TWI318630B - Wt1 modified peptide - Google Patents
Wt1 modified peptide Download PDFInfo
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- TWI318630B TWI318630B TW091105633A TW91105633A TWI318630B TW I318630 B TWI318630 B TW I318630B TW 091105633 A TW091105633 A TW 091105633A TW 91105633 A TW91105633 A TW 91105633A TW I318630 B TWI318630 B TW I318630B
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- peptide
- cancer
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- antigen
- cell
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Classifications
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- C07K14/82—Translation products from oncogenes
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
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- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
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- A—HUMAN NECESSITIES
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Description
1318630 A7 B7 五、發明説明(,) 技術領域 (請先閱讀背面之注意事項再填寫本頁) 本發明係有關基於Wilms腫瘤之癌抑制基因W T 1之產 物之癌抗原。該癌抗原可用作對白血病、骨髓形成異常症 候群、多發性骨髓腫、惡性淋巴腫等血癌、或固體癌、例 如胃癌、大腸癌、乳癌、胚細胞癌、皮膚癌、膀胱癌、前 列腺癌、子宮癌、子宮頸癌、卵巢癌等,甚至於會出現 W T 1之癌的抗癌疫苗。 先行技術 用以排除異物之免疫機構,一般有辨識抗原充當抗原 提示細胞之巨噬細胞,辨識該巨噬細胞之抗原提示產生淋 巴細胞活素活化其它Τ細胞等之輔助Τ細胞,藉該淋巴細 胞活素之作用分化成抗體產生細胞之Β淋巴球等所摻與之 液性免疫,及以接收抗原之提示而分化之殺手Τ細胞(亦 稱細胞傷害性Τ細胞(C T L ))爲目標細胞加以攻擊破 壞之細胞性免疫。 經濟部智慧財產局Μ工消費合作社印製 目前,癌之免疫被認爲主要係殺手Τ細胞所參與之細 胞免疫。藉殺手Τ細胞之癌免疫當中,辨識以主要組織相 容性複合體(Major Histocompatibility Complex;MH C )第 I類抗原(MHC第I類抗原,人類之HLA抗原)與癌 抗原複合體形式呈現之癌抗原之前驅T細胞分化增生成之 殺手T細胞攻撃,破壞癌細胞。此時,癌細胞於其細胞表 面提示MH C第I類抗原與癌抗原之複合體,成爲殺手T 細胞之目標(Cur. Opin,Immunol.,5,709,1993; Cur. Opin, -4- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) % 7 Ο 1318630 A7 B7 五、發明説明(2 )
