TWI468173B - Treatment of graft-versus-host disease with an interstitial-6 receptor inhibitor as an active ingredient - Google Patents
Treatment of graft-versus-host disease with an interstitial-6 receptor inhibitor as an active ingredient Download PDFInfo
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- TWI468173B TWI468173B TW97137932A TW97137932A TWI468173B TW I468173 B TWI468173 B TW I468173B TW 97137932 A TW97137932 A TW 97137932A TW 97137932 A TW97137932 A TW 97137932A TW I468173 B TWI468173 B TW I468173B
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Description
本發明係關於治療移植物抗宿主疾病用治療劑。更詳細而言,本發明係以間白素-6(IL-6)受體抑制劑為有效成分之治療移植物抗宿主疾病用治療劑。
白血病等之造血器官腫瘤之治療雖然最先係進行抗癌劑之化學療法,但對於以通常的化學療法不易治癒,或是治癒的可能性低之患者,進行造血幹細胞(末梢血幹細胞、骨髓細胞等)移植。然而,造血幹細胞移植時,指出發生移植物抗宿主疾病(graft-versus-host disease:GVHD)。
GVHD係所移入或移植之負責免疫細胞,因對宿主之組織引起免疫反應而發生疾病之總稱。認為所移入或移植之末梢血液等所含之成熟T細胞等之負責免疫細胞,對接受者之組織引起免疫反應係主要原因。GVHD係有急性及慢性之疾病,作為該症狀係皮膚症狀、腹瀉、黃疸等,有時發生成為致死之嚴重作用。
至今,抑制GVHD係使用甲氨蝶呤(methotrexate)或環孢靈A(Cyclosporine A)等之免疫抑制劑之方法,及自移植細胞群(移植物)除去成熟T細胞之方法等。使用甲氨蝶呤或環孢靈A時,將有此等造成生物體副作用之問題。已知作為環孢靈A之副作用係強烈的腎臟毒性,已知作為甲氨蝶呤之副作用係抑制骨髓。
另外,藉由自移植細胞群(移植物)除去成熟T細胞之方法雖可抑制GVHD,但有認為白血病再發等之抗腫瘤效果減弱之缺點(非專利文獻1)。
間白素-6(IL-6)係被稱為B細胞刺激因子2(BSF2)或干擾素β2之細胞激素(cytokine)。發現IL-6係作為參與B淋巴球系細胞活性化之分化因子(非專利文獻2)。之後,顯示係對各種細胞機能造成影響之多機能細胞激素(非專利文獻3)。報告IL-6誘導T淋巴球系細胞之成熟化(非專利文獻4)。
IL-6係介在於細胞上之二種蛋白質傳遞該生物學活性。一種係IL-6結合之分子量約為80kD之配體(ligand)結合性蛋白質之IL-6受體(非專利文獻5、6)。IL-6受體係除了貫穿細胞膜,於細胞膜上表現之膜結合型之外,主要亦作為該細胞外區域所形成之可溶性IL-6受體。
另一種係非配體結合性之訊號傳遞相關之分子量約為130kD之膜蛋白質gp130。IL-6及IL-6受體形成IL-6/IL-6受體複合物,接著,由與gp130結合,傳遞IL-6之生物學活性於細胞內(非專利文獻7)。
IL-6抑制劑係抑制IL-6之生物學活性傳遞之物質。至今,已知有對IL-6之抗體(抗IL-6抗體)、對IL-6受體之抗體(抗IL-6受體抗體)、對gp130之抗體(抗gp130抗體)、IL-6改變體、IL-6或IL-6受體部份胜肽等。
關於抗IL-6受體抗體,有幾個報告(非專利文獻8、9、專利文獻1至3)。其中之一係移植小鼠抗體PM-1(非專利文獻10)之互補性決定區(CDR;complementarity determining region)於人抗體所得之人化PM-1抗體(專利文獻4)。
對IL-6受體之抗體係使用於治療風濕等之發炎性疾病。然而,因為IL-6等之發炎性細胞激素形成複雜的網路,對於治療移植物抗宿主疾病等之其他疾病,仍不明白IL-6受體抑制劑是否有效。
實際上,已有報告指出於IL-6表現之GVHD模式小鼠,即使投予抗IL-6抗體,仍不能得到治療效果(非專利文獻11)。
另外,有關本申請書之發明之先前技術文獻資料如下所示。
[非專利文獻1]Blood,78:2120-2123,1991
[非專利文獻2]Hirano,T. et al.,Nature(1986)324,73-76
[非專利文獻3]Akira,S. et al.,Adv. in Immunology(1993)54,1-78
[非專利文獻4]Lotz,M. et al.,J. Exp. Med.(1988)167,1253-1258
[非專利文獻5]Taga,T. et al.,J. Exp. Med.(1987)166,967-981
[非專利文獻6]Yamasaki,K. et al.,Science(1988)241,825-828
[非專利文獻7]Taga,T. et al.,Cell(1989)58,573-581
[非專利文獻8]Novick,D. et al.,Hybridoma(1991)10,137-146
[非專利文獻9]Huang,Y.W. et al.,Hybridoma(1993)12,621-630
[非專利文獻10]Hirata,Y. et al.,J. Immunol.(1989)143,2900-2906
