TWI523663B - 供治療表現表皮生長因子受體(EGFR)和GM3 N-羥乙醯基神經節苷酯(NeuGcGM3)之腫瘤用的醫藥組成物 - Google Patents
供治療表現表皮生長因子受體(EGFR)和GM3 N-羥乙醯基神經節苷酯(NeuGcGM3)之腫瘤用的醫藥組成物 Download PDFInfo
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- TWI523663B TWI523663B TW101146617A TW101146617A TWI523663B TW I523663 B TWI523663 B TW I523663B TW 101146617 A TW101146617 A TW 101146617A TW 101146617 A TW101146617 A TW 101146617A TW I523663 B TWI523663 B TW I523663B
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- neugcgm3
- ganglioside
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明關於人醫藥之領域,特別是關於治療過度表現表皮生長因子受體(EGFR)及N-羥乙醯基神經節苷酯(NeuGcGM3)之腫瘤。
表皮生長因子受體(EGFR)係目前臨床評估上最常使用之分子標靶之一。此分子過度表現於多種人上皮組織(Yarden,Y.,and Sliwkowski M.X.,Nat.Rev.Mol.Cell Biol.2001,2:127-137)。兩種最常被用於抑制EGF受體功能之治療係單株抗體(MAb)中和及抑制酪胺酸激酶活性之小分子(酪胺酸激酶抑制劑(TKI))(Ciardiello,F.,and Tortora G.,N.Engl.J.Med.2008,358:1160-1174)。不過也有研究顯示含有EGFR胞外域之疫苗以極小粒徑顆粒(VSSP)作為佐劑時,在Lewis大鼠肺癌模型中產生抗轉移作用(Sánchez Ramírez B.,et al,Int.J.Cancer.2006,119:2190-2199)。抗EGFR單株抗體治療藉由干擾致癌信號及誘導由Fc受體所媒介之先天免疫反應機轉以媒介腫瘤緩解(Martinelli,E.,et al,Clin.Exp.Immunol.2009,158:1-9)。
一些已被產製之針對EGFR之人單株抗體包括:西妥昔單抗(Cetuximab)(Garrett CR,and Eng C.,Expert Opin Biol Ther.2011;11:7,937-49)及尼妥珠單抗
(Nimotuzumab)(Mateo C,Immunotechnology 1997;3:71-81)。尼妥珠單抗於治療過度表現EGFR之不同腫瘤的抗腫瘤效果已被描述(Crombet T,et al,Cancer Biol Therapy.2006,5:375-379),與其他治療之組合亦被描述(Crombet T,et al,J Clin Oncol.2004,22:1646-1654;Zhao KL,et al,Invest New Drugs.2011 Pre published online September 8)。另一方面,針對鼠EGFR所產製之7A7 MAb於Lewis肺癌之治療中顯示由T細胞媒介之抗腫瘤效果(Garrido G.,et al,Cancer Immunol Immunother.2007,56:1701-1710)。
