TWI696632B - 抗-類egf結構域多重6(egfl6)抗體及其於癌症診斷及治療中之應用 - Google Patents
抗-類egf結構域多重6(egfl6)抗體及其於癌症診斷及治療中之應用 Download PDFInfo
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Abstract
本發明係關於抗-類EGF結構域多重6抗體(抗-EGFL6抗體)及使用該抗-EGFL6抗體之癌症檢測(或診斷)及治療。本發明產生能夠結合至EGFL6且抑制血管生成及癌細胞生長之抗-EGFL6抗體,尤其係單鏈抗體片段(scFv)及人類化抗體。
Description
本發明係關於癌症檢測(或診斷)及治療之領域。特定而言,本發明係關於抗-類EGF結構域多重6抗體(抗-EGFL6抗體)及使用該抗-EGFL6抗體之癌症檢測(或診斷)及治療。
癌症係在身體任何部位中異常細胞之不受控生長。異常細胞稱為癌細胞、惡性細胞或腫瘤細胞。癌症之早期診斷通常增加了成功治療或治癒該疾病之可能性。
生物標記物係檢測癌症之潛在工具。EGFL6係表皮生長因子(EGF)重複超家族蛋白之成員且由類EGF重複區及整聯蛋白締合基序(RGD)組成。EGFL6促進內皮細胞遷移及血管生成。George Yeung等人報導,EGFL6編碼預期信號肽,從而表明其得以分泌,且其轉錄物表現於腦及肺腫瘤及胎兒組織中(George Yeung等人,Genomics 62, 1999, pp. 304-307)。實施研究以鑑別卵巢腫瘤血管系統之分子特徵且展示腫瘤血管標記物可用作卵巢癌之潛在生物標記物及分子靶,其中EGFL6係該等標記物之一(Ronald J. Buckanovich等人,Journal of Clinical Oncology, 2007,第25卷,第7期,pp. 852-861)。然而,一文章報導,EGFL6 mRNA以高含量發現於卵巢癌中,其與良性腦膜瘤中相當,且與纖維母細胞腦膜瘤相比,EGFL6 mRNA含量在所有其他所研究腫瘤中(包含神經膠質瘤、肺癌、肝細胞癌、胰臟癌、胃癌、乳癌、前列腺癌、結腸直腸癌及膀胱癌)顯著降低(Xuanchun Wang等人,PLOS ONE;2012,第7卷,第12期,e52707)。
亦報導,EGFL6過度表現於W1TR細胞系中且係促進內皮細胞遷移及血管生成之分泌蛋白(Radoslaw Januchowski等人,Oncology Reports 32: 1981-1990, 2014)。另一文章報導,EGFL6係乳癌中之候選腫瘤血管系統配體(Benjimin M Larimer, J. Mol Biomark Diagn. 2014, 5(3): doi:10.4172/2155-9929.1000178)。WO2009057849揭示用於結腸癌之診斷組合物,其包括量測一或多種選自KLK6、CKS2、IFITMl、SPPl、DPEPl、CSTl、CDH3、ANLN、CXCLl、MELK、CDCAl、CTHRCl、CEACAM6、MMPl、LCN2、HS6ST2、EGFL6及CA9之基因之mRNA或蛋白質含量之藥劑。
然而,實際上並無單獨EGFL6應用於臨床癌症診斷。此外,亦需要研發用於癌症治療之抗-EGFL6抗體。
本發明提供經分離抗-EGFL6抗體或其抗原結合部分,其包括以下中之至少一者:由SEQ ID NO: 1或2之胺基酸殘基組成之輕鏈CDR1 (L-CDR1),或具有與SEQ ID NO: 1及2中之任一者具有至少80%一致性之胺基酸序列之變體;由SEQ ID NO: 3或4之胺基酸殘基組成之輕鏈CDR2 (L-CDR2),或具有與SEQ ID NO: 3及4中之任一者具有至少80%一致性之胺基酸序列之變體;及由SEQ ID NO: 5或6之胺基酸殘基組成之輕鏈CDR3 (L-CDR3),或具有與SEQ ID NO: 5及6中之任一者具有至少80%一致性之胺基酸序列之變體;及
以下中之至少一者:由SEQ ID NO: 7或8之胺基酸殘基組成之重鏈互補決定區1 (H-CDR1),或具有與SEQ ID NO: 7及8中之任一者具有至少80%一致性之胺基酸序列之變體;由SEQ ID NO: 9或10之胺基酸殘基組成之重鏈CDR2 (H-CDR2),或具有與SEQ ID NO: 9及10中之任一者具有至少80%一致性之胺基酸序列之變體;及由SEQ ID NO: 11或12之胺基酸殘基組成之重鏈CDR3 (H-CDR3),或具有與SEQ ID NO: 11及12中之任一者具有至少80%一致性之胺基酸序列之變體;從而該經分離抗體或其抗原結合部分結合至EGFL6。
本發明抗體之某些實施例包含單株抗體、嵌合抗體、人類化抗體及人類抗體。在一些實施例中,經分離抗-EGFL6抗體係單鏈Fv (scFv
)、IgG、Fab、(Fab)2
或(scFv'
)2
。
本發明一實施例包含含有具有選自由SEQ ID NO: 13或14組成之群之序列之胺基酸序列的輕鏈。
本發明一實施例包含含有具有選自由SEQ ID NO: 15或16組成之群之序列之胺基酸序列的重鏈。
在另一實施例中,本發明包括含有具有如SEQ ID NO: 13中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 15中所陳述胺基酸序列之重鏈之經分離抗體(EL6_S12)。在另一實施例中,本發明包括含有具有如SEQ ID NO: 14中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 16中所陳述胺基酸序列之重鏈之經分離抗體(EL6_E5)。
本發明提供一種醫藥組合物,其包括本發明之抗-EGFL6抗體及醫藥上可接受之載劑或賦形劑。
本發明亦提供治療或預防個體之血管生成病症之方法,其包括向個體投與本發明之抗-EGFL6抗體。
本發明亦提供抑制個體中之癌細胞生長或癌症轉移之方法,其包括向個體投與本發明之抗-EGFL6抗體。
在一些實施例中,上文所鑑別組合物及治療方法中之每一者可另外包含其他抗腫瘤藥物及投與一或多種其他抗腫瘤藥物。
本發明進一步提供檢測或診斷個體中之癌症或升高之未來癌症發生風險或預測癌症之轉移或預後的方法,其包括使來自個體之生物樣本與本發明之抗-EGFL6抗體接觸,量化樣本中之EGFL6抗原與抗體之結合,及比較該結合與代表抗-EGFL6抗體與來自未患有癌症之對照個體之樣本中所測定EGFL6抗原間之結合的參考值。
本發明進一步提供監測已經診斷患有癌症之個體中之癌症進展之方法。
本發明進一步提供用於檢測或診斷個體中之癌症或升高之未來癌症發生風險或預測癌症之轉移或預後或監測癌症進展的套組,其包括本發明之抗-EGFL6抗體。
使用本文術語來闡述本發明之具體實施例,但其使用並不界定本發明,除非在申請專利範圍中概述。應理解,前述一般說明及下列詳細說明兩者皆僅係實例及解釋性的且並不限制本申請案中所主張之標的物。
諸如「一個(a、an)」及「該(the)」等術語並不僅意欲係指單數實體,但包含一般種類,可使用特定實例來闡釋該一般種類。