[非專利文獻11]Knulst A. C. et al.,Mediators of Inflammation(1994)3,33-40
[專利文獻1]國際專利申請書公開號碼WO 95-09873
[專利文獻2]法國專利申請書公開號碼FR 2694767
[專利文獻3]美國專利申請書號碼US 5216128
[專利文獻4]國際專利申請書公開號碼WO92-19759
關於GVHD中IL-6受體之詳細角色並未明朗。另外,投予IL-6受體抑制劑,對於GVHD顯示何種效果並未明朗。
本發明係有鑑於如此狀況所實施者,其目的係提供新穎的GVHD治療劑。
本發明者等為解決上述目的,努力研究的結果係發現於GVHD模式小鼠,抗IL-6受體抗體顯示明顯的治療效果,完成本發明。
亦即,本發明係更具體地提供下述之[1]至[5]者。
[1]以間白素-6(IL-6)受體抑制劑為有效成分之治療移植物抗宿主疾病(GVHD)用治療劑。
[2]如[1]記載之GVHD治療劑,其中IL-6受體抑制劑係人類IL-6受體抑制劑。
[3]如[1]記載之GVHD治療劑,其中IL-6受體抑制劑係抗IL-6受體抗體。
[4]如[3]記載之GVHD治療劑,其中抗IL-6受體抗體係嵌合抗體、人化抗體或人抗體。
[5]如[1]至[4]中任一項記載之GVHD治療劑,治療末梢血幹細胞移植後之GVHD為特徵。
[6]包含投予療法有效量之間白素-6(IL-6)受體抑制劑之治療移植物抗宿主疾病(GVHD)之方法。
本發明中,所謂「IL-6受體抑制劑」係指遮斷介在IL-6受體之訊號傳遞,抑制IL-6受體生物學活性之物質。IL-6受體抑制劑係可為結合於IL-6受體,直接抑制IL-6受體生物學活性之物質,亦可為結合於gp130等之其他物質,間接抑制IL-6受體生物學活性之物質,但以結合於IL-6受體,具有抑制IL-6與IL-6受體結合之活性之物質為宜。
作為本發明之IL-6受體抑制劑,可舉例如抗IL-6受體抗體、可溶性抗IL-6受體改變體、抗IL-6受體部份胜肽、顯示與此等相同活性之低分子物質等,但並非受局限者。作為本發明之IL-6受體抑制劑之適合例,可舉例如辨識IL-6受體之抗體。
本發明所使用之抗IL-6受體抗體之來源雖非特別受局限者,但以哺乳動物來源之抗體為宜。
本發明所使用之抗IL-6受體抗體係可使用已知手段,作為多株抗體或單株抗體而得。作為本發明所使用之抗IL-6受體抗體,以哺乳動物來源之單株抗體尤佳。作為哺乳動物來源之單株抗體係融合瘤所產生者、及由基因工程的手法,以含抗體基因之表現載體進行轉型之宿主所產生者等。此抗體係藉由與IL-6受體結合,抑制IL-6結合於IL-6受體,遮斷傳遞IL-6之生物學活性於細胞內。
作為如此抗體例,可列舉MR16-1抗體(Tamura,T. et al. Proc. Natl. Acad. Sci. USA(1993)90,11924-11928)、PM-1抗體(Hirata,Y. et al.,J. Immunol. (1989) 143,2900-2906)、AUK12-20抗體、AUK64-7抗體或AUK146-15抗體(國際專利申請書公開號碼WO 92-19759)、tocilizumab等。此等中,作為對人IL-6受體適合之單株抗體係列舉PM-1抗體,另外,作為對小鼠IL-6受體適合之單株抗體係列舉MR16-1抗體,但不局限於此。
抗IL-6受體單株抗體產生融合瘤,基本上係可使用已知技術,如下述製作。亦即,使用IL-6受體作為敏化抗原,依據通常的免疫方法,使其進行免疫,由通常的細胞融合法,使所得之免疫細胞與已知之親細胞融合,由通常的篩選法,藉由篩選單株抗體產生細胞而可製作。
具體上,製作抗IL-6受體抗體係可如下所述進行。例如作為取得抗體之敏化抗原所使用之人IL-6受體係揭示於歐洲專利申請書公開號碼EP325474,小鼠IL-6受體係由使用日本專利申請書公開號碼特開平3-155795所揭示之IL-6受體基因/胺基酸序列所得。
IL-6受體蛋白質係有表現於細胞膜上者及脫離自細胞膜者(可溶性IL-6受體)(Yasukawa,K. et al.,J. Biochem.(1990)108,673-676)二種。可溶性IL-6受體係由結合於細胞膜之IL-6受體之實質上細胞外區域所構成,就細胞膜貫穿區域或細胞膜貫穿區域與細胞內區域缺損上,與膜結合型IL-6受體相異。IL-6受體蛋白質係只要可作為製作本發明中所使用之抗IL-6受體抗體之敏化抗原所使用,可使用任一種IL-6受體。
插入IL-6受體之基因序列於已知之表現載體系,將適當的宿主細胞進行轉型後,自該宿主細胞中或培養上清液中,以已知方法精製目的IL-6受體蛋白質,使用此精製IL-6受體蛋白質作為敏化抗原即可。另外,亦可以表現IL-6受體之細胞或IL-6受體蛋白質與其他蛋白質之融合蛋白質作為敏化抗原使用。
作為以敏化抗原所免疫之哺乳動物,雖非特別限定者,但考慮細胞融合時與使用之親代細胞之適合性而選擇為宜,可使用一般的齧齒類動物,例如小鼠、大鼠、倉鼠等。
敏化抗原引起動物免疫係依據已知方法進行。例如,作為一般方法係藉由注射敏化抗原於哺乳動物之腹腔內或皮下所進行。具體上,以PBS(Phosphate-Buffered Saline)或生理食鹽水等稀釋、懸濁敏化抗原成適當量者,依據所需,適量混合通常之佐劑,例如佛氏完全佐劑(Complete Freund Adjuvant),乳化後,每4-21日投予數次於哺乳動物為宜。另外,敏化抗原免疫時,可使用適當的載體。
如此進行免疫,確認血清中所需抗體程度上升後,自哺乳動物取出免疫細胞,付予細胞融合,作為適合細胞融合之免疫細胞,尤其可列舉脾細胞。