另一種受到廣泛研究之標靶係神經節苷酯,其係結構中包含唾液酸之鞘糖脂。該等分子存在於正常組織,並過度表現於腫瘤組織(Zhang S,et al.Int J Cancer 73:42-49,1997)。唾液酸有兩種形式:N-乙醯基化及N-羥乙醯基化,後者被發現存在於人腫瘤(Malykh Y N.,et al,Biochimie.2001,83:7623-634),兩者皆為神經節苷酯(Kawai T.et al,1991 Cancer.Res.(51)1242-1246)及N-羥乙醯基化糖蛋白(Devine P.L.,et al,Cancer Research,1991,51:21,5826-5836)。由於該等分子被識別於許多惡性腫瘤中,因此它們是很引人注意之癌治療標靶。特別地,NeuGcGM3神經節苷酯係由14F7 MAb專一性辨識(Carr A.et al,Hybridoma,2000,19:3,241-247)。該神經節苷酯已藉由多種方法在不同的腫瘤中識別(Blanco R.,et al,ISRN Pathology.2011,Article ID 953803,10
pag.,Marquina et al,Cancer Research.1996,56:22,5165-5171)。
針對腫瘤之NeuGcGM3的主動免疫療法已被發表,該療法使用NeuGcGM3/VSSP分子疫苗(Estevez F.,et al,Vaccine.1999,18:190-197),在乳癌後期病患顯示其具有免疫原性及安全性(Carr A.,et al,JCO.2003,21:1015-1021)。另外,臨床前試驗顯示彼之抗腫瘤(抗轉移)療效係由NK及CD8+細胞之細胞性反應機轉媒介(Labrada M.,et al,Expert Opin.Biol.Ther.2010,10:2,153-162)。同時,抗腫瘤療效也見於經抗遺傳性型疫苗(1E10抗遺傳性型單株抗體雷妥莫單抗(Racotumomab),其模擬N-羥乙醯基神經節苷酯)免疫之非小細胞肺癌病患(Alfonso S.,et al,Cancer Biology & Therapy.2007,6:12,1847-1852)。此疫苗已發表之結果顯示彼之免疫原性及安全性(Alfonso M.,et al,Journal of Immunology.2002,168:2523-2529)。
細胞膜微環境中之EGFR對於腫瘤細胞之生長扮演重要的控制角色。研究顯示GM3神經節苷酯抑制許多細胞系之EGFR依賴性增生(不論體內或體外)。GM3抑制EGFR激酶活性(EGFR自體磷酸化)。GM3神經節苷酯抑制EGFR之激酶結構域之自體磷酸化。GM3具有別位調節不活化形式之結構轉變成可傳訊之EGFR二聚體之潛力,以防止該激酶之細胞內結構域自體磷酸化成配體結合位點(Coskun Ü.,et al,PNAS.2011,108:22,9044-
9048)。細胞膜之神經節苷酯組成之改變對於調節EGFR信號傳導非常重要(Zurita AR.,et al,Biochem.J.2001,35:465-472)。
醫學界預期同步或交替使用抗腫瘤療法會帶來好消息(Takeda K.et al,Cancer Sci.,2007;98:9,1297-1302)。但實際上不是所有使用多重抗腫瘤療法之情況都得到正面及協同之效果。一項轉移性結直腸癌之第三期臨床試驗使用抗EGFR MAb(西妥昔單抗(Cetuximab))及抗血管內皮生長因子MAb(貝伐珠單抗(Bevacizumab)),同時併用強效之化學治療藥物療法,有病例顯示癌病程之惡化,該等治療相較於僅接受貝伐珠單抗加化學療法之病患亦造成嚴重不良反應(Tol J.,et al,NEngl J Med.2009;360:6,563-72)。在病患成功進行多種治療係該等治療之選擇標靶、腫瘤位置及應用於各例之治療的性質(抗體、疫苗或其他)之間的特定功能關係之結果。
現在文獻證據顯示腫瘤細胞中之神經節苷酯與EGFR之間有結構性及功能性關係。然而,實際應用此關係以於相同病患成功應用針對EGFR及神經節苷酯標靶之治療尚未於臨床或臨床前試驗中討論。本發明之新穎性在於這是第一次有臨床前及臨床證據顯示,使用抗EGFR治療及抗NeuGcGM3疫苗對於共同表現該等標靶之腫瘤具有協同增強之抗腫瘤活性。
