TW499436B - Vaccine - Google Patents
Vaccine Download PDFInfo
- Publication number
- TW499436B TW499436B TW087117493A TW87117493A TW499436B TW 499436 B TW499436 B TW 499436B TW 087117493 A TW087117493 A TW 087117493A TW 87117493 A TW87117493 A TW 87117493A TW 499436 B TW499436 B TW 499436B
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- Prior art keywords
- leu
- pro
- gly
- ala
- protein
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Description
499436 A: β· 經濟部中央標準局員工消费合作社印製 五、發明説明(1 ) 〜- 尽發明是有關新穎的HIV蛋白質構體,彼在醫學上之用 途,含彼之藥學組成物及製法。 特言之,本發明是有關含有HIV-1 Tat及/或Nef蛋白質 之融合蛋白質。 HIV-1是後天免疫缺失症候群(AIDS)之主因,此疾視爲 王世界王要健康問題之一。雖然全世界已有充份的研究致 力於疫苗之產生,但此努力如此遙遠以致尚未能成功。 HI\ -1典包膜之蛋白質已有所述,且包括如内部結構蛋 白質,如gag及p〇l基因產物%及其他非結構蛋白質,如Rev,Nef,Vif 及 Tat (Greene et al” New England J. Med,324, 5, 308et Seq (1991)及 Bryant et al· (Ed pizz〇),pediatr Infect. Dis· J·,11,5, 390 et seq (1992)。 HIV Nef及Tat蛋白質爲早期蛋白質,即,其在感染之早 期表現,且無結構蛋白質。 依據本發明提出一種蛋白質,其中含有: (a) HIV Nef蛋白質或其衍生物,連接至⑴融合配對或(η) HIV Tat蛋白質或其衍生物;或 (b) HIV Tat蛋白質或其衍生物,連接至⑴融合配對或(ϋ) HIV Nef蛋白質或其衍生物;或 (c) HIV Nef蛋白質或其衍生物,連接至HIV Tat蛋白質或 其衍生物及融合配對。 所謂”融合配對π意指非Tat或Nef之任何蛋白質序列。較 好融合配對是蛋白質D或其來自流感病毒b之脂化衍生物 脂蛋白D。特言之,較好利用N-末端,即大約是前100-130 -4- 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X 297公釐) 請r閱讀背面之審事項 本頁) 裝. ,ιτ 線 499436 A; B7 五、發明説明(2 ) 胺基酸此以Lipo D 1/3代表。在本發明較佳具體實例中 ,Nef蛋白質或其衍生物可連接至Tat蛋白質或其衍生物 。此Nef-Tat融合體也可視所需連接至融合配對,如蛋白質 D〇 融合配體通常可連接至Nef或Tat蛋白質之N-末端。 包含在本發明内之衍生物包括具有c末端組胺酸尾之分 子,其較好含有約5-10個組胺酸殘基。一般而言,含有幾 個殘基之組胺酸尾在此以His (n)代表。組胺酸(或”His")尾 之存在有助於純化。較特別地;本發明提出具有以下結構 之原白質 (請£-'-閲讀背面之&意事頊^^|^本頁) 裝
Lipo D 1/3 -Nef -His (6) Lipo D 1/3 -Nef-Tat -His (6) Prot D 1/3 -Nef -His (6) Prot D 1/3 ** N c f - T a. t -His (6) Nef-T at -His (6) -訂 圖1提出用於此構體之融合配對之胺基酸(Seq. ID. No. 7) 及 DNA 序列(Seq· ID. No· 6)。 在較佳具體實例中,蛋白質在有組胺酸尾下表現,其中 含有約5至10個之間,且較好是6個组胺酸殘基。其在純 化上有助益。已有報告是關於Nef (Macreadie I. G· et al., 1993, Yeast 9 (6) 565嶋573)及 Tat (Braddock M et al” 1989, Cell 58 (2) 269-79)在酵母(穰酒酵母)中分別的表現。Nef 蛋白質僅是肉豆蔻酸化。本發明是第一次提出Nef及丁at 本紙張尺度適用中國國家標準(CNS ).A4規格(210X 297公楚) 線 經濟部中央標準局員工消費合作社印製 499436 A, ___ B1 五、發明説明(3 ) 在畢赤酵母屬表現系統中分別表現(Nef-His及Tat-His構體 )’以及融合構體(Nef-Tat-His)成功的表現。代表性之 Nef-His (Seq. ID· No. 8 及 9),Tat- His (Seq· ID· No. 10 及 11)及 Nef-Tat-His 融合蛋白質(seq. ID. No. 12 及 13)之 DNA 及胺基酸序列示於圖2。 包括在本發明内之衍生物也有經突變之蛋白質。所謂” 經突變的’f在此表示分子利用位置指令之突變作用或其他 任何傳統方法之熟知技術進行一個以上胺基酸之刪除,加 入或置換。 * 經突變的丁at於圖2中説明(Seq· ID· No. 22及23),爲 Nef-Tat 突變子-His (Seq. ID· No. 24 及 25)。 本發明也提出一段編碼本發明蛋白質之dna。此序列可 嵌入適合的表現載體中,並在適合的宿主中表現。 編碼本發明蛋白質之DNA序列可利用標準的DNA合成 技術合成’如酵素連結,如D· M. Roberts et al7 in
Biochemistry 1985, 24, 5 090-5 098 所述,如化學合物,試管 内酵素聚合化作用,利用如熱穩定性聚合酶之PCR技術, 或這些技術之組合。 經濟部中央標準局員工消費合作社印製 DNA之酵素聚合化作用可於試管内進行,利用DNA聚合 酶如DNA聚合酶I (Klenow片段)於適合的緩衝溶液中,其 中依所需含有核苷三嶙酸dATP,dCTP,dGTP及dTTP ,溫度10。~37。(:,通常體積爲50微升以下。DNA片段之 酵素連結作用可利用DNA連接酶來進行,如T4 DNA連接 酶,於適合的緩衝溶液中,如0 05 M Tris (pH 7.4),0·01 Μ _ 冬 本紙張尺度適i?中國國家Μ規格 〇χ 297公^一 ~~ 499436 經漓部中央標準局員工消費合作社印製 A 7 B*7 —-----------—------- 五、發明説明(4 ) MgCl2,0.01 Μ二硫異赤絲藻醇’ 1 mM亞精胺,1 mM ATP及0.1毫克/毫升牛血清白蛋白,於4 °C至環境溫度下 ,通常體積在50毫升以下·。DNA聚合物或片段之化學合 成可利用傳統的轉酸三醋’亞轉酸或胺基嗓酸酯化學進行 ,禾J 用固才目技称口述 ^"”Chemical and Enzym^tic Synthesis of Gene Fragments-A Laboratory Manual” (ed. HL G. Gassen and A. Lang),verlag Chemie,Weinheim (1982),或在其他 的科學刊物,如 M. J· Gait,H. W· D· Matthes,Μ· Singh,B.S. Sproat, and R. C. Titmas, Nucleic Acids Research, 1982, 10, 6243 ; B. S. Sproat, and W. Bannwarth, Tetrahedron Letters, 1983m 24? 5771 ; M. D. Matteucci and Μ. H. Caruthers, Tetrahedron Letters, 1980, 21,719 ; M. D. Matteucci and M. H. Caruthers, Journal of the American Chemical Society, 1981,103,3185 ; S.P. Adams et al., Journal fo the American Chemical Society, 1983, 105, 661 ; N, D. Sinha, J. Biernat, J· McMannus, and H. Koester,Nucleic Acids Research,1984, i2, 45j9 , and H. W. D. Matthes et al., EMBO Journal, 1984. 3, 801 〇 本發明也提出製備本發明蛋白質之方法,此方法包括以 下步驟·· 1)製備可複製或整合之表現載體,可在宿主細胞中表現 含有核签酸序列之DN a聚合物,此核苷酸可、縞碼蛋白 質或其衍生物 π)以該載體轉形宿主細胞 -7- 本—用中國ΐ家―---— (請先閱讀背面之注意事項 再 本頁) •裝. 訂 線 499436 A; B1 經濟部中央標準局員工消f合作社印製 五、發明説明(5 ) iii) 培養该經轉形之宿主細胞,所在之條件令該Dna聚合 物可表現以產生蛋白質;及 iv) 回收該蛋白質 本發明方法可以傳統的重組體技術進行,如Maniatis et al.5 Molecular Cloning- A Laboratory Manual ; Cold Spring Harbor,1982-1989 所述。 所謂”轉形”此中所用的表示將外來DNA引入宿主細胞内 。此可利用轉形作用,轉感作用或感染作用,採用適合的 質體或病毒载體以如傳統技-術進行,如述於Genetic Engineering ; Eds. S. M. Kingsman and A. J. Kingsman ; Blackwell Scientific Publications ; Oxford, England, 1988 。所謂”轉形”或”轉形子”在下文中用以生成含有及可表現 外來重點基因之宿主細胞。 表現載體是新穎的,且也構成本發明一部份。 可複製之表現載體可依本發明製備,即解離與宿主細胞 相容之載體,生成有完整複製子之直線DN A片段,並組合 該直線片段與一個以上的DN A分子,其加上該直線片段可 編碼欲求產物,如編碼本發明蛋白質或其衍生物之DNA聚 合物,此在連接條件下進行。 因此,DNA聚合物可在載體構築之中,依所欲求預先進 行或形成。 載體(選择部份由宿主細胞決定,其可爲原核或興核細 胞’但权好是大腸桿菌或酵母。適合的載體包括質體’兔 菌體,粘接質體及重组病毒。 -8 - ΙΞ 1 j-....... .........1 II · (請先閱讀背面之注意事項 再 π本百〇 -裝 線 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公#) 4994J6 Λ 7 --____ _Β7五、發明説明(6 ) 經濟部中央標準局員工消費合作社印製 可1製之表現载體,可以適合的限制,聚合及連接用酵 素傳統地製備,步驟述於如Maniatlsetal中。〜 丄依本發明可製備重組體宿主細胞,即以本發明可複製之 衣現載禮在轉形條件下轉形於宿主細胞。適合的轉形條件 爲傳統的且述於如Maniatis et虬上示,或”〇ΝΑ a〇ning,·Vol. II,D. Μ· Gl〇ver ed” IRL Press Ud,1985。 轉形條件之選擇由宿主細胞決定。因此,細菌宿主如E. coli 可以 CaCl2 落液處理(c〇hen et al,pr〇e Nat,Sci, 197j’ 69,2110)或以含有Rbcl,MnC12,醋酸鉀及甘治之 混合物溶液處理,再以3_[N-嗎福啉基]_丙烷_磺酸,RbC1 及甘油處理。在培養中之哺乳動物細胞可由載體A鈣共 沈澱土細胞中而轉形。本發明也擴及以本發明可複製表現 載體所轉形之宿主細胞。 在可令DNA聚合物表現之條件下培養經轉形之宿主細 /龙,可傳、%地進行,如述於Maniatis et al及,,dna 吨,, 上不。因此較好細胞添加有營養物,並在5〇以下之活度培養。 ,f物依宿主細胞以傳統方法回收。因此,當宿主細跑是 、^菌’如E· coli ’或酵母如畢赤酵母屬時;其可拘理性, 化學性或酵素性溶解,且蛋白質產物自生成之溶胞產钕中 为離。當值王細胞是哺乳動物時,產物通常自營養培養基 或無細胞萃取物中分離。傳統的蛋白質分離技術包括選擇 性沈毀’吸附層析及親和力層析包括單株抗體親和力管柱。 關於本發明加有組胺酸之蛋白f,使用金屬離子親和力 ____________, - 9 - 氏掁又度i用中國國家標準(cns ) (請先閱讀背面之&意事項再本頁) ---私衣. ,1Τ ml II ·1 ίιϋ ϋιϋ ί—- i ------· 499436 經濟部中央標準局員工消費合作社印製 A; 〜一~——________B -五、發明説明(7 ) 一 & ,王可容易地芫成純化作用。於一個較佳具體實例中,蛋 白貝接雙陽離子離子交換層析及/或凝膠過濾層析可再進 步純化。蛋白質再通過〇·22微米膜滅菌之。 本發明蛋白質可調和成疫苗,或將組胺酸殘基酵素地解離。 本發明蛋白質較好呈至少8〇0/。純度以上,較好9〇0/。純度 ’由SDS PAGE可具象化。較好蛋白質在sds PAGE上呈 單一帶狀。 本發明也提出藥學組成物,其中含有本發明蛋白質於藥 學上可接受之賦形劑中。疫苗之製備大體上述於Nwe Trends and Developments in Vaccines, Voller et al. (eds), University Park Press, Baltimore,Maryland,1978 。在脂質體内之包膠作用述於 Fullenon,US 專利案 4,235,877。 本發明蛋白質較好調和於本發明之疫苗調和物中。適合 的佐劑包括鋁鹽如氫氧化鋁(鋁土)或磷酸鋁,但也可以是 鈣、鐵或鋅鹽,或可爲醯化酪胺酸之不溶懸液,或醯化之 糖,陽離子或陰離子衍生之多酷,或聚罐腈。 在本發明之#1和物中,較好佐劑组成物可謗生差別性 TH i反應。適合的佐劑系統包括如單嶙醯基脂質a或其衍 生物,罕父好疋去化心單蹲醯脂質a (3d_mPL)加上 鋁鹽之组合。 一個加強的系統涉及單蹲醯基脂質A及皂素衍生物之組 合,特別是QS2 1及3D-MPL之组合,如\V〇 94/00153 Φ所 -10- 本纸張尺度適用中國國家標準(CNS ) A4規^72丨0X 297公楚) :-^-— C請先閱讀背面之注意事項 本頁) -裝 線 499436 A7 B7 五、發明説明( 經濟部中央標率扃員工消f合作社印裝 返’或較不致反應之組成物,其中SQ2 1以膽固醇壓制,如 W0 96/33739中所揭示的。’ 一個特別強力的佐劑調和物係涉及QS21,3D-MPL &生 同醇’於油水乳液中,如W0 95/1 72 10中所述,且爲較佳 之調和物。 依據本發明一個具體實例,此中提出一種含有本發明蛋 白質^疫苗’其中並佐以單磷醯脂質A或其衍生物,尤其 是 3D-MPL 〇 較好疫苗额外地含有皂素,車ί妤是QS2 1。 字交好調和物另外含有油水乳劑及生育醇。本發明也提出 產製疫苗碉和物之方法;其中包括混合本發明蛋白質加上 藥學上可接受之賦形劑,如3D-MPL。 本發明的疫苗可另外含有進一步的HIV蛋白質,如包膜 糖蛋白gp 160或其衍生物gp 120。 在另一方面,本發明是有關HIV Nef或HIV Tat蛋白質 或其衍生物於巴斯德畢赤酵母中表現。 本發明參考以下實例進一步說明: 實例 總則 Nef及Tat蛋白係人類免疫不全病毒(HIV-1)編碼之二個 調節蛋白且在E· c〇li及嗜甲基酵母菌pichia past〇Hs中產 生。 針對這些構體自Bru/La!分離物中選出nef基(Cell 4〇 : 9-17,198:)),因此基因是此中與固有的Nef最有關係者。 11 本纸浪尺度適用中國國家標準(CNS ) Λ4規格(2l0X 297公焱) (請先閱讀背面之注意事項再頁) 裝 線 499436 A7 B? 經濟部中央標準局員工消费合作社印製 五、發明説明(9 ) 於Bru/Lai nef基因之起始物質爲一段選殖在哺乳動物表 現載體 pc DNA3 之 1170 bp DNA 片段(pcDNA3-nef)。 tat基因源自BH 10分子純學。此基因呈HTLV III cDNA 純學般獲得,命名爲pCVl且述於Science,229, p 69-73, 1985 〇 1 · HIV-1 nef及tat序列於大腸样菌中之表現 編碼Nef蛋白質之序列及nef及tat序列之融合置於質體 载體中·· pRIT 14586 及 pRIT 14589(見圖 1)。 Nef及Nef-Tat融合體利用部份蛋白質D之融合配對呈融 合蛋白質型式產生。蛋白質D是免疫球蛋白D結合蛋合質 ,曝露在革蘭氏陰性菌流感嗜血桿菌之表面。 pRIT 14586在λΡΙ>啓動子控制之下,含有衍自細菌流感 嗜血捍菌之DNA序列,其可指導合成蛋白質D前127個胺 基酸(Infect· Immun· 60 : 1336_1342,1992),緊接著是多重 選殖位置區域加上指導合成一個甘胺酸,六個組胺酸殘基 及一個停止密碼子之DNA序列(圖1A)。 此載體經設計可表現經處理且脂化His加尾之融合蛋白 質(LipoD融合蛋白質)。融合蛋白質合成前驅體型式,具有 1 8個胺基酸殘基長之訊號序列,且於處理修飾後,在前驅 體分子第19位置之半胱胺酸變成胺基末端殘基,其再以共 知結合之脂肪酸修飾之(圖1 B)。 pRIT 145 89幾乎和pRiT 14586相同,除了 protD衍生之 序列在半胱胺酸第1 9個密碼子後立即開始。自此載體表現 可造成有His加尾但無脂化之融合蛋白質(Pr〇tD融合蛋白 質)。 -12 (請先閲讀背面之注意事項 本頁} .裝. 、11 線 ^纸張尺度適用中國國家標準(CNS ) 八4規格(2丨οχ 297公浚) 499436 Ατ