作為與前述免疫細胞融合之另一方之親代細胞之哺乳動物之骨髓瘤細胞,已經適合使用已知的各種細胞株,例如P3X63Ag8. 653(Kearney J. F. et. Al. J. Immnol.(1979)123,1548-1550)、P3X63Ag8U.1(Current Topics in Microbiology and Immunology(1978)81,1-7)、NS-1(Kohler. G. and Milstein,C. Eur. J. Immunol.(1976)6,511-519)、MPC-11(Margulies. D. H. et aI.,Cell(1976)8,405-415)、SP2/0(Shulman,M. et al.,Nature(1978)276,269-270)、FO(de St. Groth,S. F. et al.,J. Immunol. Methods(1980)35,1-21)、S194(Trowbridge,I. S. J. Exp. Med.(1978)148,313-323)、R210(Galfre,G. et al.,Nature(1979)277,131-133)等。
前述免疫細胞與骨髓瘤細胞之細胞融合係可依據基本上已知方法,例如Milstein等之方法(Kohler. G. and Milstein,C.,Methods Enzymol.(1981)73,3-46)等進行。
更具體上,前述細胞融合係例如於細胞融合促進劑之存在下,於通常之營養培養劑液中實施。作為融合促進劑,可使用聚乙二醇(PEG)、仙台病毒(Sendai virus,HVJ)等,另外,因應所需,亦可添加使用提高融合效率用之二甲亞碸等之補助劑。
免疫細胞與骨髓瘤細胞之使用比率係以免疫細胞相對於骨髓瘤細胞為1至10倍為宜。作為使用於前述細胞融合之培養液,可使用例如適合前述骨髓瘤細胞株增殖之RPMI1640培養液、MEM培養液、其他之此種細胞培養所使用之通常的培養液,另外,亦可併用牛胎兒血清(FCS)等之血清補液。
細胞融合係所定量之前述免疫細胞與骨髓瘤細胞於前述培養液中充份混合,通常添加30至60%(w/v)濃度之預先加溫成37℃程度之PEG溶液,例如平均分子量為1000至6000程度之PEG溶液,由混合而形成目的之融合細胞(融合瘤)。接著,逐次添加適當的培養液,進行離心,除去上清液,重複操作而可除去不利於融合瘤生育之細胞融合劑等。
該融合瘤係藉由通常的選擇培養液,例如由HAT培養液(含次黃嘌呤(Hypoxanthine)、胺蝶砱(aminopterin)及胸腺嘧啶(thymidine)之培養液)培養以選擇。為使目的融合瘤以外的細胞(非融合細胞)死亡,該HAT培養液之培養係持續進行充份的時間,通常為數日、數週。接著,實施一般限數稀釋法(limiting dilution assay),進行產生目的抗體之融合瘤之篩選及選殖(Cloning)。
另外,使人類以外的動物對抗原發生免疫而得到上述融合瘤以外,使人淋巴球,於體外(in vitro),以所需之抗原蛋白質或抗原表現細胞敏化,使敏化B淋巴球與人類骨髓瘤細胞,例如U226融合,亦可得到對所需之抗原或抗原表現細胞具有結合活性之所需人抗體(參考特公平1-59878號公報)。另外,投予抗原或抗原表現細胞於具有人抗體基因建構之基因轉殖動物,依據上述方法取得所需人抗體(參考國際專利申請書號碼WO 93/12227、WO 92/03918、WO 94/02602、WO 94/25585、WO 96/34096、WO 96/33735)。
如此所製作之產生單株抗體之融合瘤係可於通常的培養液中繼代培養,另外,可於液態氮中長期培養。
自該融合瘤取得單株抗體,採用依據通常的方法培養該融合瘤,取得該培養上清液之方法,或投予融合瘤於具有與其適合性之哺乳動物,使增殖,得到該腹水之方法等。前者之方法係適合得到高純度抗體,另一方面,後者之方法係適合抗體的大量生產。
例如製作產生抗IL-6受體抗體之融合瘤係可依據特開平3-139293所揭示之方法而進行。注入PM-1抗體產生融合瘤於BALB/c小鼠之腹腔內而得腹水,自此腹水精製PM-1抗體之方法、或將本融合瘤以適當的培養基,例如含有10%牛胎兒血清、5%BM-Condimed H1(Boehringer Mannheim製)之RPMI1640培養基、融合瘤SFM培養基(GIBCO-BRL製)、PFHM-Ⅱ培養基(GIBCO-BRL製)等,可以自該培養上清液精製PM-1抗體之方法進行。
本發明中作為單株抗體,可使用自融合瘤選殖抗體基因,嵌入適當的載體,將此導入宿主,使用基因重組技術,使產生之重組型抗體(例如參考Borrebaeck,C. A. K. and Larrick,J. W.,THERAPEUTIC MONOCLONAL ANTIBODIES,Published in the United Kingdom by MACMILLAN PUBLISHERS LTD,1990)。
具體上,產生目的抗體之細胞,例如自融合瘤,單離編碼抗體可變(V)區之mRNA。單離mRNA係可由已知方法,例如脈超離心法(Chirgwin,J. M. et al.,Biochemistry(1979)18,5294-5299)、AGPC法(Chomczynski,P. et al.,Anal. Biochem.(1987)162,156-159)等,調製總RNA,使用mRNA Purification Kit(Pharmacia製)等,調製mRNA。另外,亦可由使用QuickPrep mRNA Purification Kit(Pharmacia製),直接調製mRNA。