本發明關於專一性針對EGFR及GM3 N-羥乙醯基神經節苷酯癌症標靶之醫藥組成物,目的為增進由針對該等標靶之治療所分別產生之療效。在一實施態樣中,本發明包含針對GM3 N-羥乙醯基之疫苗及針對EGFR之抗體。在另一實施態樣中,本發明包含針對N-羥乙醯基GM3之疫苗及針對EGFR之疫苗。
在本發明之其他實施態樣中,該針對神經節苷酯標靶之疫苗包含如下列疫苗:NeuGcGM3/VSSP疫苗及/或抗遺傳性型疫苗(經氧化鋁佐劑化之雷妥莫單抗(Racotumomab))。在另一實施態樣中,本發明包含抗EGFR治療如尼妥珠單抗(Nimotuzumab)及/或EGFR疫苗。
在另一實施態樣中,本發明包含用於治療癌之組成物,該組成物包含針對EGF受體之化合物及針對NeuGcGM3神經節苷酯之化合物。
在另一態樣中,本發明提供醫藥組成物,該醫藥組成物包含與醫藥上可接受之賦形劑混合之上述化合物之任一者。
本發明之化合物可作為藥物,也可用於製造藥物,包括用於治療如癌之病狀之藥物。
在另一實施態樣中,本發明之治療性組成物可用於癌治療,特別是不同部位之人腫瘤。較佳地,本發明之治療性組成物可用於治療該等同時表現EGFR及神經節苷酯之N-羥乙醯基變異體之腫瘤。最佳係用於治療肺癌、乳癌、
消化道癌、泌尿生殖系統癌及源自神經外胚層組織及淋巴細胞增生性疾病之肉瘤。
任何適當之上述化合物之調製劑可經製備以藉由該領域已知之方法投予。可用之賦形劑或載劑可根據意圖投予途徑及該經投予之化合物的物理性質加以選擇,無須過度實驗。
任何適當之投予途徑皆可被使用,根據醫師治療病患之標準,包括但不限於:非經腸、靜脈、肌肉內、經皮、局部及皮下。製備適用於各種投予途徑之適當調製劑係該領域已知。
各種物質之調製劑通常包括稀釋劑,有些調製劑還包括佐劑、緩衝劑、保存劑等。該等化合物亦可以脂質體或微乳化液組成物投予。
以注射而言,調製劑可經製備為習用形式,如液體溶液或懸浮液,或適合在注射前經溶解或懸浮於液體中之固體形式。適當之賦形劑包括例如水、鹽水、葡萄糖及類似化合物。
本發明之化合物可單獨使用或與另一治療劑組合使用。在特定實施態樣中,本發明關於與用於所欲治療之腫瘤類型之習用化學治療及/或放射線治療組合。
在另一實施態樣中,本發明亦關於同時、交錯或輪流使用針對癌治療之EGFR及GM3 N-羥乙醯基神經節苷酯標靶之療法。
針對EGFR之化合物與針對GM3 N-羥乙醯基神經節
苷酯標靶之化合物係分開投予,甚至在不同時間點以不同之頻率投予。兩種化合物皆可經任何已知途徑投予,如皮下、靜脈、皮內、肌肉內、腹腔內或類似途徑。在許多實施態樣中,至少一種及可任意選擇地二種治療劑可非經腸投予。
當本發明之化合物或組成物係與另一抗癌劑組合使用時,本發明提供例如同時、交錯或輪流治療。因此,本發明之化合物可於分開之醫藥組成物同時投予,且其中本發明之化合物可在另一抗癌劑投予之前或之後相隔數秒、數分鐘、數小時、數天或數周投予。
本發明提供控制及/或抑制腫瘤生長之方法,該方法包含對需要控制及/或抑制腫瘤生長之個體投予可有效控制或減少腫瘤增生之量的此處所述之化合物之組合。在某些實施態樣中,腫瘤增生係與腫瘤之不同臨床階段有關,惟其腫瘤共同表現EGFR及N-羥乙醯基GM3。在特定實施態樣中,本發明關於肺癌、乳癌、消化道癌、泌尿生殖系統癌及源自神經外胚層組織及淋巴細胞增生性疾病之肉瘤。
本發明亦包括治療需要該等治療之個體的癌之方法,該等治療方法包含對該個體投予治療有效量之針對EGFR以用於治療該疾病之化合物,及對該個體投予有效增進該所欲效應之量的NeuGcGM3疫苗或抗遺傳性型疫苗。本發明之改善係關於部分或完全緩解或穩定該疾病之臨床症狀。在本發明之另一實施態樣中,改善係指減少腫瘤體積
及/或誘導個體之存活增加。