在本申請案中,除非另外陳述,否則所用之「或」意指「及/或」。另外,所用之術語「包含(including)」以及其他形式(例如「包含(includes)」及「包含(included)」)不具有限制意義。定義
如本文中所使用,術語「腫瘤」、「癌症」及「癌瘤」可互換使用且係指所有贅瘤性細胞生長及增殖(不論惡性抑或良性)及所有癌前期及癌性細胞及組織。
如本文中所使用,術語「標記物」或「生物標記物」可在本文中互換使用,且在本發明之上下文中係指與自對照個體(例如具有陰性診斷者、正常或健康個體)獲取之相當樣本相比以不同方式表現於自患有癌症之個體所獲取樣本中的基因。
如本文中所使用,術語「生物樣本」係指自患者獲得之樣本。舉例而言,生物樣本可自血液、組織(例如腫瘤)、血清、糞便、尿、痰液、腦脊髓液、乳頭抽吸物及來自細胞溶解物之上清液獲得。
如本文中所使用,術語「診斷」意指鑑別病理學病狀之存在或性質且包含鑑別處於發生癌症之風險下之個體。診斷方法之不同之處在於其敏感性及特異性。診斷分析之「敏感性」係測試為陽性之患病個體之百分比(「真陽性」百分比)。藉由分析檢測之患病個體係「假陰性」。未患病且在分析中測試為陰性之個體稱為「真陰性」。診斷分析之「特異性」係由此正確鑑別之陰性之比例(例如未患病且正確鑑別為未患有病狀之個體之百分比)的量度。
如本文中所使用,術語「檢測(detection)」、「檢測(detecting)」及諸如此類可用於檢測生物標記物或檢測癌症(例如在獲得陽性分析結果時)之背景中。在後一背景中,「檢測」與「診斷」視為同義。
標記物之「測試量」係指存在於所測試樣本中之標記物之量。
標記物之「對照量」可為與標記物之測試量比較之任一量或量範圍。
術語「在……之風險下」欲指與正常個體相比或與對照組相比處於增加之風險下。因此,「在發生癌症之風險下」之個體與正常群體相比處於增加之風險下,且「在癌症復發之風險下」之個體可視為與所有經治療癌症患者中之復發風險相比處於增加之復發風險下。
如本文中所使用,術語「增加之風險」或「升高之風險」意指(例如)個體發生癌症或其復發之機率之任一統計學顯著增加。
如本文中所使用術語「預後」係指預測可歸因於癌症之死亡或進展(包含贅瘤性疾病(例如卵巢癌)之復發、轉移性擴散及藥物抗性)之可能性。術語「較差預後」意指,存活及疾病恢復之願景係不可能的,即使使用標準護理(亦即手術、輻射、化學療法)來治療癌症(例如前列腺癌)。不良預後係存活小於中值存活之患者類別。
如本文中所使用,術語「轉移」定義為癌症自身體之一個部分擴散至另一部分。由擴散細胞形成之腫瘤稱為「轉移性腫瘤」或「轉移」。
如本文中所使用,術語「轉移風險」係指基於統計學預測因子特定患者,尤其人類患者之癌症進展至轉移性狀態之預後適應症。未必實際上進展至轉移性狀態,且預計採用治療方式來試圖延遲或預防實現該風險。
如本文中所使用,表達「參考值」係指用作藉助自個體所獲得樣本獲得之值/數據之參考之實驗室值。
如本文中所使用,「測定含量(determination of a level、determining a level)」或「量測含量」通常係指計算特定物質之量或濃度或量化來自代表特定物質之量或濃度之探針之信號的強度。
如本文中所使用,術語「抗體」係以最廣泛意義使用且具體而言涵蓋(例如)單一單株抗體(包含激動劑、拮抗劑及中和抗體)、具有多表位特異性之抗體組合物、多株抗體、單鏈抗抗體及抗體片段(參見下文),只要其特異性結合天然多肽及/或展現本發明之生物活性或免疫活性。根據一實施例,抗體結合至靶蛋白之寡聚形式(例如三聚形成)。片語抗體之「功能片段或類似物」係與所提及抗體具有公用定性生物活性之化合物。舉例而言,本發明抗體之功能片段或類似物可為可特異性結合至EGFR者。在一實施例中,抗體可預防或實質上減小EGFR誘導細胞增殖之能力。
如本文中所使用,「經分離抗體」係已經鑑別並自其自然環境組分中分離及/或回收之抗體。其自然環境之污染組分係將干擾抗體之診斷或治療用途之材料,且可包含酶、激素及其他蛋白質性溶質或非蛋白質性溶質。在較佳實施例中,將抗體純化至以下程度:(1)大於95重量%之抗體,如藉由勞裡法(Lowry method)所測定,及最佳地大於99重量%;(2)足以獲得N-末端或內部胺基酸序列之至少15個殘基之程度,如藉由使用旋杯式序列分析儀所測定;或(3)均質,如藉由SDS-PAGE在還原或非還原條件下使用考馬斯藍(Coomassie blue)或較佳地銀染色所測定。經分離抗體包含重組細胞內之原位抗體,此乃因抗體天然環境之至少一種組分將不存在。然而,通常藉由至少一個純化步驟來製備經分離抗體。
如本文中所使用,關於肽、多肽或抗體序列之「胺基酸序列一致性百分比(%)」係指在比對序列並引入空位(若需要)以達成最大序列一致性百分比之後,且不將任何保守取代視為序列一致性之一部分之情況下,候選序列中與特定肽或多肽序列中之胺基酸殘基一致之胺基酸殘基的百分比。出於確定胺基酸序列一致性百分比之目的,比對可以熟習此項技術者所熟知之各種方式來達成,例如使用可公開獲得之電腦軟體,例如BLAST、BLAST-2、ALIGN或MEGALIGN (DNASTAR)軟體。熟習此項技術者可測定用於量測比對之適當參數,包含在所比較序列之全長範圍內達成最大比對所需之業內已知之任何算法。
如本文中所使用,術語「Fab」指示包含可變結構域及第一恆定結構域之Ig (不論如何製備)之抗原結合片段。
如本文中所使用,「Fv」係含有完全抗原識別及結合位點之最小抗體片段。此片段由重鏈一個可變區結構域與一個輕鏈可變區結構域呈緊密非共價締合形式之二聚體組成。該兩個結構域之摺疊會產生有助於胺基酸殘基之抗原結合且賦予抗體抗原結合特異性之6個超變環(各來自H鏈及L鏈之3個環)。然而,即使單一可變結構域(或Fv之一半,其僅包括三個對抗原具有特異性之HVR)亦具有識別並結合抗原之能力,但其親和力低於完整結合位點。
如本文中所使用,術語「單鏈Fv」 (亦縮寫為「sFv」或「scFv」)係包括連結成單一多肽鏈之VH及VL抗體結構域之抗體片段。較佳地,sFv多肽進一步包括VH結構域與VL結構域之間之多肽鏈接體,其使得sFv能夠形成用於抗原結合之期望結構。關於sFv之綜述,參見Pluckthun,The Pharmacology of Monoclonal Antibodies,第113卷,Rosenburg及Moore編輯,Springer-Verlag, New York,第269-315頁(1994)。
如本文中所使用,術語「互補決定區」 (CDR)係指出現在重鏈及輕鏈多肽之可變區內之非鄰接抗原組合位點。CDR已由以下文獻闡述:Kabat等人,J. Biol. Chem. 252:6609-6616 (1977);Kabat等人,U.S. Dept. of Health and Human Services, 「Sequences of proteins of immunological interest」 (1991);Chothia等人,J. Mol. Biol. 196:901-917 (1987);及MacCallum等人,J. Mol. Biol. 262:732-745 (1996),其中該等定義包括在彼此比對時之胺基酸殘基重疊或子組。