IT 五、發明説明(1〇 ) 製備 4 個構體:LipoD-nef-His,LipoD-nef-tat-His, ProtD-nef-His,及 ProtD-nef-tat_His 前二個構體利用表現 載體pRIT 145 86,後二個構體利用pRIT 145 89製成。 1.1 構築可產生LipoD-nef-His融合蛋白質之重組體 ECLD-N1 株 1.1.1 構築 lipoD-nef-His 表現質體 pRIT 14595 自pcDNA3/Nef質體,以引子01及02利用PCR擴大nef 基因(Bru/Lai分離物)。
Ncol
引子 01 (Seq ID NO 1) : S^TCGTCCATG.GGT.GGC.AAG.TGG TV
Spel 引子 02 (Seq ID NO 2) : 5,CGGCTACTAGTGCAGTTCTTGAA3, 所擴大的nef DNA區域始自8357核苷酸,並中止在8971 核苷酸(Cell, 40 : 9-17,1985)。 在PCR片段之5’末端引入一個Ncol限制位置(其帶有nef 基因之ATG密碼子),而在3’末端引入Spel位置。 經濟部中央標隼局員工消費合作社印製 所得的PCR片段及表現質體pRIT 14586均以Ncol及Spel 限制水解之,於瓊脂糖凝膠上純化,連接及轉形於適合的 大腸桿菌宿主細胞株,AR58。此株爲由N99衍生之隱性λ 溶源性細菌,爲 galE ::Tnl0,A8(chlD-pgl),AHl(cro-chlA), Ν' 及 CI857 〇 所生成之重組體質體,經由自動化定序證實nef擴大區 域後(見下1,1,2段)可接受prit 14595之命名。 11,2選擇有pRIT 14595之E· Coli AR58株轉形子 -13- I紙張尺中國標準(210X 297^* )~~ ^ 499436 A7 B7 五、發明説明(11 ) 當轉形於AR5 8 E. coli宿主株時,重组體質體可指令異 質蛋白質熱可謗導之產製。 許多重組體lip〇D-Nef-His轉形子熱可謗導之蛋白質之 產製,以Coomassie Blue(考馬斯藍)染色於SDS-PAGE而分 析。所有經分析之轉形子顯示有熱可謗導之異質蛋白質之 產生。豐富的重組體LipoD-Nef-Tat-His融合蛋白質經估計 占總蛋白質之10%。 選出其中一個轉形子,並給予實驗室登記號ECLD-N1。 自ECLD-N1株中再分離出重-組質體,且以自動定序證實 nef-His编碼區之序列。此質體接受正式命名爲pRIT14595。 由ECLD-N1株產生之完全處理修飾且醯化之重組體 LipoD-nef-His融合蛋白質含有下列·· °脂肪酸 。:109個胺基酸之蛋白質D(始自a. a. 19並延伸至a. a.】27)。 。一個甲硫胺酸,由使用pRIT14586 Ncol選殖位置而生 成(圖1)。 。205個胺基酸之Nef蛋白質(始自a.a.2並延伸至a.a.206)。 。一個蘇胺酸及絲胺酸,由選殖步驟生成(在pRIT 14586 , tSpel位置處選殖 ^ 一個甘胺酸及六個組胺酸。 1.2 構築可產生protD-Nef-His蛋白質之重组體ECD-N1 株
表現質體PRIT14600可縞碼ProtD-Nef-His融合蛋白質, 其構築和實例1. 1. 1所述之質體構築法相同,除了於PCR -14 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公漦) 請 先 閲 讀 背 面 之 注 意 事 項 I· 本 頁 裝 經濟部中央標準局員工消費合作社印製 499436 ΕΠ 五、發明説明(12 ) 擴大之nef片段使用pRIT145 89爲受者質體。 £.(:〇1丨八1158株以?111丁14600轉形,再如實例1.1.2般分 析轉形子。所選擇之轉形子接受實驗室編號ECD-N 1。 1.3 構築可產生LipoD-Nef-Tat-His融合蛋白質之重組體 ELD-NT6 株 1·3· 1 構築 lipoD-Nef-Tat-His 表現質體 pRIT 14596 tat基因(HB 10分離物)自pCVl質體衍生物以引子03及引 子04利用PCR擴大。在PCR片段二端均引入Spel限制位 置。 _
Spel 引子 03 (SeqIDN0 3) : 5,ATCGTACTAGT.GAG.CCA.GTA.GAT.C3,
Spel 引子 04 (Seq ID NO 4) : 5,CGGCTACTAGTTTCCTTCGGGCCT3, 經擴大的tat基因其核甞酸序列説明於pCVI純系 (Science 229 ·· 69-73, 1985),且涵蓋核答酸5414直到核苷 酸 7998 。 經濟部中央標準局負工消f合作社印製 所得之PCR片段及質體pRIT 14595(表現lipoD-Nef-His 蛋白質)均以Spel限制酶水解,在瑗脂糖凝膠上純化,連接 並轉形至勝任的AR5 8細胞中。所生成之重組質體,經以 自動定序證實tat經擴大的序列後(見下1.3.2段),接受pRIT 14596之命名。 1.3.2選擇有pRIT 14596之AR58轉形子株 轉形子生長,熱誘導,再以考馬斯藍染色凝膠分析其蛋 白質。重组體蛋白質之產製水平經估計占總蛋白質之1 %。 15- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210x797公^~~~ 499436 A, B" 經濟部中央標準局貝工消費合作社印製 五、發明説明(13 ) 選出一個重組體株,並接受實驗室命名ECLD-NT6。 自ECLD-NT6株中分離HpoD-nef-tat-His重組質體,定序 及接受正式命名PRIT14596。 由ECLD-N6株產生之經完全處理修飾且醯化之重組赠 Lip〇D-Nef-Tat-His融合蛋白質含有下歹!j : °脂肪酸 °1〇9個胺基酸之蛋白質d(始自a.a.19並延伸至a.a.12 。一個甲硫胺酸,由使用pRIT14586之Ncol選殖位置而 生成。 - 。205個胺基酸之Nef蛋白質(始自a.a.2及延伸至a.a.206)。 。一個蘇胺酸及一個絲胺酸,由選殖步驟生成。 °85個胺基酸之Tat蛋白質(始自a.a.2及延伸至a.a.86)。 。一個蘇胺酸及一個絲胺酸,由選殖步驟引入。 。一個甘胺酸及六個組胺酸。 14 構築可產生ProtD-Nef-Tat-His融合蛋白質之重組體 ECD-NT1 株 可編碼ProtD-Nef-Tat-His融合蛋白質之表現質體 pRIT 14601,其構築和實例1.3.1所述之質體之構築相同, 除了於PCR擴大之nef片段中使用pRIT 14600爲受者質體。 E. coli AR58株以pRIT 14601轉形,且如先前所述地分析 轉形子。所選擇之轉形子可接受實驗室編號ECD-NT1。 2. 在巴斯德畢赤酵母中表現HIV-1 nef及tat序列 Nef蛋白質,Tat蛋白質及融合的Nef-Tat,在可謗導之 乙醇氧化酶(A0X 1)啓動子控制下,可在甲基營養性酵母巴 -16 請 閱 讀 背 之 養 裝 訂 丨線 本纸張尺度適用中國國家標準(CNS ) Λ4規格( 210X 297 公趁) 499436 五、發明説明(14 ) 斯德畢赤酵母中表現。 爲衣現這些HIV-1基因,使用可整合之载體pHIL-D2之 經修飾版(IN VITROGEN)。此載體以此方式修飾,其中異質 蛋白質之表現在AOX1基因天然的ATG密碼子之後開始, 且可產生有一個甘胺酸及六個組胺酸殘基尾部之重組體蛋 質。此PHIL-D2-M0D載體,由在PHIL-D2载體相鄰的AsuII 及EcoRI位置間選殖一個寡核嘗酸連接子而構築。(見圖3) 。除了 His尾邵,此連接子在引入nef,tat及nef-tat融合 體之間攜有,Ncol,Spel及Xbal限制位置。 21 構築整合載體pRIT14597(編碼Nef-His蛋白質)。 pRIT 14598(編碼Tat-His蛋白質)及pRIT 14599(編碼融合 體 Nef-Tat-His) 〇 nef基因自pCDNA3/Nef質體,以引子01及02利用pcR 擴大(見1.1.1 PRIT145 95之構築)。所得的PCR片段及整合 PHIL-D2-MOD載體均以Ncol及Spel限制水解,在瓊脂糖 凝膠上純化並連接以生成整合質體pRITl 4597(見圖3)。 tat基因自pCV 1質體衍生物中,以引子05及04利用pcr 擴大(見1.3」pRIT14596之構築): 經濟部中央標準局員工消費合作社印製
Ncol 引子 05 (Seq ID NO 5) : 5,ATCGTCCATGGAGCCAGTAGATC3, 在PCR片段的5·端引入Ncol限制位置,而在1端以引子 04引入一個Spel位置。所得的PCR片段及PHIL-D2-MOD 載體均以Ncol及Spel限制水解,於瓊脂糖凝膠上純化,再 連接生成整合質體pRIT14598。 -17- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公漦) ^ ' 499436 經濟部中央標準局員工消費合作社印製 A7 ____ B7五、發明説明(15 ) 爲構築pRIT14599,一個相當於nef-tat-His編碼序列之 910bp DNA片段,連接在PHIL-D2-M0D載體之EcoRi平銳 的(T4聚合酶)及Ncol位置之間。由Xbal平鈍化(T4聚合酶 )及Ncol水解pRIT 145 96,可得到nef_tat-His編碼片段。 2.2 巴斯德畢赤酵母株GS115 (his4)之轉形 爲狻得可表現Nef-His,Tat-His及融合體Nef-Tat-His 之巴斯德畢赤酵母株,於是以攜有個別的表現更加上ΗI s 4 基因(以補充宿主基因體中之his4)之直線Notl片段轉形於 GS115株。有Notl-直線片段之'GS115轉形作用喜於A〇X1 區域處重組。 以定量點吸漬分析選擇多套數之整合純系,並決定整合 、嵌入(ΜιιΓ表現型)或轉置(Muts表現型)之型式。 自各轉形作用中,選出可顯示重組蛋白質有高產製水平 之轉形子: 、1738株(Mut+表現型),其可產生重組體Nef-His蛋白質 ’一種肉旦產酸化,215個胺基酸之蛋白質,其含有以下: 。肉豆蔻酸 。一個甲硫胺酸,由使用PHIL-D2-M0D載體之Ncol選殖 位Z而k成。 °20:)個胺基酸之Nef蛋白質(始自a.a.2及延伸至a.a.206)。 。一個蘇胺酸及絲胺酸,由選殖步驟生成(在PHIL-D2-M〇D戴體之Spel位置處選殖)。。一個甘胺酸及六個組胺酸。 Y1?39株(ΜιιΓ表現型),可產生Tat-His蛋白質,一種95__ -13-本纸&尺度適i中^^^準(CNS )刎規格(―7公楚卜~ —-------- (請先閱讀背面之满意事嗔 本頁) -裝·
、1T 499436 經濟部中央標準局員工消f合作社印製 A? __B7五、發明説明(16 ) ~〜 個胺基酸之蛋白質,其含有以下: 。一個甲硫胺酸,由使用Ncol選殖位置而生成。。85個胺基酸的Tat蛋白質(始自a a 2並延伸至a.a.86)。 。一個蘇胺酸及絲胺酸,由選殖步囅引入。 。一個甘胺酸及六個組胺酸。 Y1737株(Muts表現型),可產生重組體Nef-Tat-His融合 蛋白質,是一種肉豆蔻酸化,302個胺基酸之蛋白質,其 含有:。肉豆蔻酸 ~ 。一個甲硫胺酸,由使用Ncol選殖位置而產生。°205個胺基酸之Nef蛋白質(始自a.a.2並延伸至a a.2〇6)。 。一個甲硫胺酸及絲胺酸,由選殖步驟生成。°85個胺基酸之Tat蛋白質(始自a.a.2並延伸至3.a.8 6)。 ◦一個蘇胺酸及絲胺酸,由選殖步驟引入。 ° 一個甘胺酸及六個組胺酸。 ) HIV-1 Tat-突變株在巴斯德畢赤之表現 和Nef-Tat突變融合蛋白質相同,突變的重組體Tat蛋白 質也可表現。突變的T at蛋白質必需是生物上無活性的, 同時保持其免疫原性表位。 針封這些構體,選用雙重突變子Tat基因,此由D. Clements 所構築(Tulane University)。 此tat基因(源自BH10分子純系)在其活性位置區 (Lys41 —Ala)及 RGD 特色區(Arg78 — Lys 及 Asp8〇4Glu)中 攜有突變(Virology 235 : 48-64, 1997)。 -19- 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>«.意事項再1^?本頁} •裝 、11 線 499436 經濟部中央標準局員工消費合作社印製 A 7 B7五、發明説明(17 ) 突變子tat基因呈cDNA片段型式接受,其繼代選殖在 CMV 表現質體之 EcoRI 及 Hindlll 位置之間 (pCMVLys41/KGE)。 3.1 整合載體pRIT 14912(編碼Tat突變子-His蛋白質)及 pRIT 14913(編碼融合體Nef-Tat突變子-His)之構築 tat突變子基因自pCMVLys41/KGE質體,以引子05及04 利用PCR擴大(見2.1段,pRIT145 98之構築)。 Ncol限制位置引入PCR片段之5’端,而Spel位置以引子 04引入3’端。所得之PCR片段—及PHIL-D2-MOD載體均以 Ncol及Spel限制水解,在瓊脂糖凝膠上純化,並連接生成 整合質體PRIT14912。 爲構築 PRIT14913 ’ tat突變子基因以 PCR 自 pCMVLys41/KGE質體中,以引子03及04擴大(見1.3.1段 ,pRIT14596 之構築)。 所得之PCR片段及質體pRIT 14597(表現Nef-His蛋白質) 均以Spel限制酶水解,在瓊脂糖凝膠上純化,並連接生成 整合質體PRIT14913。 3.2 巴斯德畢赤酵母GS 115之轉形 應用在2.2段中先前所述之整合及重組株選擇策略,可 得到表現Tat突變子-His蛋白質及融合體Nef-Tat突變子-H i s之巴斯德畢赤酵母株。 選出可產製Tat突變子-His蛋白質的二個重組體株,此 爲一種95個胺基酸之蛋白質:Y1775 (Mut'表現型)及 Y1776 (Muts 表現型)。 _ 20 _ 本紙後尺度適用中國國家標準(CNS ) A4規格(210X 297公t ) _ (請先閱讀背面之注意事項 再 本頁) •裝 、-口 線 499436 A? B7 五、發明説明(18 ) 選出可表現Nef-Tat突變子-His融合蛋白質之重組體株 ,其爲一種3 02個胺基酸之蛋白質:丫1774(]^1^+表現型)。 4. Nef-Tat-His融合蛋白質之純化(巴斯德畢赤酵母) 純化流程甴146克重組體巴斯德畢赤酵母細胞(濕重)或2 升Dyno-輾磨機之勻漿物0D 55展開。層析步驟在室溫下 進行。於各步驟間,Nef-Tat陽性流份保持在冷室〇4 °C ) 下一夜;爲更長時期則冷凍在-20 °C下。 146克巴斯德畢赤酵母細胞 _ 請 先 閱 讀 背 之 rJt 意 事 項
