TWI697333B - 經由Globo系列抗原之免疫活化或免疫調節之癌症免疫療法 - Google Patents
經由Globo系列抗原之免疫活化或免疫調節之癌症免疫療法 Download PDFInfo
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Abstract
本發明提供了一種針對癌症患者的免疫治療方法,包含投予Globo系列抗原(即,Globo H、階段特異性胚胎抗原3「SSEA3」以及階段特異性胚胎抗原4「SSEA4」)的疫苗。具體而言,該方法包含在轉移性乳癌患者中投予Globo H-KLH (OBI-822)。本發明亦提供一種方法,其包含選擇適合作為免疫治療的治療候選人的癌症患者。此外,本發明提供治療藥劑,包括特異性結合Globo系列抗原的單株抗體(mAb)以及可用於聚焦此種治療及診斷方案的相關生物標記。
Description
本發明涉及癌症患者的免疫治療方法,包含對該患者投予Globo系列抗原的疫苗。
碳水化合物抗原Globo H (Fucα1→2 Galβ1→3 GalNAcβ1→3 Galα1→4 Galβ1→4 Glc)首次被分離作為神經醯胺連接的醣類,並於1984年由Hakomori等人自乳癌MCF-7細胞中所鑑定出來。(Bremer E G等人,(1984年) J Biol Chem 259: 14773-14777)。Globo H的單株抗體進行的進一步研究顯示,Globo H存在於許多其他癌症中,包括***癌、胃癌、胰臟癌、肺癌、卵巢癌以及直腸癌,且在正常分泌組織的腔表面上只有小量表現,其不容易進入免疫系統。(Ragupathi G等人(1997年) Angew Chem Int Ed 36: 125-128)。此外,已經確定乳癌患者的血清含有高量的抗Globo H抗體。(Gilewski T等人(2001年)Proc Natl Acad Sci USA 98: 3270-3275;Huang C-Y等人(2006年) Proc Natl Acad Sci USA 103: 15-20;Wang CC等人(2008年) Proc Natl Acad Sci USA 105(33): 11661-11666)。與Globo H陰性腫瘤患者相比,Globo H陽性腫瘤患者的存活期較短。(Chang, Y-J等人(2007年) Proc Natl Acad Sci USA 104(25): 10299-10304)。這些發現使得Globo H,一種六醣抗原表位,成為一種有吸引力的腫瘤標記及癌症疫苗開發的可行標的。
本發明的各方面及具體實施例提供了透過免疫療法治療患有癌症的個體之方法,包含對有需要的個體投予以Globo系列抗原為標的之免疫原性藥劑(例如OBI-822),其係有助於誘導/調節免疫反應(IgG及/或IgM),該方法包含透過調節Globo系列抗原交互作用以改善存活期(包括總體存活期及/或無惡化存活期),從而改善個體的存活期。在一方面,以Globo系列抗原為標的之免疫原性藥劑為,例如OBI-822。請參考我們先前的PCT專利申請案(公開號:WO2015159118A2以及WO2016044326A1)。這些申請公開內容涵蓋了包括Globo H-KLH醣共軛物(OBI-822)及/或治療性佐劑(OBI-821/OBI-834)的免疫原性/治療組合物,以及製備及使用它們來治療增殖性疾病如癌症的方法。部分設想治療組合物作為癌症疫苗,以通過免疫系統增強身體的自然保護能力,避免由受損或異常細胞如癌細胞所引起的危險。
在一具體實施例中,該免疫原性藥劑可包括OBI-822與相關變體。
在某些具體實施例中,該免疫反應可以包括:針對Globo H系列抗原/腫瘤的IgG (包括IgG1、IgG2、IgG3、IgG4亞型)、IgM、CTL (細胞毒性淋巴細胞)。
在某些具體實施例中,臨床上有意義的益處可以包括以下調節:無惡化存活期;總體存活期;(良好的耐受性及/或沒有重大安全問題);客觀反應率;惡化時間;無疾病存活期;腫瘤反應;生活品質的改善;固態腫瘤大小的減少及/或腫瘤相關抗原的減少(主要或包括Globo H)。
在某些方面,投予方案可以包括:投予二次或更多次疫苗(例如,3、4、5、6、7、8、9、10次或更多次);調整在二次連續投予之間的時間間隔及/或劑量方案;調整投予途徑及/或更改/交替投予的注射部位/投予位置或任何上述之任何組合,由此每次投予增加該免疫反應[例如,效價 - IgG及/或IgM 抗體量,及/或增加親和力/結合性;誘導抗體較少對該Globo H抗原-共軛物的Globo H部分的免疫原性部位共軛(例如,在該共軛物中可能較不易接近的Globo H抗原的部分)]。在某些方面,注射可以透過增加免疫反應增強劑來改變及/或補充。
於某些方面,Globo系列抗原交互作用的調節可以包括:以多次接種疫苗誘導具有增加親和力的抗Globo H抗體;B細胞增殖中心擴增至Globo H系列腫瘤抗原;含有高親和力抗Globo H抗體的增殖中心的優先擴增;誘導通常不存在足夠數量的B細胞以產生具有單次(或低重複暴露於抗原)的有意義的反應(例如,它們可能與幾個抗體結合的抗原表位結合);抗體分泌漿細胞(「抗體分泌漿細胞」為B細胞分化而成的)以及對於長期維持抗腫瘤反應可能是重要的記憶B細胞的擴增;增加抗體類轉換的動力學[需要良好的T細胞輔助功能或B細胞不會轉換為IgG];增加抗體反應的動力學(例如,連續的接種可能導致抗體較快速擴增,相較於沒有結合至KLH、沒有與環磷醯胺共同投予,及/或沒有重複接種所得的抗體更快的擴增);減少干擾發育的調節性T細胞活性並維持上述抗腫瘤反應;誘導用於殺傷腫瘤的抗體依賴性細胞毒性(Antibody-Dependent Cellular Cytotoxic,ADCC)以及補體依賴性細胞毒性(Complement-Dependent Cytotoxicity,CDC);誘導抗Globo系列抗原IgM/IgG免疫反應以引發CDC及ADCC調節的腫瘤細胞殺傷;誘導抗Globo系列抗原的抗體捕捉從腫瘤細胞流出的Globo系列抗原-神經醯胺以阻斷轉位蛋白相關因子X (translin-associated factor X,TRAX)依賴性血管生成;誘導抗Globo系列抗原的抗體以阻斷Globo系列抗原-神經醯胺誘導的Notch 1依賴性免疫抑制,從而增強T細胞的增殖及細胞激素的產生;誘導抗Globo系列抗原的抗體以導致細胞凋亡;抑制Globo系列抗原誘導的血管生成;OBI-822疫苗接種誘導細胞凋亡;誘導CTLs (細胞毒性淋巴細胞)。
本發明係關於患有例如癌症或感染性疾病的個體的免疫治療方法,該方法包含對該個體投予包含一治療有效量的增強內源性免疫反應的化合物或藥劑之組合物以刺激內源性反應的活化或抑制內源性反應的抑制作用。更具體而言,本發明提供了在患有癌症的個體內增強內源性免疫反應的方法,從而治療該患者,該方法包含對該個體投予一治療有效量的免疫原性藥劑。
定義:
「投予」如本文所用,投予方案的具體實施例可以包括以下特徵:1) 投予二次或更多次疫苗(例如,3、4、5、6、7、8、9、10次或更多次);2) 每次投予增加免疫反應(見上文)[效價 - IgG及/或IgM抗體量,及/或增加親和力/結合性;誘導抗體較少對該Globo H抗原-共軛物的Globo H部分的免疫原性部位結合(例如,在該共軛物中可能較不易接近的Globo H抗原的部分)]。
如本文所用,「治療」係指試圖改變被治療的個體或細胞的自然過程的臨床干預,並且可以在預防或在臨床病理過程中進行。治療的期望效果包括預防疾病的發生或復發、症狀緩解、減輕疾病的任何直接或間接的病理後果,預防或減少炎症及/或組織/器官損害、降低疾病進展速度、改善或緩解疾病狀態、緩解或改善預後。於一些具體實施例中,本發明的抗體用於延緩疾病或病症的發展。
「有效量」係指在達到期望的治療或預防結果所需之劑量及時間期間內之有效的量。
本發明的物質/分子的「治療有效量」可以根據個體的疾病狀態、年齡、性別,以及體重等因素,以及物質/分子的能力而定,以引起在該個體內所希望的反應。治療有效量也是該物質/分子的治療有益效果超過任何有毒或有害效果的量。「預防有效量」係指在達到期望的預防結果所需的劑量及時間期間內有效的量。通常但非必需的,因為在疾病發生前或疾病早期時在個體中使用預防劑量,所以預防有效量將小於治療有效量。
「不良事件」(Adverse Event,AE)毒性將根據美國國家癌症研究所癌症治療評估計劃所開發的美國NCI常見毒性標準第4版進行測量。無法接受的毒性的標準應包括任何≥4級毒性,除了局部皮膚反應、發燒、寒冷、出汗、蕁麻疹,及/或瘙癢症,因為這些是抗體/佐劑投予常見的副作用是可逆的,且可透過支持性處理來控制。理論上可以發生皮膚、關節、腎臟或其他表徵的免疫複合疾病,但是在沒有接觸小鼠蛋白質的情況下,這些應該是罕見的。這些將表示在受影響的個體中停止治療,但新個體的累積可能繼續。不良事件係指個體從隨機分組之日起及自隨機分組至多二年的持續追蹤期間所經歷的任何身體或臨床變化或疾病,無論是否考慮與試驗藥物的使用相關。這包括新疾病的發病以及預先存在的疾病的惡化。對於在治療期間退出治療的個體,應在最後一次投予試驗藥物(OBI-822/OBI-821或控制組)後28天期間記錄不良事件。
「抗體」(Ab)、「抗體群」(Abs)以及「免疫球蛋白」(Igs)為具有相同結構特徵的醣蛋白。雖然抗體對特異性抗原顯示結合特異性,但免疫球蛋白包括抗體以及通常缺乏抗原特異性的其他類抗體分子。後一種的多胜肽為,例如,由淋巴系統以較低量產生,並透過骨髓瘤增加含量。「抗體」及「免疫球蛋白」等詞在最廣泛的意義上可互換使用,並且包括單株抗體(例如,全長或完整的單株抗體)、多株抗體、單價、多價抗體、多特異性抗體(例如,雙特異性抗體,只要它們表現出所需的生物活性)並且還可以包括某些抗體片段(如本文更詳細描述的)。抗體可以是嵌合的、人類的、人源化的,及/或親和力成熟的。
「可變」及「互補決定區」( Complementarity Determining Regions,CDR)
「可變」乙詞係指可變區的某些部分在抗體之間的序列廣泛不同,並且用於每種特定抗體對於其特定抗原的結合及特異性。然而,變異性不均勻分佈在抗體的整個可變域中。它集中在輕鏈及重鏈可變區中稱為互補決定區(CDR)或高變區的三個區段。可變區的較保守部分被稱為框架(framework,FR)。天然重鏈及輕鏈的可變區各自包含四個FR區,主要採用由三個CDR連接的β-折疊構型,其形成環連接,並且於某些情況下形成β-片狀結構的一部分。每個鏈中的CDRs被FR區域緊密地保持在一起,且來自另一個鏈的CDRs有助於抗體的抗原結合位點的形成(參見Kabat等人,Sequences of Proteins of Immunological Interest,第五版,National Institute of Health,Bethesda,Md. (1991年))。恆定區不直接涉及抗體與抗原的結合,而是表現出各種效應子功能,例如抗體參與抗體依賴性細胞毒性。木瓜蛋白酶分解的抗體產生兩個相同的抗原結合片段,稱為「Fab」片段,每個具有單個抗原結合位點及殘留的「Fc」片段,其名稱反映其容易結晶的能力。胃蛋白酶處理產生具有兩個抗原結合位點並且還能夠交聯抗原的F(ab')2片段。
「Fv」為含有完整的抗原識別及結合位點的最小抗體片段。在雙鏈Fv物種中,該區域由緊密、非共價締合的一個重鏈以及一個輕鏈可變區的二聚體組成。在單鏈Fv物質中,一個重鏈及一個輕鏈可變區可以通過彈性胜肽連接子共價連接,使得輕鏈及重鏈可以類似於在雙鏈的Fv物種中的「二聚」結構締合。在這種配置中,每個可變區的三個CDR交互作用以限定VH-VL二聚體表面上的抗原結合位點。總共六個CDR賦予抗體抗原結合特異性。然而,即使以比整個結合位點低的親和力,甚至單個可變區(或僅包含針對抗原特異性的三個CDR的Fv的一半)仍具有識別及結合抗原的能力。
Fab片段還包含輕鏈的恆定區及重鏈的第一恆定區(CH1)。Fab'片段不同於Fab片段,通過在重鏈CH1區的羧基端添加少量殘基,包括來自抗體鉸鏈區的一個或多個半胱胺酸。Fab'-SH在本文中係指Fab',其中恆定區的半胱胺酸殘基具有游離巰基。F(ab')2抗體片段最初產生作為成對的Fab'片段,它們之間具有鉸鏈半胱胺酸。