在某些實施態樣中,本發明包含包括第一誘導期及第二維持期之方法。在特定實施態樣中,該誘導期包含在大約8至14周期間,大約每7至14天對病患投予劑量範圍約0.1至2 mg之抗EGFR疫苗。在該期間,病患將被投予NeuGcGM3抗神經節苷酯治療,該治療包含劑量範圍約0.1至2 mg之NeuGcGM3疫苗或抗遺傳性型疫苗,投予間隔約7至14天。
本發明包括一種方法,該方法包含在約6至10周之時間期間對病患投予劑量範圍約100至400 mg之抗EGFR之被動治療。在另一實施態樣中,該抗EGFR治療包含大約每7至14天之時間間隔投予劑量範圍約0.1至2 mg之針對EGFR之疫苗。在該期間,病患將額外接受劑量範圍約0.1至2 mg之NeuGcGM3疫苗或抗遺傳性型疫苗,投予間隔約7至14天。
在另一實施態樣中,本發明之治療方法的第二期包含在無毒性及/或疾病之臨床症狀出現時,經設計作為維持治療投予之治療計畫。在維持期中,疫苗係較佳地以上述劑量及約1至3個月之時間間隔投予。在另一實施態樣中,被動治療係以自約14天至3個月之間隔投予。該治療計畫可於自約1至5年之期間投予。
在一些實施態樣中,針對EGFR之治療劑及NeuGcGM3疫苗或抗遺傳性型疫苗係同時投予。針對EGFR之治療劑及NeuGcGM3疫苗或抗遺傳性型疫苗有時
同時使用於個體。
在一些實施態樣中,NeuGcGM3抗神經節苷酯治療可藉由皮下、靜脈、皮內、肌肉內或腹腔內注射投予,而抗EGFR治療可藉由皮下、靜脈或肌肉內注射途徑投予。在其他實施態樣中,該投予部位係藉由輸入淋巴結之存在決定。
在另一實施態樣中,在施用治療期間紀錄病患之某些生化及影像參數。細胞性及體液性免疫較佳係利用病患之血液分析。血液測試之實施頻率自每周一次至每六個月一次。
本發明所使用之「共同表現」係指兩種標靶皆表現但不一定具有靠近之結構關係,此定義之操作標準係藉由雙重染色測定EGFR及N-羥乙醯基神經節苷酯(NeuGcGM3)之表現,使用螢光顯微鏡及能夠重疊影像之處理器。
本發明所使用之「共同位置」係指兩種標靶在結構上相近,此定義之操作標準係使用共軛焦顯微鏡藉由雙重染色測定EGFR及N-羥乙醯基神經節苷酯(NeuGcGM3)之表現。
在另一實施態樣中,本發明包含一種針對EGFR之化合物及針對NeuGcGM3神經節苷酯之化合物於製備根據下列療程供延緩病患之腫瘤生長的藥物之用途:(a)首先對該病患投予包含針對EGF受體之化合物之藥物,及(b)接著對同一名病患投予包含針對NeuGcGM3神
經節苷酯之化合物之藥物。
投予可依照此順序或相反順序,也就是先對該病患投予包含針對NeuGcGM3神經節苷酯之化合物之藥物,接著對同一名病患投予包含針對EGF受體之化合物之藥物。
在特定實施態樣中,本發明包含一種用於治療共同表現EGFR及NeuGcGM3神經節苷酯標靶之腫瘤的試劑套組,該套組包含同時、交錯或輪流投予針對EGFR之化合物及另一針對NeuGcGM3神經節苷酯之化合物。
測量腫瘤之EGFR及NeuGcGM3治療性標靶之表現,可利用該領域所述之為達該等目的之任何方法進行。該測量係於不同位置及來源之腫瘤進行,腫瘤樣本可先經福馬林固定或為新鮮之組織切片。在較佳之實施態樣中,該檢測係藉由實施辨識EGFR及GM3 N-羥乙醯基變異體之免疫技術進行。特別是,免疫組織化學及亮視野顯微鏡檢法可被分開用於免疫辨識兩種分子,或利用免疫螢光及螢光顯微鏡檢測定共同表現,或利用免疫螢光及共軛焦顯微鏡檢測定共同位置。
在本發明之較佳實施態樣中,EGFR可利用ior egf/R3m MAb(5-20μg/ml)檢測(於EP 0586002B1說明),NeuGcGM3可利用14F7 MAb(5-25μg/ml)檢測(於US 6,429,295或EP 0972782B1說明)。在本發明之
一實施態樣中,要分開免疫辨識兩種分子(簡單染色),可使用Dako,LSABR過氧化酶系統DAB(Dako,Carpinteria,California,USA)作為檢測系統。
由於EGFR係位於腫瘤細胞之細胞膜,而GM3 N-羥乙醯基係位於細胞膜及細胞質內,因此當反應強度等於或大於20%陽性時,免疫辨識被視為陽性。