經濟部中央標举局員工消费合作社印製 勻漿化 Dyno-輾磨機瓦解(4次) 離心 Dyno-輾磨圑塊 洗i傺 (1 小時-4°C) 離心 緩衝溶液*· 2升50 mM PO4 pH 7.0,最終 OD : 50 JA10轉子/9500 rpm/30分鐘/室溫 缓衝溶液:+2升10 mM P04 pH 7.5-150 mM NaCl 0.5% emipigen JA10轉子/9500 rpm/30分鐘/室溫 -21 - 本纸張尺度適用中國國家標準(CNS ) 規格(210X 297公嫠) 499436 A7 B7 五、發明説明(19 經濟部中央標準局工消f合作社印製 請 先 闊 讀 背 面 之> 注 意 事 項 頁 裝 訂 團境 助溶溶解 (0/Ν-4Ό) 4 還原 (4H-室溫-暗處) 4 羧甲基化作用 (1/2小時-室溫-暗處) 經固化之金屬離子親和力層析 於ΝΓ+-ΝΤΑ-瓊脂糖 (Qiagen-30毫升樹脂) 缓衝溶液:+660亳升10 mM P〇4 pH 7.5-150 mM NaCl-4.0 M GuHCl +0·2 M 2-鲩基乙烷磺酸,鈉鹽( 粉末加入)/pH調至7.5(以0.5 Μ NaOH溶液)再行培育 +0.25 Μ磺乙醯胺(粉末加入)/pH 調至7.5(以0·5 M NaOH溶液)再 行培育 平衡缓衝溶液:10 mM PO4 pH 7.5-150 mM NaCl-4.0 M GuHCl 洗綠缓衝溶液:1)平衡缓衝溶液 2) 10 mM P04 pH 7.5-150 miM NaCl-6 M 尿素 3) 10 mM PO4 pH 7.5»150 mM NaCl-6 M 尿素· 25 mM咪嗤 -22 本紙張尺度適用中國國家標準(CNS ) A4規格(2〗0X297公犮} 499436 AT B7 五、發明説明(2〇 溶離緩衝溶液:10 mM P〇4 pH 7.5-150 mM NaCl-6 Μ 尿素-0.5 Μ 咪峻 稀釋 下降至18 mS/公分2離子強度 稀釋缓衝溶液:10 mM PO4 pH 7.5- 6 Μ尿素 (請先閲讀背面之>1意事項< 陽離子交換層析 在 SP Sepharose FF (Pharmacia-30 毫升樹脂) 平衡緩衝溶液:10 mM PO4 pH 7.5-150 mM NaCl-6.0 Μ 尿素 洗滌缓衝溶液:1)平衡緩衝溶液 2) 10 mM PO4 pH 7.5-250 mM NaCl-6M 尿素 溶離缓衝溶液:10 mM硼酸鹽 pH 9.0-2 M NaCl-6 Μ 尿素 裝丨 方马本頁 線 濃縮 直到5毫克/毫升 10 kDa Omega 膜(過滤) 經濟部中央標準局員工消費合作社印^^ 凝膠過濾層析 在 Superdex 200 XK 16/60 (Pharmacia-120 毫升樹脂) 溶離緩衝溶液:10 mM PO4 pH 7.5-150 πιΜ NaCl-6 Μ 尿素 5毫升樣品/注射+ 5次注入 -23- 本纸張尺度適用中國國家標準(CNS ) Α4規格(210X 297公| ) 499436 經濟部中央標準局員工消費合作社印製 A7 -----B7___ 五 ' 發明説明(21 ) 透析 緩衝溶液:10 mM P〇4 pH 6.8. (0/N-4°C) 150 mM NaCl-0.5 M 精胺酸* 無菌過濾 MillexGV0.22微米 *比例:0.5 M精胺酸,蛋白質濃度1600微克/毫升 純度 以SDS-PAGE估計之純度水平示於圖4,利用Daiichi銀 染色,於圖5利用考馬斯藍G250。 於 Superdex 200 步驟後: >95% 於透析及無菌過濾步驟後: >95% 回收 51毫克的Nef-Tat-His蛋白質自146毫克重組體巴斯德畢 赤酵素細胞中純化(=2升的Dyno-輾磨的勻漿物OD 55)。 5· 疫苗製備 . 依本發明製備之疫苗含有DNA重組體之表現產物,其编 碼如實例1或2中所示範之抗原,及充作佐劑之調和物, 後者含有3 de-O-醯化之單磷醯基脂質A 3D-MPL及QS21 於油水乳劑之混合物。 3D-MPL :是革蘭氏陰性菌-明尼蘇達沙門氏菌 (Salmonella minnes ota)脂多醣(LPS)之化學去毒型式。 在 Smith Kline Beecham Biologicals 進行的實驗顯示, 3D-MPL組合以各種溶媒可強烈地加強體液及TH1型細跑 免疫力。 QS21 :係一種皂素,由 Quillaja Saponaria Molina 樹皮 -24- _______________^ 本纸張尺度適用中國國家標準(CNS ) A4規格(2Hrx 297公漦) (請先閲讀背面之:y意事嘎 本頁) •裝_ 訂 線 499436 A- Β· 濟 部 中 央 標 準 局 消 f 合 社 印 製 五、發明説明(22 ) 之粗製萃取物中純化,其有強烈佐劑活性;其可活化抗原 特定性淋巴增生及對數種抗原之CTL反應。Smith Kline Beecham Biologicals 進行實驗已證實 3D-MPL 及 QS21 結 合會在體液及Τ Η 1細胞免疫反應之謗導作用有具體協同 功效。 油水乳劑由二種油(生育醇及鯊晞),及含有Tween 80爲 乳化劑之PBS所組成。乳劑含有5%鯊烯、5%生育醇、 0.4% Tween 80,且有180毫微米之平均粒子大小(見WO 95/17210) 。 _ 在Smith Kline Beech am Biologic als所進行之實驗已證明 ,此O/W乳劑佐加至3D-MPL/QS21可進一步增加其免疫 刺激劑特性。 油/水乳劑之製備(2倍濃縮液) Tween 80溶於轉酸鹽缓衝之食鹽水(pbs)使在PBS中呈 2%溶液。爲提供1〇〇毫升的二倍濃縮乳液,將5克dl α生 育醇及5毫升鯊烯渦旋以充份混合。加入9〇毫升Pbs/ Tween落液,並充份混合。生成之乳劑再通過注射器,最 後利用M110S微流化機器微流化。生成之油滴有约18()毫 微米之大小。 油水調和物之製備 依κ例1或2製備之抗原(5微克)稀釋於丨〇倍濃縮之pBs pH 6.8及H20中,再以5分鐘間隔相繼加入SB62,3D_MpL (5微克),QS21(5微克)及充作保藏劑之5〇微克/亳升硫柳 汞。乳劑體積相當於總體積之50%(5〇微升於1〇〇微升劑量)。 -25- 本纸張尺度適用中國國家標準( CNS ) A4規格(210X 297公犮 (請先閱讀背面之注意事項本頁 -裝. ---線 1.......... j一__=囂 f 層**............ 499436 A? B7 五、發明説明(23 ) 所有的培育均在攪動下之室溫進行。 6. Tat及Nef-Tat於齧鼠類中之免疫原性 於以Tat及Nef Tat免疫接種後進行所謗生之免疫反應之 鏗定。爲了獲得在同型概況及細胞調介之免疫力上之資料 ,於老鼠身上進行二種免疫接種實驗。於第一個實驗中, 老鼠以呈氧化或還原型式之Tat或Nef Tat,以二週間隔免 疫接種至腳趾二之。抗原係調和在油水乳劑中,其中含有 鯊晞,吐溫8 0 ^ (聚氧乙晞山梨聚醣單油酸g旨),Q S 2 1 , 3D-MPL及α-生育醇,而對照组則僅接受佐劑。於最後一次 免疫接種後二週,取得血清並接受Tat-特異的ELISA (利用 還原型Tat以爲塗佈),以決定抗體效價及同型(圖6a)。抗 體效價在接受氧化型Tat之老鼠中最高。一般而言,氧化 型分子謗生之抗體效價較還原型爲高,且Tat單獨時謗生 之抗體效價高於Nef Tat。後一觀察於第二個實驗中可證實 。最令人感興趣的,Tat-特異之抗體,其同型概況依免疫 時所用之抗原而定。單獨的Tat可謗生平衡的IgGl及IgG2a 概況,而Nef Tat謗生較強的TH2偏差(圖6b)。此點於第二 實驗中可再次證實。 於第二個老鼠實驗中,動物僅接受分子之還原型式或單 獨的佐劑。除了血清學分析外(見上文),也評估來自淋巴 結細胞之淋巴增殖性反應。這些細胞於Tat或Nef Tat試管 内再剌激後,於培養4天後偵測3H-胸苷納入情況。以胸激 指數呈現結果顯示,在接受抗原的二組老鼠群中,均可謗 生極強之反應(圖7)。 -26- 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公犮) (請先閱讀背面之注意事嗔\^^寫本頁
、1T 經濟部中央標準局貝工消f合作社印製 五、 發明説明(24 ) A7 B? 結論而言’在老鼠的研究中顯示,Tat以及Nef-Tat均爲 /、鬲度兄疫原生之候選疫苗抗原。直接拮抗二分子之免疫 反應可由具至少50% IgG 1之高抗體反應鏗知。再者,也可 歲察到強的CMI反應(由淋巴增殖作甫測知)。 7· Tat及Nef-Tat蛋白質之功能特性 檢視呈氧化或還原型Tat及Nef Tat分子,與人類T細胞 株結合之能力。再者,也評估其在這些細胞株生長上之影 響。ELISA盤以不同濃度的Tat及Nef Tat蛋白質來自單純 疱疹病毒II型之不相關gD,或以單獨的缓衝溶液對照組塗 佈一夜。在移去塗佈溶液後,在孔洞中加入HUT-78細胞 。經2小時培育後,洗滌孔洞並以顯微鏡檢評估細胞與孔 洞底部之結合。爲了定量偵測,以曱苯胺藍染細胞,以SDS 心角宁,丹以ELIS A碩盤計決定上清液中甲苯胺藍之濃度。 結果顯示所有四種蛋白質,即氧化或還原型之Tat及Nef Tat ,均可#1介細胞與ELISA盤之結合(圖8)。不相關之蛋白質 (數據未示出)及缓衝溶液無法固定細胞。此顯示,經重組 表現之含Tat蛋白質可與人類τ細胞株特異地結合。 在第二貫驗中’令HUT-78細胞與蛋白質接觸16小時。 於培育期末了,細胞以[3H]-胸苷標記之,再由細胞生長之 測定來決定纳入率。納入此分析中的4種蛋白質均可抑制 細胞生長’此點可由減弱t放射活性納入予以判斷(圖9) 。緩衝溶液對照組並不調介此作用。這些結果證明,含有 重组體Tat之蛋白質可抑制人類τ細胞株之生長。 總而呂之’ Tat及Nef Tat蛋白質之功能鐘定顯示,這些 -27- 本紙依尺度適用中國國家標準(〇奶)/\4規格(21(^ 297公浼) 請 先 閱 讀 背 之 注 意 Ψ 項 ¥ 本 頁 裝 訂 經濟部中央標準局員工消f合作社印製 ^436 A7 B7 經濟部中央標準局員工消费合作社印裂 五、發明説明(25 ) 蛋白質可與人類τ細胞株結合。再者,蛋白質可抑制此細 胞株之生長。 序列表 (1) 一般資料 ⑴申請人:SmithKline Beecham Biologicals S· A· (ii) 發明名稱:疫苗 (iii) 序列數:27 (iv) 通訊住址 (A) 收信人:SmithKline Beecham (B) 街:Two New Horizons Court (C) 市·· Brentford (D) 州: (E) 國:Middx,UK (F) ZIP : TW8 9EP (v) 電腦可讀型式: (A) 媒體型式:軟式磁碟 (B) 電腦:IBM可相容 (C) 操作系統:DOS (D) 軟體·· FastSEQ for Windows Version 2.0 (vi) 目前申談資料: (A) 申請號: (B) 立檔曰期·· 1997年9月26曰 (C) 分類: (vii) 先前申請資料·· -28- 本紙浪尺度適用中國國家標準(CNS ) Λ4規格(210x297公t ) (請先閱讀背面之注意事項寫本頁)
訂 線 499436 A7 B7 五、發明説明(26 ) (A) 申請號: (B) 主檔曰期·· (viii) 法律事務資料:
(A) 名稱:Bor,Fiona R (B) 註册號: (C) 參考/索引號·· (ix) 電傳資料: (A) 電話:0181 975 2817 (B) 電傳:0181 975 6141 _ (C) 電報交換: (2) SEQ ID NO : 1 : (i)序列特性: (A) 長度·· 28個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明:SEQ ID NO : 1 : 广 广广广rp 广广η\ ,广 rp 广广 rp
i ό 'w wri -l i . . H no . 1 ov? . I 經濟部中央標準局員工消費合作社印製 (2) SEQ ID NO : 2 : (i)序列特性: (A) 長度:23個驗基基 (B) 型式:核酸 (C) 股性:單股 -29- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公漦) 499436 A7 B1 經濟部中央標準局負工消费合作社印製 五、發明説明(27 ) (D)拓撲學 :線型 (XI)序列説明 :,SEQ ID NO : 2 : CGGCTACTAG TGCAGTTCTT GAA 23 (2) SEQ ID NO • 3 : (i)序列特性: (A)長度: 2 9個驗基基 (B)型式: 核酸 (C)股性: 單股 (D)拓撲學 :線型 (xi)序列説明 :SEQ ID NO : 3 : ATCGTACTAG T.GAG.CCA. GTA.GAT.C 29 (2) SEQ ID NO :4 : (i)序列特性: (A)長度: 24個鹼基基 (B)型式: 核酸 (C)股性: 單股 (D)拓撲學 :線型 (xi)序列説明 :SEQ ID NO : 4 : CGGCTACTAG TTTCCTTCGG GCCT 24 (2) SEQ ID NO :5 : (1)序列特性: -30- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公I ) 499436 A7 B? 五、發明説明(28 (A) 長度:23個驗基基 (B) 髮式:核酸 (C) 股性··單股 (D) 拓撲學:線型 (xi)序列説明:SEQIDNO · ATCGTCCATG GAGCCAGTAG ATC(2) SEQ ID NO : 6 : (i)序列特性: (A) 長度·· 441個绘基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明·· SEQ ID NO : 23 請 先 閲 讀 背 之 意 事 Ρ 本 頁 裝 訂 6
ATGGATCCAA
AGCCATTCAT
CGTGGTGCTA
CAACAGGCTG
ATTCACGATC
CGTAAAGATG
ATGACAGAAA
CACCATCACC
AAACTTTAGC
CAAATATGGC
GCGGTTATTT
ATTATTTAGA
ACTTTTTAGA
GCCGTTACTA
ACTTTGAAAC
ATTAATCTAG
CCTTTCTTTA
GAATACCCAA
ACCAGAGCAT
GCAAGATTTA
TGGCTTGACT
TGTCATCGAC
CATGGCCACG
A
TTAGCAGCTG
ATGAAATCAG
ACGTTAGAAT
GCAATGACTA
GATGTTGCGA
TTTACCTTAA
TGTGATCAGA
GCGTACTAGC
ACAAAATCAT
CTAAAGCACT
AGGATGGTCG
AAAAATTCCC
AAGAAATTCA
GCTCAACTAG
AGGTTGTAGC
TATTGCTCAC
TGCTTTTGCA
TTTAGTGGTT
ACATCGTCAT
AAGTTTAGAA
TGGCCACCAT 60 120 180 240 300 360 420 441 經濟部中央標準局員工消費合作社印製 (2) SEQ ID NO : 7 : (i)序列特性·· (A) 長度:144胺基酸 (B) 型式··胺基酸 (C) 股性:單股 -31 - 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公t ) 499436 A7 B7 五、發明説明(29 ) (D)拓撲學··線型 (xi)序列説明:SEQ ID NO : 7 :
Met Asp Pro Lys Thr Leu Ala Leu 〇er Leu Leu Ala Ala G-ly Val Leu 1 5 10 15
Ala Gly Cys Ser Ser His Ser Ser Asn Met Ala Asn Thr Gin Met Lys 20 25 30
Ser Asp Lys lie lie lie Ala His Arg Gly Ala Ser Gly Tyr Leu Pro 35 40 45
Glu His Thr Leu Glu Ser Lys Ala Leu Ala Phe Ala Gin Gin Ala Asp 50 55 60
Tyr Leu Glu Gin Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val 65 70 75 80 lie His Asp His Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe 85 90 95
Pro His Arg His Arg Lys Asp Gly Arg Tyr Tyr Val 工le Asp Phe Thr 100 105 110
Leu Lys Glu He Gin Ser Leu Glu Met Thr Glu Asn Phe Glu Thr Met 115 120 125
Ala Thr Cys Asp Gin Ser Ser Thr Ser Gly His Kis Kis His His His 130 135 140 (2) SEQ ID NO : 8 : (i)序列特性: (A) 長度:648個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 經濟部中央標準局負工消费合作社印製 (xi)序列説明·· SEQ ID NO : 8 ·· -32- 本纸痕尺度適用中國國家標準(CNS ) Λ4規格(210X 297公犮) 499436 A7 B7 五、發明説明(3〇
ATGGGTGGCA AGACGAGCTG GGAGCAATCA CAAGAGGAGG TACAAGGCAG ATTCACTCCC TTCCCTGATT TGGTGCTACA AACACCAGCT TTAGAGTGGA GAGTACTTCA
AGTGGTCAAA AGCCAGCAGC CAAGTAGCAA AGGAGGTGGG CTGTAGATCT AACGAAGACA GGCAGAACTA AGCTAGTACC TGTTACACCC GGTTTGACAG AGAACTGCAC