基於其恆定區的胺基酸序列,來自任何脊椎動物物種的抗體(免疫球蛋白)的「輕鏈」可以分配為兩種明顯不同的類型之一,稱為kappa (κ)及lambda (λ)。
根據其重鏈的恆定區的胺基酸序列,可以將抗體(免疫球蛋白)分配給不同的類別。免疫球蛋白有五種主要類型:IgA、IgD、IgE、IgG,以及IgM,其中幾種可進一步分為亞型(同種型),例如IgG1、IgG2、IgG3、IgG4、IgA1,以及IgA2。對應於不同類別的免疫球蛋白的重鏈恆定區分別稱為α、δ、ε、γ,以及μ。不同類別的免疫球蛋白的亞型結構及三維構型是公知的,一般描述於例如Abbas等人所著Cellular and Mol. Immunology,第四版 (2000年)。抗體可以是通過抗體與一種或多種其它蛋白質或胜肽的共價或非共價締合形成的較大融合分子的一部分。
如本文所用,「分離的抗體」可以包括已經辨認出並從其天然環境的組分中分離及/或回收的「分離的」抗體。其自然環境的污染成分是會干擾抗體的研究、診斷或治療用途的物質,且可以包括酵素、激素及其它蛋白質或非蛋白質溶質。在一具體實施例中,抗體將被純化(1)至大於95重量%的抗體,例如通過Lowry方法測定,並且於一些具體實施例中大於99重量%,(2)至足夠的程度以通過使用例如旋轉杯定序儀獲得至少15個N端或內部胺基酸序列的殘基,或(3)通過SDS-PAGE在還原或非還原條件下使用例如考馬斯藍或考馬斯亮胺酸銀染來均質。分離的抗體在重組細胞內包括原位的抗體,因為抗體的天然環境的至少一種成分將不存在。然而,通常通過至少一個純化步驟製備分離的抗體。
本文所用之「單株抗體」 (mAB)乙詞係指從基本上同質的抗體群體中獲得的抗體,例如,包含群體的單個抗體是相同的,除了可存在少量的可能的天然存在的突變。因此,修飾語「單株」表示抗體的特徵不是離散抗體的混合物。這種單株抗體通常包括包含結合一標的之多胜肽序列的抗體,其中透過包括從多個多胜肽序列中選擇單個標的結合多胜肽序列的方法,來獲得標的結合多胜肽序列。例如,選擇過程可以是從多個選殖株中選擇獨特的選殖株,例如雜交瘤選殖株、噬菌體選殖株,或重組DNA選殖株的集合庫。應當理解的是,可以進一步改變所選擇的標的結合序列,例如提高對標的之親和力,使標的結合序列人源化,改善其在細胞培養物中的產生,降低其在體內的免疫原性,從而產生多特異性抗體等,且包含改變的標的結合序列的抗體也是本發明的單株抗體。與通常包括針對不同決定簇(抗原表位)的不同抗體的多株抗體製劑相反,單株抗體製劑的每個單株抗體係針對抗原上的單一決定簇。除了其特異性之外,單株抗體製劑的優點在於它們通常不被其他免疫球蛋白污染。修飾語「單株」表示抗體的特徵是從基本上同質的抗體群體獲得,且不被解釋為需要通過任何特定方法產生抗體。例如,根據本發明使用的單株抗體可以通過多種技術製備,包括,例如,雜交瘤方法(例如,Kohler等人,Nature, 256: 495(1975);Harlow等人,Antibodies: A Laboratory Manual,(冷泉港實驗室出版社,第二版1988年); Hammerling等人,in: Monoclonal Antibodies and T-Cell hybridomas 563-681 (Elsevier出版社,紐約,1981年))、重組DNA方法(參見例如美國專利號4,816,567)、噬菌體展示技術(參見例如Clackson等人,Nature, 352: 624-628 (1991年); Marks等人,J. Mol. Biol, 222: 581-597(1992年);Sidhu等人,J. Mol. Biol. 338(2): 299-310 (2004年);Lee等人,J. Mol. Biol. 340(5): 1073- 1093 (2004年);Fellouse,Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004年);以及Lee等人,J. Immunol. Methods 284(1-2): 119-132 (2004年),以及用於在具有部分或全部人類免疫球蛋白基因座或編碼人類免疫球蛋白序列的基因的動物中產生人類或類人類抗體的技術(參見,例如,WO98/24893;WO96/34096;WO96/33735;WO91/10741;Jakobovits等人,Proc. Natl. Acad. Sci. USA 90: 2551 (1993年); Jakobovits等人,Nature 362: 255-258 (1993年); Bruggemann等人,Year in Immunol. 7:33 (1993年);美國專利號5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;5,661,016;Marks等人,Bio. Technology 10: 779-783 (1992年);Lonberg等人,Nature 368: 856-859 (1994年);Morrison,Nature 368: 812-813 (1994年);Fishwild等人,Nature Biotechnol. 14: 845-851 (1996年);Neuberger,Nature Biotechnol. 14: 826 (1996年)以及Lonberg與Huszar,Intern. Rev. Immunol. 13: 65-93 (1995年)。
「人類單株抗體」 (HuMAb) 「人類單株抗體」是具有與人類產生的抗體相當的胺基酸序列及/或已經使用本文公開的任何製備人類抗體的技術製備的單株抗體。人類抗體的這種定義特異地排除包含非人類抗原結合殘基的人源化抗體。
「人源化抗體」 非人類(例如,鼠)抗體的人源化形式是含有來自非人類免疫球蛋白的最小序列的嵌合抗體。在一具體實施例中,人源化抗體為人類免疫球蛋白(受體抗體),其中來自接受者的高變區的殘基被來自非人類物種(供體抗體)的高變區的殘基替代,例如小鼠、大鼠、兔或具有所需特異性、親和性及/或能力的非人類靈長類動物。在一些情況下,人類免疫球蛋白的框架區(FR)殘基被相應的非人類殘基代替。此外,人源化抗體可以包含在受體抗體或供體抗體中未發現的殘基。進行這些修飾以進一步改善抗體性能。通常,人源化抗體將包含實質上所有的至少一個,通常為二個的可變區,其中所有或實質上所有的高變環對應於非人類免疫球蛋白的高變環,且所有或實質上所有的框架區為人類免疫球蛋白序列的框架區。人源化抗體任選地更包含至少一部分免疫球蛋白恆定區(Fc),通常為人類免疫球蛋白的恆定區。更多細節見Jones等人,Nature 321: 522-525 (1986年);Riechmann等人,Nature 332: 323-329 (1988年);以及Presta,Curr. Op. Struct. Biol. 2:593-596 (1992年)。另見以下引用的評論文章及參考文獻:Vaswani與Hamilton,Ann. Allergy, Asthma & Immunol. 1:105-115 (1998年);Harris,Biochem. Soc. Transactions 23:1035-1038 (1995年);Hurle與Gross,Curr. Op. Biotech. 5:428-433 (1994年)。
「嵌合抗體」 本文中的單株抗體特定包括「嵌合」抗體,其中重鏈及/或輕鏈的一部分與衍生自特定物種或屬於特定抗體類別或亞型的抗體中的相應序列相同或同源,而其餘部分的鏈與來自另一物種的抗體或屬於另一抗體類別或亞型的抗體中的相應序列以及這些抗體的片段相同或同源,只要它們表現出所需的生物學活性(美國專利號4,816,567;以及Morrison等人,Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984年))。
「抗原結合部分」或「抗體片段」 「抗體片段」僅包含完整抗體的一部分,其中當存在於完整抗體中時,該部分保留通常與該部分相關聯的功能中至少一個,且可多達大部分或全部。在一具體實施例中,抗體片段包含完整抗體的抗原結合位點,因此保留結合抗原的能力。
在另一具體實施例中,抗體片段,例如包含Fc區的抗體片段,當存在於完整抗體中,例如FcRn結合、抗體半衰期調節、ADCC功能,以及補體結合,保留通常與Fc區相關的生物學功能中的至少一種。在一具體實施例中,抗體片段為具有與完整抗體基本相似的體內半衰期的單價抗體。例如,這樣的抗體片段可以包含與能夠賦予該片段體內穩定性的Fc序列連接的抗原結合臂。
「癌症」及「癌性」等詞係指或描述哺乳動物的生理狀態,其通常以不受調節的細胞生長/增殖為特徵。癌症的實例包括,但不限於,癌、淋巴瘤(例如,何杰金淋巴瘤以及非何杰金淋巴瘤)、胚細胞瘤、肉瘤,以及白血病。這樣的癌症的更具體的實例包括,鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺鱗狀細胞癌、腹膜癌、肝細胞癌、胃癌、胰臟癌、神經膠質母細胞瘤、子宮頸癌、卵巢癌、肝癌、膀胱癌、乳癌、大腸癌、直腸癌、子宮內膜或子宮癌、唾液腺癌、腎癌、***癌、外陰癌、甲狀腺癌、白血病及其他淋巴組織增生性疾病,以及各種類型的頭頸癌。本文使用之「腫瘤」係指所有腫瘤細胞生長及增殖,無論是惡性還是良性,以及所有癌前及癌細胞及組織。「癌症」、「癌性」、「細胞增殖性疾病」、「增殖性疾病」,以及「腫瘤」等詞在本文中不是相互排斥的。
「免疫反應」係指免疫系統的細胞(例如T淋巴細胞、B淋巴細胞、天然殺手細胞、巨噬細胞、嗜酸性粒細胞、肥大細胞、樹突細胞及嗜中性粒細胞)的作用,以及由任何這些細胞或肝臟(包括抗體、細胞因子,及補體)產生的可溶性大分子,其導致從脊椎動物體侵入的病原體、感染病原體的細胞或組織的選擇性標的、結合、損傷、破壞及/或消除病原體、癌性或其他異常細胞,或在自體免疫或病理性炎症的情況下,為正常的人類細胞或組織。
「免疫調節劑」係指調節免疫反應的物質、藥劑、訊號傳導途徑或其組分。「調控」、「修飾」或「調節」免疫反應係指免疫系統的細胞或這種細胞的活性中的任何改變。這種調節包括免疫系統的刺激或抑制,其可以通過各種細胞類型的數量的增加或減少,這些細胞的活性的增加或減少或可能在免疫系統內發生的任何其它變化來表現。已經鑑別出有抑制及刺激性免疫調節劑,其中一些可能在癌症微環境中具有增強的功能。
「免疫治療」係指通過包含誘導、增強、抑制或以其他方式修飾免疫反應的方法,治療患有疾病、或患有疾病復發、或患有復發的風險的個體。
個體的「治療」或「療法」係指對該個體進行或給予活性劑的任何類型的干預或治療,其目的為逆轉、緩解、改善、抑制、減緩或預防與疾病相關的症狀、併發症、病症或生化標誌的發作、進展、發展、嚴重性或復發。
「增強內源性免疫反應」意指提高一個體中現有免疫反應的有效性或效力。可以通過克服抑制內源性宿主免疫反應的機制,或通過刺激增強內源性宿主免疫反應的機制,來實現這種有效性及效力的增加。
「個體」包括任何人類或非人類的動物。
藥物或治療劑,如本發明之抗體,的「治療有效量」或「治療有效劑量」為當單獨使用或與另一種治療劑組合使用時,可以保護一個體對抗疾病發作或促進疾病退化的該藥物的任何量,由疾病症狀嚴重程度的降低、疾病無症狀期的頻率及持續時間的增加,或由於疾病的影響而預防損傷或殘疾所證明。治療劑促進疾病消退的能力可以使用本領域技術人員已知的各種方法來評估,例如在臨床試驗期間的人類個體、預測人類功效的動物模型系統中,或通過體外測定藥劑的活性。
「促進癌症消退」係指單獨或與抗腫瘤劑聯合投予有效量的藥物導致腫瘤生長或大小減少、腫瘤壞死、至少一種疾病症狀的嚴重程度降低、疾病無症狀期的頻率及持續時間的增加,或由於疾病的影響而預防損傷或殘疾。此外,關於治療的「有效」與「有效性」包括藥理學有效性及生理安全性。藥理有效性係指藥物在患者中促進癌症消退的能力。生理安全性係指由藥物投予引起的細胞、器官及/或生物體層次的毒性含量或其他不良生理作用(副作用)。
「免疫相關」反應模式係指通過用免疫治療劑治療的癌症患者中經常觀察到的臨床反應模式,其通過誘導癌症特異性免疫反應或通過修飾天然免疫過程產生抗腫瘤作用。這種反應模式的特徵在於隨著腫瘤負荷的初始增加或新病變的出現而得到有益的治療效果,其在傳統化學治療劑的評估中將被分類為疾病進展並且將與藥物失效同義。因此,對免疫治療劑的適當評估可能需要長期監測這些藥物對目標疾病的影響。