Immunol., 5,7 19, 1993; Cell, 82, 1 3, 1995; Immunol. Rev, 146, 167, 1995)。 (請先閲讀背面之注意事項再填寫本頁) 於目標細胞癌細胞上以ΜΗ C第I類抗原呈現之上述 癌抗原,被認係癌細胞內合成之抗原蛋白經細胞內蛋白酶 處理生成之約8至1 2個胺基酸所成之肽(Cur. Opin, Immunol., 5,709, 1 993; Cur. Opin, Immunol., 5,7 1 9, 1 993; Cell, 82,13,1995; Immunol. Rev, 146,167,1995 )。 目前査閱種種癌之抗原蛋白,可發現少有經證明爲癌 特異抗原者。
Wilms腫瘤之癌抑制基因WT1 (WT1基因),係分 離自合倂Wilms腫瘤、無紅彩、泌尿生殖器異常、精神發展 遲滯等之WAGR症候群之分析所得之Wilms腫瘤之起因基 因之一,染色體 llpl3( Gessler,M.等,Nature,Vol· 343, ρ.774-778 (1990)),基因組 DNA 係約 5〇kb 之 10表現序列所成,其cDNA約3kb。從cDNA推 定之胺基酸序列如序列號:1所示(Mol. Cell. Biol.,11, 1707,1991 )。 經濟部智慧財產局W工消費合作社印製 WT 1基因常見於人類白血病,因白血病細胞以 W T 1反義低聚物處理則其細胞增生受抑制(日本專利特 開平9 一 1 0 4 6 2 7號公報)等,暗示WT 1基因有促 進白血病細胞增生之作用。又,WT 1基因亦常見於胃癌 、大腸癌、肺癌、乳癌、胚細胞癌、肝癌、皮膚癌、膀胱 癌、***癌、子宮癌、子宮頸癌、卵巢癌等固體癌(特 願平9 — 1 9 1 6 3 5),可見WT1基因乃白血病及固 -5- 本紙張又度適用中國國家標準(CNS ) A4規格(210X 297公釐) A7 1318630 B7 五、發明説明(3 ) 體癌之新腫瘤標記。 W 0 00/06602記載由部份WT1基因出現 (請先閲讀背面之注意事項再填寫本頁) 生成物所成之若干癌特異抗原肽,並記載,其中有希望的 是〇6,胺基酸序列如下:Cys Met Thr T r p A s n Gin Met A s n Leu (序 列號:2 )(本發明中稱作"W T 1野生肽〃)。 發明之揭示 因此,本發明在提供活性高於所有已知癌特異坑原肽 ,可望作爲癌病毒之肽。 本發明人等,爲解決上述課題作種種探討,結果發現 將所有已知之上述胺基酸序列(序列號:2 )之第二號胺 基酸Me t變更爲Tyr ,具胺基酸序列:Cys T y r Thr Trp A s n Gin Met A s n L e u (序列號:3 )之肽(稱作"W T 1改質肽〃)活 性極高,而完成本發明》 經濟部智慧財產局S工消費合作社印製 因此本發明係在提供含以下胺基酸序列:C y s Tyr Thr Trp A s n Gin Met
Asn Leu (序列號:3)而成,9至30個胺基酸 所成之肽(W T 1改質肽)。以含序列號:3之胺基酸序 列,由9至1 2個胺基酸所成之多肽爲佳,序列號:3之 胺基酸序列所成之肽爲更佳。 本發明亦在提供,以上述W T 1改質肽爲有效成分之 癌疫苗。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1318630 A7 B7 五、發明説明(4 ) . 本發明亦在提供,以上述之肽爲編碼之D N A爲有效 成分之對於癌之D NA疫苗。 (請先閲讀背面之注意事項再填寫本頁) 本發明亦在提供,呈現HLA抗原(MHC第I類抗 原)及上述肽之複合體之抗原呈現細胞。 本發明亦在提供,辨識H L A抗原及上述肽之複合體 之細胞傷害性T細胞。 圖面之簡單說明 經濟部智慧財產局員工消費合作社印製 第1圖係經W T 1野生肽(序列號:2 )或本發明之 W T 1改質肽(序列號:3 )刺激之動器細胞(E ),對 脈衝或無脈衝C 1 R2 4 0 2目標(Target)細胞(T )之 殺細胞效果(比細胞溶解活性)圖。