使用逆轉錄酵素,自所得之mRNA,合成抗體V區之cDNA。cDNA之合成亦可使用AMV Reverse Transcriptase First-strand cDNA Synthesis Kit等而進行。另外,進行cDNA的合成及增幅係可使用5’-Ampli FINDER RACE Kit(Clontech製)及使用PCR(聚合酶鏈反應,polymerase chain reaction)之5’-RACE法(Frohman,M. A. et al.,Proc. Natl. Acad. Sci. U.S.A(1988)85,8998-9002;Belyavsky,A. et al.,Nucleic Acids Res.(1989)17,2919-2932)。自所得之PCR產物,精製目的之DNA片段,與載體DNA連接。進一步,由此製作重組載體,導入於大腸菌等,選擇菌落,調製所需之重組載體。目的之DNA鹽基序列係可由已知的方法,例如雙去氧核醣鏈停止法(dideoxynucleotide chain termination)法而確認。
若可得到目的之抗體V區之DNA,連接其與編碼所需之抗體恆定區(C區)之DNA,嵌入其於表現載體。或是亦可嵌入編碼抗體之V區之DNA於含抗體C區之DNA之表現載體。
製造本發明所使用之抗體係嵌入如後述之抗體基因於表現載體,使於表現控制區,例如增強子(enhancer)、啟動子之控制下表現。接著,由此表現載體將宿主細胞轉型,可使抗體表現。
本發明中,使對人之異種抗原性降低等為目的,可使用人為改變之基因重組型抗體,例如嵌合(Chimeric)抗體、人化(Humanized)抗體等。此等改變抗體係可使用已知方法製造。
嵌合抗體係連接如前述所得之編碼抗體V區之DNA與編碼人抗體C區之DNA,將其嵌入於表現載體,導入宿主,使生產而可得(參考歐洲申請專利說明書公開號碼EP 125023、國際專利申請書公開號碼WO 92-19759)。使用此已知方法,可得到本發明有效之嵌合抗體。
人化抗體亦稱為再構成(reshaped)人抗體或人型化抗體,將人以外之哺乳動物,例如小鼠抗體之互補性決定區(CDR),移植於人抗體之互補性決定區者,亦已知該一般基因重組手法(參考歐洲申請專利說明書公開號碼EP 125023、國際專利申請書公開號碼WO 92-19759)。
具體上,將連接小鼠抗體之CDR與人抗體之抗體架構區(FR;framework region)而設計之DNA序列,製作數個寡聚核苷酸,使末端部份具有重疊(overlap)部份,由PCR法合成。連接所得之DNA與編碼人抗體C區之DNA,接著嵌入表現載體,將其導入宿主,使產生而可得(參考歐洲申請專利說明書公開號碼EP 239400、國際專利申請書公開號碼WO 92-19759)。
介在CDR所鍵結之人抗體之FR係選擇互補性決定區形成良好抗原鍵結部位者。因應需要,亦可取代抗體之可變區之抗體架構區之胺基酸,以使再構成人抗體之互補性決定區形成適當的抗原鍵結部位(Sato,K. et al.,Cancer Res.(1993)53,851-856)。
嵌合抗體、人化抗體通常係使用人抗體C區。作為人抗體重鏈C區之例,可列舉Cγ、Cα、Cμ、Cδ、Cε。例如可使用Cγ1、Cγ2、Cγ3或Cγ4。作為人抗體輕鏈C區之例,可列舉κ或λ。另外,為改善抗體或該產生之安定性,亦可修飾人抗體C區。
嵌合抗體係由人以外之哺乳動物來源抗體之可變區與人抗體來源之C區所形成,另外,人化抗體係由人以外之哺乳動物來源抗體之互補性決定區域與人抗體來源之架構區及C區所形成,因為此等於人體內之抗原性降低,所以有效地作為本發明所使用之抗體。
作為本發明所使用之人抗體之適合具體例,可列舉人化PM-1抗體(tocilizumab)(國際專利申請書公開號碼WO 92-19759)。另外,亦可為對人化PM-1抗體之胺基酸序列,進行取代、欠缺、附加等之取代體。
另外,作為取得人抗體之方法係除了先前敍述之方法以外,亦已知使用人抗體庫,由盤選(Panning)取得人抗體之技術。例如,使用人抗體之可變區作為單鏈抗體(scFv),由噬菌體呈現法,使表現於噬菌體表面,可選擇結合於抗原之噬菌體。若分析所選擇之噬菌體之基因時,可決定編碼結合於抗原之人抗體可變區之DNA序列。若明白結合於抗原之scFv之DNA序列時,製作含該序列之適當的表現載體,可取得人抗體。此等方法係已眾所皆知,可參考WO 92/01047、WO 92/20791、WO 93/06213、WO 93/11236、WO 93/19172、WO 95/01438、WO 95/15388。
如上述建構之抗體基因係可由已知方法表現。使用哺乳類細胞時,可由所常用之有效的啟動子、所表現之抗體基因、使於該3’側下游機能的結合poly A訊號之DNA或含其之載體使表現。例如,作為啟動子/增強子,可列舉人類巨細胞病毒前期啟動子/增強子(human cytomegalovirus immediate early promoter/enhancer)。
另外,其他作為可使用於本發明所使用之抗體表現之啟動子/增強子,可使用反轉錄病毒(Retrovirus)、多瘤病毒(polyoma virus)、腺病毒(Adenovirus)、猿猴病毒40(SV40)等之病毒啟動子/增強子或人延長因子1α(HEF1α)等之哺乳類細胞來源之啟動子/增強子。
例如,使用SV40啟動子/增強子時,依據Mulligan 等之方法(Mulligan,R. C. et al.,Nature(1979)277,108-114),另外,使用HEF1 α啟動子/增強子時,依據Mizushima之方法(Mizushima. S. and Nagata,S. Nucleic Acids Res.(1990)18,5322),可容易實施。
使用原核細胞作為宿主時,有使用細菌細胞之產生系。作為細菌細胞,已知大腸桿菌(E. coli)、枯草菌。
大腸桿菌時,可使機能地結合所常用之有效啟動子、抗體分泌用之訊號序列、使表現之抗體基因而使表現。例如作為啟動子,可列舉lacZ啟動子、araB啟動子。使用lacZ啟動子時,可依據Ward等之方法(Ward,E. S. et al.,Nature(1989)341,544-546;Ward,E. S. et al.,FASEB J.(1992)6,2422-2427),使用araB啟動子時,可依據Better等之方法(Better,M. et al. Science(1988)240,1041-1043)。