藥物的治療有效量包括「預防有效量」,其係為當單獨或與抗腫瘤劑組合投予於具有罹癌風險(例如,具有惡性前病症的個體)或患有癌症復發的個體時的藥物的任何量,以抑制癌症的發展或復發。在優選的具體實施例中,預防有效量完全阻止癌症的發生或復發。「抑制」癌症的發生或復發代表減少癌症發展或復發的可能性,或完全阻止癌症的發生或復發。
「腫瘤浸潤性炎症細胞」為通常參與個體的炎症反應並且滲透腫瘤組織的任何類型的細胞。這些細胞包括腫瘤浸潤淋巴細胞(tumor-infiltrating lymphocytes,TILs)、巨噬細胞、單核細胞、嗜酸性粒細胞、組織細胞,以及樹突狀細胞。
本發明產生的免疫原性藥劑及抗體可以由組合物,例如含有一種抗體或其組合的組合物,或其抗原結合部分及醫藥上可接受的載體構成。如本文所用,「醫藥上可接受的載體」包括生理上相容的任何及所有溶劑、分散介質、包衣、抗菌及抗真菌劑、等滲及吸收延遲劑及其類似物。優選地,載體適合於靜脈內、肌肉內、皮下、腸胃外、脊髓,或表皮投予(例如,通過注射或輸注)。本發明的醫藥組合物可以包括一種或多種醫藥上可接受的鹽、抗氧化劑、水性及非水性載體,及/或佐劑,例如防腐劑、潤濕劑、乳化劑,以及分散劑。
優選的個體包括需要增強免疫反應的人類患者。本文公開的免疫治療方法特別適用於治療具有可通過增強免疫反應治療的病症之人類患者。於某些具體實施例中,該方法用於治療患有由感染因子引起的疾病的個體。在優選的具體實施例中,該方法用於治療患有癌症或有罹癌風險的個體。
「癌症免疫治療」 如本文中所使用,癌症免疫治療可包括,但不限於,能夠減少患有轉移性癌症的患者的腫瘤大小的基於免疫的療法。目前,有三種主要的癌症免疫治療方法,通過刺激效應細胞及/或抑制調節細胞的非特異性刺激免疫反應、主動免疫以增強特異性抗腫瘤反應(稱為癌症疫苗),以及被動轉移的抗腫瘤抗體或具有抗腫瘤活性的活化免疫細胞,也稱為過繼性免疫治療(DeVita等人,2008年)。
「組合療法」 於某些具體實施例中,本文所討論的免疫調節劑可與一種或多種抗增殖/化學治療劑組合使用,該抗增殖/化學治療劑有效降低腫瘤負荷,而沒有顯著的全身毒性,且可以促進該免疫反應的效果。這些藥物可以作為共同投予組合療法及/或共同配製的組合療法組合。
二種或更多種藥物以一些投予方案或投予形式一起使用的組合療法通常具有一個或多個目標:(i) 通過組合具有最小交叉耐藥性的藥物,以減少獲得性抗性增加的頻率,(ii) 降低具有非重疊毒性及相似治療特徵的藥物劑量,以達到副作用更小的效果,即增加治療指數,(iii) 通過使用另一種藥物使細胞對一種藥物的作用敏感,例如改變細胞週期階段或生長特性,以及(iv) 通過利用兩種藥物的生物學活性的加成性,或高於加成性,效應來實現增強的效力(Pegram, M. 等人(1999年) Oncogene 18: 2241 -2251;Konecny, G. 等人(2001年) Breast Cancer Res. and Treatment 67: 223-233; Pegram, M. 等人(2004年) J.of the Nat.Cancer Inst. 96(10): 739 -749;Fitzgerald等人(2006年) Nature Chem. Biol. 2(9): 458-466;Borisy等人(2003年) Proc. Natl. Acad. Sci. 100(13):7977-7982)。Loewe加成性 (Chou, T.C.與Talalay, P. (1977年) J. Biol. Chem. 252:6438-6442; Chou, T.C.與Talalay, P. (1984年) Adv. Enzyme Regul. 22: 27-55;Berenbaum, M. C. (1989年) Pharmacol. Rev. 41:93-141),以及Bliss獨立/協同作用(Bliss, C.I. (1956年) Bacteriol. Rev. 20:243-258;Greco等人(1995年) Pharmacol. Rev. 47:331-385)為用於計算組合治療與單一療法相比的預期劑量 - 反應關係的方法,其基於參數例如IC50,在最簡單的情況下實現50%標的抑制所需藥物的劑量以及等於Ki。
「化學治療劑」為用於治療癌症的化合物,不論其作用機制如何。化學治療劑的類別包括,但不限於:烷化劑、抗代謝物、紡錘體毒素植物生物鹼、細胞毒性/抗腫瘤抗生素、拓撲異構酶抑制劑、抗體、光敏劑,以及激酶抑制劑。化療劑包括用於「標的治療」以及常規化療的化合物。化學治療劑的實例包括:埃洛替尼(erlotinib)(TARCEVA®
, Genentech/OSI Pharm.公司)、多西他賽(docetaxel) (TAXOTERE®
, Sanofi-Aventis公司)、5-FU (氟尿嘧啶、5-氟尿嘧啶,CAS編號51-21-8)、吉西他濱(gemcitabine)(GEMZAR®
,Lilly公司),PD-0325901 (CAS編號391210-10-9,Pfizer公司)、順鉑(cisplatin)(舒癌特二胺、二氯鉑(II),CAS編號15663-27-1)、卡鉑(carboplatin)(CAS編號41575-94-4)、紫杉醇(paclitaxel) (TAXOL®
,Bristol-Myers Squibb Oncology公司,普林斯頓,紐澤西州)、曲妥單抗(trastuzumab)(HERCEPTIN®
,Genentech公司)、替莫唑胺(temozolomide)(4-甲基-5-氧代-2,3,4,6,8-五氮雜雙環[4.3.0]壬-2,7,9-三烯-9-甲醯胺,CAS編號85622-93-1,TEMODAR®
, TEMODAL®
,Schering Plough公司)、泰莫西芬(tamoxifen)((Z)-2- [4-( 1,2-二苯基丁-1-烯基)苯氧基] -N,N-二甲基 -乙胺,NOLVADEX®
, ISTUBAL®
, VALODEX®
),以及多柔比星(doxorubicin)(ADRIAMYCIN®
)、Akti-1/2、HPPD,以及雷帕黴素(rapamycin)。
化學治療劑的更多實例包括:奧沙利鉑(oxaliplatin) (ELOXATIN®
,Sanofi公司)、硼替佐米(bortezomib) (VELCADE®
,Millennium Pharm.公司)、舒癌特(sutent) (SUNITINIB®
, SU11248,Pfizer公司)、復乳納(letrozole) (FEMARA®
,Novartis公司)、甲磺酸伊馬替尼(imatinib mesylate) (GLEEVEC®
,Novartis公司)、XL-518 (MEK抑制劑,Exelixis,WO 2007/044515)、ARRY-886 (Mek抑制劑,AZD6244,Array BioPharma公司,Astra Zeneca)、SF-1126 (PI3K抑制劑,Semafore Pharmaceuticals公司)、BEZ-235 (PI3K抑制劑,Novartis公司)、XL-147 (PI3K抑制劑,Exelixis公司)、PTK787/ZK 222584 (Novartis公司)、氟維司群(fulvestrant) (FASLODEX®
,AstraZeneca公司)、leucovorin (亞葉酸)、雷帕黴素(rapamycin) (西羅莫司(sirolimus), RAPAMUNE®
,Wyeth公司)、拉帕替尼(lapatinib) (TYKERB®
, GSK572016,Glaxo Smith Kline公司)、羅非那泊(lonafarnib) (SARASAR™, SCH 66336,Schering Plough公司)、索拉非尼(sorafenib) (NEXAVAR®
, BAY43-9006,Bayer Labs公司)、吉非替尼(gefitinib) (IRESSA®
,AstraZeneca公司)、伊立替康(irinotecan) (CAMPTOSAR®
, CPT-11,Pfizer公司)、替伐尼泊(tipifarnib) (ZARNESTRA™,Johnson & Johnson公司)、ABRAXANE™ (無聚氧乙烯蓖麻油,Cremophor-free)、紫杉醇的白蛋白工程奈米粒子製劑(American Pharmaceutical Partners, Schaumberg, Il)、凡丹他尼(vandetanib) (rINN, ZD6474, ZACTIMA®
,AstraZeneca公司)、瘤克寧錠(chloranmbucil)、AG1478、AG1571 (SU 5271;Sugen公司)、替西羅莫司(temsirolimus) (TORISEL®
,Wyeth公司)、匹多巴尼(pazopanib) (GlaxoSmithKline公司)、茨佛胺(canfosfamide) (TELCYTA®
,Telik公司)、噻替派(thiotepa)以及環磷醯胺(cyclosphosphamide) (CYTOXAN®
, NEOSAR®
);烷基磺酸鹽,如白消安(busulfan)、英丙舒凡(improsulfan)以及哌泊舒凡(piposulfan);氮丙啶(aziridines),如苯並多巴(benzodopa)、卡泊酮(carboquone)、美妥替哌(meturedopa),以及尿烷亞胺(uredopa);亞乙基亞胺(ethylenimines)以及甲基三聚氰胺類(methylamelamines),包括十八胺(altretamine)、三乙烯三聚氰胺(triethylenemelamine)、三亞乙基磷醯胺(triethylenephosphoramide)、三亞乙基硫代磷醯胺(triethylenethiophosphoramide),以及三羥甲基三聚氰胺(trimethylomelamine);乙醯青黴素(acetogenins)(特別是牛油菌素(bullatacin)以及布拉他寧(bullatacinone));喜樹鹼(camptothecin)(包括合成模擬拓撲替康(topotecan));抑素(bryostatin);海绵他汀(callystatin);CC-1065(包括其阿多來新(adozelesin)、卡折來新(carzelesin),以及比折來新(bizelesin)合成類似物); 克力托懷辛(cryptophycins) (特別是克力托懷辛 1以及克力托懷辛 8);多拉司他汀(dolastatin);倍癌黴素(duocarmycin) (包括合成類似物,KW-2189以及CB1-TM1);軟珊瑚醇(eleutherobin);pancratistatin;匍枝珊瑚醇(sarcodictyin);海綿抑制素(spongistatin);氮芥,如氯氮芥(chlorambucil)、氯萘嗪(chlornaphazine)、氯磷醯胺(chlorophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、氮芥(mechlorethamine)、氮芥氧化物鹽酸鹽(mechlorethamine oxide hydrochloride)、美法崙(melphalan)、諾維生素(novembichin)、酚酯(phenesterine)、潑尼昔汀(prednimustine)、曲伐沙星(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲(nitrosoureas),如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine),以及雷莫司汀(ranimustine);抗生素,如恩二烯抗生素(例如,加利車黴素(calicheamicin)、加利車黴素γ1I、加利車黴素ω1I (Angew Chem. Intl. Ed. Engl. (1994年) 33:183-186);dynemicin、dynemicin A;雙磷酸鹽(bisphosphonates),如氯磷酸鹽(clodronate);埃曲霉素(esperamicin);以及新碳青黴素發色團(neocarzinostatin