圖中黑圓點示對野生 肽脈衝C 1 R 2 4 0 2目標細胞,經W T 1改質肽刺激之 動器細胞之細胞溶解效果,黑方塊示對野生肽脈衝 C 1 R 2 4 0 2目標細胞,經W T 1野生肽刺激動器細胞 之細胞溶解效果,中空圓示對不經野生肽脈衝之 C 1 R 2 4 0 2目標細胞,經W T 1改質肽刺激之動器細 胞之細胞溶解效果,而中空方塊示對無野生肽脈衝之 c 1 R 2 4 0 2目標細胞,經w T 1野生肽刺激之動器細 胞之細胞溶解效果。 第2圖係,以經W T 1野生肽或本發明之W T 1改質 肽刺激之動器細胞,對於內生出現WT 1抗原之急性骨髓 性白血病細胞或不出現之急性骨髓性白血病細胞之細胞溶 解活性圖。 本紙張尺度適用中國國家標举(CNS ) A4規格(2丨〇 X 29"7公釐) 1318630 A7 B7 五、發明説明(5 ) (請先閲讀背面之注意事項再填寫本頁) 第3圖係,以經W T 1野生肽或本發明之w T 1改質 肽刺激之動器細胞,作肽之脈衝或不作脈衝之 C 1 R 2 4 0 2目標細胞之殺細胞效果(比細胞溶解活性 )圖。圖中黑圓點示對野生肽脈衝之C 1 R 2 4 0 2細胞 ,經W T 1改質肽剌激之動器細胞之細胞溶解效果,黑方 塊示對野生肽脈衝C 1 R 2 4 0 2目標細胞,經W T 1野 生肽刺激動器細胞之細胞溶解效果,中空圓示對無野生肽 脈衝C 1 R 2 4 0 2目標細胞,經W T 1改質肽刺激之動 器細胞之細胞溶解效果,而中空方塊示對無野生肽脈衝之 C 1 R2 4 0 2目標細胞,經WT 1野生肽刺激之動器細 胞之細胞溶解效果。 第4圖係以W T 1野生肽或本發明之W T 1改質肽刺 激之動器細胞,對於.內因出現W T 1之肺癌細胞株或不出 現之肺癌細胞株之細胞溶解活性圖。 經濟部智慧財產局員工消費合作社印製 第5圖係,以經W T 1野生肽或本發明之W T 1改質 肽刺激之動器細胞,對脈衝野生肽之C 1 R 2 4 0 2目標 細胞之殺細胞效果(比細胞溶解活性),抗H L A第I類 抗體,抗HLA第I I類抗體,抗CD 8抗體之阻礙效果 圖。 發明之實施形態 本發明之肽係含序列號:3之9個胺基酸所成之胺基 酸序列,由9至3 0個胺基酸所成之肽。更從結合於 H L A抗原而提示之觀點,以含序列號:3之胺基酸序列 本紙張·尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1318630 A7 經濟部智慧財產局S工消費合作社印製 B7五、發明説明(6 ) ,胺基酸9至1 2個所成之肽爲佳。此際,以具結合H L Α抗原提示之抗原肽之序列規則性(型主)之肽爲更佳(J. Immunol., 152, p.3913, 1994, Immunogenetics, 41:pl78, 1995, J. Immunol., 155: p4307, 1 994, J. Immunol., 155: p4749, 1995 )。又,以序列號:3之9個胺基酸之胺基酸序列所成之 肽爲最佳。 而,上述"含序列號:3之胺基酸序列之肽',具體 有例如,含序列號:3之胺基酸序列,W T 1 (序列號: 1)上該位置(第235至243位),或人類WT1 ( N C B I資料庫Accession No., XP 01 2009 )上對應位置起往 未端方向及/或C末端方向延伸之肽,並且癌抗原肽活性 者。 本發明之癌抗原肽之活性測量法,有例如J. Immunol., 154,p2257,1995之方法。以下,本方法之槪要,取HL A 爲HLA—A24型之情形爲例作說明。首先,自HLA - A 2 4抗原陽性之人體分離出末梢血淋巴球。其次,對 該末梢血淋巴球體外添加本發明之肽加以刺激,誘導特異 辨識提示本發明之肽與HLA - A2 4之複合體之抗原提 示細胞之CTL (細胞傷害性T細胞)。 該C T L之誘導,可藉例如抗原肽與H L A _ A 2 4 之複合體反應,CTL產生之種種細胞***素(例如 I F N - τ )量之以例如E L I S A法測量,加以調整。 又,亦可藉C T L對以5 1 C r ,銪標記之抗原肽提示細胞 之傷害性的測量方法(5 1 C r釋放化驗,Int.Canecr. 