如本文中所使用,術語「人類化抗體」係指如下重組蛋白:其中來自一種物種之抗體(例如鼠類或雞抗體)之CDR自該物種抗體之重可變鏈及輕可變鏈轉移至人類重鏈及輕鏈可變結構域(框架區)中。抗體分子之恆定結構域係衍生自人類抗體之彼等結構域。在一些情形下,人類化抗體之框架區之特定殘基(尤其指彼等接觸或靠近CDR序列者)可加以修飾,例如經來自原始鼠類、齧齒類動物、近似人類之靈長類動物或其他動物抗體之相應殘基置換。可藉由各種方法來達成人類化抗體,該等方法包括:(a)僅將非人類CDR接枝於人類框架區及恆定區上且保留或不保留關鍵框架殘基;或(b)移植整個非人類可變結構域,但使用人類樣區段藉由置換表面殘基來將其「偽裝」。可用於實踐本發明之該等方法包括揭示於Padlan, Mol. Immunol., 31(3):169-217 (1994)中者。
如本文中所使用,術語「嵌合抗體」係指含有抗體重鏈及輕鏈之可變結構域(包含衍生自一種物種之抗體、較佳地齧齒類動物抗體或雞抗體、更佳地鼠類抗體之互補決定區(CDR))之重組蛋白,而抗體分子之恆定結構域係衍生自人類抗體之彼等結構域。
如本文中所使用,術語「治療(treatment或treating)」疾病係獲得有益或期望結果(包含臨床結果)之方式。出於本發明目的,有益或期望臨床結果包含(但不限於)下列結果中之一或多者:緩解一或多種源自疾病之症狀,減弱疾病程度,穩定疾病(例如預防或延遲疾病惡化),預防或延遲疾病擴散(例如轉移),預防或延遲疾病復發,延遲或減緩疾病進展,改善疾病狀態,緩解(部分或完全)疾病,降低治療疾病所需之一或多種其他藥劑之劑量,延遲疾病進展,增加或改良生化品質,增加增重,及/或延長存活。「治療」亦涵蓋減小癌症之病理學結果(例如腫瘤體積)。本文所提供之方法涵蓋該等治療態樣中之任一者或多者。
如本文中所使用,術語「投與(administer或administration)」係指將存在於身體外部之物質(例如本發明調配物)注射或另外以物理方式遞送至患者之動作,例如黏膜、真皮內、靜脈內、肌內遞送及/或本文所闡述或業內已知之任一其他物理遞送方法。在治療疾病或其症狀時,通常在疾病或其症狀發作之後投與物質。在預防疾病或其症狀時,通常在發作疾病或其症狀之前投與物質。
如本文中可互換使用,術語「個體(individual)」、「個體(subject)」、「宿主」及「患者」係指哺乳動物,包含(但不限於)鼠類(大鼠、小鼠)、非人類靈長類動物、人類、犬類、貓、有蹄動物(例如馬、牛、綿羊、豬、山羊)等。
如本文中所使用,術語「治療有效量」或「有效量」係指標的抗-EGFL6抗體在投與哺乳動物或其他個體以用於治療疾病時足以實現該疾病治療之量。抗 -EGFL6 抗體及其在癌症治療中之應用
本發明產生能夠結合至EGFL6且抑制血管生成及癌細胞生長之抗-EGFL6抗體,尤其係單鏈抗體片段(scFv)及人類化抗體。
在另一態樣中,本發明提供經分離抗-EGFL6抗體或其抗原結合部分,其包括以下中之至少一者:由SEQ ID NO: 1或2之胺基酸殘基組成之輕鏈CDR1 (L-CDR1),或具有與SEQ ID NO: 1及2中之任一者具有至少80%一致性之胺基酸序列之變體;由SEQ ID NO: 3或4之胺基酸殘基組成之輕鏈CDR2 (L-CDR2),或具有與SEQ ID NO: 3及4中之任一者具有至少80%一致性之胺基酸序列之變體;及由SEQ ID NO: 5或6之胺基酸殘基組成之輕鏈CDR3 (L-CDR3),或具有與SEQ ID NO: 5及6中之任一者具有至少80%一致性之胺基酸序列之變體;及
以下中之至少一者:由SEQ ID NO: 7或8之胺基酸殘基組成之重鏈互補決定區1 (H-CDR1),或具有與SEQ ID NO: 7及8中之任一者具有至少80%一致性之胺基酸序列之變體;由SEQ ID NO: 9或10之胺基酸殘基組成之重鏈CDR2 (H-CDR2),或具有與SEQ ID NO: 9及10中之任一者具有至少80%一致性之胺基酸序列之變體;及由SEQ ID NO: 11或12之胺基酸殘基組成之重鏈CDR3 (H-CDR3),或具有與SEQ ID NO: 11及12中之任一者具有至少80%一致性之胺基酸序列之變體;從而該經分離抗體或其抗原結合部分結合至EGFL6。較佳地,如上文所提及之序列一致性為至少81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
輕鏈及重鏈中之互補決定區之胺基酸序列及列示於下文中。
在一些實施例中,經分離抗-EGFL6抗體係單株抗體、嵌合抗體、人類化抗體或人類抗體。在一些實施例中,經分離抗-EGFL6抗體係單鏈抗體(例如Fv (scFv
)、IgG、Fab、(Fab)2
或(scFv'
)2
)。
在一些實施例中,本發明提供包括具有選自由SEQ ID NO: 13或14組成之群之序列之胺基酸序列的輕鏈。
在一些實施例中,輕鏈包括具有如SEQ ID NO: 13所示序列之胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分別經SEQ ID NO: 2、SEQ ID NO: 4及SEQ ID NO: 6置換。在另一實施例中,輕鏈包括具有如SEQ ID NO: 14所示序列之胺基酸序列,其中L-CDR1、L-CDR2及L-CDR3分別經SEQ ID NO: 1、SEQ ID NO: 3及SEQ ID NO: 5置換。
在一些實施例中,本發明提供包括具有選自由SEQ ID NO: 15或16組成之群之序列之胺基酸序列的重鏈。
在一些實施例中,重鏈包括具有如SEQ ID NO: 15所示序列之胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分別經SEQ ID NO: 8、SEQ ID NO: 10及SEQ ID NO: 12置換。在另一實施例中,重鏈包括具有如SEQ ID NO: 16所示序列之胺基酸序列,其中H-CDR1、H-CDR2及H-CDR3分別經SEQ ID NO: 7、SEQ ID NO: 9及SEQ ID NO: 11置換。
在其他實施例中,本發明包括經分離抗體,該抗體包括:具有如選自由SEQ ID NO: 13及14組成之群之序列所示胺基酸序列的輕鏈,或與SEQID NO: 13及14中之任一者具有至少80%一致性之變體;及(ii)具有如選自由SEQ ID NO: 15及16組成之群之序列所示胺基酸序列的重鏈;或與SEQ ID NO: 15至16中之任一者具有至少80%一致性之變體。較佳地,如上文所提及之序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