作為抗體分泌用之訊號序列,使於大腸桿菌之周邊胞質(periplasm)產生時,可使用pelB訊號序列(Lei,S. P. et al J. Bacteriol.(1987)169,4379-4383)。分離周邊胞質所產生之抗體後,適當地折疊(refold)抗體的結構後使用(例如參考WO 96/30394)。
作為複製起源,亦可使用來自SV40、多瘤病毒、腺病毒、牛乳頭瘤病毒(BPV)等者。進一步,為增幅於宿主細胞系基因複製數,表現載體係可含有作為選擇標誌之胺基糖甘磷酸轉移酶(APH)基因、胸腺嘧啶激酶(TK)基因、大腸菌茶鹼鳥糞嘌呤磷酸核糖基轉基酶(Ecogpt)基因、二氫葉酸還原酵素(dhfr)基因等。
製造本發明所使用之抗體,可使用任意產生系。製造抗體用之產生系係有體外(in nitro)及體內(in vivo)產生系。作為in vitro產生系,可列舉使用真核細胞之產生系或使用原核細胞之產生系。
使用真核細胞作為宿主時,有使用動物細胞、植物細胞、或真菌細胞之產生系。作為動物細胞,已知(1)哺乳類細胞,例如CHO、COS、骨髓瘤(myeloma)、BHK(baby hamster kidney)、Hela、Vero等,(2)兩生類細胞,例如南非有爪蟾蜍(xenopus laevis)卵母細胞、或(3)昆蟲細胞,例如Sf9、Sf21、Tn5等。作為植物細胞,已知來自菸草(Nicotiana tabacum)之細胞,將其作癒合組織培養(Callus culture)即可。作為真菌細胞,已知酵母,例如酵母菌(Saccharomyces)屬,如釀酒酵母(Saccharomyces cerevisiae)、絲狀菌,例如麴菌(Aspergillus)屬,如黑麴黴(Aspergillus niger)等。
於此等細胞,由轉型導入目的之抗體基因,於in vitro培養轉型細胞而可得到抗體。培養係依據已知的方法進行。例如作為培養液,可使用DMEM(Dulbecco's Modified Eagle Media)、MEM(Modified Eagle Media)、RPMI(Rosewell Park Memorial Institute)1640、IMDM(Iscove's Modified Dulbecco's Medium),亦可併用牛胎兒血清(FCS)等之血清補液。另外,亦可藉由移入導入抗體基因之細胞於動物之腹腔等,於in vivo產生抗體。
另一方面,作為in vivo之產生系,可舉例如使用動物之產生系或使用植物之產生系。使用動物時,有使用哺乳類動物、昆蟲之產生系等。
作為哺乳類動物,可使用山羊、豬、綿羊、小鼠、牛等(Vicki Glaser,SPECTRUM Biotechnology Applications,1993)。另外,作為昆蟲,可使用蠶。使用植物時,例如可使用菸草。
導入抗體基因於此等動物或植物,使於動物或植物的體內產生抗體而回收。例如插入抗體基因於編碼如山羊β酪蛋白之乳汁中原有產生之蛋白質之基因,調製成融合基因。注入含有插入抗體基因之融合基因之DNA片段於山羊的胚胎,導入此胚胎於雌山羊。自接受胚胎之山羊所產生之基因轉殖山羊或其子孫所產生之乳汁,可得到所需之抗體。為增加自基因轉殖山羊所產生之含有所需抗體之乳汁量,可使用適當的激素於基因轉殖山羊(Ebert,K. M. et al.,Bio/Technology(1994)12,699-702)。
使用蠶時,使蠶感染插入目的抗體基因之DNA之桿狀病毒(baculovirus),可自此蠶的體液,得到所需之抗體(Maeda. S. et al.,Nature(1985)315,592-594)。另外,使用菸草時,插入目的抗體基因於植物表現用載體,例如pMON530,將此載體導入如冠纓農桿菌(Agrobacterium tumefaciens)之細菌。使菸草感染此細菌,例如菸草(Nicotiana tabacum),由本菸草葉得到所需之抗體(Julian K.-C. Ma et al.,Eur. J. Immunol.(1994)24,131-138)。
如上所述,於in vitro或in vivo之產生系產生抗體時,可分別嵌入編碼抗體重鏈(H鏈)或輕鏈(L鏈)之DNA於表現載體,同時使宿主轉型,或亦可嵌入編碼H鏈及L鏈之DNA於單一表現載體,使宿主轉型(參考國際專利申請書公開號碼WO94-11523)。
本發明所使用之抗體係只要適合使用於本發明即可,可為抗體之片斷或其修飾物。例如,作為抗體片段,可列舉Fab、F(ab’)2、Fv或H鏈及L鏈之Fv,以適當的連結區段(linker)連接之單鏈Fv(scFv)。
具體上,將抗體以酵素,例如木瓜酵素(Papain)、胃蛋白脢(pepsin)處理而產生抗體片段,或建構編碼此等抗體片段之基因,將此導入表現載體後,使於適當的宿主細胞表現(例如參考Co,M. S. et al.,J. Immunol.(1994)152,2968-2976;Better,M. and Horwitz,A. H.,Methods in Enzymology(1989)178,476-496;Plueckthun,A. and Skerra,A.,Methods in Enzymology(1989)178,497-515;Lamoyi,E.,Methods in Enzymology(1989)121,652-663;Rousseaux,J. et al.,Methods in Enzymology(1989)121,663-669;Bird,R. E. et al.,TIBTECH(1991)9,132-137)。