5 8, 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX 297公釐) -9- (請先閱讀背面之注意事項再填寫本頁) 1318630 A7 經濟部智葸財產局員工消費合作社印製 B7五、發明説明(7 ) p317,1994,銪釋放化驗,J. Immunol·,154,p3991,1 995 ) 加以調整。亦可參考後敘實施例爲之。 本發明並係有關以上述抗原爲有效成分之癌疫苗。該 疫苗可用於伴有WT 1基因出現水準上升之癌,例如白血 病、骨髓形成異常症候群、多發性骨髓腫、惡性淋巴腫等 之血癌、胃癌、大腸癌 '肺癌、乳癌、胚細胞癌、肝癌、 皮膚癌、膀胱癌、***癌、子宮癌、子宮頸癌、卵巢癌 等之固體癌之預防或治療。而該疫苗尤適用於H L A -A 2 4陽性之病患。該疫苗係經口或不經口投用,例如藉 腹腔內投用、皮下投用、皮內投用、肌肉投用、靜脈投用 、鼻腔投用等投用。 又’本發明疫苗之投用方法係,自病患之末梢血採集 單核球,取出樹狀細胞,以本發明之肽脈動,經皮下投用 送返病患之方法。 本發明乃係細胞療法,或亦稱D C (樹狀細胞)療法 ,詳細後敘"抗原提示細胞〃項。 疫苗除上述作爲有效成分投用之肽以外,可含醫藥用 載體,如適當之佐劑(Clin-Microbiol. Rev. 7,277-289,1994 ),例如氫氧化鋁之礦物膠;溶血卵磷脂、Piuronic多元醇 之類的界面活性劑;多元陰離子;肽;或油乳化液。或亦 可混入脂質體,或含配合於多糖及/或疫苗中之其它集合 體。投用量一般係每日0 . 1微克至1毫克//公斤。 本發明中亦可以上述多肽疫苗爲編碼之〇 N A用作疫 苗(DNA疫苗)。亦即,含本發明之WT1改質肽爲編 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) -10- 1318630 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明(8 ) 碼之核酸,較佳者爲DNA,***適當之媒介,較佳者爲 出現媒介後投用於動物,可產生癌之免疫。如此DNA疫 苗之具體手法,可參照W〇 00/06 6 02 ,J. Immunol·, 160,ρ1717, 1998等。 本發明亦係有關H L Α抗原及上述肽之複合體的提示 之抗原提示細胞。實施例中,以本發明肽之刺激可見強力 細胞殺傷活性,此惟末梢血單核球中有本發明肽及H L A 抗原(HLA — A2 4抗原)之複合體的提示之抗原提示 細胞存在,並且誘導出特異辨識該抗原提示細胞之CTL (細胞傷害性T細胞)。如此之H L A抗原及本發明肽之 複合體的提示之抗原提示細胞,可有效用於如下述之細胞 療法(D C療法)。 用於細胞療法之抗原提示細胞,係從腫瘤病患分離出 具抗原提示能之細胞,以本發明之肽於體外脈衝該細胞, 將H L A抗原及本發明之肽的複合體提示於細胞表面而製 成。在此"具抗原提示能之細胞",若係將可提示本發明 肽之H L A抗原出現於細胞表面之細胞即無特殊限制,以 提高抗原提示能之樹狀細胞爲佳。 又,脈衝上述具抗原提示能之細胞之本發明肽,不僅 肽之形態,亦可係以該肽爲編碼之D N A,R N A之形態 〇 本發明抗原提示細胞之具體調製法,可參考例如0&1^61· Immunol Immunother., 46:82, 1 998, J. Immund., 158, pl796, 1997, Cancer Res·, 59, pll 84, 1999等。使用樹狀細胞時,可 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X297公釐) -11 - 1318630 A7 B7 經濟部智慧財產局W工消費合作杜印製 五、發明説明(9 ) 例如自腫瘤病患之末梢血以菲可爾法分離淋巴球,然後去 除非附著細胞,附著細胞於GM— C S F及I L — 4存在 下培養誘導樹狀細胞,以該樹狀細胞與本發明之肽一倂培 養,經脈衝等調製本發明之抗原提示細胞。 又,具上述抗原提示能之細胞,經以本發明之肽爲編 碼之DNA,RNA之導入調製本發明之抗原提示細胞時 ,例如 DMA 者可參考 Cancer Res.,56: p5672,1996,J. Immunol., 161 : p5 607,1998 等爲之,而 RNA 者可參考 J. Exp. Med.,184: p465,1996 等爲之。 