在另一實施例中,本發明包括含有具有如SEQ ID NO: 13中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 15中所陳述胺基酸序列之重鏈之經分離抗體(EL6_S12)。在另一實施例中,本發明包括含有具有如SEQ ID NO: 14中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 16中所陳述胺基酸序列之重鏈之經分離抗體(EL6_E5)。在另一實施例中,本發明包括含有具有如SEQ ID NO: 13中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 16中所陳述胺基酸序列之重鏈之經分離抗體。在另一實施例中,本發明包括含有具有如SEQ ID NO: 14中所陳述胺基酸序列之輕鏈及具有如SEQ ID NO: 15中所陳述胺基酸序列之重鏈之經分離抗體。
用於製備實際上針對任一靶抗原之單株抗體之技術在業內已眾所周知。例如參見Kohler及Milstein, Nature 256: 495 (1975)及Coligan等人(編輯), CURRENT PROTOCOLS IN IMMUNOLOGY,第1卷,第2.5.1-2.6.7頁(John Wiley & Sons 1991)。簡言之,可藉由以下方式來獲得單株抗體:向小鼠或雞注射包括抗原之組合物,取出脾以獲得B-淋巴球,使B-淋巴球與骨髓瘤細胞融合以產生雜交瘤,選殖雜交瘤,選擇產生針對抗原之抗體之陽性純系,培養產生針對抗原之抗體之純系,且自雜交瘤培養物分離抗體。
各種技術(例如產生嵌合或人類化抗體)可涉及抗體選殖及構築之程序。可藉由各種分子選殖程序(例如RT-PCR、5'-RACE及cDNA庫篩選)來獲得所關注抗體之抗原結合可變輕鏈及可變重鏈序列。可藉由PCR擴增來選殖來自表現鼠類抗體之細胞之抗體之可變重鏈或輕鏈序列基因且測序。為證實其真實性,可使經選殖VL
及VH
基因作為嵌合抗體表現於細胞培養物中,如由Orlandi等人(Proc. Natl. Acad. Sci., USA, 86: 3833 (1989))所闡述。基於可變重鏈或輕鏈基因序列,然後可設計並構築人類化抗體,如由Leung等人(Mol. Immunol., 32: 1413 (1995))所闡述。
嵌合抗體係重組蛋白,其中人類抗體之可變區已由(例如)小鼠抗體之可變區(包含小鼠抗體之互補決定區(CDR))置換。在投與個體時,嵌合抗體展現降低之免疫原性及增加之穩定性。構築嵌合抗體之方法在業內已眾所周知(例如Leung等人,1994, Hybridoma 13:469)。
可藉由將來自小鼠免疫球蛋白之重可變鏈及輕可變鏈之小鼠CDR轉移至人類抗體之相應可變結構域中來使嵌合單株抗體人類化。嵌合單株抗體中之小鼠框架區(FR)亦經人類FR序列置換。為保留人類化單株之穩定性及抗原特異性,可藉由小鼠對應體殘基置換一或多個人類FR殘基。人類化單株抗體可用於個體之治療性治療。產生人類化單株抗體之技術在業內已眾所周知(例如參見Jones等人,1986, Nature, 321:522;Riechmann等人,Nature, 1988, 332:323;Verhoeyen等人,1988, Science, 239:1534;Carter等人,1992, Proc. Nat'l Acad. Sci. USA, 89:4285;Sandhu, Crit. Rev. Biotech., 1992, 12:437;Tempest等人,1991, Biotechnology 9:266;Singer等人,J. Immun., 1993, 150:2844)。
可使用噬菌體顯示技術自來自未免疫化供體之免疫球蛋白可變(V)結構域基因譜在活體外產生抗-EGFL6抗體及抗體片段。根據此技術,將抗體V結構域基因框架內選殖至絲狀噬菌體(例如M13或fd)之主要或次要外殼蛋白基因中,並在噬菌體顆粒表面上顯示為功能抗體片段。因絲狀顆粒含有噬菌體基因體之單股DNA拷貝,故基於抗體功能性質之選擇亦導致對編碼展現彼等性質之抗體之基因的選擇。因此,噬菌體模擬B細胞之一些性質。噬菌體顯示可以各種形式實施,且綜述於(例如) Johnson, Kevin S.及Chiswell, David J., Curr. Opin Struct. Biol. 3:564-571 (1993)中。可使用若干V-基因區段來源進行噬菌體顯示。Clackson等人,Nature, 352:
624-628 (1991)自衍生自經免疫小鼠脾臟之V基因之小型隨機組合庫分離出抗-噁唑酮抗體之多樣性陣列。在其他實施例中,可使用核糖體顯示技術在活體外產生抗-EGFL6抗體及抗體片段。
已研發各種技術來產生抗體片段。傳統上,經由完整抗體之蛋白質水解性消解作用來衍生該等片段。然而,該等片段現可藉由重組宿主細胞,例如:使用編碼本發明抗-EGFL6抗體之核酸,直接產生。Fab、Fv及scFv抗體片段可皆於大腸桿菌(E. coli)中表現且由其分泌,由此容許直接產生大量該等片段。亦可自如上文所論述之抗體噬菌體庫來分離抗-EGFL6抗體片段。或者,可自大腸桿菌直接回收Fab'-SH片段且以化學方式偶合以形成F(ab')2
片段。根據另一方式,可自重組宿主細胞培養物直接分離F(ab')2
片段。具有延長之活體內半衰期之Fab及F(ab')2
抗體片段之生產法闡述於US 5,869,046中。在其他實施例中,所選抗體係單鏈Fv片段(scFv)。
可對編碼本文所闡述多肽之核酸進行修飾而不減弱其生物活性。可進行一些修飾以促進靶向分子在融合蛋白中之選殖、表現或納入。該等修飾為熟習此項技術者所熟知且包含(例如)終止密碼子、添加於胺基末端以提供起始位點之甲硫胺酸、置於任一末端以產生合宜定位之限制位點之其他胺基酸、或有助於純化步驟之其他胺基酸(例如聚His)。除重組方法外,亦可完全或部分地部分使用業內熟知之標準肽合成來構築本發明抗體。
雙鏈抗體純化方案之修改係由重鏈及輕鏈區分開溶解及還原,然後於再摺疊溶液中組合。當這兩種蛋白質混合時之莫耳比例可以使其中一種蛋白質超過另一種蛋白質之莫耳量不超過5倍時,獲得實例性產率。在完成氧化還原-改組之後,可向再摺疊溶液中添加過量已氧化之麩胱甘肽或其他氧化性低分子量化合物。
除重組方法外,亦可完全或部分地使用標準肽合成來構築本文所揭示之抗體及其變體。可藉由將序列之C-末端胺基酸附接至不溶性載體、隨後依序添加序列中之剩餘胺基酸來達成多肽之固相合成。用於固相合成之技術闡述於以下文獻中:Barany & Merrifield, The Peptides: Analysis, Synthesis, Biology.第2卷:Special Methods in Peptide Synthesis,部分A. pp. 3-284;Merrifield等人,J. Am. Chem. Soc. 85:2149-2156, 1963;及Stewart等人,Solid Phase Peptide Synthesis,第2版,Pierce Chem. Co., Rockford, Ill., 1984。可藉由縮合較短片段之胺基及羧基末端來合成較大長度之蛋白質。
包括抗EDFL6抗體之醫藥組合物及抗EDFL6抗體之治療或預防應用
某些實施例係關於包括本發明之抗-EGFL6抗體及醫藥上可接受之載劑或賦形劑之醫藥組合物。術語「醫藥上可接受之載劑」意欲包含(但不限於)熟習此項技術者已知之任一類型之無毒固體、半固體或液體填充劑、稀釋劑、囊封材料或調配助劑。可使用稀釋劑(例如多元醇、聚乙二醇及右旋糖酐)來增加偶聯物之生物半衰期。