scFv係可由連接抗體H鏈V區及L鏈V區所得。於此scFv中,H鏈V區及L鏈V區係介在連結區段(linker),以胜肽連結區段所連接為宜(Huston,J. S. et al.,Proc. Natl. Acad. Sci. U.S.A.(1988)85,5879-5883)。scFv中之H鏈V區及L鏈V區係可為上述作為抗體所記載者中任一種。作為連接V區之胜肽連結區段,可使用例如由胺基酸12-19所形成之任意單鏈胜肽。
編碼scFv之DNA係以前述編碼抗體之H鏈或H鏈V區之DNA、及編碼L鏈或L鏈V區之DNA為鑄模,將編碼此等序列中所需胺基酸序列之DNA部份,使用規定該兩端之引子對,由PCR法進行增幅,接著,進一步,組合編碼胜肽連結區段之DNA及規定連接其兩端與各個H鏈、L鏈之引子對,進行增幅所得。
另外,一旦製作編碼scFv之DNA時,依據常法,可得到含有此等之表現載體、及由該表現載體所轉型之宿主,另外,使用該宿主,依據常法,可得到scFv。
此等抗體之片段係與前述相同操作,取得該基因而使表現,可使由宿主產生。本發明中所謂的「抗體」,亦包含此等抗體之片段。
作為抗體修飾物,亦可使用與聚乙二醇(PEG)等之各種分子鍵結之抗體。本發明中所謂的「抗體」亦包含此等之抗體修飾物。為得到如此之抗體修飾物,可由施以化學修飾於所得之抗體而得。此等方法已於此領域確立。
如前述所產生、表現之抗體係可自細胞內外、宿主分離,精製至均勻。本發明中所使用之抗體之分離、精製係可由親和層析法進行。作為親和層析法所使用之管柱,可舉例如蛋白質A管柱、蛋白質G管柱。作為使用於蛋白質A管柱之載體,可舉例如Hyper D,POROS,Sepharose F. F.等。可使用其他通常蛋白質所使用之分離、精製之方法,並非受任何限定者。
若適當選擇、組合例如前述親和層析法以外之層析管柱、過濾器、超濾、鹽析、透析等,可分離、精製本發明所使用之抗體。作為層析法,可舉例如離子交換層析法、疏水性層析法、凝膠過濾等。此等層析係可適用於HPLC(High performance liquid chromatography)。另外,亦可使用逆相HPLC(reverse phase HPLC)。
測定前述所得抗體之濃度係可依據測定吸光度或ELISA等而進行。亦即,依據測定吸光度時,以PBS(-)適當稀釋後,測定280nm之吸光度,算出1.350D為1mg/ml。另外,依據ELISA時,係可如下述測定。亦即,加入100μl之以0.1M重碳酸緩衝溶液(pH9.6)稀釋成1μg/ml之山羊抗人IgG(TAG製)於96孔培養盤(Nunc製),以4℃培養一晚,使抗體固相化。結塊後,添加100μl之經適當稀釋之本發明所使用之抗體或含抗體之檢品、或作為標準品之人IgG(CAPPEL製),於室溫下培養1小時。
洗淨後,加入100μl之5000倍稀釋之鹼性磷酸酵素(alkaline phosphatase)標識抗人IgG(BIO SOURCE製),於室溫下培養1小時。洗淨後,加入基質溶液,進行培養後,使用MICROPLATE READER Model 3550(Bio-Rad製),測定於405nm時之吸光度,算出目的抗體之濃度。
IL-6受體部份胜肽係於IL-6受體之胺基酸序列中,IL-6與IL-6受體結合之相關區域之部份或全部之胺基酸序列所形成之胜肽。如此胜肽通常為10至80個,以20至50個為宜,以20至40個尤佳之胺基酸殘基所形成。
IL-6受體部份胜肽係於IL-6受體之胺基酸序列中,特定IL-6與IL-6受體結合之相關區域,基於該特定區域之部份或全部之胺基酸序列,可由通常已知之方法,例如基因工程的方法或胜肽合成法而可製作。
由基因工程的方法製作IL-6受體部份胜肽係可依據嵌入編碼所需胜肽之DNA序列於表現載體,前述重組型抗體之表現、產生及精製方法而得。
由胜肽合成法製作IL-6受體部份胜肽係可使用胜肽合成時通常所使用之方法,例如固相合成法或液相合成法。
具體上,亦可依據續醫藥品之開發第14卷胜肽合成監修矢島治明廣川書店1991年記載之方法進行。作為固相合成法,例如可使用於有機溶劑不溶解性之支持體,使結合對應於欲合成胜肽之C端之胺基酸,將以適當的保護基保護α-胺基及側鏈官能基之胺基酸,自C端至N端方向之順序,使縮合各1個胺基酸之反應以及使結合於樹脂上之胺基酸或胜肽之α-胺基之該保護基脫離之反應,藉由交互重複,使胜肽鏈延長之方法。固相胜肽合成法係依所使用之保護基之種類,大致分為Boc法及Fmoc法。
如此操作,合成目的胜肽後,進行脫保護反應及自支持體之切斷胜肽鏈之反應。與胜肽鏈之切斷反應通常係可使用Boc法中之氟化氫或三氟甲磺酸,或Fmoc法中之TFA。Boc法係例如於氟化氫中,於茴香醚存在下,處理上述保護胜肽樹脂。接著,脫離保護基及自支持體切斷,回收胜肽。將其藉由冷凍乾燥,得到粗胜肽。另一方面,於Fmoc法中,例如TFA中,以與上述同樣的操作,可進行脫保護反應及自支持體切斷胜肽鏈之反應。
所得之粗胜肽係可藉由適用於HPLC而分離、精製。關於該溶出係可使用蛋白質精製時通常所使用之水-乙腈系溶劑,於最適合條件下進行。分取該符合所得層析圖之波峰之部份,將其冷凍乾燥。關於如此操作,經精製之胜肽部份,藉由質譜儀分析之分子量分析、胺基酸組成分析、或胺基酸序列分析等而鑑定。
本發明之GVHD治療劑係可使用於治療及/或預防GVHD。本發明之GVHD治療劑亦包含抑制GVHD發病之GVHD預防劑。因此,本發明中所謂「GVHD治療」係指抑制GVHD、降低GVHD發生率、治療GVHD、改善GVHD症狀等。
本發明治療劑對象之GVHD係任何GVHD皆可。本發明治療劑對象之GVHD亦包含急性GVHD及慢性GVHD。本發明之GVHD治療劑係特別有效地使用於末梢造血幹細胞移植後(同種末梢造血幹細胞移植等)之GVHD、骨髓移植後(同種骨髓移植等)之GVHD等之造血幹細胞移植後之GVHD等。