上述抗原提示細胞,可用作腫瘤治療劑之有效成分。 此際,爲維持抗原提示細胞安定,以含生理食鹽水、磷酸 緩衝生理食鹽水(PBS)、培養基等爲佳。投用方法有 靜脈內投用、皮下投用、皮內投用。 本發明更係有關辨識H L A抗原與上述肽之複合體之 細胞傷害性T細胞(C T L )。本發明之C T L可有效用 於以下之養子免疫療法。 亦即於黑色素瘤大量體外培養病患本人之腫瘤內浸潤 T細胞,將之送返病患之養子免疫療法具療效(〗.Natl. Cancer. Inst·,86: 1 1 59,1994 )。又知,於小鼠之黑色素瘤 ,以腫瘤抗原肽之T R P - 2體外刺激脾細胞,繁殖腫瘤 抗原肽之特異CTL,將該CTL投用於黑色素瘤移殖小 鼠可抑制轉移U. Exp. Med·, 185 : 453,1997 )。此乃基於 ,抗原提示細胞之H L A抗原及腫瘤抗原肽之複合體的獨 特辨識CTL之體外繁殖之結果。因此,用本發明之肽, (請先閱讀背面之注意事項再填寫本頁) 本紙张尺度適用中國國家標準(CNS ) Λ4規格(210X297公釐) -12- 1318630 A7 _B7 _ 五、發明説明(1〇) 體外刺激病患末梢血淋巴球,增生腫瘤特異C T L後,將 該C T L送返病患之治療法中應係有用。 (請先閱讀背面之注意事項再填寫本頁) 如此,本發明之C T L可作爲腫瘤治療劑之有效成分 。此時,爲維持C T L·之安定,以含生理食鹽水、磷酸緩 衝生理食鹽水(PBS)、培養基等爲佳。投用方法有靜 脈內投用、皮下投用、皮內投用。 實施例 以下藉實施例說明本發明肽之有用於癌抗原及癌疫苗 實施例1 分離出有HLA — A*2 4 0 2之人類末梢血單核球, 將之以2 X 1 0 6細胞/穴之量分配於2 4穴盤,添加 WT 1野生肽或WT 1改質肽至濃度達2 0 ,培養1 週。此際之培養基係用45% RPMI ,45% A I V > 1 0 % FCS,IX非必須胺基酸,SM/ 經濟部智慧財產局8工消費合作钍印製 P c G。上述之培養後,將細胞調製爲2 X 1 0 6細胞/穴 ,作爲應答(responder)細胞。 另一方面,從同上HLA — A*2 4 0 2之人體另分離 出末梢血單核球,與上述之肽2 0 // Μ —倂培養4小時作 肽脈衝,再以3 0格雷之放射線照射後,將細胞調製爲4 X 1 0 6細胞/穴,作爲刺激細胞。 混合如上調製之應答細胞與刺激細胞,再以5 0單位 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) ~ 1318630 A7 B7 五、發明説明(n) /毫升之濃度添加I L 一 2,培養1週。結果,所得細胞 之狀態如下。 表1 肽 細胞數 CD4 CD8 WT1野生肽 2.4x 106/穴 5% 35% WT1改質肽 3.0x 106/穴 18% 3 8% (請先閲讀背面之注意事項再填寫本頁) 其次依5 1 C r釋放法作殺傷試驗(Killing assay J. Immunol. 1 64:1 873,2000 )。目標細胞係用 C1R2402細胞,及以上述肽脈衝之C1R2402 細胞,各於其目標細胞(T ),將如上以W T 1野生肽或 w T 1改質肽刺激之細胞以E : T比1 ,5或2 0作用, 測量細胞溶解。結果示於第1圖。由該圖可知,與經 W T 1野生肽刺激之細胞比較,經w T 1改質肽刺激之細 胞其細胞殺傷活性較強。 實施例2 經濟部智慧財產局員工消費合作社印製 以5 1 C r釋放法測試經w T 1野生肽或W T 1改質肽 刺激之動器細胞對出現內生WT 1抗原之白血病細胞(目 標細胞)之細胞殺傷活性。目標細胞係用W T 1 + / A * 2 4 0 2 +細胞(# 1 A M L病患之白血病細胞), WT1 - /Α*2402+細胞(#2AML病患之白血病 細胞)’WT1+/A*2402-細胞(#3AML病患 之白血病細胞),及W T 1 _ / A * 2 4 0 2 —細胞( 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 14 1318630 A7 ____ B7 五、發明説明(12 ) # 4 A M L病患之白血病細胞)。 (請先聞讀背面之注意事項再填寫本頁) 將實施例1中調製之動器細胞(Ε )與上述目標細胞 (τ ) ’以E / Τ比2 0 : 1混合,培養4小時,測量細 胞溶解裎度。結果示於第2圖。 由該圖知’經W Τ 1野生肽或W Τ 1改質肽刺激之細 胞均對W Τ 1 +/ A * 2 4 0 2細胞出現細胞毒性活性,該 活性以w T 1改質肽爲高。 實施例_ 如同實施例1 ,另以HLA — A*2402陽性之正常 人之末梢血單核球調製動器細胞作試驗。結果示於第3圖 〇 由該圖知’如同實施例1 ,w T 1改質肽刺激之細胞 比W T 1野生肽刺激之細胞呈示較高之細胞傷害活性。 實施例4 經濟部智慈財產局貞工消費合作社印製 以5 1 C r釋放法測試W Τ 1野生肽或W Τ 1改質肽剌 激之動器細胞對來自內生W T 1抗原出現之肺癌細胞株( 目標細胞)之細胞傷害活性。目標細胞係用R E R F — LCAI (WT1+/A*2402 + ) - L C 1 s q ( WT1+/a*2402 + ),11-18(WT1- / A * 2 4 0 2 + ),:LK87(WT1+/A*2402-)° 以如實施例1之方法調製之動器細胞(E )與5 1 C r 本紙張尺度適用中國國家標準(CNS ) A4規格(2!OX297公釐) 仏 1318630 Α7 Β7 五、發明説明(13 ) (請先閲讀背面之注意事項再填寫本頁) 標記之上述目標細胞(T ),如同實施例2,以E / τ比 2 0 : 1混合,培養4小時,測量細胞溶解程度。結果示 於第4圖。 由該圖知’ W Τ 1野生肽或w T 1改質肽刺激之細胞 均對WT 1 +/A*2 4 0 2 +目檩細胞呈示細胞傷害活性 。該活性以W T 1改質肽爲高。 實施例5 以使用抗體之封閉試驗確認,WT 1野生肽或WT 1 改質肽刺激之動器細胞,係H L A第I類拘束性C D 8陽 性殺手細胞。抗體係用抗HLA第I類抗體,抗HLA第 ϊ I類抗體,抗C D 8抗體。以如實施例1之方法調製之 動器細胞(E ),以經5 1 C r標記之c 1 R 2 4 0 2或 WT 1野生肽脈衝之C 1 R2 4 0 2細胞爲目標細胞(T ),以E / T比2 0 : 1與抗體一倂混合,培養4小時, 依51 C r釋放法測量細胞溶解程度。結果示於第5圖。 經濟部智慧財產局員工消費合作社印製 由圖知,W τ 1野生肽或w T 1改質肽刺激之細胞均 可阻礙抗H L A第I類抗體及抗C D 8抗體之細胞傷害活 性,呈示細胞傷害活性之細胞,以H L A第I類拘束性 C D 8陽性殺手細胞。 實施例6 探討了WT1改質肽及WT1野生肽對HLA-A * 2 4 0 2之結合親和性。C 1 R A 2 4 0 2細胞以酸緩 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公釐) -16- A7 B7 1318630 ^、發明説明(14 ) (請先閲讀背面之注意事項再填寫本頁) 衝液(1 3 ImM檸檬酸,66mM磷酸鈉),290m 〇 smo 1 ,pH3 . 3)處理1分鐘,添加含5%牛血 漿蛋白之D Μ E Μ培養液中和。以培養液淸洗後,將細胞 懸浮於含200ηΜ之冷2 -微球蛋白(Sigma公司)及 0 . 5 %牛血漿蛋白之D Μ E Μ培養液,以2 X 1 〇 6細胞 /毫升之濃度。1 5微升之細胞懸浮液,與各種濃度之含 W Τ 1肽之培養液5 0微升混合,於室溫培養4小時。細 胞淸洗後,以對經F I TC標記之HLA — A24之單株 抗體(克隆名7Α 1 2 )染色’以流動式細胞測量器分析 HLA-A 2 4出現量。以同樣操作施於文獻中結合於 HLA — Α*2402之黑色素瘤抗原之pmel 15抗 原肽(Ala T y r G 1 y Leu Asp Phe T y r lie Leu)(序列號:4) (J.