chromophore)以及相關的染色質烯二烯抗生素發色團(chromoprotein enediyne antibiotic chromophores)、阿曲酸溶蛋白(aclacinomysins)、放線菌素(actinomycin)、奧拉黴素(authramycin)、疊西他星(azaserine)、博來黴素(bleomycins)、仙人球黴素(cactinomycin)、卡他賓黴素(carabicin)、卡黴素(caminomycin)、卡介絲黴素(carzinophilin)、染色質黴菌(chromomycinis)、更生黴素(dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮胺酸(6-diazo-5-oxo-L-norleucine)、嗎啉代多柔比星(morpholino-doxorubicin)、氰基嗎啉代多柔比星(cyanomorpholino-doxorubicin)、2-吡咯啉-多柔比星(2-pyrrolino-doxorubicin),以及脫氧多柔比星(deoxydoxorubicin)、表柔比星(epirubicin)、伊索比星(esorubicin)、伊達比星(idarubicin)、馬可菌黴素(marcellomycin)、絲裂黴素(mitomycins),例如絲裂黴素C、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、紫菜黴素(porfromromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,如甲氨蝶呤(methotrexate)以及5-氟尿嘧啶(5-FU);葉酸類似物,如二甲葉酸(denopterin)、甲氨蝶呤(methotrexate)、蝶呤(pteropterin)、三甲氧嘧啶(trimetrexate);嘌呤類似物,如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、噻蟲胺(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,如阿米巴胺(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脫氧尿苷(dideoxyuridine)、多西菌定(doxifluridine)、依諾沙星(enocitabine)、氟尿苷(floxuridine);雄性激素,如卡普睪酮(calusterone)、丙酸丁香豆酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯;抗腎上腺素,如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺醣苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);貝斯布西(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);美可辛(demecolcine);地吖醌(diaziquone); 依氟鳥胺酸(elfornithine);醋酸鋁(elliptinium acetate);埃坡黴素(epothilone);乙環氧啶(etoglucid);硝酸鎵(gallium nitrate);羥基脲(hydroxyurea);香菇多醣(lentinan);氯尼達明(lonidainine);美登木素類(maytansinoids),如美登素(maytansine)以及安曲霉素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;硝嗪(nitraerine);噴司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蔥醌(losoxantrone);鬼臼胺酸(podophyllinic acid);2-乙基醯肼(2-ethylhydrazide);甲基芐肼(procarbazine);PSK®
多醣複合物(JHS Natural Products,Eugene,Oreg.);雷佐生(razoxane);根黴素(rhizoxin);西索菲蘭(sizofiran);螺環鍺(spirogermanium);柚子酸(tenuazonic acid);三亞胺(triaziquone);2,2’,2’’-三氯三乙胺(2,2’,2’’-trichlorotriethylamine);單端孢(trichothecenes) (T-2毒素、撫孢菌素A (verracurin A)、桿孢菌素A (roridin A),以及蛇形菌素(anguidine));胺基甲酸乙酯(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托新(gacytosine);***醣苷(arabinoside) (Ara-C);環磷醯胺(cyclophosphamide);塞替派(thiotepa); 6-硫鳥嘌呤(6-thioguanine);巰基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);鉑(platinum)類似物,如順鉑以及卡鉑;長春鹼(vinblastine);依托泊苷(etoposide) (VP-16);異環磷醯胺(ifosfamide);米托蒽醌(mitoxantrone);長春新鹼(vincristine);長春瑞濱(vinorelbine) (NAVELBINE®
);米托蔥醌(novantrone);替尼泊苷(teniposide);依達曲塞(edatrexate);柔紅黴素(daunomycin);氨基蝶呤(aminopterin);卡培他濱(capecitabine) (XELODA®
,Roche公司);伊班磷酸鈉(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(difluoromethylornithine,DMFO);維甲酸(retinoids),如視黃酸(retinoic acid);以及任何上述醫藥上可接受的鹽類、酸,以及衍生物。
「化學治療劑」的定義中還包括:(i) 用於調節或抑制激素作用於腫瘤,如抗***,以及選擇性***受體調節劑(selective estrogen receptor modulators,SERM)的抗激素劑,包括,例如,泰莫西芬(tamoxifen) (NOLVADEX®
;檸檬酸泰莫西芬)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基泰莫西芬(4-hydroxytamoxifen)、三昔芬(trioxifene)、克昔西芬(keoxifene)、LY117018、阿托司酮(onapristone),以及FARESTON®
(檸檬酸托美標,toremifine citrate);(ii) 芳香酶抑制劑,其抑制調節腎上腺中的***產生的酶芳香酶,例如,4(5) - 咪唑(4(5)-imidazoles)、胺基丁二醯亞胺(aminoglutethimide)、MEGASE®
(醋酸甲地孕酮,megestrol acetate)、AROMASIN®
(依西美坦,exemestane;Pfizer公司)、甲霜靈(formestanie)、法羅唑(fadrozole)、RIVISOR®
(氟唑胺, vorozole)、FEMARA®
(復乳納,letrozole;Novartis公司),以及ARIMIDEX®
(阿那曲唑,anastrozole;AstraZeneca公司);(iii) 抗雄激素,如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide),以及戈舍瑞林(goserelin);以及曲西他濱(troxacitabine,α-1,3-二氧戊環核苷胞嘧啶類似物); (iv) 蛋白激酶抑制劑,如MEK抑制劑(WO 2007/044515);(v) 脂質激酶抑制劑;(vi) 反義寡核苷酸,特別是那些抑制涉及異常細胞增殖的訊息傳導途徑中的基因表現者,例如PKC-α、Raf以及H-Ras,例如奧利美生反義寡核苷酸(oblimersen,GENASENSE®
, Genta Inc.公司);(vii) 核酶,如VEGF表現抑制劑(例如,ANGIOZYME®
)以及HER2表現抑制劑;(viii) 例如基因治療疫苗之類的疫苗,例如,異維甲酸(ALLOVECTIN®
)、拉維克汀疫苗(LEUVECTIN®
),以及瓦昔得疫苗(VAXID®
);PROLEUKIN®
rIL-2;拓撲異構酶1抑制劑,如勒托替康(LURTOTECAN®
);阿巴瑞克(ABARELIX®
rmRH);(ix) 抗血管生成劑,如貝伐珠單抗(bevacizumab,AVASTIN®
,Genentech公司);以及任何上述醫藥上可接受的鹽類、酸,及衍生物。
「化學治療劑」的定義中還包括治療性抗體,例如,阿倫單抗(alemtuzumab,Campath公司)、貝伐珠單抗(bevacizumab,AVASTIN®
,Genentech公司)、西妥昔單抗(cetuximab,ERBITUX®
,Imclone公司)、帕尼單抗(panitumumab,VECTIBIX®
,Amgen公司)、利妥昔單抗(rituximab,RITUXAN®
,Genentech/Biogen Idec公司)、帕妥珠單抗(pertuzumab,OMNITARG™,2C4,Genentech公司)、曲妥珠單抗(trastuzumab,HERCEPTIN®
,Genentech公司)、托西莫單抗(tositumomab,Bexxar,Corixia公司),以及抗體藥物共軛,吉妥珠單抗(gemtuzumab)、奧佐黴素(ozogamicin,MYLOTARG®
,Wyeth公司)。
具有作為化學治療劑的治療潛力的人源化單株抗體與本發明的免疫原性/治療劑組合可以包括或排除以下一種或多種:阿倫單抗(alemtuzumab)、阿非珠單抗(apolizumab)、阿塞珠單抗(aselizumab)、阿提珠單抗(atlizumab)、貝匹珠單抗(bapineuzumab)、貝伐珠單抗(bevacizumab)、比伐珠單抗美登素(bivatuzumab mertansine)、坎妥珠單抗美登素(cantuzumab mertansine)、賽代珠單抗(cedelizumab)、賽妥珠單抗(certolizumab pegol)、西芙細珠單抗(cidfusituzumab)、西得珠單抗(cidtuzumab)、達珠單抗(daclizumab)、依庫珠單抗(eculizumab)、依法利珠單抗(efalizumab)、依帕珠單抗(epratuzumab)、鄂珠單抗(erlizumab)、弗利珠單抗(felvizumab)、封突利珠單抗(fontolizumab)、吉妥珠單抗奧佐米星(gemtuzumab ozogamicin)、依諾圖珠單抗奧佐米星(inotuzumab ozogamicin)、依匹單抗(ipilimumab)、拉貝珠單抗(labetuzumab)、林妥珠單抗(lintuzumab)、馬妥珠單抗(matuzumab)、美泊利單抗(mepolizumab)、莫他維珠單抗(motavizumab)、莫圖維珠單抗(motovizumab)、那他珠單抗(natalizumab)、尼妥珠單抗(nimotuzumab)、諾羅維珠單抗(nolovizumab)、努瑪維珠單抗(numavizumab)、奧瑞珠單抗(ocrelizumab)、奧馬珠單抗(omalizumab)、帕利珠單抗(palivizumab)、帕考珠單抗(pascolizumab)、派福昔珠單抗(pecfusituzumab)、派圖珠單抗(pectuzumab)、帕妥珠單抗(pertuzumab)、培克珠單抗(pexelizumab)、拉利維珠單抗(ralivizumab)、雷珠單抗(ranibizumab)、雷西維珠單抗(reslivizumab)、雷西珠單抗(reslizumab)、雷塞維珠單抗(resyvizumab)、羅維利珠單抗(rovelizumab)、盧利珠單抗(ruplizumab)、西博圖珠單抗(sibrotuzumab)、西普利珠單抗(siplizumab)、桑圖珠單抗(sontuzumab)、他卡圖珠單抗四西坦(tacatuzumab tetraxetan)、他朵西珠單抗(tadocizumab)、他利珠單抗(talizumab)、天貝珠單抗(tefibazumab)、托珠單抗(tocilizumab)、托羅利珠單抗(toralizumab)、曲妥珠單抗(trastuzumab)、妥珠單抗西莫白介素(tucotuzumab celmoleukin)、圖庫西珠單抗(tucusituzumab)、烏瑪維珠單抗(umavizumab)、俄突夏珠單抗(urtoxazumab),以及維希利珠單抗(visilizumab)。