作為本發明所使用之IL-6受體抑制劑之GVHD治療劑之功效係可評估例如訊號傳遞抑制活性作為指標,但不局限於此。IL-6受體抑制劑之訊號傳遞抑制活性,可由通常所使用之方法評估。具體上,培養IL-6依賴性入骨髓瘤株(S6B45,KPMM2)、人LennertT淋巴瘤細胞株KT3、或IL-6依賴性細胞MH60、BSF2,添加IL-6於其中,藉由使IL-6受體抑制劑同時共存,測定IL-6依賴性細胞之3
H-胸腺嘧啶取用即可。另外,藉由培養IL-6受體表現細胞之U266,添加125
I標誌IL-6,同時加入IL-6受體抑制劑,測定結合於IL-6受體表現細胞之125
I標誌IL-6。於上述分析系統中,除了使存在IL-6受體抑制劑組以外,並加上設置不含IL-6受體抑制劑之陰性對照組,比較兩者所得結果時,可評估IL-6受體抑制劑之IL-6受體抑制活性。
投予本發明之GVHD治療劑之對象係哺乳動物。哺乳動物係以人為宜。
本發明之GVHD治療劑係可以醫藥品之形態投予,可經口或非經口的全身或局部地投予。例如可選擇點滴等之靜脈內注射、肌肉內注射、腹腔內注射、皮下注射、坐藥、注腸、經口性腸溶劑等,可依患者的年齡、症狀而選擇適當的投予方法。有效投予量雖無特別限制,但每一次每1kg體重,選擇0.01mg至100mg之範圍。或者,可選擇每個患者1至1000mg,以5至50mg為宜之投予量。作為適合之投予量,投予方法之具體例,例如抗IL-6受體抗體時,每1kg體重1個月(4週),0.5mg至40mg,以1mg至20m為宜,分為1次至數次,例如2次/週、1次/週、1次/2週、1次/4週等之投予時間表,以點滴等之靜脈內注射、皮下注射、肌肉內注射等方法進行投予之方法。投予時間係觀察患者狀態及觀察血液檢查值之變化下,亦可延長投予間隔等以調整,使自2次/週或1次/週成1次/2週、1次/3週、1次/4週等。
如後述實施例所示,本發明之GVHD治療劑係於造血幹細胞移植前及移植後,藉由投予於移植受體(recipient),可明顯地抑制GVHD發病。因此,本發明之GVHD治療劑係於造血幹細胞移植前投予,進一步觀察GVHD的狀況,移植後亦投予為宜。
本發明之GVHD治療劑亦可與至少1個已知之GVHD治療劑或治療法一同投予。例如可同時或依序投予預防GVHD用之免疫抑制劑(環孢靈、Tacrolimus、甲氨蝶呤)。另外,亦可併用自移植細胞群(移植物)除去成熟T細胞之方法。
本發明之GVHD治療劑中亦可添加保存劑或安定劑等之製劑上所容許的載體。所謂製劑上所容許的載體係指可與上述藥劑一同投予的材料。作為製劑上所容許之材料,可舉例如滅菌水或生理食鹽水、安定劑、賦形劑、緩衝劑、防腐劑、界面活性劑、螯合劑(EDTA等)、結合劑等。
本發明中,可列舉作為界面活性劑之非離子界面活性劑,可舉例如山梨糖醇酐單辛酸酯、山梨糖醇酐單月桂酸酯、山梨糖醇酐單棕櫚酸酯等之山梨糖醇酐脂肪酸酯;甘油單辛酸酯、甘油單肉豆蔻酸酯、甘油單硬脂酸酯等之甘油脂肪酸酯;十甘油基單硬脂酸酯、十甘油基二硬脂酸酯、十甘油基單亞油酸酯等之多甘油脂肪酸酯;聚氧乙烯山梨糖醇酐單月桂酸酯、聚氧乙烯山梨糖醇酐單油酸酯、聚氧乙烯山梨糖醇酐單硬脂酸酯、聚氧乙烯山梨糖醇酐單棕櫚酸酯、聚氧乙烯山梨糖醇酐三油酸酯、聚氧乙烯山梨糖醇酐三硬脂酸酯等之聚氧乙烯山梨糖醇酐脂肪酸酯;聚氧乙烯山梨糖醇四硬脂酸酯;聚氧乙烯山梨糖醇四油酸酯等之聚氧乙烯山梨糖醇脂肪酸酯;聚氧乙烯甘油基單硬脂酸酯等之聚氧乙烯甘油脂肪酸酯;聚乙二醇二硬脂酸酯等之聚乙二醇脂肪酸酯;聚氧乙烯月桂醚等之聚氧乙烯烷基醚;聚氧乙烯聚氧丙烯乙二醇、聚氧乙烯聚氧丙烯丙基醚、聚氧乙烯聚氧丙烯十六烷基醚等之聚氧乙烯聚氧丙烯烷基醚;聚氧乙烯壬基苯基醚等之聚氧乙烯烷基苯基醚;聚氧乙烯箆麻油、聚氧乙烯硬化箆麻油(聚氧乙烯氫化箆麻油)等之聚氧乙烯硬化箆麻油;聚氧乙烯山梨糖醇蜂蠟等之聚氧乙烯蜂蠟衍生物;聚氧乙烯羊毛脂等之聚氧乙烯羊毛脂衍生物;聚氧乙烯硬脂酸醯胺等之聚氧乙烯脂肪酸醯胺等之具有HLB6至18者等作為典型例。
亦可列舉陰離子界面活性劑作為界面活性劑,可舉例如十六烷基硫酸鈉、月桂基硫酸鈉、油基硫酸鈉等之具有碳數10至18之烷基之烷基硫酸鹽;聚氧乙烯月桂基硫酸鈉等之環氧乙烷之平均加成莫耳數為2至4,烷基之碳數10至18之聚氧乙烯烷基醚硫酸鹽;月桂基磺基琥珀酸酯鈉等之烷基之碳數8至18之烷基磺基琥珀酸酯鹽;天然系之界面活性劑,例如卵磷脂、甘油磷脂;鞘髓磷脂等之鞘磷酯;碳數12至18之脂肪酸之蔗糖脂肪酸酯等作為典型例。
本發明之藥劑係可添加1種或組合2種以上之此等界面活性劑。本發明製劑使用之適合的界面活性劑係聚山梨酸酯20、40、60或80等之聚氧乙烯山梨糖醇酐脂肪酸酯,以聚山梨酸酯20及80尤佳。另外,以Poloxamer(Pluronic F-68(註冊商標)等)所代表之聚氧乙烯聚氧丙烯乙二醇為宜。
界面活性劑之添加量係依使用的界面活性劑之種類而異,但於聚山梨酸酯20或聚山梨酸酯80時,一般為0.001至100mg/mL,以0.003至50mg/mL為宜,以0.005至2mg/mL尤佳。
作為本發明中之緩衝劑,可舉例如磷酸、檸檬酸緩衝液、醋酸、蘋果酸、酒石酸、琥珀酸、乳酸、磷酸鉀、葡糖酸、辛酸、脫氧膽酸、水楊酸、三乙醇胺、富馬酸等、其他有機酸等、或碳酸緩衝液、Tris緩衝液、組織胺酸緩衝液、咪唑緩衝液等。
另外,可於溶液製劑之領域,藉由溶解於已知水性緩衝液,調製溶液製劑。緩衝液之濃度一般為1至500mM,以5至100mM為宜,以10至20mM尤佳。
另外,本發明之治療劑係可含有其他低分子量之多胜肽、血清白蛋白、明膠或免疫球蛋白等之蛋白質、胺基酸、多醣及單醣等之醣類或碳水化合物、糖醇。