AAGTAGTGTG AGATGGGGTG TACAGCAGCT TTTTCCAGTC TAGCCACTTT AGATATCCTT CACACCAGGG AGTTGAGCCA TGTGAGCCTG CCGCCTAGCA TAGTGGCCAC
GTTGGATGGC GGAGCAGCAT ACCAATGCTG ACACCTCAGG TTAAAAGAAA GATCTGTGGA CCAGGGGTCA GATAAGGTAG CATGGAATGG TTTCATCACG CATCACCATC
CTACTGTAAG CTCGAGACCT CTTGTGCCTG TACCTTTAAG AGGGGGGACT TCTACCACAC GATATCCACT AAGAGGCCAA ATGACCCTGA TGGCCCGAGA ACCATTAA
GGAAAGAATG GGAAAAACAT GCTAGAAGCA ACCAATGACT GGAAGGGCTA ACAAGGCTAC GACCTTTGGA TAAAGGAGAG GAGAGAAGTG GCTGCATCCG 60 120 180 240 300 360 420 480 540 600 648 請 先 閱 讀 背 之 'Jir 意 事 項- (2) SEQ ID NO : 9 : (i)序列特性:(A) 長度:216胺基酸 (B) 型式:胺基酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明:SEQ ID NO :
裝 1 丁 經濟部中央標.準局員工消費合作社印製
Met Gly 1 Arg Glu Ala Ser Ala Ala 50 Glu Val 65 Tyr Lys Leu Glu Trp lie Pro Gly 130
Gly Lys Arg Met 20 Arg Asp 35 * Thr Asn Gly Phe Ala Ala Gly Leu 100 Tyr His 115 Pro Giy
Trp Ser Lys 5* Arg Arg Ala Leu Glu Lys Ala Ala Cys 55 Pro Val Thr 70 Vai Aso Leu 85 * lie His Ser Thr Gin Gly Val Arg Tyr 135
Ser Ser Glu Pro 25 His Gly 40 Ala Trp Pro Gin Ser His Gin Arg 105 Tyr Phe 120 Pro Leu 9 : Val Val 10 Ala Ala Ala He Leu Glu Val Pro 75 Phe Leu 90 Arg Gin Pro Asp Thr Phe
Gly Trp Asp Gly Thr Ser 45 Ala Gin 60 Leu Arg Lys Glu Asp lie Trp Gin 125 Gly Trp 140
Pro Thr Val 15 Val Gly Ala 30 Ser Asn Thr Glu Glu Glu Pro Met Thr 80 Lys Gly Gly 95 Leu Aso Leu 110 Asn Tyr Thr Cys Tyr Lys 33- 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公炎) 499436
AT B7 五、發明説明(31 )
Leu Val Pro Val Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu 145 150 155 160
Asn Thr Ser Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro 165 170 175
Glu Arg Glu Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His 180 185 190
His Val Ala Arg Glu Leu His Pro Glu Tyr Phe Lys Asn Cys Thr Ser 195 200 205
Gly His His His His His His 210 215 (2) SEQ ID NO ·· 10 ·· (i)序列特性·· (A) 長度:288個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 ㈤)序列説明:SEQ ID NO : 1〇 : 0 0 0 0 8 6 2 8 4 8 112 2
ATGGAGCCAG TAGATCCTAG ACTAGAGCCC TGGAAGCATC CAGGAAGTCA GCCTAAAACT GCTTGTACCA ATTGCTATTG TAAAAAGTGT TGCTTTCATT GCCAAGTTTG TTTCATAACA AAAGCCTTAG GCATCTCCTA TGGCAGGAAG AAGCGGAGAC AGCGACGAAG ACCTCCTCAA GGCAGTCAGA CTCATCAAGT TTCTCTATCA AAGCAACCCA CCTCCCAATC CCGAGGGGAC CCGACAGGCC CGAAGGAAAC TAGTGGCCAC CATCACCATC ACCATTAA (2) SEQ ID NO : 11 : 經濟部中央標準局男工消费合作社印製 (i)序列特性: (A) 長度:96胺基酸 (B) 型式··胺基酸 (C) 股性:單股 、 (D) 拓撲學··線型 (XI)序列説明:SEQ ID NO : Η : 34- 本纸張尺度適用中國國家標隼(CNS ) A4規格(210X 297公及) 499436 Λ7 B7 五、發明説明(32 ) 經濟部中央標擎局員工消费合作社印製
Met Glu Pro Val Asp Pro Arg Leu Glu Pro Trp Lys His Pro Gly Ser 15 10 15 Gin Pro Lys Thr Ala Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe 20 25 30 His Cys Gin Val Cys Phe lie Thr Lys Ala Leu Gly lie Ser Tyr Gly 35 40 45 Arg Lys Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin Gly Ser Gin Thr 50 55 60 His Gin Val Ser Leu Ser Lys Gin Pro Thr Ser Gin Ser Arg Gly Asp 65 70 15 B0 Pro Thr Gly Pro Lys Glu Thr Ser Gly His His His His His His 85 90 95 (2) SEQ ID NO : 12 :(i)序列特性·· (A) 長度·· 909個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明·· SEQ ID NO ·· 12 : ATGGGTGGCA AGTGGTCAAA AAGTAGTGTG GTTGGATGGC CTACTGTAAG GGAAAGAATG AGACGAGCTG AGCCAGCAGC AGATGGGGTG GGAGCAGCAT CTCGAGACCT GGAAAAACAT GGAGCAATCA CAAGTAGCAA TACAGCAGCT ACCAATGCTG CTTGTGCCTG GCTAGAAGCA CKAGAGGAGG AGGAGGTGGG TTTTCCAGTC ACACCTCAGG TACCTTTAAG ACCAATGACT TACA^.GGCAG CTGTAGATCT TAGCCACTTT TTAAAAGAAA AGGGGGGACT GGAAGGGCTA ATTCACTCCC AACGAAGACA AGATATCCTT GATCTGTGGA TCTACCACAC ACAAGGCTAC TTCCCTGATT GGCAGAACTA CACACCAGGG CCAGGGGTCA GATATCCACT GACCTTTGGA TGGTGCTACA AGCTAGTACC AGTTGAGCCA GATAAGGTAG AAGAGGCCAA TAAAGGAGAG AACACCAGCT TGTTACACCC TGTGAGCCTG CATGGAATGG ATGACCCTGA GAGAGAAGTG TTAGAGTGGA GGTTTGACAG CCGCCTAGCA TTTCATCACG TGGCCCGAGA GCTGCATCCG GAGTACTTCA AGAACTGCAC TAGTGAGCCA GTAGATCCTA GACTAGAGCC CTGGAAGCAT CCAGGAAGTC AGCCTA^AAC TGCTTGTACC AATTGCTATT GTAAAAAGTG TTGCTTTCAT TGCC^AGITT GTTTCATAAC AA^AGCCTTA GGCATCTCCT ATGGCAGGAA GAAGCGGAGA CAGCGACGAA GACCTCCTCA AGGCAGTCAG ACTCATCAAG TTTCTCTATC AAAGCAACCC ACCTCCCAAT CCCGAGGGGA CCCGACAGGC CCG^GGAAA CTAGTGGCCA CCATCACCAT CACCATTAA 000 0000000000009 62840 6 2840 -.0 28400 112334 4 5 66 7 7899 (請先閲讀背面之一注意事項再填寫本頁) -裝· -35 - 本紙張尺度適用中國國家標隼(CNS ) Λ4規格(2丨OXM7公垃) 499436 Λ7 B7 五、發明説明(33 (2) SEQ ID NO : 13 (i)序列特性: (A) 長度: (B) 型式: (C) 股性: 303胺基酸 胺基酸 單股
(D)拓撲學:線型 (xi)序列説明:SEQIDNO 13 請 先 閱 讀 背 面 之 注· 意 事 項-再』
Met Gly Gly Lys Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Val 1 5 10 15
Arg Glu Arg Met Arg Arg Ala Glu Pro Ala Ala Asp Gly Val Gly Ala 20 25 30
Ala Ser Arq Aso Leu Glu Lys His Gly Ala lie Thr Ser Ser Asn Thr 35 ^ 40 45
Ala Ala Thr Asn Ala Ala Cys Ala Trp Leu Glu Ala Gin Glu Glu Glu 50 55 60
Glu Val Gly Phe Pro Val Thr Pro Gin Val Pro Leu Arg Pro Met Thr 65 70 75 80
Tyr Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly 85 90 ^ *95
Leu Glu Gly Leu lie His Ser Gin Arg Arg Gin Asp lie Leu Asp Leu 100 · 105 " 110
Trp lie Tyr His Thr Gin Gly Tyr Phe Pro Asp Trp Gin Asn Tyr Thr 115 120 125 ^
Pro Gly Pro Gly Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys 130 135 140
Leu Val Pro Val Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu 145 150 · * 155 160
Asn Thr Ser Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro 165 170 175
Glu Arg Glu Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His 180 * 185 190
His Val Ala Arg Glu Leu His Pro Glu Tyr Phe Lys Asn Cys Thr Ser 195 200 205
Glu Pro Val Asp Pro Arg Leu Glu Pro Trp Lys His Pro Giy Ser Gin 210 215 ^ 220
Pro Lys Thr Ala Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe His 225 230 235 240
Cys Gin Val Cys Phe lie Thr Lys Ala Leu Gly lie Ser T-yr Gly Arg 245 250 ^ 255
Lys Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin Gly Ser Gin Thr His 260 265 270
Gin Val Ser Leu Ser Lys Gin Pro Thr Ser Gin Ser Arg Gly Asp Pro 275 280 285
Thr Gly Pro Lys Glu Thr Ser Gly His His His His His His 290 ^ 295 “ 300 36- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公旋) I裝 頁 訂 經濟部中央標準局員工消費合作社印製 499436 A7 五、發明説明(34 (2) SEQ ID NO : 14 : (i)序列特性: (A) 長度:1029個鹼基基 (B) 型式··核酸 (C) 股性:單股 - (D) 拓撲學:線型 (xi)序列説明·· SEQIDNO : 14 ·· 請 先閱 讀 背之注 意 事 項· Ρ 裝
ATGGATCCAA
AGCCATTCAT
CGTGGTGCTA
CAACAGGCTG
ATTCACGATC
CGTAAAGATG
ATGACAGAAA
CCTACTGTAA
TCTCGAGACC
GCTTGTGCCT
GTACCTTTAA
AAGGGGGGAC
ATCTACCACA
AGATATCCAC
GAAGAGGCCA
GATGACCCTG
GTGGCCCGAG
CACCATTAA
AAACTTTAGC
CAAATATGGC
GCGGTTATTT
ATTATTTAGA
ACTTTTTAGA
GCCGTTACTA
ACTTTGAAAC
GGGAAAGAAT
TGGAAAAACA
GGCTAGAAGC
GACCAATGAC
TGGAAGGGCT
CACAAGGCTA
TGACCTTTGG
ATAAAGGAGA
AGAGAGAAGT
AGCTGCATCC
CCTTTCTTTA
GAATACCCAA
ACCAGAGCAT
GCAAGATTTA
TGGCTTGACT
TGTCATCGAC
CATGGGTGGC
GAGACGAGCT
TGGAGCAATC
ACAAGAGGAG
TTACAAGGCA
AATTCACTCC
CTTCCCTGAT
ATGGTGCTAC
GAACACCAGC
GTTAGAGTGG
GGAGTACTTC
TTAGCB.GCTG
ATGAAATCAG
ACGTTAGAAT
GCAATGACTA
GATGTTGCGA
TTTACCTTAA
AAGTGGTCAA
GAGCCAGCAG
ACAAGTAGCA
GAGGAGGTGG
GCTGTAGATC
CAACGAAGAC
TGGCAGAACT
AAGCTAGTAC
TTGTTACACC
AGGTTTGACA
AAGAACTGCA
GCGTACTAGC
ACAAAATCAT
CTAAAGCACT
AGGATGGTCG
AAAAATTCCC
AAGAAATTCA
AAAGTAGTGT
CAGATGGGGT
ATACAGCAGC
GTTTTCCAGT
TTAGCCACTT
AAGATATCCT
ACACACCAGG
CAGTTGAGCC
CTGTGAGCCT
GCCGCCTAGC
CTAGTGGCCA
AGGTTGTAGC
TATTGCTCAC
TGCTTTTGCA
TTTAGTGGTT
ACATCGTCAT
AAGTTTAGAA
GGTTGGATGG
GGGAGCAGCA
TACCAATGCT
CACACCTCAG
TTTAAAAGAA
TGATCTGTGG
GCCAGGGGTC
AGATAAGGTA
GCATGGAATG
ATTTCAT.CAC
CCATCACCAT 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1029 訂 經濟部中央標準局員工消費合作社印製 (2) SEQ ID NO : 15 (i)序列特性: (A) 長度: (B) 型式: (C) 股性: 325胺基酸 胺基酸 單股 (D)拓撲學:線型 (xi)序列説明:SEQ ID NO : 15 -37- 本纸張尺度適用中國國家標準(CNS )八4規格(210X297公浼) 499436 A / B7 五、發明説明(35 ) 經濟部中央標準局員工消费合作社印製