「標準護理治療」是一種治療程序,包括藥物或藥物組合、放射治療(radiation therapy,RT)、手術或其他醫療干預,被醫生認可為適當、接受及/或廣泛用於某種類型的患者、疾病或臨床情況。不同類型癌症的標準護理療法是本領域技術人員公知的。例如,國家綜合癌症網絡(the National Comprehensive Cancer Network,NCCN),是一個在美國21個主要癌症中心的聯盟,發布了NCCN腫瘤學臨床實踐指南(NCCN GUIDELINES®
),提供針對各種癌症的標準護理治療的詳細最新資訊(參見NCCN GUIDELINES®
,2013版)。
套組:本發明之範圍還包括用於治療用途的套組,包括醫藥套組及診斷套組。
如本文中所使用的,本發明之附加方面包括與劑量升級相關的方面及因素;病人群;安全;以及藥物動力學/藥效學分析。
廣義而言,免疫系統可分為先天免疫及適應性免疫。先天免疫力,係為兩者中較原始的,且由非特異性防禦所組成,例如物理障礙(例如,皮膚)、非特異性防禦細胞(例如,巨噬細胞),以及多種細胞激素(例如,IL-1)。一般而言,疫苗不會上調對特定病原體或疾病的固有系統,但是添加到疫苗中的佐劑可能非特異性活化先天免疫,這進而可能改善適應性免疫反應。適應性免疫可進一步分為體液(即,抗體)以及細胞(例如,細胞毒性T細胞)免疫反應。體液免疫反應的效應細胞由僅適合於適應性免疫的細胞(例如,T及B淋巴細胞)組成;然而,先天免疫的細胞提供基本功能(例如,抗原呈現)。因此,例如,對病毒的抗體產生的誘導將需要幾種細胞類型的一系列複雜的交互作用。簡言之,這些將包括通過樹突狀細胞捕獲及處理病毒組成分(例如,病毒的包膜蛋白),其又將呈現
給所呈現的抗原特異性的T細胞。一旦被呈現的抗原活化,T細胞將「幫助」病毒特異性B細胞產生抗入侵病原體的抗體。
耐受性
長久以來所公認的,儘管免疫系統具有識別宿主抗原的能力,但通常沒有觀察到這種反應(即,免疫系統顯示出對自身的耐受性)。這種對自身的耐受性包括「正常」以及腫瘤抗原。
在一方面,本發明的特徵在於能夠破壞免疫系統對腫瘤抗原Globo H的耐受性的疫苗。
耐受性的類型
耐受性可能來自中樞及/或周圍耐受性。中樞耐受性可以防止識別自身的T及B淋巴細胞的成熟。自身耐受性不是絕對的,一些產生抗自身抗體的B細胞可能在正常個體中被發現。然而,由於缺乏抗自身T細胞有助於自身抗原B細胞活化的重要組成部分--很少發現自身抗體。周圍耐受性是對自身的免疫反應的持續主動抑制,被認為主要由調節性T細胞細胞維持。調節性T細胞被認為是阻止T細胞誘導自身抗原,其包括正常及腫瘤抗原。
打破自我耐受性的策略
在一方面,本發明的特徵在於克服Globo H系列腫瘤抗原的中樞及周圍耐受性的組合物及方法。例如,在一些方面,該組合物及方法可用於減少調節性T細胞抑制作用,並刺激T細胞幫助產生抗Globo H抗體的B細胞。
在一些方面,本發明的特徵為共同投予調節性T細胞低度調節劑以克服周圍耐受性。在這方面,調節性T細胞低度調節劑可以是環磷醯胺、抗調節性T細胞抗體,或[選擇性地]抑制調節性T細胞活性(多於適應性免疫系統的其他細胞)的其它藥劑。
因此,在一些方面,可以將環磷醯胺與Globo H-KLH共軛物同時投予於患者,從而抑制抗Globo H抗體產生的調節性T細胞抑制。在一些方面,調節性T細胞低度調節劑也可以刺激細胞毒性T淋巴細胞向Globo H抗原陽性細胞的擴增,從而直接殺死表現Globo-H的腫瘤細胞。
B細胞抗體產生需要來自識別抗原的T細胞的幫助係被公認的。然而,中樞耐受性及/或抗原呈現缺陷可導致Globo H (自身)抗原缺乏T細胞識別。因此,在一些具體實施例中,本發明的特徵在於通過將Globo H系列抗原與強免疫原性藥劑(例如KLH)共軛來刺激T細胞幫助產生抗Globo H抗體的B細胞之組合物及方法。KLH是一種系統發育遠離的生物體,具有大分子量(超過390,000),這兩個屬性都已知提高了免疫原性。當將Globo H共軛物投予於患者時,樹突細胞及/或其它抗原呈現細胞將Globo H共軛物,例如,Globo H-KLH共軛物加工成Globo H及KLH組分。T細胞識別KLH抗原,其然後幫助B細胞產生所需的抗Globo H抗體。
腫瘤疫苗的其他作用
增加的抗體效價:在一些具體實施例中,本發明的組合物及方法通過產生高於閾值效價的抗體反應而具有臨床益處。低於閾值效價,抗腫瘤反應可能不足以產生有意義的臨床益處。
抗Globo H抗體的親和力增加:在一些具體實施例中,本發明的方法的特徵在於向患者投予Globo H共軛物2、3、4、5、6、7、8、9、10次或更多次。
在一些具體實施例中,重複投予增加了所得抗體反應的親和力,因為具有對Globo H的最高親和力的B細胞表現表面抗體優先被注射的抗原所刺激,因為它們比表現較低親和力抗體的B細胞能更好的結合該抗原。在一些具體實施例中,每個投予週期增加抗體反應,增加抗體的親和力及/或結合性,及/或誘導針對Globo H共軛物的Globo H部分較少免疫原性位點產生抗體。
在一些具體實施例中,重複投予進一步誘導通常不存在足夠數量的B細胞,以產生具有單次(或低重複暴露於抗原)的有意義的反應(例如,它們可能與少數抗體結合的抗原表位結合),抗體分泌漿細胞(「體分泌漿細胞」是B細胞分化而成的)及記憶B細胞的擴增,其可能對長期維持抗腫瘤反應是重要的,並且增加抗體類轉換的動力學。
在一些具體實施例中,重複投予還導致B細胞增殖中心擴增至Globo H系列腫瘤抗原,並優先擴增含有高親和力抗Globo H抗體的增殖中心。
IgG亞型的擴增:T細胞的幫助能夠誘導B細胞轉換其重鏈類以及亞型的表現。在人類中,有四個IgG亞型 - IgG1、IgG2、IgG3,以及IgG4。每個IgG亞型具有將其與其他亞型區分開的生物效應子功能。所有四個亞型的表現皆可以使抗Globo H反應的腫瘤殺傷活性最大化。
抗體反應中增加的動力學:於一些具體實施例中,Globo H-KLH共軛物、環磷醯胺,以及佐劑的重複的接種可能導致抗體較快速擴增,相較於沒有偶聯到KLH、環磷醯胺,或沒有重複注射佐劑所得之抗體更快的擴增。
在某些具體實施例中,OBI-822可通過減少Globo-H誘導的Notch訊號傳導來阻斷癌症免疫抑制。
在某些方面,OBI-822可以抵抗Globo-H在癌症治療中的某些負面特徵。
在某些具體實施例中,OBI-822消耗Globo H,其反過來增加Notch1降解,阻斷腫瘤免疫抑制作用,導致腫瘤退化。
在某些具體實施例中,OBI-822可以抵消Globo-H相關的T細胞增殖及細胞因子分泌的降低。
在某些具體實施例中,OBI-822可抵消Globo-H相關的B細胞分化及Ig分泌的抑制。
Globo系列抗原在癌症發展中的作用很重要。在某些具體實施例中,它們可通過抑制半胱天冬酶3的活化來影響腫瘤的存活。在某些具體實施例中,恢復半胱天冬酶3不活化,導致細胞凋亡。
在某些具體實施例中,Globo系列聚類通過抑制半胱天冬酶3級聯來增強腫瘤存活。實例
直到申請人的本發明內容及支持肯定的免疫原性反應及治療功效的示例性數據之前,沒有關於如本文所公開的免疫調節劑有效使用有關成功使用OBI-821作為佐劑的先前的結論性證明/報告,如實施例部分所示,包括Globo H疫苗的臨床前研究;在第I期試驗中使用QS-21的OBI-822;以及在癌症臨床試驗中的OBI-822與OBI-821。
試驗概述:Globo H為一種被發現在乳癌中高度表現的醣類。以OBI-822 (一種Globo H-KLH共軛物)以及OBI-821 (在二個第I期試驗中的佐劑)進行主動免疫治療,誘導Globo H特異性抗體,其可以調節體外結合與對表現乳癌細胞的Globo H的細胞毒性。
方法:在國際上、隨機、雙盲,以及安慰劑控制組的第II/III期試驗(NCT01516307)中,具有≤2次疾病進展(progressive disease,PD)事件的轉移性乳癌患者,以及在≥1次抗癌方案後至少達到疾病穩定(stable disease,SD)的轉移性乳癌患者,以2:1比例隨機分配,接受皮下投予OBI-822 (30 μg Globo H)/OBI-821 (100 μg)或控制組(PBS處理),結合低劑量環磷醯胺(300 mg/m2
)在第1、2、3、5、9、13、17、25、37週投予,或者投予直到疾病進展(PD)。激素治療是被允許的。主要及次要療效終點為無惡化存活期(progression-free survival,PFS)以及總體存活期(overall survival,OS),與體液抗體反應相關。
結果:349例患者隨機分組,348例接受試驗藥物(ITT),168例(48%)接受全部9次注射。70%具有激素受體呈現陽性的乳癌,13%為三陰性乳癌,62%接受激素治療。在所有患者中,包括發展出Globo H特異性IgG的反應,以及那些沒有發展出Globo H特異性IgG反應的患者,在PFS (HR,0.96 [95% CI,0.74-1.25] P=0.77)或期中分析的總體存活期(OS) (HR,0.79 [95% CI,0.51-1.22] P=0.29)沒有觀察到差異。然而,50%對OBI-822/OBI-821發展出Globo H特異性IgG反應且效價 ≥ 1:160的患者中,其PFS及OS在任何治療期間的時點皆有顯著地改善,這些改善是相對於控制組(HR,對於PFS 0.71 [95% CI,0.52-0.97] P=0.029; HR,對於OS 0.57 [95% CI,0.33-0.97] P=0.04)以及相對於對OBI-822/OBI-821沒有反應者(HR,對於PFS 0.52 [95% CI,0.37-0.71] P< .0001; HR,對於OS 0.52 [95% CI,0.29-0.92] P=0.025),並根據基線疾病狀態及/或激素使用進行調整。在時間依賴性Cox模型中,相對於控制組患者,接受所有9次OBI注射的患者的PFS獲得了改善(HR,0.66 [95% CI,0.42-1.01] P=0.057)。OBI-822/OBI-821耐受性良好;最常見的藥物相關不良事件為1/2級注射反應。
結論:OBI-822/OBI-821接種疫苗沒有改善在試驗藥物(ITT)中的PFS。然而,對疫苗發生免疫反應的患者中,PFS與期中分析的總體存活期(OS)則有顯著改善。這些子群組數據用於設計一個確定的第III期試驗。
試驗設計的理論基礎:OBI-822為一種新的研究性抗癌治療藥物,其屬於一類新穎的主動免疫治療劑。它是由腫瘤相關的碳水化合物抗原(tumor-associated carbohydrate antigen,TACA)、Globo H,與載體蛋白共價結合的鑰孔蟲戚血藍蛋白(Keyhole Limpet Hemocyanin,KLH)所組成的合成醣蛋白。OBI-821是一種基於皂素的佐劑。Globo H在許多上皮癌,如,乳癌、***癌、胃癌、肺癌、直腸癌、胰臟癌,以及卵巢癌等惡性腫瘤的表面具有高量的表現。通過將Globo H與 KLH載體蛋白共軛形成OBI-822 (Globo H-KLH),以及與佐劑OBI-821共同投予來提升抗原的免疫原性。
研究設計:在國際上、隨機、雙盲,以及安慰劑控制組的第II/III期試驗(NCT01516307)中,包括在41週治療期間9次的OBI-822注射,疾病進展追蹤期為自隨機分組後至多2年,以及存活期追蹤期為至多5年(2:1),以皮下投予OBI-822 (30 μg Globo H)/OBI-821 (100 μg)或控制組(PBS)治療,並與低劑量環磷醯胺(300 mg/m2