在較佳之實施態樣中,兩種分子之共表現可利用雙重染色技術檢測並藉由螢光顯微鏡分析,僅於先前兩種分子之分開免疫辨識皆呈陽性之該等腫瘤樣本中進行。兩種分子之共同位置可利用雙重染色技術檢測,且藉由共軛焦螢光顯微鏡分析。在較佳之實施態樣中,EGFR之免疫辨識係藉由與Ior egf/R3m mAb(5-20μg/ml)培養1小時,隨後與經若丹明共軛之IgG抗體(Dako,Carpinteria,California,USA)培養進行。在另一較佳之實施態樣中,NeuGcGM3免疫檢測係利用生物素基化14F7 mAb(5-20μg/ml)進行30分鐘。接著使用經FITC共軛之鏈黴抗生物素蛋白(Dako,Carpinteria,California,USA)。
下列實例說明本發明之較佳實施態樣,因此作為本發明之示例但絕不應被視為本發明之限制。
腫瘤樣本係經固定於中性福馬林緩衝液並以石蠟包埋
技術處理,此為該領域之技藝人士所知。
將如此獲得之厚度5微米之組織切片置於60℃ 30分鐘,於一系列濃度漸減之醇中脫蠟及復水,置於蒸餾水中10分鐘,然後以TBS清洗5分鐘。總組織蛋白之反應性係利用市售溶液(Dako,Carpinteria,California,USA)封閉30分鐘。EGFR係利用ior egf/R3m(20μg/ml)進行免疫檢測1小時。NeuGcGM3之免疫辨識係利用14F7(MAb 20μg/ml)進行30分鐘。在與一級抗體反應後,兩者皆利用Dako之LSABR過氧化酶系統DAB(Dako,Carpinteria,California,USA)作為檢測系統。組織切片經脫水後,使用Mayer's蘇木精對比(Dako,Carpinteria,California,USA)。以TBS清洗液(1X)取代一級抗體(Ior egf/R3m MAb或14F7 MAb)以獲得陰性對照,乳腺管癌被用來作為陽性對照。
EGFR之免疫辨識係位於腫瘤細胞之細胞膜,NeuGcGM3神經節苷酯係於細胞之細胞質及/或細胞膜檢測。
雙重染色:EGFR係藉由Ior egf/R3m MAb(抗EGFR)檢測,然後與經FITC共軛之鏈黴抗生物素蛋白(Dako,Carpinteria,California,USA)一起培養。NeuGcGM3係藉由生物素基化之14F7 MAb檢測,然後與經若丹明共軛之抗鼠IgG抗體(Dako,Carpinteria,California,USA)培養。兩種分子於腫瘤細胞之共表現係經識別為圖中之黃色。組織切片影像經過數位化,利用連
接至Olympus BX51螢光顯微鏡(Olympus,Japan)之相機分析。數位影像之分析使用ImageJ影像處理軟體1.43u版。
使用之鼠腫瘤模型係Lewis肺癌(3LL-D122)及骨髓瘤P3-X63-Ag8.653(X63)。
進行雙重染色以測定共表現/共位。EGFR之免疫辨識係藉由與經生物素基化之7A7 MAb(20μg/ml)培養1小時,然後與經FITC共軛之鏈黴抗生物素蛋白(Dako,Carpinteria,California,USA)培養。NeuGcGM3之免疫染色係藉由與14F7 MAb(20μg/ml)培養30分鐘測定,然後與經若丹明共軛之抗鼠IgG抗體(Dako,Carpinteria,California,USA)培養。陰性對照係藉由以TBS清洗液(1X)取代一級抗體(7A7 MAb或14F7 MAb)獲得。共表現係藉由使用Olympus BX51螢光顯微鏡(Olympus,Japan)測定,並利用ImageJ影像處理軟體1.43u版分析數位影像。共位係藉由共軛焦雷射顯微鏡Flouview FV500(Olympus,Japan)測定。
圖1顯示EGFR與NeuGcGM3於多種鼠模型腫瘤樣本中之共位。EGFR係藉由生物素基化之7A7 MAb及接著經FITC偶合之鏈黴抗生物素蛋白識別。黃色代表兩種分子於鼠模型之腫瘤細胞中共位(C及F),因為顏色重疊所致。