Immunol·,154: 5994,1995 ),以之爲標準,依文獻(
Immunogenetics,51: 816,2000)之方法算出WT 1 肽之解離 常數(Kd)。結果示於表2。 表2 肽 解離常數 Kd(M) WT1野生肽 WT1改質肽 1.82χ ΙΟ'5 6.40x 10'7 經濟部智慧財產局員工消費合作社印製 由表知,WT 1改質肽比WT 1野生肽對HLA — A * 2 4 0 2之結合親和性較強。 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X297公釐)
fv4'T A7 1318630 __ B7 五、發明説明(15) 產業上之利用可能性 以上結果證明’本發明之肽確具癌抗原機能,對癌細 胞可誘導增生殺手τ -細胞(癌細胞傷害性τ細胞)。因 此,本發明之癌抗原肽,可用作伴隨WT 1基因出現上升 之白血病及固體癌之癌疫苗。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局g(工消費合作社印製 "18- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) A7 1318630 B7 五、發明説明(16 ) 序列表: <110> (請先閲讀背面之注意事項再填寫本頁) <120〉改質WT1肽 <130> J939 <150> JP 2001-83250 <151> 2001-03-22 <160〉 4 <210〉 1 <211> 449 <212> PRT < 213 >小鼠 <400> 1
Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Ser 5 10 15
Ser Leu Gly Gly Gly Gly Gly Gly Cys Gly Leu Pro Val Ser Gly Ala - 20 25 30
Arg Gin Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala 35 40 45 經濟部智慧財產局員工消費合作社印製^:
Tyr Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro 50 55 60
Pro Pro Pro Pro His Ser Phe lie Lys Gin Glu Pro Ser Trp Gly Gly 65 70 75 80
Ala Glu Pro His Glu Glu Gin Cys Leu Ser Ala Phe Thr Leu His Phe 85 90 95
Ser Gly Gin Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe 100 105 110 -19- 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX 297公釐) 1318630 A7 B7 五、發明説明(17)
Gly Pro Pro Pro Pro Ser Gin Ala Ser Ser Gly Gin Ala Arg Met Phe 115 120 125 (請先閲讀背面之注意事項再填寫本頁)
Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gin Pro Thr lie 130 135 140
Arg Asn Gin Gly Tyr Ser Thr Val Thr Phe Asp Gly Ala Pro Ser Tyr 145 150 155 160
Gly His Thr Pro Ser His His Ala Ala Gin Phe Pro Gin His Ser Phe 165 170 175
Lys His Glu Asp Pro Met Gly Gin Gin Gly Ser Leu Gly Glu Gin Gin 180 185 190
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser 195 200 205
Cys Thr Gly Ser Gin Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp 210 215 220
Asn Leu Tyr Gin Met Thr Ser Gin Leu Glu Cys Met Thr Trp Asn Gin 225 230 235 240
Met Asn Leu Gly Ala Thr Leu Lys Gly Met Ala Ala Gly Ser Ser Ser 245 250 255 經濟部智慧財產咼員工消費合作社印製
Ser Val Lys Trp Thr Glu Gly Gin Ser Asn His Gly lie Gly Tyr Glu 260 265 270
Ser Glu Asn His Thr Ala Pro lie Leu Cys Gly Ala Gin Tyr Arg lie 275 280 285
His Thr His Gly Val Phe Arg Gly lie Gin Asd Val Arg Arg Val Ser 290 295 300