)組合使用。
資格標準:(建立納入及排除的標準) 1. 納入標準 2. 排除標準
研究程序時程表: 1. 篩選期 - 隨機化的前3週(第1次訪視) 2. 治療期:第1週 - 第3週(訪視2 - 訪視5) 3. 治療期:第5週 - 第41週(訪視6 - 訪視19) 4. 追蹤期(每8週) 5. 建立提前終止標準 6. 存活期追蹤期(每12週) 7. 考慮其他研究程序的完整性
治療方案:(考慮的項目) 1. 隨機化與盲測法 2. 環磷醯胺投予時程表 3. OBI-822/OBI-821與安慰劑投予時程表
毒性與治療停藥管理(被認為是設計的一部分的示例性因素) 1. 一般管理 2. 藥物誘導毒性的管理 3. 個別個體研究治療(OBI-822/OBI-821,安慰劑)停藥的規範 4. 環磷醯胺治療停藥的規範
在研究期間允許及禁止的治療:(被認為是設計的一部分的示例性因素) 1. 研究期間允許的治療 2. 研究期間禁止的治療
藥物資訊:(被認為是設計的一部分的示例性因素) 1. 環磷醯胺 2. OBI-822 (Globo H-KLH) 3. OBI-821 4. 臨床試驗材料(Clinical Trial Material,CTM)供應、包裝、標籤,以及儲存
研究終點: 1. 功效評估 2. 安全評估 3. 安全變量
回應標準: 1. 腫瘤病變的可測量性之定義 2. 記錄腫瘤病變 3. 反應評估 4. 從計畫書治療中移除之標準 5. 結束研究的標準
統計考量: 1. 目標與假設 2. 標的樣品大小 3. 研究終點的評估 4. 統計方法 5. 安全性分析
不良事件: 1. 不良事件的定義: 2. 與治療關係的評估
效力的證明:於某些具體實施例中,與帶有轉移性乳癌的「無反應者」 (沒有IgG/IgM反應)相比,與環磷醯胺一起投予的OBI-822/OBI-821改善了帶有轉移性乳癌的「反應者」 (增加Globo H特異性IgG/IgM)。
免疫後體液免疫反應(Globo H特異性IgG/IgM)的頻率及幅度,及其與轉移性乳癌患者的PFS及OS的相關性。
OBI-822/OBI-821合併環磷醯胺相對於PBS合併環磷醯胺的安全性及毒性特徵。
作為特定實施例的臨床試驗:使用Globo H-KLH (OBI-822)與OBI-821佐劑在患有轉移性乳癌的個體中的主動免疫治療的雙盲、隨機、第II/III期試驗。
治療計劃:這是一項針對患有轉移性乳癌患者的雙盲、隨機、雙臂,第II/III期試驗。
篩選時的腫瘤評估:篩選時進行全身性CT掃描(胸部、腹部,以及骨盆),並作為基線掃描。若在篩選掃描的2週內進行了全身CT掃描,則可以將該進行的掃描作為基線掃描。若篩選前全身CT掃描是不可行的,則診斷為轉移性乳癌後的病變部位必須具有來自CT或MRI掃描的影像,以確認腫瘤狀態。
腫瘤反應狀態(SD、PR、CR)係基於RECIST1.1標準。將在篩選(基線)時的確診CT掃描與在篩選前先前的全身CT掃描進行比較。篩選掃描之前的掃描的疾病狀態必須與篩選掃描時為相同的疾病狀態。SD需要至少6週的間隔,PR及CR需要至少4週的時間間隔。
如果在篩選時檢測到新的病變(即,先前成像上不明顯的腫瘤及/或以前未記錄在成像上的腫瘤),則該病例被認為是PD,因此不符合納入標準。
分層用的疾病狀態被分為疾病證據(PR/SD)或無疾病證據(CR)。
對於在篩選之前由於切除轉移性病變而沒有疾病證據(CR)的個體,研究者需要確保在手術切除之前通過成像記錄腫瘤反應狀態。
如果登記,腫瘤狀態被記錄為疾病的證據(PR/SD)。
成像由現場放射科醫師進行評估,並將副本發送至中央放射實驗室進行獨立審查,不會影響現場的解釋及決定。
個體被隨機以2:1的分配接受OBI-822/OBI-821(治療組)或PBS(控制組)。
個體根據其在激素治療中的用途進行分層,同時研究其入選時的疾病狀態。
當被納入作為激素治療的非使用者時,患者在研究期間不得開始激素治療。
若被納為激素治療的使用者,患者應該進行激素治療。
允許因為先前的激素治療產生的毒性不耐受而改用另一種激素治療方案。
有四個層次: 1. 激素治療使用者 - 有疾病證據(PR/SD) 2. 激素治療使用者 - 無疾病證據(CR) 3. 激素治療非使用者 - 有疾病證據(PR/SD) 4. 激素治療非使用者 - 無疾病證據(CR)
收集患者腫瘤活組織切片/組織樣本以測試腫瘤Globo H表現並與治療反應的關聯。
於某些組合治療的具體實施例中,治療個體在第1、5、9、13、17、25,以及37週 (於第2、6、8、10、12、14,以及17週訪視)或直到疾病進展時,以靜脈注射投予環磷醯胺(300 mg/m2
)。
在第1、2、3、5、9、13、17、25,以及37週皮下注射投予OBI-822/OBI-821或控制組(PBS)(於第3、4、5、7、9、11、13、15,以及18週訪視)。隨機追蹤個體直至疾病進展或最多2年。
收集血液樣品用於評估治療期間Globo H-KLH的免疫反應,且追蹤期間從治療開始起最多2年或至疾病進展。
研究期間的腫瘤評估 1. 全身CT掃描(胸部、腹部,及骨盆)每8週進行一次,直到研究結束或直到疾病進展。 2. 根據RECIST 1.1標準,將每個時間點的CT掃描與基線掃描(在篩選時)及先前的無惡化存活期(PFS)及腫瘤反應狀態(PD、SD、PR、CR)時間點進行比較。
所有存活的個體在整體存活期(OS)隨機分組,並以12週間隔進行追蹤達5年。
對於患有PD的個體,在進展時或抽取研究對象之前抽取血液及尿液樣品。實例 1 :針對 OBI-822 的改良意圖治療( Modified Intent-to-treat , Mitt )群體的無惡化存活期( PFS )的臨床試驗數據
Kaplan-Meier繪製OBI-822 (原始名稱為OPT-822)的修改意圖治療(mITT)群體的無惡化存活期(PFS)及總體存活期(OS)顯示,與安慰劑相比,患者在完成9次OBI-822注射後,具有較高的PFS與OS。
藉由ELISA測定人類抗Globo H IgG效價的臨床試驗數據 藥劑/緩衝液製備
塗覆抗原:將1 mg/mL Globo H-神經醯胺溶於乙醇(OBI Pharma公司);人類血清的二級抗體:山羊抗人類IgG-AP (Jackson Immunoresearch公司,型號109-055-008);10X PBS,pH 7.4 (Gibco公司,型號70011-044);Tween-20 (Sigma-Aldrich公司,型號P2287);基質溶液:鹼性磷酸酶黃(pNPP)液體基質(Sigma-Aldrich公司,型號P7998);阻斷緩衝液(Sigma-Aldrich公司,型號B6429); PBST:溶於PBS的0.05% tween-20;終止溶液:鹼性磷酸酶終止液(Sigma-Aldrich公司,型號A5852)。 測定程序
將Globo H-神經醯胺在乙醇中稀釋至4 μg/mL。將50 μL稀釋的Globo H-神經醯胺溶液加入到標準反應盤的每個孔中。將具有反應混合物的盤在室溫下隔夜培養。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。向每個孔中加入100 μL阻斷緩衝液,並在室溫下培養30分鐘。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。
血清樣品稀釋:將樣品在阻斷緩衝液中進行兩倍連續稀釋,範圍為20、40、80、160、320、640、1280至2560倍(將40 μL血清樣品加入到760 μL阻斷緩衝液中以製備20倍稀釋)。將50 μL血清樣品加入到塗覆以及未塗覆的盤中的每個孔,並在室溫下培養60分鐘。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。將40 μL 0.3 mg/mL抗人類IgG-AP二級抗體原液加到7960 μL阻斷緩衝液中進行1:200倍的稀釋。將50 μL稀釋的抗人類IgG-AP抗體加入到塗覆以及未塗覆的盤中的每個孔,並在室溫下培養45分鐘。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。將100 μL基質溶液加入到塗覆以及未塗覆的盤中的每個孔,並於37°C下培養20分鐘。向每個孔中加入50 μL終止溶液。以ELISA讀取器以405 nm的波長讀取吸光值。 數據分析
通過僅來自塗覆盤的二級抗體的平均吸光值,與來自未塗覆盤加0.1的二級抗體的平均吸光值之差異獲得判定閾值。
效價定義為每次稀釋時塗覆盤的吸光值與未塗覆盤的吸光值的差。高於判定閾值的最高稀釋度為抗Globo H IgG的效價。 使用GraphPad Prism 6軟體進行統計學分析。
臨床患者的特徵列於表1。
無惡化存活期(PFS)表示OBI-822在幾種乳癌的生物亞型 (第I期、第II期、第III期、ER(+)、PR(+)、HER2(+)或三陰性)有反應。表2中列出了不同腫瘤亞型之間Globo H表現概況。
圖4及圖5顯示了9次注射試驗藥物後的無惡化存活期(PFS)。其表明OBI-822疫苗可以延長乳癌患者的存活時間。
圖6及圖7顯示在接受試驗藥物後產生/未產生IgG免疫反應(IgG標準1:640)的無惡化存活期(PFS)/總體存活期(OS)。其表明OBI-822疫苗可誘導IgG免疫反應,並延長乳癌患者的存活時間。
以聚醣陣列測定的人類抗Globo H IgM效價的臨床試驗數據 背景
聚醣陣列平台使用自動Agnitio BioIC系統,其中在微流控盒內進行ELISA。微流控盒包含微流體泵浦及閥的陣列、通道網絡、藥劑儲存容器、聚醣陣列反應區,以及廢棄物儲存容器。自動Agnitio BioIC系統將藥劑及樣品從其各自的容器中抽取送到反應區,以進行化學發光的多重ELISA反應。收集的數據由Agnitio Science and Technology公司提供的LabIT軟體分析。在先前的PCT專利申請(WO2017041027A1)中公開了Agnitio BioIC系統的設備的說明書。 藥劑/緩衝液製備
在594 μL樣品稀釋緩衝液(BioCheck公司,型號MB10175)中加入66 μL正常人類血清(Normal Human Serum,NHS)或來自220位乳癌患者樣品以及124個安慰劑樣品的血清,以形成十倍稀釋。通過將2 μL辣根過氧化物酶(HRP) - 共軛的山羊抗人類IgM (KPL公司,型號474-1003)在98 μL共軛物緩衝液(SuperBlock (TBS)阻斷緩衝液加0.2% Tween 20,Thermo Fisher Scientific公司,型號37535),以形成50倍稀釋,來製備二次抗體溶液。將40 μL稀釋的二次抗體溶液抽取加入2360 μL共軛物緩衝液中,以形成二次抗體溶液(3000x稀釋)。 測定程序
將620 μL微量洗滌緩衝液(在0.2% (v/v) Tween 20 (J.T. Baker公司,型號JTB-X251-07)中的磷酸緩衝鹽溶液(Thermo Fisher Scientific公司,型號70011))加入「清洗」容器中。將120 μL阻斷緩衝液(無蛋白質阻斷緩衝液,Thermo Fisher Scientific公司,型號37571)加入「阻斷」容器中。將120 μL二級抗體溶液加入「共軛」容器中。將100 μL血清加入「血清」容器中。在10分鐘內將120 μL基質緩衝液(SuperSignal ELISA Femto Maximum Sensitivity Substrate,Thermo Fisher Scientific公司,型號37074)加入到「基質」容器中。 數據分析
聚醣陣列以Agnitio BioIC泵浦機加壓30分鐘。使用Agnitio BioIC 分析儀目視監測結合的血清。陣列的吸收強度相對於抗人類Globo H IgG被轉化為「Ab含量(μg/mL)」。使用0.0625、0.125、0.25、0.5、0.75,以及1 μg/mL的人類IgM進行內部曲線繪製。使用每個晶片的內部曲線的線性回歸來計算斜率與截距。於某些實例中,抗體含量(μg/mL) = [(原始數據截距)/斜率]×0.1。