Cys Ser Ser His Ser Ser Asn Met Ala Asn Thr Gin Met Lys Ser Asp 1 5 10 15 Lys He He He Ala His Arg Gly Ala Ser Gly Tyr Leu Pro Glu His 20 25 30 Thr Leu Glu Ser Lys Ala Leu Ala Phe Ala Gin Gin Ala Asp Tyr Leu 35 __________ 40 45 Glu G.ln Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val lie His 50 55- 60 Asp Kis Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe Pro His 65 70 75 80 Arg His Arg Lys Asp Gly Arg Tyr Tyr Val lie Asp Phe Thr Leu Lys 85 90 * 95 Glu lie Gin Ser Leu Glu Met Thr Glu Asn Phe Glu Thr Met Gly Gly 100 105 li〇 Lys Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Vai Arg Glu Arg 115 120 ' 125 Met Arg Arg Ala Glu Pro Ala Ala Asp Gly Val Gly Ala Ala Ser Arg 130 135 * 140 Aso Leu Glu Lys His Gly Ala lie Thr Ser Ser Asn Thr Ala Ala Thr 145 ^ 150 155 160 Asn Ala Ala Cvs Ala Trp Leu Glu Ala Gin Glu Glu Glu Glu Val Gly "165 170 175 ?he Pro Val Thr Pro Gin Val Pro Leu Arg Pro Met Thr Tyr Lys Ala 180 185 190 Ala Val Aso Leu Ser His Phe Leu Lys Glu Lys Gly Gly Leu Glu Gly 195 200 205 Leu lie His Ser Gin Arg Arg Gin Asp lie Leu Asp Leu Trp lie Tyx 210 215 220 Kis Thr Gin Gly Tyr Phe Pro Asp Trp Gin Asn Tyr Thr -Pro Gly Pro 225 ▲ 230 235 240 Gly Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys Leu Val Pro ^ 245 250 255 Val Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu Asn Thr Ser 260 265 270 Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro Glu Arg Glu 275 280 285 Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His His Val Ala 290 295 300 Arg Glu Leu Kis Pro Glu Tyr Phe Lys Asn Cys Thr Ser Gly His His 305 310 315 320 His His His His (2) SEQ ID NO : 16 : (i)序列特性: -38- 本纸乐尺度適用中國國家標隼(CNS ) /Μ規格(210X 297公犮) (請先閱讀背面之注意事項再填寫本頁) 裝丨· --訂 499436 ΛΤR7 五、發明説明,(36 (Α)長度 (B) 型式 (C) 股性 1290個鹼基基 核酸 單股 16 (D)拓撲學:線型
〇i)序列説明·· SEQ ID NO
ATGGATCCAA
AGCCATTCAT
CGTGGTGCTA
CAACAGGCTG
ATTCACGATC
CGTAAAGATG
ATGACAGAAA
CCTACTGTAA
TCTCGAGACC
GCTTGTGCCT
GTACCTTTAA
AAGGGGGGAC
ATCTACCACA
AGATATCCAC
GAAGAGGCCA
GATGACCCTG
GTGGCCCGAG
AGACTAGAGC
TGTAAAAAGT
TATGGCAGGA
GTTTCTCTAT
ACTAGTGGCC
AAACTTTAGC
CAAATATGGC
GCGGTTATTT
ATTATTTAGA
ACTTTTTAGA
GCCGTTACTA
ACTTTGAAAC
GGGAAAGAAT
TGGAAAAACA
GGCTAGAAGC
GACCAATGAC
TGGAAGGGCT
CACAAGGCTA
TGACCTTTGG
ATAAAGGAGA
AGAGAGAA'GT
AGCTGCATCC
CCTGGAAGCA
GTTGCTTTCA
AGAAGCGGAG
CAAAGCAACC
ACCATCACCA
CCTTTCTTTA
GAATACCCAA
ACCAGAGCAT
GCAAGATTTA
TGGCTTGACT
TGTCATCGAC
CATGGGTGGC
GAGACGAGCT
TGGAGCAATC
ACAAGAGGAG
TTACAAGGCA
AATTCACTCC
CTTCCCTGAT
ATGGTGCTAC
GAACACCAGC
GTTAGAGTGG
GGAGTACTTC
TCCAGGAAGT
TTGCCAAGTT
ACAGCGACGA
CACCTCCCAA
TCACCATTAA
TTAGCAGCTG
ATGAAATCAG
ACGTTAGAAT
GCAATGACTA
GATGTTGCGA
TTTACCTTAA
AAGTGGTCAA
GAGCCAGCAG
ACAAGTAGCA
GAGGAGGTGG
GCTGTAGATC
CAACGAAGAC
TGGCAGAACT
AAGCTAGTAC
TTGTTACACC
AGGTT.TGACA
AAGAACTGCA
CAGCCTAAAA
TGTTTCATAA
AGACCTCCTC
TCCCGAGGGG
GCGTACTAGC
ACAAAATCAT
CTAAAGCACT
AGGATGGTCG
AAAAATTCCC
AAGAAATTCA
AAAGTAGTGT
CAGATGGGGT
ATACAGCAGC
GTTTTCCAGT
TTAGCCACTT
AAGATATCCT
ACACACCAGG
CAGTTGAGCC
CTGTGAGCCT
GCCGCCTAGC
CTAGTGAGCC
CTGCTTGTAC
CAAAAGCCTT
AAGGCAGTCA
ACCCGACAGG
AGGTTGTAGC
TATTGCTCAC
TGCGTTTGCA
TTTAGTGGTT
ACATCGTCAT
AAGTTTAGAA
GGTTGGATGG
GGGAGCAGCA
TACCAATGCT
CACACCTCAG
TTTAAAAGAA
TGATCTGTGG
GCCAGGGGTC
AGATAAGGTA
GCATGGAATG
ATTTCATCAC
AGTAGATCCT
CAATTGCTAT
AGGCATCTCC
GACTCATCAA
CCCGAAGGAA 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1290
訂 經濟部中央標準局員工消費合作社印製 17 (2) SEQ ID NO (i)序列特性: (A) 長度:412胺基酸 (B) 型式:胺基酸 (C) 股性··單股 (D) 拓撲學:線型 -39- 本纸&尺度適用中國國家標準(CNS ) Λ4規格(210Χ 297公趁) 499436 Λ7B* 五、發明説明(37 (xi)序列説明:SEQ ID NO : 17 :
Cys Ser Ser His 1 Lys lie Thr Leu 經濟部中央標準局員工消費合作社印製
Glu Gin 50 Asp His 65 Arg His Glu Ue Lys Trp Met Arg 130 Aso Leu 145 Asn Ala Phe Pro Ala Val Leu lie 210 His Thr 225 Gly Val Val Glu Leu Leu Val Leu 290 Arg Glu 305 Asp Pro Ala Cys Cys Phe Arg Gin 370 lie lie 20 Glu Ser 35 Aso Leu
Phe Leu Arg Lys Gin Ser 100 Ser Lys 115 Arg Ala Glu Lys Ala Cys Vai Thr 180 Asp Leu 195 His Ser Gin Gly Arg Tyr Pro Asp 260 His Pro 275 Glu Trp Leu His Arg Leu Thr Asn 340 lie Thr 355 Arg Arg
Ser Ser 5 Ala His Lys Ala Ala Met Asp Gly 70 Asp Gly 85 Leu Glu Ser Ser Glu Pro His Gly 150 Ala Trp 165 Pro Gin Ser His Gin Arg Tyr Phe "* 230 Pro Leu 245 Lys Val Val Ser Arg Phe Pro Glu 310 Glu Pro 325 Cys Tyr Lys Ala Arg Pro
Asn Met Ala Arg Gly Ala 25 Leu Ala Phe 40 Thr Lys Asp 55 Leu Thr Asp Arg Tyr Tyr Met Thr Glu 105 Val Val Gly 120 Ala Ala Asd 135 * Ala lie Thr Leu Glu Ala Val Pro Leu 185 Phe Leu Lys 200 Arg Gin Asp 215 * Pro Asp Trp Thr Phe Gly Glu Glu Ala 265 Leu His Gly 280 Asp Ser Arg 295 Tyr Phe Lys Trp Lys Ris Cys Lys Lys * 34 5 Leu Gly lie 3β0 Pro Gin Gly 375
Asn Thr 10 Ser Gly Ala Gin Gly Arg Val Ala 75 Val lie 90 Asn Phe Trp Pro Gly Val Ser Ser 155 Gin Glu 170 Arg Pro Glu Lys lie Leu Gin Asn 235 Trp Cys 250 Asn Lys Met Asp Leu Ala Asn Cys 315 Pro Gly 330 ^ Cys Cys Ser Tyr Ser Gin
Gin Met Tyr Leu Gin Ala 45 Leu Val 60 Lys Lys Asp Phe Glu Thr Thr Val 125 Gly Ala 140 Asn Thr Glu Glu Met Thr Glv Gly 205 Asp Leu 220 Tyr Thr Tyr Lys Gly Glu Asp Pro 285 Phe His 300 . Thr Ser Ser Gin Phe His GIv Arg 365 Thr His 380
Lys Ser Asp 15 Pro Glu His 30 Asp Tyr Leu Val lie His Phe Pro His 80 Thr Leu Lys 95 Met Gly Gly 110 Arg Glu Arg A-la Ser Arg Ala Ala Thr 160 Glu Val Gly 175 Tyr Lys Ala 190 Leu Glu Gly Trp lie Tyr Pro Gly Pro 240 Leu Val Pro 255 Asn Thr Ser 270 Glu Arg Glu His Val Ala Glu Pro Val 320 Pro Lys Thr 335 Cys Gin Val 350 ' Lys Lys Arg Gin Val Ser 請 先 閱 讀 背 面 之 注 意 事 項· 本 頁 裝 訂 -40- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公犮) 499436 A/ B7 五、發明説明(38 )
u 5 S β 8 y L 3 L
Ser Lys Gin Pro Thr Ser Gin Ser Arg Gly Asp Pro Thr Glv Pro 390 395 400 Glu Thr Ser Gly His His Kis His Kis His 405 410 (2) SEQ ID NO : 18 : (i)序列特性: (A) 長度:981個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學··線型 ~ (xi)序列説明:SEQ ID NO : 18 : ATGGATCCAA GCAGCCATTC ATCAAATATG GCGAATACCC AAATGAAATC AGACAAAATC ATTATTGCTC ACCGTGGTGC TAGCGGTTAT TTACCAGAGC ATACGTTAGA ATCTAAAGCA CTTGCGTTTG CACAACAGGC TGATTATTTA GAGCAAGATT TAGCAATGAC TAAGGATGGT CGTTTAGTGG TTATTCACGA TCACTTTTTA GATGGCTTGA CTGATGTTGC GAAAAAATTC CCACATCGTC ATCGTAAAGA TGGCCGTTAC TATGTCATCG ACTTTACCTT AAAAGAAATT CAAAGTTTAG AAATGACAGA AAACTTTGAA ACCATGGGTG GCAAGTGGTC AAAAAGTAGT GTGGTTGGAT GGCCTACTGT AAGGGAAAGA ATGAGACGAG CTGAGCCAGC AGCAGATGGG GTGGGAGCAG CATCTCGAGA CCTGGAAAAA CATGGAGCAA TCACAAGTAG CAATACAGCA GCTACCAATG CTGCTTGTGC CTGGCTAGAA GCACAAGAGG AGGAGGAGGT GGGTTTTCCA GTCACACCTC AGGTACCTTT AAGACCAATG ACTTACAAGG CAGCTGTAGA TCTTAGCCAC TTTTTAAAAG AAAAGGGGGG ACTGGAAGGG CTAATTCACT CCCAACGAAG ACAAGATATC CTTGATCTGT GGATCTACCA CACACAAGGC TACTTCCCTG ATTGGCAGAA CTACACACCA GGGCCAGGGG TCAGATATCC ACTGACCTTT GGATGGTGCT ACAAGCTAGT ACCAGTTGAG CCAGATAAGG TAGAAGAGGC CAATAAAGGA GAGAACACCA GCTTGTTACA CCCTGTGAGC CTGCATGGAA TGGATGACCC TGAGAGAGAA GTGTTAGAGT GGAGGTTTGA CAGCCGCCTA GCATTTCATC ACGTGGCCCG AGAGCTGCAT CCGGAGTACT TCAAGAACTG CACTAGTGGC CACCATCACC ATCACCATTA A * ooooooooooooooool 6284062840 6 2840 6 8 11-233 4 4 566778999 經濟部中央標準局員工消費合作社印制π (2) SEQ ID NO : 19 ·· (i)序列特性·· (A) 長度·· 327胺基酸 (B) 型式:胺基酸 -41 -
本纸張尺度適用中國國家標準(CNS〉Α4規格(210X 297公澄) 499436 A7 B7 五、發明説明(39 ) (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明·· SEQIDNO : 19 ··
Met Asp Pro Ser Ser His Ser Ser Asn Met Ala Asn Thr Gin Met Lys 1 5 10 15
Ser Asp Lys lie lie lie Ala His Arg Gly Ala Ser Gly Tyr Leu Pro 20 25 30
Glu His Thr Leu GIu Ser Lys Ala Leu Ala Phe Ala Gin Gin Ala Asp 35 40 45 ^
