,KLH部分次單元是KLH-1或KLH-2部分或其組合。本文中使用的「KLH」乙詞是指KLH-1、KLH-2、及/或其組合。
本發明的另一具體實施例包括包含KLH部分次單元的醫藥組合物,其中每個KLH部分次單元皆包含與鑰孔蟲戚血藍蛋白(KLH)部分次單元共價連接的一個或更多個Globo系列抗原部分。在某些具體實施例中,醫藥組合物包含至少兩個KLH部分次單元的二聚體,其中每個KLH部分次單元皆包含與KLH部分次單元共價連接的一個或更多個Globo系列抗原部分。在某些具體實施例中,醫藥組合物包含至少三個KLH部分次單元的三聚體,其中每個KLH部分次單元皆包含與KLH部分次單元共價連接的一個或更多個Globo系列抗原部分。在某些具體實施例中,醫藥組合物包含至少四個KLH部分次單元,其中每個KLH部分次單元皆包含與KLH部分次單元共價連接的一個或更多個Globo系列抗原部分。在某些具體實施例中,醫藥組合物包含KLH部分次單元(例如單體、二聚體、三聚體、四聚體、五聚體、六聚體等)的混合物,其中每個KLH部分次單元皆包含與KLH部分次單元共價連接的多個Globo系列抗原部分。
在某些具體實施例中,某些例示性組合物具體實施例及其使用方法可以包括或排除(例如附帶條件)本文所述的其它代表性化合物及/或組合物具體實施例中之任一者或更多者。
在另一具體實施例中,醫藥組合物包含佐劑。本文中使用的「免疫佐劑」乙詞是指與免疫原結合使用的物質,其增強或修飾對免疫原的免疫反應。特定而言,「佐劑」和「免疫佐劑」等詞在本發明中可互換使用,並指當被單獨投予宿主時可不產生免疫反應、但當被與另一抗原結合投予宿主時可增強宿主對該抗原的免疫反應的化合物或混合物。可以藉由所屬技術領域中習知的任何方法來評估佐劑調節的增強、及/或免疫反應持續時間的延長,該方法包括但不限於以下中之一者或更多者:(i)佐劑/抗原組合所產生的免疫反應其抗體數量增加對比單獨抗原所產生的免疫反應的抗體數量增加;(ii)識別抗原或佐劑的T細胞數量的增加;及(iii)一種或更多種I型細胞介素的含量的增加。
可以將佐劑作為包含抗原的醫藥或疫苗組合物的一部分投予,或作為分開的製劑與含有抗原的第二組合物一起投予。在此等組合物的任一組合物中,可以將醣神經鞘脂質(GSL)與其它佐劑及/或賦形劑/載體組合。此等其它佐劑包括、但不限於油乳劑和基於乳化劑的佐劑,例如完全弗氏(Freund's)佐劑、不完全弗氏佐劑、MF59或SAF;礦物凝膠例如氫氧化鋁(明礬)、磷酸鋁或磷酸鈣;微生物衍生的佐劑例如霍亂毒素(CT)、百日咳毒素、大腸桿菌熱不穩定毒素(LT)、突變毒素(例如LTK63或LTR72)、卡介苗(BCG)、短棒桿菌(Corynebacterium parvum)、DNA CpG結構區域、胞壁醯二肽、或單磷醯脂質A;微粒佐劑例如免疫刺激複合物(ISCOM)、脂質體、可生物降解微球、或皂素(例如QS-21);細胞介素例如IFN-γ、IL-2、IL-12或GM-CSF;合成佐劑例如非離子嵌段共聚物、胞壁醯肽類似物(例如N-乙醯-胞壁醯-L-蘇胺醯-D-異麩醯胺[thr-MDP]、N-乙醯-間-胞壁醯-L-丙胺醯-D-異麩醯胺、N-乙醯胞壁醯-L-丙胺醯-D-異麩醯胺基-L-丙胺酸-2-[1'-2'-二棕櫚醯基-sn-甘油基-3-羥基磷醯氧基]-乙胺)、聚磷腈或合成多核苷酸、以及表面活性物質例如溶血卵磷脂、多聚體多元醇、聚陰離子、肽、烴乳劑或鑰孔蟲戚血藍蛋白(KLH)、類鐸受體分子、LPS、脂蛋白、脂肽、鞭毛蛋白、雙鏈RNA、病毒DNA、未甲基化CpG位點、左旋咪唑、卡介苗、異丙肌苷(Isoprinosine)、日達仙(Zadaxin)、PD-1拮抗劑、PD-1抗體、CTLA拮抗劑、CTLA抗體、介白素、細胞介素、GM-CSF、醣類、鋁鹽類、磷酸鋁、明礬、氫氧化鋁、脂質體、TLR2致效劑、脂肽、奈米顆粒、單磷醯脂質A、OBI-821佐劑、皂素、OBI-834佐劑、C34佐劑、水包油奈米乳液、及細菌樣顆粒。較佳的是,此等附加佐劑用於人類也是醫藥上可接受的。
在另一具體實施例中,醫藥組合物包含選自由IL-2、IL-12、IL-18、IL-2、IFN-γ、TNF、IL-4、IL-10、IL-13、IL-21、GM-CSF及TGF-β所組成之群組的細胞介素。在另外的具體實施例中,醫藥組合物包含趨化介素。
在另外的具體實施例中,免疫/治療劑作為醫藥組合物投藥。
在另一具體實施例中,醫藥組合物包含單株抗體、化學治療劑、激素治療劑、類視色素受體調節劑、細胞毒性/細胞增殖抑制劑、抗惡性腫瘤劑、抗增殖劑、抗-mTOR劑、抗Her2劑、抗EGFR劑、異戊烯基-蛋白轉移酶抑制劑、HMG-CoA還原酶抑制劑、氮芥、亞硝基脲、血管新生抑制劑、貝伐單抗、細胞增殖和存活信號途徑抑制劑、凋亡誘導劑、干擾細胞週期檢查點的試劑、干擾受體酪胺酸激酶(RTK)的試劑、整合素阻斷劑、NSAIDs、PPAR致效劑、固有多重抗藥性(MDR)抑制劑、抗嘔吐劑、可用於治療貧血的藥劑、可用於治療嗜中性白血球減少症的藥劑、免疫增強藥物、雙膦酸鹽、芳香酶抑制劑、誘導腫瘤細胞末端分化的藥劑、γ-分泌酶抑制劑、癌症疫苗(例如主動免疫治療)、單株抗體治療劑(例如被動免疫治療)及上述之任意組合。
在另一具體實施例中,本發明的治療組合物可進一步包括PD-1/PD-L1抑制劑(細胞毒性T細胞淋巴細胞(CTL)免疫治療)、CTLA-4免疫治療、CDK4/6抑制劑(標靶治療)、PI3K抑制劑(標靶治療)、mTOR抑制劑(標靶治療)、AKT抑制劑(標靶治療)、Pan-Her抑制劑(標靶治療)。此等抑制劑也可以被修飾以產生相應的單株抗體。此類抗體可以被包括在本發明的治療組合物中。
在另一具體實施例中,醫藥組合物包含醫藥上可接受載體。在另外的具體實施例中,醫藥組合物是癌症疫苗。在另一具體實施例中,配製醫藥組合物用於皮下投藥。在另一具體實施例中,配製醫藥組合物用於肌內投藥。在另一具體實施例中,配製醫藥組合物用於動脈內投藥。在另一具體實施例中,配製醫藥組合物用於靜脈內投藥。
除非另有指明,否則本發明的實施將採用所屬技術領域技術內的分子生物學、微生物學及免疫學的常用技術。此類技術在文獻中有完整的說明。參見例如Molecular Cloning A Laboratory Manual,第2版,由Sambrook、Fritsch及Maniatis編著(Cold Spring Harbor Laboratory Press,1989年);DNA Cloning,第I卷和第II卷(D. N. Glover編著,1985年);Culture Of Animal Cells(R. I. Freshney, Alan R. Liss, Inc.,1987年);Immobilized Cells And Enzymes(IRL Press,1986年);B. Perbal,A Practical Guide To Molecular Cloning (1984年);the treatise, Methods In Enzymology(Academic Press, Inc., N.Y.);Gene Transfer Vectors For Mammalian Cells(J. H. Miller和M. P. Calos編著,1987年,Cold Spring Harbor Laboratory);Methods In Enzymology,第154卷和第155卷(Wu等人編著),Immunochemical Methods In Cell And Molecular Biology(Mayer和Walker編著,Academic Press, London,1987年);Antibodies: A Laboratory Manual,由Harlow和Lanes所著(Cold Spring Harbor Laboratory Press,1988年);及Handbook Of Experimental Immunology,第I卷-第IV卷(D. M. Weir和C. C. Blackwell編著,1986)。
Goebel和Avery在1929年首次證明使用合成碳水化合物共軛物可引發抗合成抗原的抗體產生(Goebel, W. F.和Avery, O. T.,J. Exp. Med., 1929, 50, 521;Avery, O. T. 和Goebel, W. F.,J. Exp. Med., 1929, 50, 533)。碳水化合物經由重氮苯醣苷與載體蛋白連接。用合成抗原使兔子的免疫產生了多株抗體。其他工作者(Allen, P. Z.和Goldstein, I. J.,Biochemistry,1967, 6, 3029;Rude, E.和Delius, M. M.,Carbohydr. Res., 1968, 8, 219;Himmelspach, K.等人,Eur. J. Immunol., 1971, 1, 106;Fielder, R. J. 等人,J. Immunol., 1970, 105, 265)開發了用於將碳水化合物與蛋白質載體共軛的類似技術。