在試驗計畫第0天,動物係經體積0.05 ml之2x105 Lewis表皮樣癌細胞(3LL-D122)接種於右足底。在試驗第3天,動物係經隨機分組為各10隻動物之四個試驗組。在第24天,當腫瘤到達8至9 mm體積時,進行原發性腫瘤切除。自第48天,開始觀察動物之臨床狀態。存活資料利用對數等級檢定分析(p<0.05),結果以卡普蘭-邁爾(Kaplan-Meier)曲線顯示。該結果包括在相同條件下進行之三個試驗。
試驗組
未治療對照組(T)
被動抗EGFR療法:7A7 MAb,於第3、5、7、9、31、33及35天經靜脈注射投予劑量56μg於200μl鹽水溶液
主動抗NeuGcGM3療法:NeuGcGM3/VSSP疫苗,於第7、21、35及47天經皮下注射投予劑量200 μg於200μl
同時投予抗EGFR及抗NeuGcGM3療法係如第2及3組所述。
圖2a顯示同時投予抗EGFR及抗NeuGcGM3療法(第4組)至經Lewis肺癌誘導之肺轉移模型,相較於其他試驗組增加60%之動物存活。存活動物(第4組一隻)於試驗結束後一周被安樂死並取出肺。巨觀分析顯示只有一隻動物顯示二個肺之轉移,也注意到其他動物之肺部正常(圖2b)。此試驗結果顯示,抗EGFR與抗NeuGcGM3
療法於此鼠腫瘤模型具有強協同性抗腫瘤活性,其中EGFR及NeuGcGM3係共位(見實施例2)。
由於在人肺腫瘤之樣本經常發現治療性標靶EGFR及NeuGcGM3神經節苷酯之共位/共表現(實施例1)及實施例3顯示之臨床前證據,我們進而研究以抗EGFR(Nimotuzumab抗體)與抗神經節苷酯(Racotumomab/Alumina抗遺傳性型疫苗)療法同時治療肺癌病患,該等病患已接受各腫瘤位置之標準療法且已發生疾病惡化。
表2顯示Racotumomab(1E10/Alumina)疫苗作為單一治療或與Nimotuzumab組合治療之擴大評估(憐憫用法)之試驗結果。末期(復發及/或轉移)非小細胞肺癌(NSCLC)病患之存活係經觀察。應注意的是,參加此試驗之病患已經接受過所有經建立之標準治療,僅能接受緩和、非腫瘤特定療法,且在被納入試驗時他們的疾病發生惡化。在接受同時針對兩種標靶之治療組的病患中,相較於僅接受單一治療之病患,觀察到治療兩年之整體存活有顯著增加。
表2。抗EGFR(Nimotuzumab抗體)與抗神經節苷酯(Racotumomab/Alumina抗遺傳性型疫苗)之兩年治療增加非小細胞肺癌病患之存活率
圖3顯示針對EGFR(Nimotuzumab)之被動治療及NeuGcGM3抗神經節苷酯疫苗(Racotumomab/Alumina)於NSCLC病患之客觀反應,該病患如上所述已接受過所有經建立之標準療法,僅能接受緩和、非腫瘤特定療法,且在被納入試驗時疾病發生惡化。圖3A顯示診斷時腫瘤之位置及範圍。圖3B顯示治療二年後之電腦斷層(CT)結果。在後圖中,僅見到與大泡性肺氣腫有關之透明度增加之纖維母細胞反應區域,未觀察到肺腫瘤病灶。三年後仍觀察到相同的放射學影像。此結果顯示該治療導致非常末期之腫瘤意外完全緩解。
圖4顯示腹膜後-胰週血管外皮細胞瘤(軟組織腫瘤)病患之腹腔連續電腦斷層掃描,該腫瘤對放射治療及化學治療無反應。該病患在初步診斷後接受抗EGFR(Nimotuzumab)及抗神經節苷酯(NeuGcGM3/VSSP疫
苗)治療18個月。病患有嚴重疼痛,在臍周區域有跳動腫瘤團塊,且體重減輕超過15公斤。圖4A及B對應治療開始時;C及D對應三年後之評估。在治療三年後可觀察到疾病穩定,兩張影像皆顯示腫瘤大小維持相同。另外,在72個月的評估期間,病患維持極佳的生活品質,他能繼續工作。亦可發現腫瘤團塊有變小之傾向。總結來說,此病患顯示意外之對治療有反應之臨床好處。
經如本發明所述之抗EGFR及抗神經節苷酯免疫療法治療之癌病患對長期治療展現絕佳之耐受性(無顯著毒性)。本發明之治療促進疾病穩定、提高生活品質、延長疾病至惡化時間及病患之整體存活。上述治療之效果優於在接受慣用之抗EGFR或抗神經節苷酯單一治療之病患所觀察到之結果。