可根據習用方法(例如Remington's Pharmaceutical Science,最新版,Mark Publishing Company, Easton, U.S.A.)來調配本發明之醫藥組合物,且該醫藥組合物亦可含有醫藥上可接受之載劑及添加劑。實例包含(但不限於)表面活性劑、賦形劑、著色劑、矯味劑、防腐劑、穩定劑、緩衝劑、懸浮劑、等滲劑、黏合劑、崩解劑、潤滑劑、流動促進劑及矯正劑,且可適宜地使用其他常用載劑。載劑之具體實例包含光無水矽酸、乳糖、結晶纖維素、甘露醇、澱粉、羧甲基纖維素鈣、羧甲基纖維素鈉、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯縮醛二乙基胺基乙酸酯、聚乙烯基吡咯啶酮、明膠、中鏈三甘油酯、聚氧乙烯硬化蓖麻油60、蔗糖、羧甲基纖維素、玉米澱粉、無機鹽等等。
一實施例係關於治療或預防個體之血管生成病症之方法,其包括向個體投與本發明之抗-EGFL6抗體。或者,一實施例係關於本發明之抗-EGFL6抗體之用途,其用以製造用於治療或預防個體之血管生成病症之藥劑。特徵在於病理學血管生成之病症係指異常或反常血管生成(單獨或與其他現象組合)有助於病症之引起、起源或症狀之病症。此病症之實例包含各種癌症(例如血管化腫瘤)、眼部病症、發炎性病症及其他病症。
另一實施例係關於抑制個體中之癌細胞生長或癌症轉移之方法,其包括向個體投與本發明之抗-EGFL6抗體。或者,另一實施例係關於本發明之抗-EGFL6抗體之用途,其用以製造用於抑制個體中之癌細胞生長或癌症轉移之藥劑。因血管生成涉及原發性癌症生長及轉移,故由本發明提供之抗血管生成治療能夠抑制一級位點處之癌細胞生長以及預防二級位點處之腫瘤轉移。實例性實體腫瘤包含(但不限於)皮膚癌、腎癌、前列腺癌、脂肪組織癌、肺癌、乳癌、骨癌、卵巢癌、胃癌、胰臟癌、喉癌、食道癌、睪丸癌、肝癌、腮腺癌、膽道癌、結腸癌、直腸癌、子宮頸癌、子宮癌、子宮內膜癌、腎癌、膀胱癌、前列腺癌、甲狀腺癌、鱗狀細胞癌、腺癌、小細胞癌、黑色素瘤、神經膠質瘤、神經膠母細胞瘤、神經母細胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)及肉瘤(例如胃腸道基質腫瘤)。在另一實施例中,癌症係結腸直腸癌、結腸癌或直腸癌。
本發明方法亦包括投與本發明之抗-EGFL6抗體(與其他標準療法同時或之後),其中該標準療法係選自由以下組成之群:放射療法、手術及化學療法。
在較佳實施例中,個體係哺乳動物。實例性哺乳動物包含人類、豬、綿羊、山羊、馬、小鼠、狗、貓、牛等。可使用抗-EGFL6抗體或其醫藥組合物治療之疾病包含癌症(例如肝癌、皮膚癌、頭頸癌、肺癌、乳癌、前列腺癌、卵巢癌、子宮內膜癌、子宮頸癌、結腸癌、直腸癌、結腸及直腸癌、膀胱癌、腦癌、胃癌、胰臟癌或淋巴系統)。較佳地,癌症係結腸直腸癌。
可經靜脈內、經腹膜腔內、經動脈內、經鞘內、經膀胱內或經腫瘤內來投與抗-EGFL6抗體或其醫藥組合物。熟習此項技術者應瞭解,可根據經驗來測定抗-EGFL6抗體之有效量。應理解,在投與人類患者時,由主治醫師在合理醫學判斷之範圍內來決定抗-EGFL6抗體或組合物之總日用量。任一特定患者之具體治療有效劑量值取決於以下多種因素:擬達成細胞反應之類型及程度;所採用具體抗-EGFL6抗體或化合物之活性;患者之年齡、體重、總體健康狀況、性別及飲食;抗-EGFL6抗體之投與時間、投與途徑及排泄速率;治療持續時間;與抗-EGFL6抗體組合或同時使用之藥物;及醫學技術中已為人熟知之類似因素。
上文所鑑別組合物及治療方法中之每一者可另外包含其他抗腫瘤藥物及投與其他一或多種抗腫瘤藥物。適用於本發明之抗腫瘤藥物包含(但不限於)誘導細胞凋亡之藥劑、抑制腺苷去胺酶功能之藥劑、抑制嘧啶生物合成之藥劑、抑制嘌呤環生物合成之藥劑、抑制核苷酸互變之藥劑、抑制核糖核苷酸還原酶之藥劑、抑制單磷酸胸苷(TMP)合成之藥劑、抑制二氫葉酸鹽還原之藥劑、抑制DNA合成之藥劑、與DNA形成加合物之藥劑、損害DNA之藥劑、抑制DNA修復之藥劑、插入DNA之藥劑、去胺基天門冬醯胺之藥劑、抑制RNA合成之藥劑、抑制蛋白質合成或穩定性之藥劑、抑制微管合成或功能之藥劑及諸如此類。其他抗腫瘤藥物之實例包含(但不限於) 1)生物鹼類,包含微管抑制劑(例如長春新鹼(vincristine)、長春鹼(vinblastine)及長春地辛(vindesine)等)、微管穩定劑(例如太平洋紫杉醇(TAXOL)及多西他賽(docetaxel)等)及染色質功能抑制劑(包含拓撲異構酶抑制劑,例如及表鬼臼毒素(epipodophyllotoxin) (例如依託泊苷(etoposide) (VP-16)及替尼泊苷(teniposide) (VM-26)等)及靶向拓撲異構酶I之藥劑(例如喜樹鹼(camptothecin)及伊絲立替康(isirinotecan) (CPT-11)等));2)共價DNA結合劑(烷基化劑),包含氮芥(nitrogen mustard) (例如雙氯乙基甲胺(mechlorethamine)、氮芥苯丁酸(chlorambucil)、環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosphamide)及白消安(busulfan) (MYLERAN)等)、亞硝基脲(例如卡莫司汀(carmustine)、洛莫司汀(lomustine)及司莫司汀(semustine)等)及其他烷基化劑(例如替莫唑胺(temozolomide)、達卡巴嗪(dacarbazine)、羥甲基三聚氰胺(hydroxymethylmelamine)、噻替派(thiotepa)及絲裂黴素(mitomycin)等);3)非共價DNA-結合劑(抗腫瘤抗生素),包含核酸抑制劑(例如更生黴素(dactinomycin) (放線菌素(actinomycin) D)等)、蒽環(例如柔紅黴素(daunorubicin) (道諾黴素(daunomycin)及正定黴素(cerubidine))、多柔比星(doxorubicin) (阿黴素(adriamycin))及伊達比星(idarubicin) (去甲氧柔紅黴素(idamycin))等)、蒽二酮(例如蒽環類似物,例如米托蒽醌(mitoxantrone)等)、博來黴素(bleomycin) (BLENOXANE)等及普利黴素(plicamycin) (光輝黴素(mithramycin))等;4)抗代謝物,包含抗葉酸劑(例如胺甲喋呤(methotrexate)、FOLEX及MEXATE等)、嘌呤抗代謝物(例如6-巰基嘌呤(6-MP、PURINETHOL)、6-硫基鳥嘌呤(6-TG)、硫唑嘌呤(azathioprine)、阿昔洛韋(acyclovir)、更昔洛韋(ganciclovir)、氯去氧腺苷、2-氯去氧腺苷(CdA)及2'-去氧助間型黴素(2'-deoxycoformycin) (噴司他丁(pentostatin))等)、嘧啶拮抗劑(例如氟嘧啶(例如5-氟尿嘧啶(5-fluorouracil) (ADRUCIL)、5-氟去氧尿苷(FdUrd) (氟尿苷(floxuridine)))等)及胞嘧啶阿拉伯糖苷(例如CYTOSAR (ara-C)及氟達拉濱(fludarabine)等);5)酶,包含L-天門冬醯胺酶及羥基脲(hydroxyurea)等;6)激素,包含糖皮質激素、抗雌激素(例如他莫昔芬(tamoxifen)等)、非類固醇抗雄激素(例如氟他胺(flutamide)等)及芳香酶抑制劑(例如阿那曲唑(anastrozole) (ARIMIDEX)等);7)鉑化合物(例如順鉑(cisplatin)及卡鉑(carboplatin)等);8)與抗癌藥、毒素及/或放射性核素等偶聯之單株抗體;9)生物反應修飾劑(例如干擾素(例如IFN-α等)及介白素(例如IL-2等)等);10)接受性免疫療法;11)造血生長因子;12)誘導腫瘤細胞分化之藥劑(例如全反視黃酸等);13)基因療法技術;14)反義療法技術;15)腫瘤疫苗;16)針對腫瘤轉移之療法(例如巴馬司他(batimastat)等);17)血管生成抑制劑;18)蛋白體抑制劑(例如VELCADE);19)乙醯化及/或甲基化抑制劑(例如HDAC抑制劑);20) NFκ B調節劑;21)細胞週期調控抑制劑(例如CDK抑制劑);及22) p53蛋白質功能調節劑。使用抗 -EGFL6 抗體之癌症檢測或診斷
本發明亦展示,EGFL6含量與癌症嚴重程度之間存在關聯;因此,EGFL6或其片段在生物樣本中之高表現程度(與EGFL6或其片段在對照樣本中之參考表現程度相比)可指示預測之轉移或較差預後。本發明出人意料地發現,本發明之抗-EGFL6抗體可用作診斷或預測個體中癌症之預後或升高之轉移或未來發生風險之指示劑。因此,本發明提供檢測或診斷個體中之癌症或升高之未來癌症發生風險或預測癌症之轉移或預後的方法,其包括使來自個體之生物樣本與本發明之抗-EGFL6抗體接觸,量化樣本中之EGFL6抗原與抗體之結合,及比較該結合與代表在來自未患有癌症之對照個體之樣本中所測定抗-EGFL6抗體與EGFL6抗原間之結合的參考值。
在一實施例中,生物樣本可為細胞、組織、器官、器官樣本、組織生檢、血液、血漿、血清、腹水液、淋巴球、尿、骨髓液、淋巴液、唾液、淚液、黏液、羊水或其組合。
適於偶聯至抗體及其他結合試劑之可檢測標記包含放射性同位素、螢光標記、酶受質標記、發色標記、化學發光標記及膠質金顆粒。
量測方法之實例包含(但不限於)螢光免疫分析(FIA)方法、酶免疫分析(EIA)方法、放射性免疫分析(RIA)方法、西方印漬方法、點印漬、免疫組織化學分析、螢光活化細胞分選儀(FACS)、活體內成像及放射性成像分析。
本發明進一步提供監測已經診斷患有癌症之個體中之癌症進展之方法。在一些實施例中,可使用監測來評估特定治療是否成功。
在一些實施例中,監測癌症進展包括:藉由本發明之抗-EGFL6抗體測定自經診斷患有癌症之個體獲得之第一生物樣本中EGFL6或其片段的第一含量;及在預定時間段之後藉由本發明之抗-EGFL6抗體測定自個體獲得之第二生物樣本中EGFL6或其片段的第二含量;比較EGFL6或其片段之第一含量及第二含量;其中第二樣本與第一樣本相比之EGFL6或其片段之較高含量指示疾病進展及惡化。類似地,第二樣本與第一樣本相比之EGFL6或其片段之較低含量指示改良。
本發明之診斷方法可與已知癌症診斷方法進行組合。
本發明之另一態樣涵蓋一種套組,其用於檢測或診斷個體之癌症或升高之未來癌症發生風險或預測癌症轉移或預後或監測癌症進展。其通常呈含有所有要素(視情況包含說明書)之包裝形式。包裝可分開,從而各組分並混合直至期望時。個別組分可單獨包裝於套組內。套組可含有檢測標記物基因之表現程度所需之試劑。套組係之任一製品(例如包裝或容器),其包括至少一種用於特異性檢測及/或量測標記物基因在樣本中之表現程度之試劑(例如抗體試劑)。
本發明涵蓋具有不同組分之各種套組。概言之,套組包含用於量化個體中之EGFL6或更多生物標記物之構件。在另一實施例中,套組包含用於收集生物樣本之構件、用於量化生物樣本中之EGFL6或更多生物標記物之構件及使用套組內容物之說明書。在某些態樣中,套組包括用於量化生物標記物之量之構件。在其他態樣中,用於量化生物標記物之量之構件包括檢測生物標記物之量所需之試劑。
已闡述本發明之若干實施例。然而,將理解,可在不背離本發明之精神及範圍之情況下作出各種修改。因此,下列實例意欲加以闡釋,但並不限制申請專利範圍中所闡述之發明範圍。實例 實例 1 抗 -EGFL6 單鏈抗體庫之構築及生物淘選
藉由肌內注射使用50 ug於等體積弗羅因德氏完全佐劑(Freund’s complete adjuvant)中之重組EGF6對雌性白色來亨雞(white leghorn) (家雞(Gallus domesticus
))實施免疫。以7天間隔使用不完全佐劑實施三個其他免疫化。在每一免疫化之後,收集蛋黃中之雞IgY抗體並藉由酶聯免疫吸附分析(ELISA)滴定以測定體液抗-EGFL6抗體免疫反應之存在。根據公開方案(Akita, E.M. 及Nakai, S. (1993). Production and purification of Fab' fragments from chicken egg yolk immunoglobulin Y (IgY). J Immunol Methods 162, 155-164
)使用10%硫酸右旋糖酐自氮白分離蛋黃以用於IgY純化。
基於先前報告(Andris-Widhopf, J., Rader, C., Steinberger, P., Fuller, R. 及Barbas, C.F. 3rd (2000). Methods for the generation of chicken monoclonal antibody fragments by phage display. J Immunol Methods 242, 159-181. Barbas, C.F., 3rd, Kang, A.S., Lerner, R.A. 及Benkovic, S.J. (1991). Assembly of combinatorial antibody libraries on phage surfaces: the gene III site. Proc Natl Acad Sci U S A 88, 7978-7982
)來確立抗體庫。簡言之,收穫雞脾並立即置於特裡佐爾(Trizol)中。將10 ug總RNA逆轉錄至第一鏈cDNA中。在使用雞特異性引子擴增之後,對具有短或長連接體之重鏈及輕鏈可變(VH及VL)區之PCR產物實施第二輪PCR,使用Sfi
I消解並選殖至pComb3X載體中。藉由電穿孔將重組DNA轉變至大腸桿菌ER2738菌株中。藉由添加VCS-M13輔助噬菌體來產生重組噬菌體,使用4%聚乙二醇8000及3% NaCl (w/v)沈澱,再懸浮於含有1%牛血清白蛋白(BSA)之磷酸鹽緩衝鹽水(PBS)中。然後,將1011