醣共軛物可用於從疫苗接種產生的主動免疫治療中,以特異性標靶腫瘤細胞上的已知靶劑。對碳水化合物抗原的反應通常不會引起T細胞的參與,此舉將有助於身體排斥腫瘤。儘管認為用共軛物接種疫苗產生完全腫瘤排斥的可能性為不太可能,但此類治療將促進免疫監控,並且可以減少新的腫瘤群落的複發。(Dennis, J.,Oxford Glycosystems Glyconews Second,1992年;Lloyd, K. O.,in Specific Immunotherapy of Cancer with Vaccines,1993年,New York Academy of Sciences,50-58)。Toyokuni和Singhal描述了一種合成的醣共軛物(Toyokuni, T.等人,J. Am. Chem. Soc., 1994, 116, 395),該醣共軛物激發了可量測的IgG效價,結果是明顯的,因為IgG反應通常與輔助T細胞的獲得有關。
因此,本揭露係針對SSEA-4標靶/調節的免疫/治療化合物、組合物、及/或醫藥製劑組合物、以及免疫治療劑、疫苗、劑型、套組及製備方法、以及其治療。
當與申請專利範圍及/或說明書中的「包含」乙詞一起使用時,使用單詞「一(a)」或「一(an)」可以意指「一個」,但也與「一個或更多個」、「至少一個」、及「一個或多於一個」的含義一致。
貫穿本申請案,「約」乙詞是用來表示值包括例如量測裝置的固有誤差變化、用於決定值的方法、或存在於研究個體間的變化。通常該用語意在包括大約或小於1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%或20%的變異性,視情況而定。
除非另有說明,否則本文中使用的「烷基」乙詞是指含有1-20個碳原子的直鏈或支鏈單價烴,例如可以是經取代或未經取代的C1-C8或C1-C4。烷基的實例包括、但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、及叔丁基。
在申請專利範圍中使用「或」乙詞是用來表示「及/或」,除非有明確表示僅指替代方案或替代方案是相互排斥的,儘管本揭露支持僅指替代方案和「及/或」的定義。
如本說明書和申請專利範圍中使用的,單詞「包含(comprising)」(以及包含(comprising)的任何形式,例如「包含(comprise)」和「包含(comprises)」)、「具有(having)」(以及「具有(having)」的任何形式,例如「具有(have)」和「具有(has)」、「包括(including)」(以及包括(including)的任何形式,例如「包括(includes)」和「包括(include)」)、或「含有(containing)」(以及含有(containing)的任何形式,例如「含有(contains)」和「含有(contain)」)是全包括的或開放的,而且不排除附加的、不需要的元素或方法步驟。構想的是,可以相對於本發明的任何方法或組合物來實施本說明書中討論的任何具體實施例,反之亦然。此外,本發明之組合物可用於實現本發明之方法。
「治療(Treating)」或「治療(treating)」在本文中是指對個體投予治療組合物,目的是治癒、減輕、緩解、補救、預防或改善病症、病症的症狀、病症的第二疾病狀態、或傾向於病症的體質。
「有效量」是能夠在治療個體體內產生本文所述醫學上期望的結果的治療組合物的量。醫學上期望的結果可以是客觀的(即可以藉由一些測試或標記)或主觀的(即個體表示有效果或感覺到效果)。
本文中提及的「可用治療組合物治療的疾病」意指可以藉由投予本文揭露的治療組合物治療的任何程序、病狀、病症、病痛及/或疾病。
「增生性病症」是其中產生太多某種類型的細胞而導致健康惡化的病症。增生性病症可以是良性或惡性的。增生性病症可以包括例如癌症。
如本文中使用的,可以藉由本文揭露的治療組合物治療的「癌症」包括具有異常生長狀態的細胞。癌細胞的特徵可以在於失去正常的控制機制從而能夠連續擴張、侵入鄰近的組織、遷移到身體的遠處、並促進新血管的生長,細胞則從新血管獲得營養物質。如本文中使用的,癌症可以是惡性的或良性的。癌症可能從體內的任何組織形成。當細胞生長繁殖時,細胞形成稱為腫瘤的組織團塊。腫瘤乙詞可以包括異常生長或團塊。腫瘤可能是癌性(惡性的)或非癌性的(良性的)。癌性腫瘤會侵入鄰近組織並遍及全身(轉移)。然而,良性腫瘤通常不會侵入鄰近組織,而且不會遍及全身。癌症可以分為血液和血液形成組織的癌症(白血病和淋巴瘤)及「實體」腫瘤。「實體」腫瘤可以包括癌或肉瘤。
可由本發明的治療組合物治療的癌症包括以位點分類的癌症,包括口腔和咽(唇、舌、唾液腺、口腔底、牙齦及其他口部、鼻咽、扁桃腺、口咽、下咽、其他口腔/咽)的癌症;消化系統(食道;胃;小腸;結腸和直腸;肛門、肛管及肛門直腸;肝;肝內膽管;膽囊;其他膽汁;胰臟;後腹腔;腹膜、網膜及腸繫膜;其他消化道)的癌症;呼吸系統(鼻腔、中耳及鼻竇;喉;肺和支氣管;胸膜;氣管、縱膈膜及其他呼吸道)的癌症;間皮瘤、骨骼和關節、及軟組織的癌症,包括心臟;皮膚癌,包括黑色素瘤和其他非上皮性皮膚癌;卡波西(Kaposi’s)肉瘤和乳癌;女性生殖系統(子宮頸;子宮體;子宮;卵巢;陰道;外陰;及其他女性生殖器)的癌症;男性生殖系統(前列腺;睪丸;陰莖;及其他男性生殖器)的癌症;泌尿系統(膀胱;腎和腎盂;輸尿管;及其他泌尿器官)的癌症;眼睛和眼眶的癌症;腦和神經系統(腦;和其他神經系統)的癌症;內分泌系統(甲狀腺及其它內分泌腺,包括胸腺)的癌症;淋巴瘤(何杰金症和非何杰金淋巴瘤)、多發性骨髓瘤、及白血病(淋巴細胞性白血病;骨髓性白血病;單核細胞白血病;及其他白血病)。
可能是用於依據本發明的治療組合物的適當標靶、根據組織學類型分類的其他癌症包括、但不限於腫瘤,惡性;癌,NOS;癌,未分化的,NOS;巨型和紡錘體細胞癌;小細胞癌,NOS;乳突癌,NOS;鱗狀細胞癌,NOS;淋巴上皮癌;基底細胞癌,NOS;毛髮基質癌;移行細胞癌,NOS;乳突移行細胞癌;腺癌,NOS;胃泌素瘤,惡性;膽管癌;肝細胞癌,NOS;聯合肝細胞癌和膽管癌;小梁腺癌;腺樣囊性癌;腺瘤息肉腺癌;腺癌,家族性大腸桿菌;實體癌,NOS;類癌腫瘤,惡性;細支氣管肺泡腺癌;乳突腺癌,NOS;嫌色細胞癌;嗜酸細胞癌;嗜氧腺癌;嗜鹼細胞癌;透明細胞腺癌,NOS;顆粒細胞癌;濾泡性腺癌,NOS;乳突和濾泡性腺癌;非包囊硬化癌;腎上腺皮質癌;子宮內膜癌;皮膚附屬癌;頂泌腺癌;皮脂腺癌;耳垢腺癌;黏液上皮樣汗腺癌;囊腺癌,NOS;乳突囊腺癌,NOS;乳突漿液性囊腺癌;黏液性囊腺癌,NOS;黏液性腺癌;印環狀細胞癌;浸潤性導管癌;髓樣癌,NOS;小葉癌;炎性癌;佩吉氏症(Paget’s disease),乳癌;腺泡細胞癌;腺樣鱗狀細胞癌;有鱗狀轉移瘤的腺癌;胸腺瘤,惡性;卵巢基質腫瘤,惡性;卵泡膜細胞瘤,惡性;粒層細胞腫瘤,惡性;男性母細胞瘤,惡性;賽特利(Sertoli)細胞癌;萊氏(Leydig)細胞瘤,惡性;脂質細胞瘤,惡性;副神經節瘤,惡性;乳腺外副神經節瘤,惡性;嗜鉻細胞瘤;皮膚絲球肉瘤(Glomangiosarcoma);惡性黑色素瘤,NOS;無黑色素瘤;表面擴張黑色素瘤;巨大色素痣中的惡性黑色素瘤;上皮樣細胞黑色素瘤;藍色痣,惡性;肉瘤,NOS;纖維肉瘤,NOS;纖維組織細胞瘤,惡性;黏液肉瘤;脂肪肉瘤,NOS;平滑肌肉瘤,NOS;橫紋肌肉瘤,NOS;胚胎橫紋肌肉瘤;齒槽橫紋肌肉瘤;基質肉瘤,NOS;混合腫瘤,惡性,NOS;穆勒混合腫瘤;腎母細胞瘤;肝母細胞瘤;癌肉瘤,NOS;間葉瘤,惡性;布倫納(Brenner)瘤,惡性;葉狀瘤(Phyllodes tumor),惡性;滑膜肉瘤,NOS;間皮瘤,惡性;惡性胚細胞瘤;胚胎癌,NOS;畸胎瘤,惡性,NOS;甲狀腺腫樣卵巢瘤,惡性;絨毛膜癌;中腎瘤,惡性;血管肉瘤;血管內皮瘤,惡性;卡波西(Kaposi’s)肉瘤;血管外皮細胞瘤,惡性;淋巴管肉瘤;骨肉瘤,NOS;骨膜外骨肉瘤;軟骨肉瘤,NOS;軟骨胚細胞瘤,惡性;間葉型軟骨肉瘤;骨巨細胞瘤;尤文氏(Ewing’s)肉瘤;齒源性腫瘤,惡性;造釉細胞性牙肉瘤;釉質母細胞瘤,惡性;造釉細胞性纖維肉瘤;松果腺瘤,惡性;脊索瘤;神經膠質瘤,惡性;室管膜瘤,NOS;星狀細胞瘤,NOS;原漿性星形細胞瘤;原纖維性星形細胞瘤;星形母細胞瘤;神經膠質母細胞瘤,NOS;寡樹突神經膠質細胞瘤,NOS;寡樹突神經膠質胚細胞瘤;原始神經外胚層腫瘤;小腦肉瘤,NOS;神經節神經母細胞瘤;神經母細胞瘤,NOS;視網膜母細胞瘤,NOS;嗅神經源性腫瘤;腦脊隨膜瘤,惡性;神經纖維肉瘤;神經鞘瘤,惡性;粒狀細胞瘤,惡性;惡性淋巴瘤,NOS;何杰金症,NOS;何杰金;類肉芽腫,NOS;惡性淋巴瘤,小淋巴細胞;惡性淋巴瘤,大細胞,瀰漫性;惡性淋巴瘤,濾泡性,NOS;蕈狀肉芽腫;其他指定的非何杰金淋巴瘤;惡性組織細胞增生症;多發性骨髓瘤;肥大細胞肉瘤;免疫增生性小腸疾病;白血病,NOS;淋巴樣白血病,NOS;血漿細胞白血病;紅血球性白血病;淋巴肉瘤細胞白血病;骨髓樣白血病,NOS;嗜鹼性白血病;嗜酸性白血病;單核細胞白血病,NOS;肥大細胞白血病;巨核母細胞性白血病;骨髓肉瘤;以及毛細胞白血病。