Tyr Leu Glu Gin Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val 50 55 60 lie His Asp Kis Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe 65 70 ' 75‘ 80
Pro His Arg His Arg Lys Asp Gly Arg Tyr Tyr Val lie Asp Phe Thr 85 90 95
Leu Lys Glu lie Gin Ser Leu Glu Met Thr Glu Asn Phe Glu Thr Met 100 105 1'10
Gly Gly Lys Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Val Arg 115 120 125
Glu Arg Met Arg Arg Ala Giu Pro Ala Ala Asp Gly Val Gly Ala Ala 130 135 140
Ser Arg Asp Leu Glu Lys His Giy Ala He Thr Ser Ser Asn Thr Ala 145 150 155 160
Ala iliir Asn A-is. Al3. Cys Als ιιγό Σίθιι Glu. Als. Gin. GXu Glu GJ.u GIn 165 * 170 175
Val Gly Phe Pro Val Thr Pro Gin Val Pro Leu Arg Pro Met Thr Tyr 180 185 190
Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly Leu 195 200 205 ^ ^
Glu Gly Leu lie His Ser Gin Arg Arg Gin Aso lie Leu Asp Leu Trp 210 215 220 lie Tyr His Thr Gin Gly Tyr Phe Pro Asp Trp Gin Asn Tyr Thr Pro 225 230 235 240
Gly Pro Gly Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys Leu 245 250 255 經濟部中央標準局負工消费合作社印製 (讀先閱讀背面之注意事項再填寫本頁
Val Pro Val Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu Asn 260 265 270
Thr Ser Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro Glu 275 280 285
Arg Glu Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His His 290 295 300
Val Ala Arg Glu Leu His Pro Glu Tyr Phe Lys Asn Cys Thr Ser Gly 305 310 315 320
His His His His His His 325 -42· 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X297公犮) 499436 A7 ΙΓ 五、發明説明(40 ) 經濟部中央標準局員工消费合作社印製 (2) SEQ ID NO : 20 : (i)序列特性: (A) 長度:1242個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明:SEQIDNO : 20 : ATGGATCCAA GCAGCCATTC ATCAAATATG GCGAATACCC AAATGAAATC AGACAAAATC ATTATTGCTC ACCGTGGTGC TAGCGGTTAT TTACCAGAGC ATACGTTAGA ATCTAAAGCA CTTGCGTTTG CACAACAGGC TGATTATTTA GAGCAAGATT TAGCAATGAC TAAGGATGGT CGTTTAGTGG TTATTCACGA TCACTTTTTA GATGGCTTGA CTGATGTTGC GAAAAAATTC CCACATCGTC ATCGTAAAGA TGGCCGTTAC TATGTCATCG ACTTTACCTT AAAAGAAA.TT CAAAGTTTAG AAATGACAGA AAACTTTGAA ACCATGGGTG GCAAGTGGTC AAAAAGTAGT GTGGTTGGAT GGCCTACTGT AAGGGAAAGA ATGAGACGAG CTGAGCCAGC AGCAGATGGG GTGGGAGCAG CATCTCGAGA CCTGGAAAAA CATGGAGCAA TCACAAGTAG CAATACAGCA GCTACCA^.TG CTGCTTGTGC CTGGCTAG^. GCACAAGAGG AGGAGGAGGT GGGTTTTCCA GTCACACCTC AGGTACCTTT AAGACCAATG ACTTACAAGG CAGCTGTAGA TCTTAGCCAC TTTTTAAAAG AAAAGGGGGG ACTGGAAGGG CTAATTCACT CCCAACGAAG ACAAGATATC CTTGATCTGT GGATCTACCA CACACAAGGC TACTTCCCTG ATTGGCAGAA CTACACACCA GGGCCAGGGG TCAGATATCC ACTGACCTTT GGATGGTGCT ACAAGCTAGT ACCAGTTGAG CCAGATAAGG TAGAAGAGGC CAATAAAGGA GAGAACACCA GCTTGTTACA CCCTGTGAGC CTGCATGGAA TGGATGACCC TGAGAGAGAA GTGTTAGAGT GGAGGTTTGA CAGCCGCCTA GCATTTCATC ACGTGGCCCG AGAGCTGCAT CCGGAGTACT TCAAGAACTG CACTAGTGAG CCAGTAGATC CTAGACTAGA GCCCTGGAAG CATCCAGGAA GTCAGCCTAA AACTGCTTGT ACCAATTGCT ATTGTAAAAA GTGTTGCTTT CATTGCCAAG TTTGTTTCAT AACAAAAGCC TTAGGCATCT CCTATGGCAG GAAGAAGCGG AGACAGCGAC GAAGACCTCC TCAAGGCAGT CAGACTCATC AAGTTTC7CT ATCAAAGCAA CCCACCTCCC AATCCCGAGG GGACCCGACA GGCCCGAAGG AAACTAGTGG CCACCATCAC CATCACCATT AA (2) SEQ ID NO : 21 : (i)序列特性: (A) 長度·· 414胺基酸 (B) 型式:胺基酸 (C) 股性··單股 (D) 拓撲學:線型
*0000 0 0000000000000002 6284062840 6 284062840 4 11233445667789900 122 I—{ f^-*-^^ Tx TX (請先閱讀背面之^意事養\^^寫本頁) •裝· 、-itr - 43- 本紙乐尺度適用中國國家標準(CNS ) A4規格(210X 297公趁) 499436 AT B7 五、發明説明(41 ) (xi)序列説明:SEQ ID NO : 21 : 經濟部中央標隼局員工消費合作社印装
Met Asp Pro Ser Ser His Ser Ser Asn Met Ala Asn Thr Gin Met Lys 1 5 ; 10 ’15 Ser Asp Lys lie lie lie Ala His Arg Gly Ala Ser Gly Tyr Leu Pro ‘ 20 25 30 Glu His Thr Leu Glu Ser Lys Ala Leu Ala Phe Ala Gin Gin Ala Asp 35 40 45 Tyr Leu Glu Gin Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val 50 * 55 60 lie His Asp His Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe 65 70 75^ * 80 Pro' Kis Arg His Arg Lys Asp Gly Arg Tyr Tyr Val lie Asp Phe Thr 85 ^ 90 95 Leu Lys Glu lie Gin Ser Leu Glu Met^Thr Glu Asn Phe Glu Thr Met 100 105~ 110 Gly Gly Lys Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Val Arg 115 120 125 Glu Arg Met Arg Arg Ala Glu Pro Ala Ala Asp Gly Val Gly Ala Ala 130 135 140 Ser Arg Asp Leu Glu Lys His Gly Ala He Thr Ser Ser Asn Thr Ala 145 150 155 160 Ala Thr Asn Ala Ala Cvs Ala Trp Leu Glu Ala Gin Glu Glu Glu Glu 165 170 175 Val Gly Phe Pro Val Thr Pro Gin Val Pro Leu Arg Pro Met Thr Tyr 180 185 190 Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Giu Lys Gly Gly Leu 195 200 205 Glu Giv Leu lie His Ser Gin Arg Arg Gin Asd lie Leu Asp Leu Trp 210 215 220 He Tyr His Thr Gin Gly Tyr Phe Pro Asp Trp Gin Asn Tyr Thr Pro 225 230 , 235 240 Gly Pro Giv Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys Leu ‘ 245 250 ^ 255 Val Pro Val Glu Pro Asp Lys Vai Glu Glu Ala Asn Lys Gly Glu Asn 260 265 ^ 270 Thr Ser Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro Glu 275 280 285 ' Arg Glu Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His His 290 295 300 Val Ala Arg Giu Leu His Pro Glu Tyr Phe Lys Asn Cys Thr Ser Glu 305 310 315 320 Pro Val Asp Pro Arg Leu Giu Pro Trp Lys His Pro Gly Ser Gin Pro 325 330 * 335 Lys Thr Ala Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe His Cys 340 345 350 -44- 本纸乐尺度適用中國國家標準(CNS ) Λ4規格(210X297公/1 ) (請先閲讀背面之注意事項再制寫本頁) 再一 裝 、-0 499436 AT五、發明説明(42 ) 經濟部中央標隼局員工消费合作社印製
Gin Val Cys Phe lie Thr Lys Ala Leu Gly lie Ser Tyr Gly Arg Lys 355 360 ^ 365 ‘ Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin Gly Ser Gin Thr His Gin 370 375 380 Val Ser Leu Ser Lys Gin Pro Thr Ser Gin Ser Arg Gly Asp Pro Thr 385 390 395 400 Gly Pro Lys Glu Thr Ser Gly His His His His Kis His 405 410 (2) SEQ ID NO : 22 : (i)序列特性: (A) 長度:288個鹼基基 (B) 型式··核酸 一 (C) 股性··單股 (D) 拓撲學:線型 (xi)序列説明;SEQ ID NO : 22 : ATGGAGCCAG TAGATCCTAG ACTAGAGCCC TGGAAGCATC CAGGAAGTCA GCCTAAAACT 60 GCTTGTACCA ATTGCTATTG TAAAAAGTGT TGCTTTCATT GCCAAGTTTG TTTCATAACA 120 GCTGCCTTAG GCATCTCCTA TGGCAGGAAG AAGCGGAGAC AGCGACGAAG ACCTCCTCAA 180 GGCAGTCAGA CTCATCAAGT TTCTCTATCA AAGCAACCCA CCTCCCAATC CAAAGGGGAG 240 CCGACAGGCC CGAAGGAAAC TAGTGGCCAC CATCACCATC ACCATTAA 288 (2) SEQ ID NO : 23 : (i)序列特性: (A) 長度:96胺基酸 (B) 型式:胺基酸 (C) 股性··單股 (D) 拓撲學:線型 (xi)序列説明:SEQ ID NO ·· 23 : -45- 本纸張尺度適用中國园家標準(CNS ).Λ4規格(210X 297公犮) (請先閱讀背面之注意事項再填寫本頁) :裝· 、11 499436
PC fT 五、發明説明(43
Met Glu Pro Val Asp Pro Arg Leu Glu Pro Trp Lys His Pro Gly Ser 1 5 10 15 Gin Pro Lys Thr Ala Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe 20 25 30 His Cys Gin Val Cys Phe He Thr Ala Ala Leu Gly He Ser Tyr Gly 35 40 45 Arg Lys Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin Gly Ser Gin Thr 50 _5_5___ _____60 His Gin Val Ser Leu Ser Lys Gin Pro Thr Ser Gin Ser Lvs Gly Giu 65 70 75 ^ 8〇 Pro Thr Gly Pro Lys Glu Thr Ser Gly His His His His His His 85 90 (2) SEQ ID NO ·· 24 : (i)序列特性: ~ (A) 長度·· 909個鹼基基 (B) 型式:核酸 (C) 股性:單股 (D) 拓撲學:線型 (xi)序列説明:SEQ ID NO : 24 95 請先 閱讀背 © 之 注"意事 項- f·丨5裝 訂 經濟部中央標準局員工消费合作社印^4
ATGGGTGGCA AGACGAGCTG GGAGCAATCA CAAGAGGAGG TACAAGGCAG ATTCACTCCC TTCCCTGATT TGGTGCTACA AACACCAGCT TTAGAGTGGA GAGTACTTCA CCAGGAAGTC TGCCAAGTTT CAGCGACGAA ACCTCCCAAT CACCATTAA
AGTGGTCAAA AGCCAGCAGC CAAGTAGCAA AGGAGGTGGG CTGTAGATCT AACGAAGACA GGCAGAACTA AGCTAGTACC TGTTACACCC GGTTTGACAG AGAACTGCAC AGCCTAAAAC GTTTCATAAC GACCTCCTCA CCAAAGGGGA
AAGTAGTGTG AGATGGGGTG TACAGCAGCT TTTTCCAGTC TAGCCACTTT AGATATCCTT CACACCAGGG AGTTGAGCCA TGTGAGCCTG CCGCCTAGCA TAGTGAGCCA TGCTTGTACC AGCTGCCTTA AGGCAGTCAG GCCGACAGGC
GTTGGATGGC GGAGCAGCAT ACCAATGCTG ACACCTCAGG TTAAAAGAAA GATCTGTGGA CCAGGGGTCA GATAAGGTAG CATGGAATGG TTTCATCACG GTAGATCCTA AATTGCTATT GGCATCTCCT ACTCATCAAG CCGAAGGAAA