個斑塊形成單位(pfu)之重組噬菌體添加至經EGFL6蛋白(0.5 ug/孔)預塗覆之孔中,並在37℃下培育2 h。使用0.1 M HCl/甘胺酸(pH 2.2)/0.1% BSA洗脫所結合噬菌體,使用2 M Tris鹼緩衝液中和並用於感染ER2738菌株。如上文所闡述回收經擴增噬菌體以用於下一輪選擇。重複淘選程序6次。純化總DNA並轉變至TOP 10F’大腸桿菌菌株中。隨機選擇20個純系並自最終淘選過程生長。裂解細菌細胞並分析scFv抗體表現及EGFL6結合反應性。使用Ni2+
-帶電瓊脂糖純化ScFv抗體,如由製造商(Amersham Biosciences, UK)所闡述。圖1展示使用ELISA測得之抗-EGFL6抗體之結合活性。使用在第6輪生物淘選之後14個隨機選自每一ELISA-陽性噬菌體庫之純系之總細胞溶解物來檢驗其抗-EGFL6活性。可發現,大部分scFv抗體可特異性結合至EGFL6蛋白(參見圖1)。實例 2 抗 -EGFL6 單鏈抗體之結合分析
純化大腸桿菌表現之scFv抗體並與固定於硝基纖維素膜上之EGFL6蛋白一起培育。隨後藉由添加山羊抗雞IgY輕鏈、隨後添加HRP偶聯之驢抗山羊Ig抗體來檢測其結合。在三次洗滌之後,使用二胺基聯苯胺(DAB)受質使膜顯影直至達到期望強度為止。圖2展示重組全長EGFL6蛋白(泳道EGFL6),且使用N-末端截短片段(泳道EGFL6-F37)及C-末端截短片段(泳道EGFL6-F396)在還原條件下進行SDS-PAGE分析。圖2A及2B展示在西方印漬中藉由E5 scFv (圖2A)及S12 scFv (圖2B)鑑別之全長EGFL6蛋白及EGFL6-F396截短片段。實例 3 結腸直腸癌患者之血清中之 EGFL6 表現
在癌症患者之血清中評估表皮生長因子樣蛋白6 (EGFL6)之表現。
如圖3中所展示,藉由西方印漬量測肺癌、結腸癌、卵巢癌、前列腺癌、腦癌、子宮癌及乳癌細胞系中之EGFL6之蛋白質表現。EGFL6未表現於正常細胞系中。該等結果表明,EGFL6可發現於癌症患者中且EGFL6可用作癌症標記物。
實例
4
在動物模型中藉由抗
-EGFL6
單鏈抗體
S12
及
E5
評估單鏈抗體對結腸直腸癌細胞系
HCT116
之細胞遷移抑制及癌症轉移抑制
實施細胞滲透遷移分析以評估單鏈抗體抑制結腸直腸癌細胞系HCT116之細胞遷移之能力。如圖4 (A)中所展示,將抗-EGFL6單鏈抗體添加至結腸直腸癌細胞系HCT116中且在細胞培養條件下抑制癌細胞生長。結果表明,抗體Ab4、Ab5 (E5)及Ab10有效抑制癌細胞遷移。
在CT26同種移植物小鼠模型中,在向小鼠投與抗-EGFL6單鏈抗體(S12及E5)及小分子藥物太平洋紫杉醇之後,觀察抑制結腸直腸癌細胞CT26向肺之轉移之能力。以15 mg/kg之劑量每三天一次來投與抗-EGFL6單鏈抗體S12及E5,而以20 mg/kg之劑量每4天一次來投與太平洋紫杉醇。如圖4 (B)中所展示,與使用太平洋紫杉醇以20 mg/kg之劑量每4天一次治療之對照組相比,使用兩種抗-EGFL6單鏈抗體以15 mg/kg之劑量每三天一次治療之組可有效地抑制腫瘤囊形成。實例 5 藉由單鏈抗體 E5 及 S12 在活體內抑制血管生成
向5週齡裸小鼠經皮下注射500 μl與EGF混合之基質膠以誘導血管生成。將裸小鼠分成以下4組:(1)僅使用基質膠,作為陰性對照組(基礎);(2)使用與EGF (150 ng/mL)混合之基質膠,作為陽性對照組(對照);(3)使用單鏈抗體E5以15 mg/kg之劑量在EGF誘導條件下治療之組;及(4)使用單鏈抗體S12以15 mg/kg之劑量在EGF誘導條件下治療之組。每一組具有3隻裸小鼠且藉由尾部靜脈注射在一週內每週三次投與單鏈抗體E5及S12。在第8天將裸小鼠處死。取出小鼠腹部中之基質膠束並藉由碾磨桿均質化,隨後量測血紅蛋白含量。
如圖5中所展示,血管生成未展示於僅注射基質膠之陰性對照組(基礎)中。與陰性對照組(基礎)相比,在24小時之後,血管生成展示於注射與EGF混合之基質膠之陽性對照組(對照)中。如圖5中所展示,顯而易見,使用兩種抗-EGFL6單鏈抗體E5及S12治療之組展示抑制血管生成之效應。另外,將裸小鼠處死且取出小鼠腹部中之基質膠束,並量測血紅蛋白含量。圖5圖解說明,使用抗-EGFL6單鏈抗體E5及S12治療之裸小鼠之基質膠束中之血紅蛋白含量展示與裸小鼠實體觀察相關之較低值。另外,如圖5中所展示,抗-EGFL6單鏈抗體E5及S12展現抑制血管生成之顯著效應。使用抗-EGFL6單鏈抗體E5及S12治療之組之血紅蛋白含量幾乎等效於陰性對照組(基礎)之含量。該等結果證實,抗-EGFL6單鏈抗體E5及S12能夠中和EGFL6,且由此達成抑制血管生成之效應。實例 6 藉由抗 -EGFL6 人類化 IgG 抗體在活體內抑制動物模型中之腫瘤生長
藉助藉由先前研究中所應用之算法生成之分子模型來實施雞scFv抗體之可變區之人類化(Tsurushita等人,2004;Zilber等人,1990)。簡言之,基於序列同源性來選擇用作抗-EGFL6 scFv抗體之CDR之受體之人類V區框架。使用雞抗-EGFL6 scFv抗體之相應殘基來取代自三維模型所預測對於適當形成CDR結構較為重要之人類化V區中之胺基酸殘基。組合其他方法且用於進一步微調人類化抗-EGFL6抗體之結構(Ewert等人,2003;Sidhu等人,2004)。
評估兩種抗-EGFL6人類化IgG抗體(S12及E5)抑制異種移植物小鼠中之結腸直腸癌細胞HCT116、非小細胞肺癌A549、三陰性乳癌細胞MDA-MB-231及神經膠母細胞瘤癌細胞U87之生長之能力。每週兩次向小鼠投與指示劑量及靜脈內注射。初始腫瘤大小約為200 mm3
。在實驗結束時,計算腫瘤生長抑制比率(TGI %)並與對照組進行比較。如圖6 (A)中所展示,使用人類化IgG抗體S12及E5之兩組皆能夠抑制腫瘤生長(結腸直腸癌細胞HCT-116)。使用S12抗體之組之TGI %為7.5%,而使用E5抗體之組為36.2%。如圖6 (B)中所展示,人類化IgG抗體E5能夠抑制非小細胞肺癌A549中之腫瘤生長。使用E5抗體(10 mg/kg)之組之TGI %為14.3%,而使用E5抗體(20 mg/kg)之組為80.8%。
如圖7 (A)中所展示,使用人類化IgG抗體E5之組能夠抑制腫瘤生長(三陰性乳癌細胞MDA-MB-231)。使用E5抗體(20 mg/kg)之組之TGI %為65.1%,而使用E5抗體(40 mg/kg)之組為65.4%。如圖7 (B)中所展示,使用單鏈抗體E5之組能夠抑制腫瘤生長(神經膠母細胞瘤癌細胞)。使用E5抗體(20 mg/kg)之組之TGI %為36.5%。
另外,分析與太平洋紫杉醇組合之人類化IgG抗體E5在人類非小細胞肺癌A549異種移植物模型中之抗癌活性。將太平洋紫杉醇(5 mg/kg)、E5 IgG (10 mg/kg)及太平洋紫杉醇(5 mg/kg)與E5 IgG (10 mg/kg)之組合經靜脈內注射至小鼠中。如圖8中所展示,使用抗體E5 IgG之組能夠抑制腫瘤生長且太平洋紫杉醇與E5 IgG之組合具有抑制腫瘤之意外效能。使用E5抗體(10 mg/kg)之組之TGI %為14.3%,而使用太平洋紫杉醇與E5 IgG之組合之組為61.8%。