本文所定義的「上皮癌」是指從皮膚、中空內臟及其他器官中的上皮或相關組織形成的癌症。上皮癌包括但不限於乳癌、肺癌、肝癌、頰癌、胃癌、直腸癌、鼻咽癌、真皮癌、腎癌、腦腫瘤、前列腺癌、卵巢癌、子宮頸癌、子宮內膜癌、腸癌、胰臟癌及膀胱癌。
本文中使用的「患者」或「個體」是指被診斷或懷疑患有或發展出增生性疾病(例如癌症)的哺乳動物個體。例示性患者可以是可有益於發展增生性疾病(例如癌症)的人、猿、狗、豬、牛、貓、馬、山羊、綿羊、囓齒動物及其他哺乳動物。
如本文中使用的,「實質上純化的」或「實質上分離的」是指分子(例如化合物)在其天然狀態下處於與其通常相關聯的大體上所有其它分子分離的狀態。較佳的是,實質上純化的分子是存在於製劑中的主要物種。具體而言,實質上純化的分子可包含多於60%、較佳75%、更佳90%、最佳95%存在於天然混合物中的其它分子(不包括溶劑)。「實質上純化的」或「實質上分離的」等詞無意包括以其天然狀態存在的分子或物質。在某些具體實施例中,「實質上純化的」或「實質上分離的」等詞包括從一個KLH部分純化另一個KLH部分(例如,從KLH三聚體部分實質上純化或實質上分離KLH二聚體部分)。在另一具體實施例中,「實質上純化的」或「實質上分離的」等詞不包括從一個KLH部分純化另一個KLH部分(例如KLH二聚體和KLH三聚體被包括在實質上純化或實質上分離的組合物中),但實質上移除了雜質。
在本文中「投予」是指對患者提供本發明的治療組合物。作為實例而非限制,組合物投藥(例如注射)可以藉由靜脈(i.v.)注射、皮下(s.c.)注射、皮內(i.d.)注射、腹膜內(i.p.)注射、或肌肉(i.m.)注射來進行。可以使用一種或更多種此類途徑。非口服投藥可以例如藉由大丸藥注射或隨著時間逐漸灌注。替代地或同時地,可以經由口服途徑投藥。另外,投藥也可以藉由手術放置大丸藥或定位醫療裝置。
在本文中「有需要的患者」是指被診斷或懷疑患有增生性病症的患者。在一具體實施例中,患者患有或可能發展出癌症。
本文中使用的「抗原」乙詞被定義為在有或無蛋白質載體及/或佐劑的輔助下能夠引發免疫反應的任何物質。較佳的是,本發明組合物的抗原包括碳水化合物,更佳包括聚醣抗原,最佳包括SSEA-4、Globo H或SSEA-3部分。
本文中使用的「免疫性」乙詞是指免疫原、抗原或疫苗刺激免疫反應的能力。
本文中使用的「免疫治療」乙詞是指基於調節免疫系統以實現預防及/或治療目標的概念的治療策略之配置。
本文中使用的用語「表位」被定義為抗原分子與抗體或T細胞受體的抗原結合位點接觸的部分。
本發明的「治療組合物」包括「免疫性共軛物及/或治療性共軛物及/或治療性抗體」。治療性共軛物包括至少一種與載體連接的抗原。較佳的是,治療性共軛物的連接是共價的。在治療性共軛物的一具體實施例中,抗原是聚醣,例如Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分,載體是KLH部分及/或KLH部分次單元。因此,治療性共軛物乙詞包含與一個或更多個Globo系列抗原部分連接的一個或更多個KLH部分次單元。在一具體實施例中,治療性共軛物乙詞包含與約或至少1個、10個、102
個或103
個或更多個Globo系列抗原部分連接的一個或更多個KLH部分。另一具體實施例包含此類連接KLH部分次單元的Globo系列抗原之分離二聚體、三聚體、四聚體、五聚體或六聚體、或上述之組合。
「治療性抗體」被定義為與本發明的治療性組合物、較佳為治療性共軛物的Globo系列抗原部分特異性結合的抗體(如下文進一步定義)。
本文中使用的「疫苗」乙詞是指含有治療性共軛物的治療組合物,該治療性共軛物係用以賦予對抗與抗原相關的疾病的免疫力。癌症疫苗被設計來通過免疫系統增強身體的自然保護能力、免於受損或異常細胞(例如癌症細胞)引起的危害。保護性免疫反應是一種降低疾病嚴重性的反應,降低疾病嚴重性包括但不限於預防疾病、延遲疾病的發作、降低症狀的嚴重性、降低發病率及延遲死亡。較佳的是,疫苗能夠活化體液免疫反應(例如刺激B淋巴細胞產生抗體)和細胞免疫反應(例如由T淋巴細胞及/或其他細胞(例如NK細胞和巨噬細胞)調節的免疫反應)兩者。已經開發了標準試驗來測定免疫反應,例如酵素連結免疫分析法(ELISA)、流式細胞儀、細胞增生試驗、CTL試驗、及ADCC/CDC試驗。
本文中使用的「聚醣」乙詞是指多醣或寡醣。本文中也使用聚醣來指稱醣接合物的碳水化合物部分,例如醣蛋白、醣類、醣肽、醣蛋白體、肽聚醣、脂多醣或蛋白聚醣。聚醣通常僅由單醣之間的O-醣苷鍵組成。例如,纖維素是由β-1,4-連接的D-葡萄醣構成的聚醣(或更特定來說是葡聚醣),而幾丁質是由β-1,4-連接的N-乙醯基-D-葡萄醣胺構成的聚醣。聚醣可以是單醣殘基的均質或異質聚合物,並且可以是直鏈或支鏈的。可以在醣蛋白和蛋白聚醣中發現聚醣與蛋白質連接。聚醣通常存在於細胞的外表面上。連接O和N的聚醣在真核生物中非常常見,但也可以在原核生物中發現,儘管並不常見。在序列子(sequon)中發現連接N的聚醣連接到天冬醯胺的R基團氮(N)。序列子是Asn-X-Ser或Asn-X-Thr序列,其中X是除了脯胺酸之外的任何胺基酸。較佳的聚醣是Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分。
表現Globo系列抗原(SSEA-4、Globo H或SSEA-3)的癌症包括但不限於肉瘤、皮膚癌、白血病、淋巴瘤、腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰臟癌、直腸癌、腎癌、子宮頸癌、卵巢癌及前列腺癌。
本文中將「SSEA-4部分」定義為係SSEA-4或其片段或類似物的聚醣(即含有醣部分的分子)。SSEA-4為含有六醣表位(Neu5Acα2→ 3Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1)及可選的非醣部分的聚醣。其片段為含有六醣表位的片段及非醣部分(若適用的話)的聚醣。
本文中將「Globo H部分」定義為係Globo H或其片段或類似物的聚醣(即含有醣部分的分子)。Globo H為含有六醣表位(Fucα1→2 Galβ1→3 GalNAcβ1→3 Galα1→4 Galβ1→4 Glc)及可選的非醣部分的聚醣。其片段為含有六醣表位的片段及非醣部分(若適用的話)的聚醣。
本文中將「SSEA-3部分」定義為係SSEA-3或其片段或類似物的聚醣(即含有醣部分的分子)。SSEA-3為含有五醣表位(Galβ1→ 3GalNAcβ1→ 3Galα1→ 4Galβ1→ 4Glcβ1)及可選的非醣部分的聚醣。其片段為含有六醣表位的片段及非醣部分(若適用的話)的聚醣。
「鑰孔蟲戚血藍蛋白」(KLH)是在巨型鑰孔蟲戚(Megathura crenulata)的血淋巴中發現的大的、多次單元的、攜氧的金屬蛋白。KLH是在分子量約400 kDa(例如KLH單體)至約8000 kDa(例如KLH二十聚體)的凝聚體中由分子量約350,000至約390,000的次單元組成的異質醣基化蛋白。KLH次單元的每個區域都含有兩個共同結合單個氧分子的銅原子。當氧與血藍蛋白結合時,分子呈現獨特的透明乳白藍色。在某些具體實施例中,KLH蛋白是在人體中可有效產生免疫性且安全的。在某些具體實施例中,KLH可以藉由一系列通常包括硫酸銨沉澱和透析的步驟從鑰孔蟲戚的血淋巴純化,並且可能涉及層析純化以獲得最高的純度。在某些具體實施例中,KLH純化還可以包括內毒素移除,但此步驟可能是不必要的,因為當被注射用於產生抗體時,內毒素可以充當佐劑。較佳的是,帶有清澈乳白藍色的高品質KLH製劑是KLH溶解度的最佳指標。在某些具體實施例中,KLH單體單元聚集成總分子量約4,000 kDa至8,000 kDa的巨型多聚體(十聚體或二十聚體)。
在某些具體實施例中,較高的KLH多聚體具有約8-10百萬的分子量,具有約92-107S的沉降係數。存在的較高的KLH多聚體的量是基於沉降平衡及/或沉降速度超速離心分析。在其它具體實施例中,本發明的KLH表現出增強的免疫活性,具體而言是增強的抗腫瘤活性。可看到增強的免疫活性,例如但不限於(a)注射KLH(無佐劑),(b)KLH用作佐劑,(c)KLH用作半抗原的載體免疫原或弱免疫性抗原,及(d)KLH用作抗腫瘤劑。本發明的KLH組合物對許多腫瘤表現出增強的抗腫瘤活性,腫瘤包括但不限於膀胱、乳腺、卵巢腫瘤等。在某些具體實施例中,兩個KLH部分可以經由KLH單體之間的氫鍵或疏水相互作用形成二聚體。在某些具體實施例中,兩個或更多個KLH部分可以經由KLH單體、二聚體、三聚體等之間的氫鍵或疏水相互作用形成二聚體、三聚體、四聚體、五聚體、六聚體等。不受理論的限制,據信KLH部分之間的鍵結是通過氫鍵或疏水相互作用。