本發明中作為胺基酸,可舉例如鹼性胺基酸,可舉例如精胺酸、賴胺酸、組織胺酸、鳥胺酸等、或此等胺基酸之無機鹽(以鹽酸鹽、磷酸鹽之形態,亦即磷酸胺基酸)。使用游離胺基酸時,適宜的pH值係由添加適當的生理上所容許之緩衝物質,例如無機酸,尤其鹽酸、磷酸、硫酸、醋酸、甲酸或此等鹽所謂整。此時,磷酸鹽之使用係尤其就得到安定的冷凍乾燥物上,尤其有效。調製物係實質上不含有有機酸,例如蘋果酸、酒石酸、檸檬酸、琥珀酸、富馬酸等時或不存在對應之陰離子(蘋果酸離子、酒石酸離子、檸檬酸離子、琥珀酸離子、富馬酸離子等)時,尤其有效。適合之胺基酸係精胺酸、賴胺酸、組織胺酸、或鳥胺酸。另外,亦可使用酸性胺基酸,例如麩胺酸及天冬胺酸、及該鹽之形態(以鈉鹽為宜)或中性胺基酸,例如異白胺酸、白胺酸、甘胺酸、絲胺酸、蘇胺酸、纈胺酸、甲硫胺酸、半胱胺酸、或丙胺酸、或芳香族胺基酸,例如苯丙胺酸、酪胺酸、色胺酸、或衍生物之N-乙醯基色胺酸。
本發明中,作為多醣及單醣等之糖類或碳水化合物,可舉例如葡聚糖、葡萄糖、果糖、乳糖、木糖、甘露糖、麥芽糖、蔗糖、海藻糖、棉子糖等。
本發明中,作為糖醇,可舉例如甘露糖醇、山梨糖醇、肌醇等。
以本發明之藥劑作為注射用之水溶液時,可與例如生理食鹽水、含葡萄糖、或其他補助藥(例如左旋山梨糖醇、左旋甘露糖、左旋甘露糖醇、氯化鈉)之等張液混合,另外,該水溶液係併用適當的溶解補助劑(例如醇(乙醇等)、多元醇(丙二醇、PEG等)、非離子性界面活性劑(聚山梨酸酯80、HCO-50)等)。
依據所需,亦可含有稀釋劑、助溶劑、pH調整劑、無痛化劑、含硫還原劑、抗氧化劑等。
本發明中,作為含硫還原劑,可舉例如N-乙醯基半胱胺酸、N-乙醯基同半胱胺酸、硫辛酸、硫代二乙酸、硫代乙醇胺、硫甘油、硫代山梨糖醇、巰基乙酸及其鹽、硫代硫酸鈉、麩胱甘肽、以及碳數1至7之硫代醇酸等之具有硫醇基者等。
本發明中,作為抗氧化劑,可舉例如異抗壞血酸、二丁基羥基甲苯、丁基羥基茴香醚、α-生育醇、生育醇醋酸鹽、左旋抗壞血酸及其鹽、左旋抗壞血酸棕櫚酸酯、左旋抗壞血酸硬脂酸酯、亞硫酸氫鈉、亞硫酸鈉、沒食子酸三戊酯、沒食子酸丙酯或二乙胺四乙酸(EDTA)、焦磷酸鈉、偏磷酸鈉等之螯合劑。
另外,因應需要,亦可密封於微膠囊(羥甲基纖維素、明膠、聚[甲基丙烯酸甲酯]等之微膠囊),形成膠體藥物載體(colloidal drug delivery systems)(微脂體、白蛋白微球體(albumin microspheres)、微乳液(Microemulsion)、奈米子及奈米膠囊等)(參考“Remington’s Pharmaceutical Science 16th
edition”,Oslo Ed.,1980等)。另外,亦已知使用使藥劑成為緩釋性藥劑之方法,可適用於本發明(Langer et al.,J. Biomed. Mater. Res. 1981,15:167-277:Langer,Chem. Tech. 1982,12:98-105;美國專利第3,773,919號;歐洲專利申請書公開(EP)第58,481號;Sidman et al.,Biopolymers 1983,22:547-556;EP第133,988號)。
所使用之製劑上所容許之載體係因應劑型,自上述中適當選擇或組合,但並非局限於此等者。
本發明係關於包含投予IL-6受體抑制劑於GVHD發病對象或可能發病之對象之步驟,對於對象進行治療及/或預防GVHD之方法。
本發明中,所謂「對象」係指投予本發明GVHD治療劑之生物體、該生物體體內之一部份。生物體並非特別限定者,但包含動物(例如人、家畜動物種、野生動物)。
本發明中,所謂「投予」係包含經口、或非經口投予。作為經口投予係可列舉經口劑形態之投予,作為經口劑,可選擇顆粒劑、散劑、錠劑、膠囊劑、溶劑、乳劑、或懸濁劑等之劑型。
作為非經口投予係可列舉注射劑形態之投予,作為注射劑可列舉皮下注射劑、肌肉注射劑、靜脈注射劑或腹腔內注射劑等。另外,使用基因治療之方法,導入含應投予寡核苷酸之基因於生物體,可達成本發明方法之功效。另外,亦可局部投予本發明藥劑於欲施以處理之區域。例如亦可藉由手術中局部注入、導管(catheter)之使用、或編碼本發明胜肽之DNA目標化基因傳送而投予。
另外,本說明書中所引用之全部先前技術文獻皆編入本說明書作為參考。
由實施例更詳細地說明本發明,但本發明不局限於此。相關業者皆可進行各種改變、修飾,此等改變、修飾亦包含於本發明。
[實施例]
實施例1:IL-6受體抗體對GVHD之功效
試驗法
將6×107
cells/mouse之得自8週齡之雌性C57BL/6J提供小鼠(日本Charles River)之脾細胞,自尾動脈移植入8週齡之雌性B6D2F1/Crlj接受小鼠(日本Charles River),使引起GVHD。
將接受小鼠分為2組,一組係將抗小鼠IL-6受體抗體MR16-1(中外製藥),於脾細胞移植前1天,進行尾靜脈投予4mg/mouse,之後,每隔7天共進行4次0.5mg/mouse腹腔投予。對照組係投予phosphate-buffered saline(PBS;SIGMA-ALDRICH Inc.)(各組10隻)。移植脾細胞後,每週測定小鼠體重3次,以體重評估GVHD發病。
結果
結果如圖1所示。對照組觀察到2相性體重減少。亦即,脾細胞移植後第9至14天,發現體重減少後,第16天暫時恢復,之後,第19至21天,體重再度減少,第33天幾乎完全恢復。另一方面,MR16-1投予組,未觀察到第9至14天之體重減少。亦即,認為抗IL-6受體抗體係抑制GVHD發病者。
[圖1]
表示引起GVHD之小鼠中,抗IL-6受體抗體投予組與對照組之體重之經時變化圖。
Claims (3)
- 一種製造移植物抗宿主疾病(GVHD)用治療劑之用途,其特徵係使用抗間白素-6(IL-6)受體抗體。
- 如申請專利範圍第1項之製造移植物抗宿主疾病(GVHD)用治療劑之用途,其中抗IL-6受體抗體係嵌合抗體、人化抗體或人抗體。
- 如申請專利範圍第1或2項之製造移植物抗宿主疾病(GVHD)用治療劑之用途,其係治療造血幹細胞移植後的GVHD。
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