CTACTGTAAG CTCGAGACCT CTTGTGCCTG TACCTTTAAG AGGGGGGACT TCTACCACAC GATATCCACT AAGAGGCCAA ATGACCCTGA TGGCCCGAGA GACTAGAGCC GTAAAAAGTG ATGGCAGGAA TTTCTCTATC CTAGTGGCCA
GGAAAGAATG GGAAAAACAT GCTAGAAGCA ACCAATGACT GGAAGGGCTA ACAAGGCTAC GACCTTTGGA TAAAGGAGAG GAGAGAAGTG GCTGCATCCG CTGGAAGCAT TTGCTTTCAT GAAGCGGAGA AAAGCAACCC CCATCACCAT 60 120 180 240 300 360 420 480 540 600 660 120 780 840 900 909 (2) SEQ ID NO : 25 : -46- 本纸ft尺度適用中國國家標準(CNS ) Λ4坭格(210X 297公兹) 499436 B7 五、發明説明(44 ⑴序列特性: (A)長度:303胺基酸 (B)型式:胺基酸 (C)股性:單股 (D)拓撲學:線型 (xi)序列説明:SEQ ID NO : 2):
經濟部中央標導局員工消费合作社印3L
Met Giy Gly Lys Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Val 15 10 15 Arg Glu Arg Met Arg Arg Ala Glu Pro Ala Ala Asp Gly Val Gly Ala 20 25 . 30 Ala Ser Arg Asp Leu Glu Lys His Gly Ala lie Thr Ser S.er Asn Thr 35 40 45 Ala Ala Thr Asn Ala Ala Cys Ala Trp Leu Glu Ala Gin Glu Glu Glu 50 55 60 Glu Val Gly Phe Pro Val Thr Pro Gin Val Pro Leu Arg Pro Met Thr 65 70 75 80 Tyr Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly ^ ^ 85 90 ^ 95 Leu Glu Gly Leu lie His Ser Gin Arg Arg Gin Asp lie Leu Asp Leu 100 105 ‘ 110 Trp lie Tyr His Thr Gin Gly Tyr Phe Pro Asp Trp Gin Asn Tyr Thr ' 115 120 ^ 125 Pro Gly Pro Gly Val Arg Tyr Pro Leu Thr Phe Giy Trp Cys Tyr Lys 130 135 140 - Leu Vsl Pro VhI Glu Pro ‘“‘sp Lys Vs.1 Glu Glu Als. Asn Lys Giy Glu 145 150 155 ^ 160 Asn Thr Ser Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro 165 170 一 175 Giu Arg Glu Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His 180 ' 185 ‘ 190 His Vai Ala Arg Glu Leu His Pro Glu Tyr Phe Lys Asn Cys Thr Ser 195 200 205 ** Glu Pro Val Asp Pro Arg Leu Glu Pro Trp Lys His Pro Gly Ser Gin 210 215 ‘ 220 Pro Lys Thr Ala Cys Thr Asn Cys Tyr Cys Lys Lys Cys Cys Phe His 225 230 235 : 240 Cys Gin Val Cys Phe lie Thr Ala Ala Leu Gly lie Ser Tyr Gly Arg 245 250 255 Lys Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin Gly Ser Gin Thr His - 260 265 270 Gin Val Ser Leu Ser Lys Gin Pro Thr Ser Gin Ser Lys Gly Giu Pro 275 280 285 Thr Giy Pro Lys Glu Thr Ser Gly His His His His His His 290 295 300 -47- 本纸浪尺度適用中國國家標準(CNS ) Λ4規格(210X 297公沒) (請先閱讀背面之注意事項再填寫本頁 :裝·
、1T 499436 A? B7 五、發明説明(45 ) (2) SEQ ID NO : 26 : (i)序列特性: (A) 長度:57個鹼基基 (B) 型式:核酸 (C) 股性··單股 (D) 拓撲學··線型 · (X!)序列説明:SEQIDNO : 26 : TTCGAAACCA TGGCCGCGGA CTAGTGGCCA CCATCACCAT CACCATTAAC GGAATTC 57 (2) SEQ ID NO : 27 : (i)序列特性: (A) 長度:17胺基酸 (B) 型式:胺基酸 (C) 股性:單股 (D) 拓撲學··線型 (xi)序列説明:8£〇10 1\1〇:27:
Thr Ser Gly Kis His His His His His 經濟部中央標準局員工消費合作社印製 - 48- 本纸張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公益)
Claims (1)
- 499436經濟部中央標準局員工消費合作社印製 第87117493號專利申請案 % 中文申請專利範圍修正本(90年8月)D8 々、申請專利範圍 1· 一種Nef-Tat-His融合蛋白質,其序列如下具有 或不具有組胺酸尾部 SEQ ID NO.13 : MGGKWSKSSWGWPTVRERMRRAEPAADGVGAASRDLEKHGAITSSNTAATNAACAW LEAQEEEEVGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGLEGLIHSQRRQDILDLWI YHTQGYFPDWQNYTPGPGVRYPLTFGWCYKLVPVEPDKVEEANKGENTSLLHPVSLH GMDDPEREVLEWRFDSRLAFHHVARELHPEYFKNCTSEPVDPRLEPWKHPGSQPKTA CTNCYCKKCCFHCQVCFITKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSR GDPTGPKETSGHHHHHH. 2· —種Mef_突變Tat -His融合蛋白質,其序列如下 具有或不具有組胺酸尾部 SEQ ID NO.25 : MGGKWSKSS WGWPTVRERMRRAEPAADGVGAASRDLEKH 40 GAITSSNTAATNAACAWLEAQEEEEVGFPVTPQVPLRPMT 80 ΥΚΆΑνΌΙ^ΗΡΙ^ΚΕΚΧ^Ι^ΕΙ_ΙΙΙΙ{2〇ΙΙ^υΜ]: YHTQGY 12 0 FPDWQNYTPGPGVRYPLTFGWCYKLVPVEPDKVEEANKGE 160 ΝΤ3ϋΗΡν3Ι^Μ30ΡΕΙΙΕνΐ£ΝΗΡ03ΚΙΑΡΗΗνΑΗΕ:ίΗΡ 2 0 0 EYFKNCTSEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFH 240 CQVCFITAALGISYGRKKRRQRRRPPQGSQTHQVSLSKQP 280 TSQSKGEPTGPKETSGHHHHHH. 302 3· —種脂蛋白D-Nef-His融合蛋白質,其序列如下 具有或不具有組胺酸尾部 SEQ ID NO.15 : 本紙張尺度適用中國國家樣準(CNS ) A4規格(210X297公釐) (請先聞讀背面之注意事項再填寫本頁)499436 A8 B8 C8 D8 經濟部中央標準局員工消費合作社印製 六、申請專利範圍 CSSHSSNMANTQMKSDK 工工工 AHRGASGYLPEHTLESKALaFAQQADYLEQDLAMTKD GRLWIHDHFLDGLTDVAKKFPHRHRKDGRYYVIDFTLICEIQSLEMTENFETMGGKW S KS S WGWPTVRERMRRAE P AADGVGAASRDLEKHGAITS SNTAATNAACAWLEAQE EEEVGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGLEGLIHSQRRQDILDLWIYHTQG YFPDWQNYTPGPGVRYPLTFGWCYKLVPVEPDKVEEANKGENTSLLHPVSLHGMDDP EREVLEWRFDSRLAFHHVARELHPEYFKNCTSGHHHHHH. 4. 一種脂蛋.白D-Nef-Tat-His融合蛋白質,其序列 如下具有或不具有組胺酸尾部 SEQ ID NO· 1 7 : CSSHSSNMANTQMKSDK 工工工 AHRGASGYLPEHTLESKALAFAQQADYLEQDLAMTKD GRLWIHDHFLDGLTDVAKKFPHRHRKDGRYYVIDFTLKE 工 QSLEMTENFETMGGKW SKSSWGWPTVRERMRRAEPAADGVGAASRDLEKHGAITSSNTAATNAACAWLEAQE EEEVGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGLEGLIHSQRRQDILDLWIYHTQG YFPDWQ3MYTPGPGVRYPLTFGWCYKLVPVEPDKVEEANKGENTSLLHPVSLHGMDDP EREVLEWRFDSRLAFHHVARELHPEYFKNCTSEPVDPRLEPWKHPGSQPKTACTNCY CKKCCFHCQVCFITKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSRGDPTG PKETSGHHHHHH. 5. —種Prot D-Nef-Tat-His融合蛋白質,其序列如 下具有或不具有組胺酸尾部 SEQ ID NO.21 : MDPSSHSSNMANTQMKSDK 工工工 AHRGASGYLPEHTLESKALAFAQQADYLEQDLAMT KDGRLWIHDHFLDGLTDVAKKFPHRHRKDGRYYV 工 DFTLKEIQSLEMTENFETMGG KWSKSSWGWPTVRERMRRAEPAADGVGAASRDLEKHGAITSSNTAATNAACAWLEA QEEEEVGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGLEGL 工 HSQRRQDILDLWIYHT QGYFPDWQNYTPGPGVRYPLTFGWCYKLVPVEPDKVEEANKGENTSLLHPVSLHGMD DPEREVLEWRFDSRLAFHHVARELHPEYFKNCTSEPVDPRLEPWKHPGSQPKTACTN CYCKKCCFHCQVCFITKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSRGDP TGPKETSGHHHHHH· -2- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ——1-------- (請先閱讀背面之注意事項再填寫本頁) 訂 499436 A8 B8 C8 D8 六、申請專利範圍 6 . —種核酸,其序列如下,係編碼如申請專利範圍 第1項之蛋白質 SEQ ID NO.12 : ATGGGTGGCAAGTGGTCAAAAAGTAGTGTGGTTGGATGGCCTACTGTAAGGGAAAGA ATGAGACGAGCTGAGCCAGCAGCAGATGGGGTGGGAGCAGCATCTCGAGACCTGGAA AAACATGGAGCAATCACAAGTAGCAATACAGCAGCTACCAATGCTGCTTGTGCCTGG CTAGAAGCAGAAGAGGAGGAGGAGGTGGGTTTTCCAGTCACACCTCAGGTACCTTTA AGACCAATGACTTACAAGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGG GGACTGGAAGGGCTAATTCACTCCCAACGAAGACAAGATATCCTTGATCTGTGGATC TACCACACACAAGGCTACTTCCCTGATTGGCAGAACTACACACCAGGGCCAGGGGTC AGATATCCACTGACCTTTGGATGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAG GTAGAAGAGGCCAATAAAGGAGAGAACACCAGCTTGTTACACCCTGTGAGCCTGCAT GGAATGGATGACCCTGAGAGAGAAGTGTTAGAGTGGAGGTTTGACAGCCGCCTAGCA TTTCATCACGTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAACTGCACTAGTGAG CCAGTAGATCCTAGACTAGAGCCCTGGAAGCATCCAGGAAGTCAGCCTAAAACTGCT TGTACCAATTGCTATTGTAAAAAGTGTTGCTTTCATTGCCAAGTTTGTTTCATAACA AAAGCCTTAGGCATCTCCTATGGCAGGAAGAAGCGGAGACAGCGACGAAGACCTCCT CAAGGCAGTCAGACTCATCAAGTTTCTCTATCAAAGCAACCCACCTCCCAATCCCGA GGGGACCCGACAGGCCCGAAGGAAACTAGTGGCCACCATCACCATCACCATTAA 7. —種核酸,其序列如下,係編碼如申請專利範圍 第2項之蛋白質 SEQ ID NO.24 : 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) ATGGGTGGCAAGTGGTCAAAAAGTAGTGTGGTTGGATGGC 40 CTACTGTAAGGGAAAGAATGAGACGAGCTGAGCCAGCAGC 80 AGATGGGGTGGGAGCAGCATCTCGAGACCTGGAAAAACAT 120 GGAGCAATCACAAGTAGCAATACAGCAGCTACCAATGCTG 160 CTTGTGCCTGGCTAGAAGCACAAGAGGAGGAGGAGGTGGG * 200 TTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATGACT 240 TACAAGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAA, 280 AGGGGGGACTGGAAGGGCTAATTCACTCCCAACGAAGACA 3 2 0 AGATATCCTTGATCTGTGGATCTACCACACACAAGGCTAC 3 60 TTCCCTGATTGGCAGAACTACACACCAGGGCCAGGGGTCA 40 0 -3- 本紙張尺度逋用中國國家標準(CNS ) A4規格(2iOX 297公釐) 499436 A8 B8 C8 D8 六、申請專利範圍 GATATCCACTGACCTTTGGATGGTGCTACAAGCTAGTACC 44 0 AGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAAGGAGAG 48 0 AACACCAGCTTGTTACACCCTGTGAGCCTGCATGGAATGG 52 0 ATGACCCTGAGAGAGAAGTGTTAGAGTGGAGGTTTGACAG 560 CCGCCTAGCATTTCATCACGTGGCCCGAGAGCTGCATCCG 600 GAGTACTTCAAGAACTGCACTAGTGAGCCAGTAGATCCTA 64 0 GACTAGAGCCCTGGAAGCATCCAGGAAGTCAGCCTAAAAC 680 TGCTTGTACCAATTGCTATTGTAAAAAGTGTTGCTTTCAT 720 TGCCAAGTTTGTTTCATAACAGCTGCCTTAGGCATCTCCT 760 