在某些具體實施例中,在Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分蛋白與KLH部分的共軛期間,KLH部分蛋白在某些具體實施例中與完整的分子相比顯現分子量降低,較佳是由於Globo系列抗原部分次單元的解離。在其它具體實施例中,本文揭露的共軛方法導致先前未報告的KLH次單元解離。雖然不希望受到任何特定理論的約束,但構想的是本發明的Globo系列抗原部分-KLH部分次單元共軛物的高醣基化含量導致Globo系列抗原部分之間形成氫鍵。因此,在某些具體實施例中,KLH部分次單元之間的凡得瓦力和疏水相互作用被Globo系列抗原氫鍵取代,而且此舉導致KLH部分次單元分離。共軛之後,Globo系列抗原部分-KLH部分共軛物的KLH部分次單元較佳聚集形成新穎的單體、二聚體、三聚體、四聚體、五聚體、六聚體或上述之任何組合,具有意想不到的大表位比值的所得。例示治療性Globo系列抗原部分-KLH部分共軛物具有令人驚奇和意想不到的優異免疫屬性。在某些具體實施例中,Globo系列抗原部分與KLH1和KLH2上的離胺酸共軛。在其它具體實施例中,Globo系列抗原部分不與KLH1和KLH2上的離胺酸共軛。
如本文中使用的,與本文揭露的治療性共軛物相關的「表位比值」是指例如治療性共軛物中抗原表位與載體分子的關係。較佳的是,「表位比值」是指Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分與KLH部分的關係。最佳的是,使用以下公式=(實際Globo系列抗原部分重量/Globo系列抗原部分分子量)/(實際KLH部分重量/KLH部分分子量)組合來計算治療共軛物的表位比值。表位比值可以由所屬技術領域中具有通常知識者輕易地決定。較佳的是,Globo系列抗原的重量例如藉由具有脈衝電流檢測的高性能陰離子交換層析(HPAEC-PAD)測定。
在某些說明性具體實施例中,本發明還包括以親和力特異性結合本文揭露的治療性共軛物的分離治療性抗體、以及其在增生性疾病的治療及/或診斷中的用途。
本文中使用的「抗體(antibody)」和「抗體(antibodies)」等詞(免疫球蛋白)包括由至少兩種完整抗體、人抗體、人源化抗體、駱駝鹿抗體、嵌合抗體、單鏈Fvs(scFv)、單鏈抗體、單域抗體、域抗體、Fab片段、F(ab’)2片段、展現所需生物活性的抗體片段、連接二硫化物的Fvs(sdFv)、及抗遺傳型(抗-Id)抗體(包括例如本發明抗體的抗-Id抗體)、胞內抗體、及上述任一者的表位結合片段形成的單株抗體(包括全長單株抗體)、多株抗體、多特異性抗體(例如雙特異性抗體)。具體而言,抗體包括免疫球蛋白分子和免疫球蛋白分子(即含有抗原結合位點的分子)的免疫活性片段。免疫球蛋白分子可以屬於任何類型(例如IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞類。
抗體對於本文所述的治療中使用的表位(例如治療性共軛物的Globo系列抗原(SSEA-4、Globo H或SSEA-3)部分)的「親和力」是所屬技術領域中很好理解的用語,並且意指抗體與表位結合的程度或強度。親和力可以以所屬技術領域中習知的多種方式量測及/或表現,包括但不限於平衡解離常數(KD或Kd)、表觀平衡解離常數(KD’或Kd’)及IC50
(在競爭試驗中達成50%抑制所需的量)。應當理解的是,為了本發明的目的,親和力是給定群體的、與表位結合的抗體的平均親和力。以mg IgG/mL或mg/mL記述的KD’值表示每毫升血清的毫克 Ig,雖然也可以使用血漿。當使用抗體親和力作為施用本文所述治療方法的基礎或本文所述治療方法的選擇時,可以在治療之前及/或治療期間量測抗體親和力,並且所獲得的值可被臨床醫生用於評估人類患者是否為治療的適當候選人。
本文中使用的「特異性結合」乙詞是指結合對(例如抗體與抗原)之間的相互作用。在各種情況下,特異性結合可以藉由至少或約10-6
莫耳/升、約10-7
莫耳/升、或約10-8
莫耳/升、或更小的親和常數來體現。
可以藉由收集被檢查所需抗體(例如血清)增加的免疫個體的體液、並藉由以任何傳統方法從血液中分離血清來製備對抗Globo系列抗原(SSEA-4、Globo H或SSEA-3)的例示性抗體。
通常藉由多次注射相關抗原和佐劑來增加抗體。將相關抗原與在待免疫物種中免疫的蛋白(例如鑰孔蟲戚血藍蛋白)共軛可能是有用的。
用抗原使動物免疫的方法是所屬技術領域中習知的。腹膜內注射或皮下注射抗原是使哺乳動物免疫的標準方法。更特定言之,可以將抗原稀釋並懸浮在適量的磷酸鹽緩衝鹽水(PBS)、生理鹽水等中。若需要的話,可將抗原懸浮液與適量的佐劑混合,然後投予個體。
在某些具體實施例中,可以藉由投予與適量佐劑混合的抗原幾次來增強個體,直到效價穩定。合適的載體也可用於免疫。如上所述進行免疫後,藉由增加所需抗體量的方法檢查血清。
疫苗可以包含碳水化合物抗原或其免疫性片段和佐劑。在又另一具體實施例中,疫苗包含碳水化合物抗原或其免疫性片段;載體蛋白和OBI-821佐劑。在另一具體實施例中,疫苗包含選自SSEA-4、KLH、及OBI-821佐劑的碳水化合物抗原。載體蛋白的非限制性實例包括KLH。
治療組合物可以包括其它抗癌/抗增生藥物以及佐劑和其它免疫調節分子,例如細胞介素或趨化介素。在某些具體實施例中,組合可以是單獨試劑/組合物或共同配方的共同投藥。此等試劑可以在套組中以分開的容器或單一容器一起遞送。
佐劑是修飾其他試劑的作用的藥理性或免疫性試劑。佐劑可以是增強對給定抗原的免疫反應的無機或有機化學物質、大分子或整個癌細胞或部分癌細胞。佐劑包括完全和不完全弗氏佐劑、類鐸受體分子及其模擬物、LPS、脂蛋白、脂肽、鞭毛蛋白、雙鏈RNA、未甲基化CpG位點、左旋咪唑、卡介苗、體抑素胜肽(octreotide)、異丙肌苷及日達仙、細菌和病毒經常釋放的各種形式DNA和RNA、PD-1拮抗劑及CTLA拮抗劑。在一具體實施例中,佐劑是皂素佐劑。
在某些具體實施例中,皂素佐劑是基本上純的OBI-821。在其它具體實施例中,OBI-821是其生物活性片段。佐劑也可以包括不純形式的OBI-821。當用本文所述的疫苗投藥或與其他基本上純的皂素或非皂素佐劑混合投藥時,純化的OBI-821表現出增強的佐劑效果。
OBI-821佐劑是天然存在的醣苷,藉由例如美國專利第5,057,540號和美國專利第6,524,584號(其內容以引用方式全部併入)中描述的高壓液相層析(HPLC)、低壓液相矽膠層析、及親水相互作用層析(HILIC)以高純度萃取自奎拉雅屬皂樹(Quillaja saponaria Molina)的樹皮。
OBI-821佐劑還可以包含式I的分離化合物,其中 (i)R1
為β-D-洋芹醣,R2
為上述脂肪醯基部分,R3
為H(1989化合物V1A); (ii)R1
為β-D-洋芹醣,R2
為H,R3
為上述脂肪醯基部分(1989化合物V1B); (iii)R1
為β-D-木醣,R2
為上述脂肪醯基部分,R3
為H(1989化合物V2A);或 (iv)R1
為β-D-木醣,R2
為H,R3
為上述脂肪醯基部分(1989化合物V2B)。 將1989化合物V1A、1989化合物V1B、1989化合物V2A及1989化合物V2B集體稱為「1989化合物混合物」。
OBI-821佐劑可以包含式I的分離化合物,其中: (i)R1
為H,R2
為上述脂肪醯基部分,R3
為H(1857化合物A); (ii)R1
為H,R2
為H,R3
為上述脂肪醯基部分(1857化合物B); 將1857化合物A和1857化合物B集體稱為「1857化合物混合物」。
OBI-821佐劑包含一種或更多種以下化合物: (i)1857化合物A; (ii)1857化合物B; (iii)1989化合物V1A; (vi)1989化合物V1B; (v)1989化合物V2A;或 (vi)1989化合物V2B。
1857化合物混合物和1989化合物混合物在OBI-821佐劑中的百分比可以具有如下的範圍: (i)約1莫耳%至約25莫耳%、包含1857化合物混合物的OBI-821;及 (ii)約75莫耳%至約99莫耳%、包含1989化合物混合物的OBI-821。
所有的莫耳%都可以有0.1%增量的變化(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化合物的混合物可以包含約60-75莫耳%的1989化合物V1A;約0-10莫耳%的1989化合物V1B;約25-40莫耳%的1989化合物V2A;及約0-10莫耳%的1989化合物V2B。所有的莫耳%都可以有0.1%增量的變化(例如65%、2.5%、35.6%)。