圖8顯示在第二週接受一次試驗藥物注射後產生/未產生早期IgM免疫反應的無惡化存活期(PFS)。其表明OBI-822疫苗可以誘導早期IgM免疫反應,並延長乳癌患者的存活時間。
使用基於人類抗鑰孔蟲戚血藍蛋白(KLH) IgG效價測定的臨床試驗數據來證明功效
使用人類抗鑰孔蟲戚血藍蛋白(KLH) IgG效價測定法顯示,藉由投予Globo系列抗原疫苗產生的免疫反應,可以被Globo系列抗原疫苗、Globo系列抗原,及/或載體蛋白所誘導。 藥劑/緩衝液的製備
KLH (Sigma-Aldrich公司,型號H1158,原液濃度5 mg/mL);塗覆緩衝液:碳酸氫鹽緩衝液pH 9.2 (Sigma-Aldrich公司,型號C3041-50CAP);二級抗體:山羊抗人類IgG-HRP (KPL公司,型號474-1002); 10X PBS,pH 7.4 (Gibco公司,型號70011-044);Tween-20 (Sigma-Aldrich公司,型號P2287);TMB基質溶液(Clinical公司,型號01016-1-500);阻斷緩衝液(Sigma-Aldrich公司,型號B6429); PBST:溶於 PBS之0.05% tween-20;終止溶液:1N H2
SO4
。 測定程序
用塗覆緩衝液將KLH稀釋至4 μg/mL。將50 µl稀釋的KLH溶液加入到標準孔盤中的每個孔中。將該盤置於4°C下隔夜培養。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。每個孔中加入100 μL阻斷緩衝液,並在室溫下培養30分鐘。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。
血清樣品稀釋:樣品用約1000、2000、4000、8000、16000、32000、64000至128000倍的阻斷緩衝液進行二倍連續稀釋(將1 μL血清樣品加入到999 μL阻斷緩衝液中,進行1000倍稀釋)。將50 μL樣品加入到塗覆及未塗覆的盤中的每個孔中,然後在室溫下培養1.5小時。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。以阻斷緩衝液將抗人類IgG-HRP二級抗體稀釋至1:20000。從1 mg/mL原液中取出1 μL,加入20 mL阻斷緩衝液中以進行1:20000稀釋。將50 μL抗人類IgG-HRP抗體加入到塗覆及未塗覆的盤中的每個孔中,並在室溫下培養45分鐘。將盤中液體倒出並以200 μL/每孔PBST洗滌三次。將100 μL TMB基質溶液加入到塗覆及未塗覆的盤的每個孔中,然後在室溫下培養5分鐘。向每個孔中加入100 μL終止溶液。通過ELISA讀取器以450 nm的波長讀取吸光值。
圖9顯示在患者接受OBI-822疫苗注射後表現出高抗KLH IgG免疫反應。共有30例臨床血清樣本被分為三組(反應者:接受OBI-822疫苗注射,增加抗Globo H IgG/IgM含量;非反應者:接受OBI-822疫苗注射,未增加抗Globo H IgG/IgM含量)。其表示OBI-822疫苗的投予確實可以誘導抗KLH免疫反應。因此,藉由投予Globo系列抗原疫苗產生的免疫反應,可以被Globo系列抗原疫苗、Globo系列抗原,或載體蛋白所誘導。實例 2 :使用代表性卵巢癌模型來證明功效
臨床試驗作為特定實施例:在患有非惡化性上皮性卵巢癌或輸卵管癌的婦女中使用Globo H-KLH (OBI-822/821)的主動免疫治療的開放標籤第II期試驗。
方法:這是一項開放式標籤的第II期試驗,在接受了細胞減量手術後接受以鉑為基礎的化療而未惡化的婦女中進行,其新診斷≥第2期上皮性卵巢癌或輸卵管癌。
對於參與接受治療的個體,在第1、2、3、4、12、20、28、36、44,以及52週皮下注射OBI-822 (30 μg Globo H)/OBI-821 (100μg ) (於第1、2、3、4、5、6、7、8、9,以及10週訪視)。疾病狀態根據包含RECIST 1.1標準的評估結果確定。根據客觀的RECIST 1.1標準對個體進行評估是否具有PD。在第28週及第52週進行RECIST標準的CT掃描/MRI。在治療期間,以約24週的間隔進行整個腹部(腹部及骨盆)CT掃描。CT掃描的空窗期為從計劃訪視依計畫書時間表的+/- 14天。不定期的腫瘤評估是根據研究者的判斷所進行的,評估時間與基線檢查一致。對於CT禁忌的個體,改以MRI進行檢查。
無病變、可測量,以及不可測量疾病的個體有資格納入本研究。 可測量的疾病由≥1個可測量病變所定義 (最長直徑[LD] ≥ 10 mm,螺旋電腦斷層[CT]掃描或 ≥ 20 mm的常規CT、磁共振成像[MRI],或X射線)。在基線時,最多可以將5個可測量的病變(每個器官最多2個病變)代表所有病變,作為目標病變(target lesions,TL)。用於確定TL的客觀腫瘤反應的RECIST 1.1標準被摘要於表3中。
未記錄為TLs的所有其他病變(或疾病部位)被辨認為非目標病變(non-target lesions,NTLs)。用於確定NTLs的客觀腫瘤反應的RECIST標準被摘要於表4中。
還記錄了任何新病變的細節;≥1個新病變的存在被評估為進展。 總體反應的RECIST評估被摘要於表5中。
研究族群:
患者的處置:對所有納入的個體進行以下患者資料的總結及報告:篩選患者的數量與百分比、接受試驗藥物、治療期間完成並終止、在追蹤期間的完成及停止。
每個分析組的患者之數量與百分比,以及排除的原因,根據所有招募患者的研究組。
在資料庫鎖定之前,研究小組審查違反規定的行為,以確定哪些違規行為使患者由EVA群體中失去資格。
臨床結果:陰性控制組(患者編號:065)(圖10):評估日期於2015年3月18日或之前開始。其顯示OBI-822治療不會在28週內導致任何腫瘤生成(訪視7)。因此,確認了OBI-822的安全性。
第III期卵巢癌(患者編號:035)(圖11):評估日期在2014年4月24日或之前開始。患者的原始症狀為「次厘米腸繫膜淋巴結腫瘤」 (病變類別:非目標腫瘤),透過CT掃描確認。其表示在治療OBI-822後28週內沒有任何腫瘤進展/轉移(SD)(訪視7)。因此,在28週內證實了OBI-822的腫瘤抑制能力。
第IV期輸卵管癌(患者編號:041)(圖12):評估日期在2014年5月22日或之前開始。患者的原始症狀為「肺腫瘤」(病變類別:非目標腫瘤),透過CT掃描確認。其表示在治療OBI-822後28週內沒有任何腫瘤進展/轉移(SD)(訪視7)。因此,在28週內證實了OBI-822的腫瘤抑制能力。
第III期卵巢癌(患者編號:060)(圖13):評估日期在2015年1月6日或之前開始。患者的原始症狀為「腹膜腫瘤」(病變類別:非目標腫瘤),透過CT掃描確認。其表示在治療OBI-822後28週內沒有任何腫瘤進展/轉移(SD)(訪視7)。因此,在28週內證實了OBI-822的腫瘤抑制能力。實例 3 : OBI-822 與 OBI-821 的混合指令
儲存條件:OBI-822及其安慰劑PBS樣品瓶儲存在2-8°C。OBI-821及其安慰劑PBS樣品瓶儲存在-15至-25°C。
研究組:
A組:主動治療組; 每次注射劑量:OBI-822 (相當於30 μg Globo H) / 100 μg OBI-821。最終總注射體積:0.8 mL。
B組:控制組; 每次注射劑量:PBS。最終總注射體積:0.8 mL。
試驗藥物:
樣品瓶1a (PBS:OBI-821控制組試驗製品)填充體積 - 0.5 mL。內容物:10 mM磷酸鈉,150 mM NaCl,pH6.8;
樣品瓶1b (OBI-821)填充體積 - 0.5 mL。內容物:在10 mM磷酸鈉、150 mM NaCl,pH6.8中含有250 μg/mL OBI-821;
樣品瓶2a (PBS:OBI-822控制組試驗製品)填充體積 - 0.75 mL。內容物:100 mM磷酸鈉,150 mM NaCl,pH7.2;
樣品瓶2b (OBI-822)填充體積 - 0.75 mL。內容物:在100 mM磷酸鈉、150 mM NaCl,pH7.2中含有相當於75 μg Globo H/mL OBI-822。
OBI-822與OBI-821的混合說明:
在處理時,以注射器取出0.5 mL的樣品瓶2a內容物(僅PBS)並放入樣品瓶1a (僅PBS)中或取出0.5 mL的樣品瓶2b內容物(在PBS中的OBI-822)並置於樣品瓶1b (在PBS中的OBI-821)。以和緩翻轉樣品瓶4-5次的方式來和緩地混合樣品瓶(樣品瓶1a或樣品瓶1b)的內容物。不要大力搖晃樣品瓶。此時,該樣品瓶含有安慰劑(僅PBS)或治療(OBI-822加OBI-821),並準備注射。然後從該樣品瓶中取出0.8mL用於注射個體。每個研究組的最終投予量摘要於表6中。
組合的OBI-822與OBI-821的穩定性在室溫下自回溶時起長達10小時是穩定的。組合產品的投予應在回溶後2小時內進行,以減少潛在的微生物生長。如果在回溶後2小時內不可能進行投予,組合產品應根據機構藥物標準作業程序進行銷毀,並記錄在藥物責任記錄中。圖14顯示試驗藥物的混合程序。實例 4 :允許與禁止的併用藥物
允許併用藥物:
鴉片:它可以用於疼痛控制,並允許對便秘進行預防性治療。
GCSF:如果醫生認為必要,將被允許。
雙磷酸鹽。
激素治療(對於已被分層為激素治療使用者的個體)。
如果使用的話,激素治療所選形式、劑量,或使用需要一致,亦即除非由於毒性不耐受,否則不能改變治療、不能添加更多療法或增加劑量。本研究中可以使用各種激素療法,常用的激素治療方法如下。
***抑制劑(例如,泰莫西芬、弗瑞斯錠)。
芳香酶抑制劑(例如,阿那曲唑[Arimidex]、依西美坦[Aromasin],以及復乳納[Femara])。
腦下垂體下調(例如,戈舍瑞林[Zoladex]、亮丙瑞林(Lupronide)) - 這些也稱為LHRH類似物。
Novaldex®
(泰莫西芬,選擇性***受體調節劑,SERM (selective estrogen-receptor modulator))。
Evista®
(雷洛昔芬,另一種SERM)。
Faslodex®
(氟維司群(fulvestrant),***受體下調劑)。
抗凝血劑(來匹盧錠(lepirudin) [Refludan]))。
酵素(拉布利酶(rasburicase) [Elitek])。
造血生長因子。
投予方法較佳係在沒有表7所列的併用藥物的情況下進行。
禁用的併用藥物
(例如,環孢菌素、雷帕黴素、他克莫司、利妥昔單抗等)。
東部合作腫瘤小組(Eastern Cooperative Oncology Group,ECOG)的表現。
醫生與研究人員使用這些量表及標準來評估個體的疾病進展情況,評估疾病如何影響個體的日常生活能力,並確定適當的治療及預後。這些被列於表8供衛生醫護專業人員使用。
雖然已經描述並展示出本發明的具體方面,但是這些方面應當僅被認為是對本發明的說明,而不是限制根據所附申請專利範圍解釋的本發明。本說明書中引用的所有出版物及專利申請的全部內容透過引用方式併入本文,用於所有目的,如同每個單獨的出版物或專利申請被全部用於所有目的而被詳細並單獨地指明透過引用方式併入本文。雖然為了清楚理解之目的,通過說明及示例的方式已經對本發明進行了一些詳細的描述,但是鑑於本發明的教導,對於本領域的普通技術人員將顯而易見的是,某些改變與修改可以在不脫離所附申請專利範圍的精神或範圍的情況下進行。
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圖1. OBI-822:活化的癌症免疫治療誘導用於殺傷腫瘤的ADCC以及CDC。由OBI-822造成的Globo H神經醯胺消耗有效地阻斷了TRAX依賴性血管生成並達到腫瘤退化。腫瘤分泌的可溶性因子結合其在內皮細胞上的各自的受體,引發磷脂酶C (phospholipase C,PLC)活化以及細胞內鈣的釋放,並促進內皮細胞的增殖、遷移以及管形成。PLC作為第二信使的「早期發生器」,驅動血管生成的早期階段。PLC活性受多個結合配偶體的調節,包括阻斷PLCβ1活性的轉位蛋白相關因子X (TRAX)。 該事件的分子機制涉及Globo-H神經醯胺與TRAX的結合,隨後釋放並活化PLCβ1。