圖1。在不同的鼠腫瘤中,EGFR係與NeuGcGM3神經節苷酯共位。於Lewis大鼠表皮樣癌中誘導之肺轉移(A至C)及鼠骨髓瘤P3-X63-Ag.8653(D-F)之EGFR及NeuGcGM3神經節苷酯之共位(C及F)。
圖2。抗EGFR治療(7A7 MAb)與NeuGcGM3(NeuGcGM3/VSSP)抗神經節苷酯疫苗之組合協同增加荷Lewis肺癌之C57BL/6小鼠的存活。
圖3。針對EGFR之被動療法(尼妥珠單抗(Nimotuzumab))及NeuGcGM3(雷妥莫單抗(Racotumomab)/
Alumina)抗神經節苷酯疫苗於非小細胞肺癌病患之客觀反應。
圖4。腹膜後-胰週血管外皮細胞瘤之病患對抗EGFR(Nimotuzumab)治療與NeuGcGM3(NeuGcGM3/VSSP)神經節苷酯疫苗療法之組合具有意外的臨床反應。
Claims (14)
- 一種用於治療癌之組成物,其包含單株抗體尼妥珠單抗(Nimotuzumab)及抑制NeuGcGM3神經節苷酯功能之化合物。
- 如申請專利範圍第1項之組成物,其中該抑制NeuGcGM3神經節苷酯功能之化合物係經調合成疫苗。
- 如申請專利範圍第2項之組成物,其中該疫苗具有NeuGcGM3/非常小體積顆粒(VSSP)作為活性成份。
- 如申請專利範圍第2項之組成物,其中該疫苗係經氧化鋁佐劑化之雷妥莫單抗(Racotumomab)抗遺傳性型(anti-idiotypic)疫苗。
- 如申請專利範圍第1項之組成物,其中該癌係共同表現EGFR及NeuGcGM3神經節苷酯標靶之腫瘤。
- 如申請專利範圍第1項之組成物,其中該腫瘤係選自由下列所組成的群組:肺癌、乳癌、消化道癌、泌尿生殖系統癌或源自神經外胚層組織及淋巴細胞增生性疾病之肉瘤的癌。
- 一種尼妥珠單抗(Nimotuzumab)及抑制NeuGcGM3神經節苷酯功能之化合物於製備根據下列療程供延緩病患之腫瘤生長的藥物之用途:(a)首先對該病患投予包含尼妥珠單抗(Nimotuzumab)之藥物,且(b)接著對同一名病患投予包含該抑制NeuGcGM3神經節苷酯功能之化合物之藥物。
- 一種尼妥珠單抗(Nimotuzumab)及抑制NeuGcGM3神經節苷酯功能之化合物於製備根據下列療程供延緩病患之腫瘤生長的藥物之用途:(a)首先對該病患投予包含該抑制NeuGcGM3神經節苷酯功能之化合物之藥物,且(b)接著對同一名病患投予包含尼妥珠單抗(Nimotuzumab)之藥物。
- 一種尼妥珠單抗(Nimotuzumab)及抑制NeuGcGM3神經節苷酯功能之化合物於製備根據療程供延緩病患之腫瘤生長的藥物之用途,其中該療程涉及同時、交錯或輪流投予針對癌治療中EGFR及GM3 N-羥乙醯基神經節苷酯標靶之療法。
- 如申請專利範圍第7至9項中任一項之用途,其中該抑制NeuGcGM3神經節苷酯功能之化合物係經調合成NeuGcGM3/VSSP疫苗或抗遺傳性型雷妥莫單抗/氧化鋁疫苗。
- 如申請專利範圍第7至9項中任一項之用途,其中該尼妥珠單抗(Nimotuzumab)的劑量係自約100至400mg。
- 如申請專利範圍第7至9項中任一項之用途,其中該NeuGcGM3疫苗或該抗遺傳性型疫苗的劑量係自約0.1至2mg。
- 一種抑制NeuGcGM3神經節苷酯功能之化合物及尼妥珠單抗(Nimotuzumab)於製備供延緩病患之腫瘤生 長的藥物之用途,其中該病患罹患肺癌、乳癌、消化道癌、泌尿生殖系統癌或源自神經外胚層組織及淋巴細胞增生性疾病之肉瘤。
- 一種試劑套組,其係用於其中EGFR及NeuGcGM3神經節苷酯標靶共同表現之腫瘤治療,其中該試劑套組包含同時、交錯或輪流投予:(a)尼妥珠單抗(Nimotuzumab),及(b)抑制NeuGcGM3神經節苷酯功能之化合物。
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