1857化合物混合物可以包含約90-100莫耳%的1857化合物A;約0-10莫耳%的1857化合物B。所有的莫耳%都可以有0.1%增量的變化(例如65%、2.5%、35.6%)。
在另一具體實施例中,從天然的奎拉雅樹皂樹萃取物中純化出實質上純的OBI-821,其中該OBI-821的特徵在於單一主峰,當在反相HPLC上、在具有5μm粒度、100 Å孔徑、4.6 mm IDx25cm L的Symmetry C18管柱上、以包含A:B為95%:5%至75%:25%的移動相的沖提程序分析11分鐘時,該單一主峰包含層析圖的所有峰的總面積的90%或更多,不包括溶劑峰,其中該移動相A為含有0.1%三氟乙酸的蒸餾水,移動相B為具有0.1%三氟乙酸的乙腈,流速為1 mL/min。
疫苗可以包含碳水化合物抗原或其免疫性片段和OBI-821佐劑。在另一具體實施例中,疫苗包含碳水化合物抗原或其免疫性片段;載體蛋白及OBI-821佐劑。在另一具體實施例中,疫苗包含選自SSEA-4、KLH及OBI-821佐劑的碳水化合物抗原。載體蛋白的非限制性實例包括KLH。
「α-半乳醣基-神經醯胺」和「α-GalCer」等詞是指刺激自然殺手T細胞以產生T輔助細胞1(TH1)和TH2細胞介素的醣類,如美國專利第8,268,969號(其內容以引用方式全部併入)中所述。在某些具體實施例中,OBI-834(也稱為C34)佐劑的特徵在於以下例示性結構:
本文中使用的「細胞介素」乙詞是指藉由影響免疫細胞分化過程來調節免疫反應的強度和持續時間的許多小分泌蛋白質中的任何一種,免疫細胞分化過程通常涉及前驅細胞藉以變成不同專用細胞類型的基因表現變化。根據推定的功能、分泌的細胞或作用的目標,細胞介素被不同地命名為淋巴介素、白血球介素及趨化介素。例如,一些常見的白血球介素包括但不限於IL-2、IL-12、IL-18、IL-2、IFN-γ、TNF、IL-4、IL-10、IL-13、IL- 21、GM-CSF及TGF-β。
本文中使用的「趨化介素」乙詞是指在感染位點釋放的各種小趨化性細胞介素中的任何一種,其提供用於移動和活化淋巴細胞的手段。趨化介素吸引白血球到感染位點。趨化介素具有保留的半胱胺酸殘基而允許其被分配成四組。具有代表性趨化介素的組是C-C趨化介素(RANTES、MCP-1、MIP-1α及MIP-1β)、C-X-C趨化介素(IL-8)、C趨化介素(Lymphotactin)、及CXXXC趨化介素(Fractalkine)。
本發明的治療組合物可進一步包括PD-1/PD-L1抑制劑(細胞毒性T淋巴細胞(CTL)免疫治療)、CTLA-4免疫治療、CDK4/6抑制劑(標靶治療)、PI3K抑制劑(標靶治療)、mTOR抑制劑(標靶治療)、AKT抑制劑(標靶治療)、Pan-Her抑制劑(標靶治療)。此等抑制劑也可以被修飾以產生相應的單株抗體。此類抗體可以被包括在本發明的治療組合物中。
治療組合物可以包括其它抗癌/抗增生或化學治療劑。在一些具體實施例中,此類試劑的實例可見於V.T. Devita和S. Hellman(編輯)的Cancer Principles and Practice of Oncology第6版(2001年2月15日),Lippincott Williams and Wilkins出版社。此類抗癌劑包括但不限於以下抗癌劑:激素治療劑(例如選擇性雌激素受體調節劑、雄激素受體調節劑)、單株抗體治療劑、化學治療劑、類視色素受體調節劑、細胞毒性/細胞增殖抑制劑、抗惡性腫瘤劑、抗增生劑、異戊烯基-蛋白轉移酶抑制劑、HMG-CoA還原酶抑制劑、氮芥、亞硝基脲、血管新生抑制劑(例如貝伐單抗)、細胞增生和存活信號途徑抑制劑、凋亡誘導劑、干擾細胞週期檢查點的試劑、干擾受體酪胺酸激酶(RTK)的試劑、哺乳動物雷帕黴素靶蛋白(mTOR)抑制劑、人類表皮生長因子受體2(HER2)抑制劑、表皮生長因子受體(EGFR)抑制劑、整合素阻斷劑、NSAIDs、PPAR致效劑、固有多抗藥性(MDR)抑制劑、抗嘔吐劑、可用於治療貧血的試劑、可用於治療嗜中性白血球減少症的藥劑、免疫增強藥物、雙磷酸鹽、芳香酶抑制劑、誘導腫瘤細胞末端分化的藥劑、γ-分泌酶抑制劑、癌症疫苗、及上述之任意組合。
治療組合物(本文中也稱為醫藥組合物)通常包括醫藥上可接受的載體。本文中使用的語言文字「醫藥上可接受的載體」包括與醫藥投予相容的溶劑、分散介質、包衣、抗細菌劑和抗真菌劑、等滲劑及吸收延遲劑及其類似物。也可以將補充的活性化合物併入組合物中。將醫藥組合物配製成與其預期的投藥途徑相容。投藥途徑的實例包括非口服,例如靜脈內、皮內、皮下、肌內、動脈內、口服(例如吸入)、透皮(局部)、經黏膜及直腸投藥。用於非口服、皮內或皮下施用的溶液或懸浮液可以包括以下組分:無菌稀釋劑,例如注射用水、鹽水溶液、磷酸鹽緩衝鹽水、三緩衝鹽水、固定油、聚乙二醇、甘油、丙二醇、或其他合成溶劑;抗細菌劑例如苯甲醇或對羥基苯甲酸甲酯;抗氧化劑例如抗壞血酸或亞硫酸氫鈉;螯合劑例如乙二胺四乙酸;緩衝劑例如乙酸鹽、檸檬酸鹽或磷酸鹽、以及用於調節張力的藥劑例如氯化鈉或葡萄醣。pH值可以用酸或鹼調節,例如鹽酸或氫氧化鈉。非口服製劑可以被封裝在安瓿、一次性注射器、或由玻璃或塑料製成的多劑量小瓶中。
適用於可注射用途的醫藥組合物包括無菌水溶液(為水溶性的)或分散液、以及用於臨時製備無菌可注射溶液或分散液的無菌粉末。對於靜脈內投藥來說,適當的載體包括生理食鹽水、抑菌水、Cremophor EL®(BASF, Parsippany, N.J.)、或磷酸鹽緩衝鹽水(PBS)。在所有情況下,組合物應是無菌的,而且應該是存在易注射的流體。組合物在製造和儲存的條件下應該是穩定的,並被以對抗微生物(例如細菌和真菌)污染作用的方式保存。載體可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇及液體聚乙二醇及其類似物)、及上述之適當混合物的溶劑或分散介質。例如,可以藉由使用諸如卵磷脂的塗層、藉由在分散的情況下維持所需的粒度、及藉由使用界面活性劑來維持合適的流動性。防止微生物作用可以藉由各種抗細菌和抗真菌劑(例如對羥苯甲酸酯、氯丁醇、苯酚、抗壞血酸、硫柳汞及其類似物)來實現。在許多情況下,在組合物中包括等滲劑(例如醣)、多元醇(例如甘露醇、山梨醣醇)、或氯化鈉將是較佳的。可以藉由在組合物中包括延遲吸收的試劑(例如單硬脂酸鋁和明膠)來實現可注射組合物的延長吸收。
無菌可注射溶液可以藉由將所需量的活性化合物摻入視需要具有以上列舉的成分之一者或組合的適當溶劑中、然後過濾滅菌來製備。通常,分散液是藉由將活性化合物摻入含有鹼性分散介質和來自以上列舉的所需其它成分的無菌媒液來製備。在用於製備無菌可注射溶液的無菌粉末的情況下,製備方法包括真空乾燥和冷凍乾燥,從而產生活性成分的粉末以及來自其先前的無菌過濾溶液的任何附加所需成分。
口服組合物通常包括惰性稀釋劑或可食載體。為了口服治療投藥的目的,可以將活性化合物與賦形劑摻合並以片劑、錠劑或膠囊劑(例如明膠膠囊)的形式使用。也可以使用流體載體製備口服組合物用來作為漱口藥。可以包括醫藥上相容的黏結劑或佐劑材料作為組合物的一部分。片劑、丸劑、膠囊劑、錠劑及其類似物可以含有任何以下成分或性質類似的化合物:黏結劑,例如微晶纖維素、黃蓍膠或明膠;賦形劑例如澱粉或乳醣;崩解劑例如藻酸、Primogel或玉米澱粉;潤滑劑例如硬脂酸鎂或sterotes;助滑劑例如膠體二氧化矽;甜味劑例如蔗醣或醣精;或調味劑,例如薄荷、水楊酸甲酯、或柳橙調味劑。
此外,對於口服投藥來說,本發明的製劑可以採用例如藉由傳統方法使用醫藥上可接受的賦形劑例如黏結劑(例如預膠化玉米澱粉、聚乙烯吡咯啶酮或羥丙基甲基纖維素);填充劑(例如乳醣、微晶纖維素或磷酸氫鈣);潤滑劑(例如硬脂酸鎂、滑石或二氧化矽);崩解劑(例如馬鈴薯澱粉或澱粉羥乙酸鈉);或潤濕劑(例如十二烷基硫酸鈉)製備的片劑或膠囊劑的形式。片劑可以藉由所屬技術領域中眾所周知的方法進行包衣。也可以將本發明的組合物引入微球或微膠囊中,例如以聚乙醇酸/乳酸(PGLA)製備(參見美國專利號5,814,344;5,100,669及4,849,222;PCT公開號WO 95/11010及WO 93/07861)。用於口服投藥的液體製劑可以採用例如溶液、醣漿、乳液或懸浮液的形式,或者可以作為乾燥產品呈現,以在使用前用水或其它適當的媒液重新配製。此類液體製劑可以藉由傳統方法使用醫藥上可接受的添加劑例如懸浮劑(例如山梨醣醇醣漿、纖維素衍生物或氫化食用脂肪);乳化劑(例如卵磷脂或阿拉伯膠);非水性媒液(例如杏仁油、油性酯、乙醇或分餾的植物油);及防腐劑(例如對羥基苯甲酸甲酯或丙酯、或山梨酸)製備。製劑也可以含有適當的緩衝鹽、調味劑、著色劑及甜味劑。可以適當地配製用於口服投藥的製劑以給予受控釋放的活性化合物。