圖2. OBI-822消耗Globo H-神經醯胺,其反過來會增加Notch 1降解,阻止腫瘤免疫抑制作用,導致腫瘤退化。Notch訊號傳導途徑為大多數生物體內進化保守的細胞訊號傳導系統,可以調節細胞增殖、分化、細胞凋亡,以及存活。Notch1的調節受E-蛋白轉錄因子E2A及其天然抑制劑ID3的控制。儘管E3泛素連接酶,ITCH,通過泛素化作用降解。對免疫細胞中添加Globo-H神經醯胺可抑制其增殖及細胞因子或免疫球蛋白分泌。Globo-H神經醯胺可誘導免疫抑制,其涉及通過誘導ID3及EGR2/3伴隨ITCH表現來抑制Notch1訊號傳導。
圖3. OBI-822導致細胞凋亡。細胞凋亡(程序性細胞死亡)有助於多細胞生物體的正常發育及組織重塑。局部黏著斑激酶(Focal adhesion kinase,FAK)已經涉及來自整合素、致癌基因,以及神經肽的訊號整合。已經報告了在人臍靜脈內皮細胞生長因子剝奪誘導的細胞凋亡的過程中半胱胺酸蛋白酶-3對FAK的蛋白水解切割,這意味著FAK與細胞凋亡之間的關聯。
圖4顯示接受9次注射試驗藥物後的無惡化存活期(mITT)(分級對數等級檢定,p
=0.0542)。
圖5顯示接受9次注射試驗藥物且在基線帶有疾病後無惡化存活期(mITT)(分級對數等級檢定,P=0.0362)。
圖6顯示有/無IgG免疫反應(IgG標準 1:640)的試驗藥物治療與安慰劑的無惡化存活期(mITT)。
圖7顯示有無IgG免疫反應(IgG標準 1:640)的試驗藥物治療與安慰劑的總體存活期(mITT)。
圖8顯示在第2週接受一次注射具有/不具有早期IgM免疫反應(IgM標準)的試驗藥物後與安慰劑的無惡化存活期(mITT)。
圖9顯示患者接受OBI-822疫苗注射後,具有高抗KLH IgG免疫反應。
圖10顯示OBI-822治療卵巢癌臨床試驗的陰性控制組(患者編號:065)。
圖11顯示具有OBI-822治療的卵巢癌臨床試驗的第III期卵巢癌(患者編號:035)。
圖12顯示具有OBI-822治療卵巢癌臨床試驗的第IV期輸卵管癌(患者編號:041)。
圖13顯示具有OBI-822治療的卵巢癌臨床試驗的第III期卵巢癌(患者編號:060)。
圖14顯示試驗藥物混合的程序。
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Claims (21)
- 一種包含Globo系列抗原疫苗及/或與Globo系列抗原交叉反應之疫苗以及佐劑的醫藥組合物在製備用於透過免疫療法治療癌症的藥物的用途,該藥物係有效於誘導或調節患有癌症之個體的免疫反應,其中,該Globo系列抗原疫苗為與KLH(鑰孔蟲感血藍蛋白)共軛的Globo H(Globo H-KLH),以及該佐劑為皂素佐劑,其中該藥物係以選自以下的一種或多種投予:(a)投予個體疫苗二次或更多次(例如,3、4、5、6、7、8、9、10、11、12次或更多次);(b)調整二次連續投予之間的時間間隔及/或劑量;(c)調整投予途徑及/或更改投予的注射位置;或(d)上述每種投予方式的任何組合,以增加抗體免疫反應及/或增加抗原-抗體結合力。
- 如請求項1之用途,其中該醫藥組合物包含OBI-822/OBI-821。
- 如請求項1之用途,其中該個體為人類。
- 如請求項1之用途,其中該免疫反應包含IgG、IgM或細胞調節的反應。
- 如請求項4之用途,其中該細胞為B細胞或T細胞。
- 如請求項1之用途,其中該藥物係有效於透過調節Globo系列抗原交互作用來增進該個體的存活期。
- 如請求項6之用途,其中該存活期包含總體存活期(OS)及/或無惡化存活期(PFS)。
- 如請求項6之用途,其中該Globo系列抗原交互作用的調節進一步包含以下一種或多種:(a)誘導用於殺傷腫瘤的抗體依賴性細胞毒性(Antibody-Dependent Cellular Cytotoxicity,ADCC)及補體依賴性細胞毒性(Complement-Dependent Cytotoxicity,CDC);(b)誘導抗Globo系列抗原的IgM/IgG免疫反應以引發ADCC及CDC調節的腫瘤細胞;(c)誘導抗Globo系列抗原的抗體捕捉從腫瘤細胞流出的Globo系列抗原-神經醯胺以阻斷轉位蛋白相關因子X(translin-associated factor X,TRAX)依賴性血管生成;(d)誘導抗Globo系列抗原的抗體以阻斷Globo系列抗原-神經醯胺誘導的Notch 1依賴性免疫抑制,從而增強T細胞的增殖及細胞激素的產生;(e)誘導抗Globo系列抗原的抗體以導致細胞凋亡;(f)抑制Globo系列抗原誘導的血管生成;或(g)OBI-822疫苗接種誘導細胞凋亡。
- 如請求項1之用途,其中該Globo H-KLH之治療有效劑量低於100μg。
- 如請求項1至9項中任一項之用途,其中該注射可以透過添加免疫反應增強劑來改變及/或補充。
- 如請求項1至9項中任一項之用途,其中該免疫反應為細胞免疫或體液免疫。
- 如請求項1至9項中任一項之用途,其中該免疫反應包含IgG、IgM或細胞調節的反應。
- 如請求項12之用途,其中該細胞為B細胞或T細胞。
- 如請求項1至9項中任一項之用途,其中該個體為人類。
- 一種如請求項1至14中任一項所述之包含Globo系列抗原疫苗及/或與Globo系列抗原交叉反應之疫苗以及佐劑的醫藥組合物在製備供實施用於鑑定有需要癌症治療的合適患者之方法的試劑之用途,該方法包含:(a)對該患者投予一有效劑量之Globo系列抗原疫苗;(b)評估該患者的免疫反應;(c)測定每位患者體內的Globo系列抗原的表現;以及(d)根據免疫反應指標以及Globo系列抗原的表現對該患者的適合性分類;其中該指標表示該患者具有良好的預後復原。
- 如請求項15之用途,其中該癌症為乳癌、肺癌、食道癌、直腸癌、膽道癌、肝癌、頰癌、胃癌、腸癌、直腸癌、鼻咽癌、腎癌、***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、膽囊癌、口咽癌、喉癌、皮膚癌、基底細胞癌、鱗狀細胞癌、黑色素瘤,或腦腫瘤。
- 如請求項15之用途,其中該癌症為乳癌。
- 如請求項17之用途,其中該乳癌為階段I、II、III、ER(+)、PR(+)、HER2(+)、三陰性、轉移或非轉移的。
- 如請求項15之用途,其中該免疫反應指標包含評估IgG效價、IgM效價、無惡化存活期(progression-free survival,PFS),及/或總體存活期(overall survival,OS)。
- 一種如請求項1至14中任一項所述之包含Globo系列抗原疫苗及/或與Globo系列抗原交叉反應之疫苗以及佐劑的醫藥組合物在製備供實施用於決定有需要的患者的癌症治療的預後及/或藥物反應之方法的試劑之用途,該方法包含:(a)鑑定出一已被診斷患有癌症的患者;(b)透過確定在接受如請求項1之治療後該患者的適合性以確定免疫反應的程度;(c)分析如請求項15所獲得之數據。
- 如請求項20之用途,其中該癌症為乳癌、肺癌、食道癌、直腸癌、膽道癌、肝癌、頰癌、胃癌、腸癌、直腸癌、鼻咽癌、腎癌、***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、膽囊癌、口咽癌、喉癌、皮膚癌、基底細胞癌、鱗狀細胞癌、黑色素瘤,或腦腫瘤。
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JP2018532990A (ja) | 2015-09-04 | 2018-11-08 | オービーアイ ファーマ,インコーポレイテッド | グリカンアレイおよび使用の方法 |
TWI704159B (zh) | 2015-10-07 | 2020-09-11 | 台灣浩鼎生技股份有限公司 | 新穎醣類抗體、醫藥組成物及其用途 |
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BR112018070097A2 (pt) | 2016-03-29 | 2019-02-12 | Obi Pharma, Inc. | anticorpo, hibridoma, composição farmacêutica, método para tratar câncer em um indivíduo, método para inibir a proliferação de células cancerígenas, método para diagnosticar o câncer em um indivíduo, método para tratar um paciente humano, método para fazer imagens de um indivíduo, conjugado de fármaco-anticorpo (adc), método para tratar câncer, anticorpo biespecífico e método para preparar uma população de anticorpos homogêneos |
SG11201809024UA (en) | 2016-04-22 | 2018-11-29 | Obi Pharma Inc | Cancer immunotherapy by immune activation or immune modulation via globo series antigens |
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JP7213549B2 (ja) | 2016-08-22 | 2023-01-27 | シーエイチオー ファーマ インコーポレイテッド | 抗体、結合性断片、および使用の方法 |
WO2018094414A1 (en) | 2016-11-21 | 2018-05-24 | Obi Pharma, Inc. | Conjugated biological molecules, pharmaceutical compositions and methods |
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2017
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Patent Citations (1)
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TW201429488A (zh) * | 2013-01-04 | 2014-08-01 | Obi Pharma Inc | 具有較高碳水化合物抗原密度之疫苗及新穎皂素佐劑 |
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CL2018002994A1 (es) | 2019-02-08 |
RU2018140976A3 (zh) | 2020-07-10 |
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SG11201809024UA (en) | 2018-11-29 |
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ZA201806919B (en) | 2020-01-29 |
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US20170304419A1 (en) | 2017-10-26 |
CA3021548A1 (en) | 2017-10-26 |
JP2019515916A (ja) | 2019-06-13 |
WO2017185089A2 (en) | 2017-10-26 |
JP2022115924A (ja) | 2022-08-09 |
US11583577B2 (en) | 2023-02-21 |
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