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu lys 305 310 315 320 -20- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) *144 1318630 經濟部智慧財產局員工消費合作社印製 A7 __ B7_五、發明説明(18 ) Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys 325 330 335 Leu Ser His Leu Gin Met His Ser Arg Lys His Thr Gly Glu Lys Pro 340 345 350 Tyr Gin Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp 355 360 365 Gin Leu Lys Arg His Gin Arg Arg His Thr Gly Val Lys Pro Phe Gin 370 375 380 Cys Lys Thr Cys Gin Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr 385 390 395 400 His Thr Arg Thr His Thr Gly lys Thr Ser Glu Lys Pro Phe Ser Cys 405 410 415 Arg Trp His Ser Cys Gin Lys Lys Phe Ala Arg Ser Asp Glu Leu Val 420 425 430 Arg His His Asn Met His Gin Arg Asn Met Thr Lys Leu His Val Ala '435 440 445 Leu 449 <210〉 2 <211> 9 <212> PRT <213>人工序列 <220〉 <223>合成肽 <400> 2 本紙張尺度適用中國國家標準(CNS >八4規格(210X297公釐) -21 - (請先閱讀背面之注意事項再填寫本頁) 1318630 A7 kl B7 經濟部智慧財產局員工消費合作社印製 五、發明説明(19) Cys Met Thr Trp Asn Gin Met Asn Leu 1 5 <210> 3 <211> 9 <212> PRT <213>人工序列 <220> <223>合成肽 <400> 3 Cys Tyr Thr Trp ksn Gin Met Asn Leu 1 5 <210> 4 <211> 9 <212> PRT <2Π>人工序列 <220> <221> <222> <223>抗原肽 <400> 4 Ala Tyr Gly Ιευ Asp Phe Tyr Ue Leu (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 22-
Claims (1)
- &ϋ 6 8 1X 13 本 告 8*- 月 u f*-— 8C ci 士 Η ί& 六、申請專利範圍 ------J 第9 1 1 0563 3號專利申請案 中文申請專利範圍修正本 (請先閱讀背面之注意事項再填寫本頁) 民國95年4月28曰修正 1 · 一種癌抗原肽’其特徵爲:以含以下胺基酸序列 :Cys Tyr T h r T r p A s n Gin Met A s n Leu (序列號:3),由9至30個 胺基酸所成。 2 .如申請專利範圍第1項之癌抗原肽,其係含序列 號:3之胺基酸序列之9至12個胺基酸所成。 3 .如申請專利範圍第1項之癌抗原肽,其係由序列 號:3之胺基酸序列所成。 4 . 一種癌疫苗,其特徵爲:以如申請專利範圍第1 至3項中任一項之肽爲有效成分者。 5 . —種對癌症之DNA疫苗,其特徵爲:以編碼如 申請專利範圍第1至3項中任一項之肽的D N A爲有效成 分。 經濟部智慧財產局員工消費合作社印製 6 . — 種抗原呈現細胞(antigen presenting cell),其 特徵爲:經H L A抗原與如申請專利範圍第1至3項中任 一項之肽的複合體所呈現者。 7 . —種細胞傷害性T細胞,其特徵爲:可辨識 H L A抗原與如申請專利範圍第1至3項中任一項之肽的 複合體。 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐)-1 -
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CN1531553A (zh) | 2004-09-22 |
EP1371664A1 (en) | 2003-12-17 |
JP3728439B2 (ja) | 2005-12-21 |
KR20030084970A (ko) | 2003-11-01 |
EP1371664A4 (en) | 2006-03-22 |
US20090325886A1 (en) | 2009-12-31 |
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JP2006034296A (ja) | 2006-02-09 |
CA2440303C (en) | 2013-03-19 |
ATE383375T1 (de) | 2008-01-15 |
BR0208183A (pt) | 2004-03-02 |
EP1371664B1 (en) | 2008-01-09 |
JPWO2002079253A1 (ja) | 2004-07-22 |
BRPI0208183B8 (pt) | 2021-05-25 |
KR100863853B1 (ko) | 2008-10-15 |
CN1281625C (zh) | 2006-10-25 |
HK1070078A1 (en) | 2005-06-10 |
US20040097703A1 (en) | 2004-05-20 |
ES2298353T3 (es) | 2008-05-16 |
DE60224508T2 (de) | 2008-12-24 |
WO2002079253A1 (fr) | 2002-10-10 |
CA2440303A1 (en) | 2002-10-10 |
JP3819930B2 (ja) | 2006-09-13 |
BRPI0208183B1 (pt) | 2018-08-28 |
DE60224508D1 (de) | 2008-02-21 |
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