對於吸入投藥,將化合物以氣溶膠噴霧的形式從含有適當推進劑(例如氣體,如二氧化碳)的壓力容器或分配器、或噴霧器遞送。
全身投藥也可以是經黏膜或透皮的。對於經黏膜或透皮的投藥,在製劑中使用適合滲透屏障的滲透劑。此類滲透劑通常是所屬技術領域中習知的,並且包括例如用於經黏膜投藥的洗滌劑、膽汁鹽及夫西地酸衍生物。經黏膜投藥可以通過使用鼻噴霧劑或栓劑來實現。對於透皮投藥,將活性化合物配製成所屬技術領域中一般習知的軟膏、油膏、凝膠或乳膏。化合物也可以以栓劑(例如使用傳統栓劑基質,如可可脂和其它甘油酯)或保留灌腸劑的形式製備用於直腸遞送。
根據實施方案,用載體製備活性化合物,載體將保護化合物免於從身體快速消失,例如受控釋放的製劑,包括植入物和微膠囊遞送系統。可以使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。用於製備此類製劑的方法將是所屬技術領域中具有通常知識者顯而易見的。這些材料也可以商購獲得。也可以使用脂質體懸浮液(包括用針對細胞特異性抗原的單株抗體標靶感染細胞的脂質體)作為醫藥上可接受的載體。此等可以根據所屬技術領域中具有通常知識者習知的方法製備,例如如美國專利號4,522,811(以引用方式併入本文中)中所述。
以劑量單位形式配製口服或非口服組合物以便於投藥和劑量一致是有利的。本文中使用的劑量單位形式是指適用於待治療個體的單位劑量的實體分離單位;每個單位皆含有預定量的活性化合物,計算該預定量以產生與所需醫藥載體相關聯的所需治療效果。
本發明的免疫性製劑可以非口服遞送,即藉由靜脈內(i.v.)、皮下(s.c.)、腹膜內(i.p.)、肌內(i.m.)、表皮下(s.d.)或皮內(i.d.)投藥、藉由直接注射、經由例如大丸藥注射、連續輸注、或基因槍(例如對個體投予載體疫苗,例如裸DNA或RNA)。用於注射的製劑可以以單位劑量的形式呈現,例如在安瓿或多劑量容器中,並加入防腐劑。組合物可以在油性或水性媒液中採用諸如賦形劑、懸浮液、溶液或乳液的形式,並且可以含有調配劑,例如懸浮劑、穩定劑及/或分散劑。或者,活性成分可以處於粉末的形式,以在使用前用適當的媒液(例如無菌無熱原的水)重新配製。
本發明還構思了各種黏膜疫苗接種策略。
劑量:此類治療組合物的毒性和治療功效可以藉由細胞培養物或實驗動物的標準醫藥程序來測定,例如用於測定LD50
(對群體的50%致命的劑量)和ED50
(在群體的50%中治療有效的劑量)。毒性與治療效果之間的劑量比為治療指數,可以表示為LD50
/ED50
的比率。表現出高治療指數的治療組合物是較佳的。儘管可以使用表現毒性副作用的化合物,但應小心設計將此類化合物標靶受影響位點的遞送系統,以盡可能減少對未感染細胞的潛在損傷,從而減少副作用。
從細胞培養試驗和動物研究獲得的數據可用於配製一個範圍的劑量用於人體。此等化合物的劑量較佳在一個範圍的循環濃度內,該範圍的循環濃度包括ED50
且具有極少或沒有毒性。劑量可以在該範圍內變化,取決於所用的劑型和使用的投藥途徑。對於本揭露的方法中使用的任何化合物來說,最初可以從細胞培養試驗估計治療有效劑量。可以在動物模型中配製劑量以實現循環血漿濃度範圍,該循環血漿濃度範圍包括在細胞培養物中測定的IC50
(即實現症狀的最大抑制的一半的測試化合物濃度)。可以使用此類資訊來更精確地決定人體中的有用劑量。血漿中的含量可以例如藉由高性能液相層析量測。
在揭露的組合物中,抗原及/或佐劑或任何其它相關成分均以免疫有效量存在。對於每種特異性抗原來說,最佳免疫有效量應以實驗測定(考量給定患者的特定特徵及/或治療類型)。通常,該量在0.01 μg-250 mg抗原的範圍內。對於本發明的某些例示性佐劑來說,免疫有效量可以在10-250 μg佐劑的範圍內。
在一些具體實施例中,治療組合物的治療有效量(即有效劑量)範圍可以從每公斤的患者體重約0.001 μg/kg至約250 g/kg、0.01μg/kg至10 g/kg、或0.1 μg/kg至1.0 g/kg或約或至少:0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009;0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09 ;0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8 、9 、10 、11 、12 、13 、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、125、150、175、200、225、或250克或微克、或本文列出的任何數值之間的任何範圍、或對技術人士來說無需過度實驗即可顯而易見且理解的其他範圍。具有通常知識的技術人士將理解,某些因素會影響有效治療個體所需的劑量和時間,包括但不限於疾病或病症的嚴重性、先前的治療、個體的一般健康或年齡、以及存在的其他疾病。
在其它具體實施例中,治療組合物中Globo系列部分的治療有效量(即有效劑量)範圍可以從每公斤的患者體重約0.001 μg/kg至約250 g/kg、0.01μg/kg至10 g/kg、或0.1 μg/kg至1.0 g/kg或約或至少:0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009;0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09;0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、125、150、175、200、225、或250克或微克、或本文列出的任何數值之間的任何範圍、或對技術人士來說無需過度實驗即可顯而易見且理解的其他範圍。具有通常知識的技術人士將理解,某些因素會影響有效治療個體所需的劑量和時間,包括但不限於疾病或病症的嚴重性、先前的治療、個體的一般健康或年齡、以及存在的其他疾病。在一具體實施例中,包含疫苗的醫藥上可接受載體的免疫有效量範圍係從約0.05 μg、0.1 μg、0.15 μg、0.2 μg、0.25 μg、0.3 μg、0.35 μg、0.4 μg、0.45 μg、0.5 μg、0.55 μg、0.6 μg、0.65 μg、0.7 μg、0.75 μg、0.8 μg、0.85 μg、0.9 μg、0.95 μg、1.0 μg、1.25 μg、1.5 μg、1.75 μg、2.0 μg、2.25 μg、2.5 μg、2.75 μg、3.0 μg、3.25 μg、3.5 μg、3.75 μg、4.0 μg、4.25 μg、4.5 μg、4.75 μg、至約5.0 mg、或本文列出的任何數之間的任何範圍。
在一些具體實施例中,將本發明的治療組合物以無惡化存活期或整體存活期比對控制組安慰劑(例如磷酸鹽緩衝鹽水安慰劑)平均延長約或至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50天、週、月或年的方法投予有需要的個體(例如患有諸如乳癌的癌症)。 實施例
將本發明的治療組合物的例示性SSEA-4六醣部分化學合成為烯丙基醣苷,然後製備用於與KLH或白喉毒素交叉反應性物質197(DT-CRM 197)共軛。
實施例1:本發明的例示性醣共軛物(SSEA-4-KLH和SSEA-4-DT)之製備
SSEA-4抗原製備:藉由加入10 mg SSEA-4-NH2
與在1.5 mL三乙胺(NEt3)中的5.0當量對硝基苯酯來製備例示性樣品。在30 ℃下反應1.5小時後,加入300 mL 1%乙酸終止反應。最後通過0.22 μm過濾器過濾並在0.1%乙酸中凍乾。
SSEA-4-KLH共軛:將凍乾的SSEA-4抗原溶於DMF中,並與pH 8.0的KLH(溶於磷酸鹽緩衝鹽水溶液,PBS)混合。在室溫下反應16小時後,藉由MAP-TFF系統純化SSEA-4-KLH混合物,並將儲存緩衝液從DMF換成PBS。
SSEA-4抗原製備:藉由加入10 mg SSEA-4-NH2
與在2 mL三乙胺(NEt3)中的5.0當量對硝基苯酯來製備例示性樣品。在30 ℃下反應1.5小時後,加入300 mL 1%乙酸終止反應。最後通過0.22 μm過濾器過濾並在0.1%乙酸中凍乾。
SSEA-4-DT共軛:將凍乾的SSEA-4抗原溶於DMF中,並與pH 9.5的白喉毒素交叉反應性物質197(DT-CRM 197)(溶於磷酸鹽緩衝鹽水溶液,PBS)混合。在室溫下反應20小時後,藉由MAP-TFF系統純化SSEA-4-DT混合物,並將儲存緩衝液從DMF換成PBS。將SSEA-4-DT和SSEA-4-KLH組合物的總結顯示在表3中。
實施例2:本發明的醣共軛物(SSEA-4-MCCa-KLH、Globo H-MCCa-KLH及SSEA-3-MCCa-KLH)之製備