ATGGCAGGAAGAAGCGGAGACAGCGACGAAGACCTCCTCA 800 AGGCAGTCAGACTCATCAAGTTTCTCTATCAAAGCAACCC 840 ACCTCCCAATCCAAAGGGGAGCCGACAGGCCCGAAGGAAA 880 CTAGTGGCCACCATCACCATCACCATTAA 909 8 . —種核酸,其序列如下,係編碼如申請專利範圍 第3項之蛋白質 SEQ ID NO.14 : ATGGATCCAAAAACTTTAGCCCTTTCTTTATTAGCAGCTGGCGTACTAGCAGGTIGT AGCAGCCATTCATCAAATATGGCGAATACCCAAATGAAATCAGAC-AAAATCATTATT GCTCACCGTGGTGCTAGCGGTTATTTACCAGAGCATACGTTAGAATCTAAAGCACTT GCTTTTGCACAACAGGCTGATTATTTAGAGCAAGATTTAGCAATGACTAAGGATGGT CGTTTAGTGGTTATTCACGATCACTTTTTAGATGGCTTGACTGATGTTGCGAAAAAA TTCCCACATCGTCATCGTAAAGATGGCCGTTACTATGTCATCGACTTTACCTTAAAA GAAATTCAAAGTTTAGAAATGACAGAAAACTTTGAAACCATGGGTGGCAAGTGGTCA AAAAGTAGTGTGGTTGGATGGCCTACTGTAAGGGAAAGAATGAGACGAGCTGAGCCA GCAGCAGATGGGGTGGGAGCAGCATCTCGAGACCTGGAAAAACATGGAGCAATCACA AGTAGCAATACAGCAGCTACCAATGCTGCTTGTGCCTGGCTAGAAGCACAAGAGGAG 經濟部中央標率局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) GAGGAGGTGGGTTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATGACTTACAAG GCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCTAATT CACTCCCAACGAAGACAAGATATCCTTGATCTGTGGATCTACCACACACAAGGCTAC TTCCCTGATTGGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCACTGACCTTT GGATGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAA GGAGAGAACACCAGCTTGTTACACCCTGTGAGCCTGCATGGAATGGATGACCCTGAG AGAGAAGTGTTAGAGTGGAGGTTTGACAGCCGCCTAGCATTTCATCACGTGGCCCGA GAGCTGCATCCGGAGTACTTCAAGAACTGCACTAGTGGCCACCATCACCATCACCAT TAA -4-本紙張尺度適用中國國家標準(CNS ) A4規格(2i〇X297公釐) 499436 A8 BB C8 D8 六、申請專利範圍 9. 一種核酸,其序列如下,係編碼如申請專利範圍 第4項之蛋白質 SEQ ID NO. 1 6 : [TGCGAAAAAA [•TACCTTAAAA 請 先 閱 讀 背 dr 之 注 意 事 項 再 填 禽 本 頁 ATGGATCCAAAAACTTTAGCCCTTTCTTTATTAGCAGCTGGCGTACTAGCAGGTTGT AGCAGCCATTCATCAAATATGGCGAATACCCAAATGAAATCAGACAAAATCATTATT GCTCACCGTGGTGCTAGCGGTTATTTACCAGAGCATACGTTAGAATCTAAAGCACTT GCGTTTGCACAACAGGCTGATTATTTAGAGCAAGATTTAGCAATGACTAAGGATGGT CGTTTAGTGGTTATTCACGATCACTTTTTAGATGGCTTGACTGATGTT TTCCCACATCGTCATCGTAAAGATGGCCGTTACTATGTCATCGACTT,1 GAAATTCAAAGTTTAGAAATGACAGAAAACTTTGAAACCATGGGTGGCAAGTGGTCA AAAAGTAGTGTGGTTGGATGGCCTACTGTAAGGGAAAGAATGAGACGAGCTGAGCCA GCAGCAGATGGGGTGGGAGCAGCATCTCGAGACCTGGAAAAACATGGAGCAATCACA AGTAGCAATACAGCAGCTACCAATGCTGCTTGTGCCTGGCTAGAAGCACAAGAGGAG GAGGAGGTGGGTTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATGACTTACAAG GCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCTAATT CACTCCCAACGAAGACAAGATATCCTTGATCTGTGGATCTACCACACACAAGGCTAC TTCCCTGATTGGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCACTGACCTTT GGATGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAA GGAGAGAACACCAGCTTGTTACACCCTGTGAGCCTGCATGGAATGGATGACCCTGAG AGAGAAGTGTTAGAGTGGAGGTTTGACAGCCGCCTAGCATTTCATCACGTGGCCCGA GAGCTGCATCCGGAGTACTTCAAGAACTGCACTAGTGAGCCAGTAGATCCTAGACTA GAGCCCTGGAAGCATCCAGGAAGTCAGCCTAAAACTGCTTGTACCAATTGCTATTGT AAAAAGTGTTGCTTTCATTGCCAAGTTTGTTTCATAACAAAAGCCTTAGGCATCTCC TATGGCAGGAAGAAGCGGAGACAGCGACGAAGACCTCCTCAAGGCAGTCAGACTCAT CAAGTTTCTCTATCAAAGCAACCCACCTCCCAATCCCGAGGGGACCCGACAGGCCCG AAGGAAACTAGTGGCCACCATCACCATCACCATTAA 經 濟 部 中 央 標 準 局 員 工 消 費 合 作 社 10. —種核酸,其序列如下,係編碼如申請專利範圍 第5項之蛋白質 SEQ ID NO.20 : ATGGATCCAAGCAGCCATTCATCAAATATGGCGAATACCCAAATGAAATCAGACAAA ATCATTATTGCTCACCGTGGTGCTAGCGGTTATTTACCAGAGCATACGTTAGAATCT AAAGCACTTGCGTTTGCACAACAGGCTGATTATTTAGAGCAAGATTTAGCAATGACT AAGGATGGTCGTTTAGTGGTTATTCACGATCACTTTTTAGATGGCTTGACTGATGTT -5-本紙張尺度適用中國國家標準(CNS > A4規格(2H)X:W公釐) 499436 A8 B8 C8 D8 六、申請專利範圍 GCGAAAAAATTCCCACATCGTCATCGTAAAGATGGCCGTTACTATGTCATCGACTTT ACCTTAAAAGAAATTCAAAGTTTAGAAATGACAGAAAACTTTGAAACCATGGGTGGC AAGTGGTCAAAAAGTAGTGTGGTTGGATGGCCTACTGTAAGGGAAAGAATGAGACGA GCTGAGCCAGCAGCAGATGGGGTGGGAGCAGCATCTCGAGACCTGGAAAAACATGGA GCAATCACAAGTAGCAATACAGCAGCTACCAATGCTGCTTGTGCCTGGCTAGAAGCA CAA.GAGGAGGAGGAGGTGGGTTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATG ACTTACAAGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAA GGGCTAATTCACTCCCAACGAAGACAAGATATCCTTGATCTGTGGATCTACCACACA CAAGGCTACTTCCCTGATTGGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCA CTGACCTTTGGATGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAG GCCAATAAAGGAGAGAACACCAGCTTGTTACACCCTGTGAGCCTGCATGGAATGGAT GACCCTGAGAGAGAAGTGTTAGAGTGGAGGTTTGACAGCCGCCTAGCATTTCATCAC GTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAACTGCACTAGTGAGCCAGTAGAT CCTAGACTAGAGCCCTGGAAGCATCCAGGAAGTCAGCCTAAAACTGCTTGTACCAAT TGCTATTGTAAAAAGTGTTGCTTTCATTGCCAAGTTTGTTTCATAACAAAAGCCTTA GGCATCTCCTATGGCAGGAAGAAGCGGAGACAGCGACGAAGACCTCCTCAAGGCAGT CAGACTCATCAAGTTTCTCTATCAAAGCAACCCACCTCCCAATCCCGAGGGGACCCG ACAGGCCCGAAGGAAACTAGTGGCCACCATCACCATCACCATTAA 11· 一種疫苗,其包括根據申請專利範圍第1至5項 中任一項之蛋白質。 12·根據申請專利範圍第1 1項之疫苗,其係摻和以 藥學上可接受之賦形劑。 13·根據申請專利範圍第1 1項之疫苗,其另外含有 佐劑。 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 14·根據申請專利範圍第13項之疫苗,其中的佐劑 是Τ Η 1謗導佐劑。 15. 根據申請專利範圍第1 3或1 4項之疫苗,其中佐 劑包括單磷醯基脂質Α或其衍生物,如3去-0 -醯化之單磷醯基脂質A。 16. 根據申請專利範圍第! 3或1 4項之疫苗,其另夕卜 -6 -本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 499436 A8 B8 C8 D8 申請專利範圍 含有急素佐劑 — - —— 一——#! (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)
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GBGB9720585.0A GB9720585D0 (en) | 1997-09-26 | 1997-09-26 | Vaccine |
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ES2123062T3 (es) * | 1992-08-21 | 1999-01-01 | Biogen Inc | Polipeptidos de transporte derivados de la proteina tat. |
NZ262582A (en) * | 1993-01-26 | 1997-10-24 | David B Weiner | Compositions and methods for delivery of genetic material |
EP0814834B2 (fr) * | 1995-03-08 | 2009-03-18 | Neovacs | Immunogenes denues de toxicite derivant d'une proteine de regulation retrovirale, anticorps diriges contre ces immunogenes, procede pour leur preparation et compositions pharmaceutiques les renfermant |
GB9720585D0 (en) * | 1997-09-26 | 1997-11-26 | Smithkline Beecham Biolog | Vaccine |
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1997
- 1997-09-26 GB GBGB9720585.0A patent/GB9720585D0/en not_active Ceased
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1998
- 1998-09-17 EP EP98952625A patent/EP1015596B2/en not_active Expired - Lifetime
- 1998-09-17 CN CNB988114321A patent/CN1188519C/zh not_active Expired - Fee Related
- 1998-09-17 JP JP2000513953A patent/JP2001518300A/ja not_active Withdrawn
- 1998-09-17 DK DK98952625.6T patent/DK1015596T4/da active
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- 1998-09-17 WO PCT/EP1998/006040 patent/WO1999016884A1/en active IP Right Grant
- 1998-09-17 NZ NZ503482A patent/NZ503482A/en not_active IP Right Cessation
- 1998-09-17 AU AU10255/99A patent/AU746564B2/en not_active Ceased
- 1998-09-17 DE DE69835756T patent/DE69835756T3/de not_active Expired - Lifetime
- 1998-09-17 HU HU0004896A patent/HUP0004896A3/hu unknown
- 1998-09-17 PT PT98952625T patent/PT1015596E/pt unknown
- 1998-09-17 ES ES98952625T patent/ES2272012T5/es not_active Expired - Lifetime
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- 1998-09-17 IL IL13510298A patent/IL135102A0/xx not_active IP Right Cessation
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- 1998-09-24 AR ARP980104779A patent/AR017147A1/es active IP Right Grant
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- 1998-10-22 TW TW087117493A patent/TW499436B/zh not_active IP Right Cessation
- 1998-12-15 SA SA98190877A patent/SA98190877B1/ar unknown
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2000
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2007
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2009
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2011
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