圖1展示使用ELISA測得之抗-EGFL6抗體之結合活性。
圖2A及2B展示在西方印漬(Western blotting)中藉由E5 scFv (A)及S12 scFv (B)鑑別之全長EGFL6蛋白及EGFL6-F396截短片段。
圖3展示藉由西方印漬量測之EGFL6在各種癌細胞系中之蛋白質表現。
圖4 (A)及(B)展示,單鏈抗體Ab4、Ab5 (E5)及Ab10可有效抑制癌細胞遷移(A),且抗-EGFL6單鏈抗體與經太平洋紫杉醇(Paclitaxel)治療之對照組相比可有效地抑制腫瘤囊之形成(B)。
圖5展示經抗-EGFL6單鏈抗體E5及S12治療之裸小鼠之基質膠束中之血紅蛋白含量。
圖6 (A)及(B)展示,人類化IgG抗體S12及/或E5能夠抑制結腸直腸癌細胞HCT-116 (A)及非小細胞肺癌A549 (B)中之腫瘤生長。
圖7 (A)及(B)展示,人類化IgG抗體E5能夠抑制三陰性乳癌細胞MDA-MB-231(A)及神經膠母細胞瘤癌細胞U87 (B)中之腫瘤生長。
圖8展示與太平洋紫杉醇組合之人類化IgG抗體E5在人類非小細胞肺癌A549異種移植物模型中之抗癌活性。
<110> 臺北醫學大學 衛生福利部國家中醫藥研究所 彰化基督教醫療財團法人彰化基督教醫院
<120> 抗-類EGF結構域多重6(EGFL6)抗體及其於癌症診斷及治療中之應用
<130> PCT/CN2018/108427
<140> 107134565
<141> 2018-09-28
<150> US 62/566,509
<151> 2017-10-01
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<210> 2
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<210> 3
<211> 3
<212> PRT
<213> 人工序列
Claims (16)
- 一種經分離抗-EGFL6抗體或其抗原結合部分,其包括由SEQ ID NO:2之胺基酸殘基組成之輕鏈互補決定區CDR1(L-CDR1);由SEQ ID NO:4之胺基酸殘基組成之輕鏈CDR2(L-CDR2);及由SEQ ID NO:6之胺基酸殘基組成之輕鏈CDR3(L-CDR3);及由SEQ ID NO:8之胺基酸殘基組成之重鏈互補決定區1(H-CDR1);由SEQ ID NO:10之胺基酸殘基組成之重鏈CDR2(H-CDR2);及由SEQ ID NO:12之胺基酸殘基組成之重鏈CDR3(H-CDR3);從而由該經分離抗體或其抗原結合部分與EGFL6結合。
- 如請求項1之抗-EGFL6抗體或其抗原結合部分,其係單株抗體、嵌合抗體、人類化抗體或人類抗體。
- 如請求項1之抗-EGFL6抗體或其抗原結合部分,其係單鏈Fv(scFv)、IgG、Fab、(Fab)2或(scFv')2。
- 如請求項1之經分離抗-EGFL6抗體或其抗原結合部分,其包括具有如SEQ ID NO:14所示胺基酸序列之輕鏈及具有如SEQ ID NO:16所示胺基酸序列之重鏈。
- 一種醫藥組合物,其包括如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分及醫藥上可接受之載劑或賦形劑。
- 如請求項15之醫藥組合物,其進一步包括其他一或多種抗腫瘤藥物。
- 一種如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分之用途,其用以製造用於治療或預防個體之血管生成病症之藥劑。
- 如請求項7之用途,其中該血管生成病症係癌症、眼部病症或發炎性病症。
- 一種如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分之用途,其用以製造用於抑制個體中之癌細胞生長或癌症轉移之藥劑。
- 如請求項9之用途,其中該藥劑進一步與其他一或多種抗腫瘤藥物一起投與。
- 如請求項9之用途,其中該癌症係皮膚癌、腎癌、前列腺癌、脂肪組織癌、肺癌、乳癌、骨癌、卵巢癌、胃癌、胰臟癌、喉癌、食道癌、睪丸癌、肝癌、腮腺癌、膽道癌、結腸癌、直腸癌、子宮頸癌、子宮癌、子宮內膜癌、腎癌、膀胱癌、前列腺癌、甲狀腺癌、鱗狀細胞癌、腺癌、小細胞癌、黑色素瘤、神經膠質瘤、神經膠母細胞瘤、神經母細胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)或肉瘤。
- 如請求項9之用途,其中該癌症係結腸直腸癌。
- 一種檢測或診斷個體中之癌症或升高之未來癌症發生風險或預測癌症之轉移或預後的方法,其包括使來自個體之生物樣本與如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分接觸,定量該樣本中之EGFL6抗原與該抗體或其抗原結合部分之結合,及比較該結合與代表在來自未患有癌症之對照個體之樣本中所測定該抗-EGFL6抗體或其抗原結合部分與該EGFL6抗原間之結合的參考值。
- 如請求項13之方法,其中該生物樣本係細胞、組織、器官、器官樣本、組織生檢、血液、血漿、血清、腹水液、淋巴球、尿、骨髓液、淋巴液、唾液、淚液、黏液、羊水或其組合。
- 一種監測已經診斷患有癌症之個體中之癌症進展之方法,其包括藉由如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分,在自經診斷患有癌症之個體獲得之第一生物樣本中測定EGFL6或其片段的第一含量;及在預定時間段之後,藉由如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分,在自該個體獲得之第二生物樣本中測定EGFL6或其片段的第二含量;比較EGFL6或其片段之該第一含量及該第二含量;其中該第二樣本之EGFL6或其片段之含量高於該第一樣本時,即指示疾病進展及惡化。
- 一種用於檢測或診斷個體中之癌症或升高之未來癌症發生風險、或 預測癌症之轉移或預後、或監測癌症進展的套組,其包括如請求項1至4中任一項之抗-EGFL6抗體或其抗原結合部分。
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NOH, Kyunghee, et al. Differential effects of EGFL6 on tumor versus wound angiogenesis. Cell reports, 2017, 21.10: 2785-2795. (5 December 2017) |
Wu, Binhua, et al. "Preparation and inhibition of proliferation and migration of human melanoma cells of monoclonal antibodies against human EGFL6 gene." 第十屆全國免疫學學術大會彙編 (2015). |
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