1. 製備例示性醣-MCCa化合物之一般程序
在環境溫度下將胺基質(Globo H-戊胺、SSEA-3-戊胺、或SSEA-4-戊胺)、MCCa-OSu及DIPEA在DMF中混合。將反應粗產物攪拌2小時。反應完成後藉由TLC評估、監測、然後將反應冷卻、中和、並用水終止反應。隨後將所得混合物加到RP-18凝膠墊上以進行純化。在通過RP-18凝膠進行層析純化之後,藉由旋轉蒸發器和高真空系統濃縮收集的分餾物,得到預期的醣-MCCa化合物,為白色固體。產率約65〜80%。SSEA-4-MCCa之製備Globo H-MCCa之製備SSEA-3-MCCa之製備
2. 製備例示性醣-MCCa-KLH共軛產物之一般程序
將經化學修飾成的KLH中間體,然後與醣-MCCa共軛,以在低氧含量的環境中提供粗醣-MCCa-KLH共軛產物。
步驟1. KLH之硫醇化 用惰性氣體充入緩衝液交換的KLH。置換後,在惰性氣體保護下將2-亞胺基硫烷鹽酸鹽(2-IT)加到KLH中。將反應在18 ℃下攪拌35分鐘。攪拌35分鐘後,將反應粗產物快速裝載到準備好的G-15管柱上進行管柱層析純化。對收集的純化物進行取樣,並以BCA和Ellman測試以確認產物。很快地對收集的蛋白質中間體修飾的KLH取樣,用於Ellman試驗和BCA試驗以測定SH值和蛋白質含量。將PBS緩衝液加入收集的經修飾KLH中以將蛋白質的濃度調節至約0.6〜1.0 mg/mL。
步驟2.中間體之共軛 將製備的中間體化合物(醣-MCCa)溶於PBS緩衝液中。將該中間體依序轉移到經修飾的KLH反應瓶中。加入PBS緩衝溶液來沖洗醣瓶,隨後將此溶液轉移到共軛反應中。混合後,在前半小時和隨後的1小時、1.5小時、2小時、及3小時對反應粗產物取樣,以監測#SH值。當#SH值低於200時,將醣-MCCa-KLH共軛物儲存在冷藏室中用於下一個操作階段。
步驟3.純化以提供預期的醣-MCCa-KLH共軛產物 藉由TFF系統過濾或使用pH 7.2 PBS離心10倍體積來純化醣-MCCa-KLH粗產物。收集濾液並取樣用於HPLC分析。將純化的醣-MCCa-KLH暫時儲存在冷藏室中用於進一步的測試。SSEA-4-MCCa-KLH共軛物之製備Globo H-MCCa-KLH共軛物之製備SSEA-3-MCCa-KLH共軛物之製備
實施例3:例示性Globo系列抗原(SSEA-4、Globo H及SSEA-3)與醣共軛物中的KLH之表位比值分析
KLH二十聚體(天然聚集形式)的分子量約為7.5 MDa至8.6 MDa。確認天然KLH的分子量約為8.6 MDa。
使用多角度雷射散射光譜儀(SEC-MALS)藉由分子篩層析評估和推導KLH和Globo系列抗原-KLH醣共軛物(SSEA-4-MCCa-KLH、Globo H-MCCa-KLH及SSEA-3-MCCa-KLH)的質量分佈。在圖1A中,觀察到KLH的多聚體(n> 7-20)和寡聚體(n> 20)。圖1B顯示二十聚體的峰面積為78.48%,多十聚體的峰面積為20.31%。KLH的平均觀察分子量(MW)為7476 kDa。圖2A顯示四聚體(n = 3)是SSEA-4-MCCa-KLH醣共軛物的主要成分(58.7%)。類似地,圖2B(Globo H-MCCa-KLH醣共軛物)和圖2C(SSEA-3-MCCa-KLH醣共軛物)也顯示四聚體(n = 3)是Globo H-MCCa-KLH醣共軛物(58.9%)和SSEA-3-MCCa-KLH醣共軛物(61.3%)中的主要成分。Globo系列抗原共軛的KLH疫苗的總結如表4所示。
實施例4:用於小鼠免疫的例示性Globo系列抗原醣共軛物疫苗之製備
從BioLasco獲得6至8週齡的雌性C57BL/6小鼠,並分別在Level Biotech Inc.和Eurofins Panlabs進行單價、二價或三價疫苗效力試驗的研究。在投藥前至少一天,基於體重藉由隨機化方法將動物選入研究組,每組包含五隻小鼠。
之後,在第0天、第7天、第14天、第21天(使用20 mg OBI-821佐劑)或第0天、第14天、第28天(使用40 mg OBI-834佐劑)將Globo系列抗原醣共軛物(Globo H-KLH、SSEA-3-KLH、SSEA-4-KLH/DT)和佐劑(OBI-821或OBI-834)皮下(s.c.)投入小鼠的左腹和右腹位點(0.5-5 mg;100 mL/位點)。在研究期間(使用OBI-821佐劑)在以下時間點收集全血樣品:預免疫(第0天,投藥前)、第10天、第17天、第24天、及第31天。在研究期間將經由頜下收集採集血液樣品,並在最後時間點第43天採血時使用心臟穿刺。對於OBI-834佐劑,將在免疫前(第0天,投藥前)、第21天、第28天、第38天、及第50天收集全血樣品。在未添加抗凝血劑之下收集血液,並在4 ℃下以1,500 g進行血清離心15分鐘。將所得血清樣品轉移到樣品採集管中,並儲存在低於-60至-80 ℃用於隨後藉由聚醣陣列試驗測定的效力試驗。
實施例5:聚醣陣列試驗
本揭露的例示性測試平台使用在微流匣內進行自動ELISA反應的Agnitio BioIC系統(分析儀BA-G2012、Cat# A12101)和泵送機(Pumping Machine BA-G2012,Cat# A15101)。每個匣皆包含一組微流體泵和閥、通道網絡、試劑儲存庫、聚醣陣列反應區、及廢物儲存庫。為了進行測試,將所有試劑和測試樣品依序從它們的個別儲庫泵送到包含聚醣陣列的反應區中以進行具有化學發光的多重ELISA反應。同時獲取結果數據,並藉由Agnitio Science and Technology Inc.提供的LabIT軟體進行數據分析。在PCT專利申請(WO2017041027A1)中報告了依據本揭露適當設置的Agnitio BioIC系統的設備規格。
例示性實驗材料: 1.樣品稀釋劑(BioCheck,Cat# MB10175)。 2. OBI-868聚醣晶片套組(Agnitio,Cat#MG03-IgG,MM03-IgM),具有聚醣晶片、阻斷緩衝液(無蛋白質封閉緩衝液,Thermo Fisher Scientific Inc.,Cat#37571)、共軛緩衝液、洗滌緩衝液[磷酸鹽緩衝鹽水(Thermo Fisher Scientific Inc.,Cat#70011)加上0.2%(vol/vol)Tween 20(J.T. Baker,Cat#JTB-X251-07)]、基質緩衝液(A)和基質緩衝液(B) [SuperSignal ELISA Femto Maximum Sensitivity Substrate,Thermo Fisher Scientific Inc.,Cat#37074]。分別用SSEA-4、SSEA-3或Globo H塗覆聚醣晶片。 3.二級抗體:山羊抗小鼠IgG-HRP(KPL,Cat#474-1806)或山羊抗小鼠IgM-HRP(KPL,Cat#074-1803)。
試劑製備: 1.對於每個血清/血漿樣品,藉由將2.5 μL樣品添加到247.5 μL的樣品稀釋液中來製備100倍稀釋液,充分混合。(樣品稀釋倍數:50x、100x、200x、300x、1,000x及10,000x)。假使任一抗Globo系列IgG/IgM平均強度超過內標曲線的最高點,則準備1,000倍及/或10,000倍的稀釋樣品。 2.二級抗體溶液:使用如下表所列的共軛緩衝液準備二級抗體的連續稀釋液。在每次添加/稀釋之間充分混合樣品。 表5:二級抗體溶液製備
3.基質準備:對於每個切片,用等量65 μL的兩種基質緩衝液(A)和(B)充分混合。混合基質應在每次測試前新鮮準備。
試驗程序:將620 μL的洗滌緩衝液加到聚醣陣列的「洗滌」孔中。接著,在聚醣陣列的「阻塞」孔中加入120 μL的阻塞緩衝液。此時,分別在聚醣陣列的「共軛」和「血清」孔中加入120 μL的二級抗體溶液和100 μL的血清。最後,在10分鐘內在聚醣陣列的「基質」孔中加入120 μL的混合基質緩衝液。將聚醣陣列放在Agnitio BioIC泵送機上加壓30分鐘。使用Agnitio BioIC分析儀可視化監測結合的血清。
藉由以下步驟進行數據分析: 1.藉由在Y軸上繪製每個IgG/IgM濃度獲得的平均強度並在X軸上繪製總IgG/IgM濃度(μg/mL)來產生內部曲線。內部曲線R2
必須>0.95。 2.計算每組內部曲線和切片的抗Globo系列IgG/IgM(抗SSEA-4、抗SSEA-3或抗Globo H)的平均強度。抗Globo系列IgG/IgM的平均強度不得超過內部曲線的最高點。 3.使用Microsoft Excel®
或等效應用程序,藉由將量測強度(Y軸)插入內部曲線中來計算未知樣品中的抗體強度。 4.對於稀釋樣品,藉由將濃度乘以稀釋倍數進行補償,以獲得樣品中的實際IgG/IgM濃度。 5.藉由以下公式計算和記述相對IgG/IgM濃度: 相對IgG/IgM濃度(μg/mL)=計算的IgG/IgM濃度´0.1
結果
1.單價疫苗效力試驗(SSEA-4-KLH或SSEA-4-DT與OBI-821或OBI-834佐劑組合)
如圖3所示,用SSEA-4-KLH疫苗+ OBI-821佐劑(圖3A)和SSEA-4-DT疫苗+ OBI-821佐劑(圖3B)處理的小鼠分別以三種不同的例示性代表疫苗劑量(0.05 mg、0.5 mg及5 mg)在第10天以抗SSEA-4 IgM含量作出反應。抗SSEA-4 IgM含量從第10天到第43天維持彼等含量。然而,SSEA-4-DT疫苗的抗SSEA-4 IgM含量低於SSEA-4-KLH疫苗。 類似地,SSEA-4-DT疫苗的抗SSEA-4 IgG含量低於SSEA-4-KLH疫苗(如圖3C和圖3D所示)。表示KLH是比DT更好的載體蛋白,可以誘導更多的抗體反應。
如圖4所示,用SSEA-4-KLH疫苗+ OBI-834佐劑(圖4A)和SSEA-4-DT疫苗+ OBI-834佐劑(圖4B)處理的小鼠分別以三種不同的例示性代表疫苗劑量(0.05 mg、0.5 mg及5 mg)在第21天以抗SSEA-4 IgM含量作出反應。抗SSEA-4 IgM含量從第21天到第50天維持彼等含量。然而,SSEA-4-DT疫苗的抗SSEA-4 IgM含量低於SSEA-4-KLH疫苗。 類似地,SSEA-4-DT疫苗的抗SSEA-4 IgG含量低於SSEA-4-KLH疫苗(如圖4C和圖4D所示)。表示KLH是比DT更好的載體蛋白,可以誘導更多的抗體反應。
2.代表性雙價疫苗效力試驗(SSEA-4-KLH + Globo H-KLH與OBI-821佐劑組合)展現功效
根據先前的結果,我們選擇KLH和OBI-821進行以下實驗。如圖5所示,用SSEA-4-KLH疫苗+ OBI-821佐劑處理的小鼠分別在第10天以抗Globo H(圖5A)、抗SSEA-3(圖5B)及抗SSEA-4(圖5C)IgM含量作出反應並從第10天到第43天維持彼等含量。類似地,用SSEA-4-KLH疫苗+ OBI-821佐劑處理的小鼠分別在第10天以抗Globo H(圖5D)、抗SSEA-3(圖5E)及抗SSEA-4(圖5F)IgG含量作出反應並從第10天到第43天維持彼等含量。
3.代表性三價疫苗效力試驗(SSEA-4-KLH + Globo H-KLH + SSEA-3-KLH與OBI-821佐劑組合)展現功效
最後,我們建立了三價疫苗(SSEA-4-KLH + Globo H-KLH + SSEA-3-KLH)用於以下試驗。如圖6所示,用三價疫苗+ OBI-821佐劑處理的小鼠在第10天以抗Globo H(圖6A)和抗SSEA-4(圖6B)IgM含量作出反應。類似地,用三價疫苗+ OBI-821佐劑處理的小鼠在第10天以抗Globo H(圖6C)和抗SSEA-4(圖6D)IgG含量作出反應。這些陽性結果表示單價或多價疫苗在Globo系列抗原(Globo H、SSEA-3及SSEA-4)中的免疫性。
除非另有定義,否則本文中使用的所有技術和科學用語以及任何縮寫字皆具有與本發明所屬技術領域中具有通常知識者通常理解的相同的含義。儘管可以使用任何組合物、方法、套組、及與本文所述者類似或等同的通訊手段來實施本發明,但較佳的組合物、方法、套組、及通訊手段已在本文中描述。
本文中引用的所有參考文獻皆在法律允許的範圍內以引用方式併入本文中。對彼等參考文獻的討論只是為了總結其作者所做的結論。不承認任何參考文獻(或任何參考文獻的一部分)與現有技術相關。申請人保留質疑任何引用參考文獻的準確性和適當性的權利。
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當結合隨後的實施方式考量時,可以參照附圖來獲得更完整的、對本發明的理解。圖式中圖示的具體實施例僅意在舉例說明本發明,不應被解讀為將本發明限制於圖示的具體實施例。
圖1A顯示使用多角度雷射散射光譜法(MALS)作為偵測器所進行的KLH之分子篩層析(Size exclusion chromatography)結果。圖1B顯示使用SEC-MALS的KLH質量分佈分析。
圖2顯示使用SEC-MALS的SSEA-4-KLH醣共軛物(圖2A)、Globo H-KLH醣共軛物(圖2B)、及SSEA-3-KLH醣共軛物(圖2C)之質量分佈分析。
圖3A和圖3B顯示使用OBI-821佐劑的不同劑量SSEA-4-KLH和SSEA-4-DT單價疫苗所誘導的五隻個別小鼠的抗SSEA-4 IgM含量和中值濃度之結果。圖3C和圖3D顯示使用OBI-821佐劑的不同劑量SSEA-4-KLH和SSEA-4-DT單價疫苗誘導的抗SSEA-4 IgG含量之結果。
圖4A和圖4B顯示使用OBI-834佐劑的不同劑量SSEA-4-KLH和SSEA-4-DT單價疫苗所誘導的五隻個別小鼠的抗SSEA-4 IgM含量和中值濃度之結果。圖4C和圖4D顯示使用OBI-834佐劑的不同劑量SSEA-4-KLH和SSEA-4-DT單價疫苗誘導的抗SSEA-4 IgG含量之結果。
圖5顯示使用OBI-821佐劑的雙價疫苗(SSEA-4-KLH與Globo H-KLH醣共軛物組合)誘導的免疫性結果。圖5A顯示抗Globo H IgM含量的結果,圖5B顯示抗SSEA-3 IgM含量的結果,圖5C顯示抗SSEA-4 IgM含量的結果。圖5D顯示抗Globo H IgG含量的結果,圖5E顯示抗SSEA-3 IgG含量的結果,圖5F顯示抗SSEA-4 IgG含量的結果。
圖6顯示使用OBI-821佐劑的三價疫苗(SSEA-4-KLH + Globo H-KLH + SSEA-3-KLH醣共軛物)誘導的免疫性結果。圖6A顯示抗Globo H IgM含量的結果,圖6B顯示抗SSEA-4 IgM含量的結果。圖6C顯示抗Globo H IgG含量的結果,圖6D顯示抗SSEA-4 IgG含量的結果。
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Claims (17)
- 如請求項1之醫藥組合物,其中該一或多種醣共軛物為具有所示SSEA4-MCCa-KLH的結構的醣共軛物。
- 如請求項1之醫藥組合物,其中該一或多種醣共軛物為具有所示SSEA3-MCCa-KLH的結構的醣共軛物。
- 如請求項1之醫藥組合物,其中該一或多種醣共軛物為具有所示的SSEA4-MCCa-KLH的結構的醣共軛物以及具有所示的SSEA3-MCCa-KLH的結構的醣共軛物。
- 一種如請求項1至8中任一項的醫藥組合物的用途,其用於製備用於治療或診斷用途的單株抗體。
- 一種如請求項1至8中任一項的醫藥組合物之用途,其用於製備治療癌症的藥物。
- 如請求項10之用途,其中該癌症為肉瘤、皮膚癌、白血病、淋巴瘤、腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰臟癌、直腸癌、腎癌、子宮頸癌、卵巢癌或前列腺癌。
- 如請求項10之用途,其中該癌症為一Globo系列抗原表現癌症。
- 如請求項12之用途,其中該Globo系列抗原為SSEA-4、Globo H或SSEA-3。
- 一種如請求項1至8中任一項的醫藥組合物之用途,其用於製備在個體體內誘導或增強免疫反應的藥物。
- 如請求項14之用途,其中該藥物結合包含Globo系列抗原(Globo H、SSEA-3、SSEA-4)的其它組合物。
- 如請求項14之用途,其中該個體為人。
- 如請求項14之用途,其中該藥物的有效量為0.01μg至250mg。
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EP3490592A1 (en) | 2019-06-05 |
BR112019001656A2 (pt) | 2019-05-28 |
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JP2019527690A (ja) | 2019-10-03 |
US11642400B2 (en) | 2023-05-09 |
CN110072545A (zh) | 2019-07-30 |
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CA3032049C (en) | 2023-11-07 |
AU2017302038B2 (en) | 2024-03-21 |
JP2022153505A (ja) | 2022-10-12 |
AU2017302038A1 (en) | 2019-02-14 |
WO2018022933A1 (en) | 2018-02-01 |
CA3032049A1 (en) | 2018-02-01 |
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