TW515715B - Vaccine compositions having immunologically active QS21 - Google Patents

Vaccine compositions having immunologically active QS21 Download PDF

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TW515715B
TW515715B TW85104841A TW85104841A TW515715B TW 515715 B TW515715 B TW 515715B TW 85104841 A TW85104841 A TW 85104841A TW 85104841 A TW85104841 A TW 85104841A TW 515715 B TW515715 B TW 515715B
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vaccine composition
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Nathalie Marie-Josephe Garcon
Martin Friede
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Smithkline Beecham Biolog
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Description

經濟部中央標準局員工消費合作社印製 515715 A7 B7 五、發明説明（3 ) A，也稱爲3D-MPL)。由英國專利第2 220 211號（Ribi)得知， 3D-MPL就像三種類型的De_0-醯基化之單磷酸脂A與4、5或 酉&基化鏈的混合物一樣，並由Ribi Immunochem，Montana製 造。較佳的形式揭示於國際專利申請案第92/116556號中。 本發明中適當的組合物，是其中開始製備微脂粒時不含 MPL，然後再加入MPL的那些，而MPL最好是100毫微米的 顆粒。因此在囊膜之中不含有MPL(稱爲MPL在外）。其中含 有在囊膜之内的MPL之組合物（稱爲MPL在内），也形成本發 明的目標。所含有的抗原可在囊膜之内或在囊膜之外。較 好是可溶解的抗原在外側，而忌水性或經過脂化之抗原則 可包含在囊膜之内或其外側。 通常本發明之疫苗不需要任何特定的載劑，並在含水的 或其他藥學可接受之緩衝溶液中調配。在一些案例中，本 發明之疫苗進一步含有明蓉或存在於水包油型乳劑或其他 適當的媒劑中，可能是有利的，該適當媒劑像是例如微脂 粒、中心體或經過包膠的抗原顆粒。 較佳的疫苗調配物將含有能夠謗發對抗人類或動物病原 之免疫反應的抗原或抗原組合物。在本發明之組合物中， 可使用此項技藝中已知的抗原或抗原组合物，包括多醣抗 原、衍生自HIV-1 (諸如gpl20或gpl60等）的抗原或抗原組合物 、任何的免疫缺乏病毒、人類或動物的苑療病毒，諸如 gD或其衍生物，或是速早蛋白，如得自HSV1或HSV2的 ICP27、巨細胞病毒（特別是人類的）(如gB或其衍生物）、帶 狀水痘病毒（如gpl、II或III)，或肝炎病毒之形式，如B型肝 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) -------訂-- 515715 A7 B7 五、發明説明（4 ) (請先閲讀背面之注意事項再填寫本頁) 炎病毒，例如B型肝炎表面抗原或其衍生物、A型肝炎病毒 、C型肝炎病毒和E型肝炎病毒，或其他病毒病原之形式， 如呼吸道融合細胞病毒（例如揭示於美國專利5,149,650號中 的HSRV F和G蛋白及其免疫原性之片段，或揭示於美國專 利第5,194,595號中，含有得自1181^蛋白質？和(3，6§?0糖蛋 白的嵌合多肽類）、衍生自腦膜炎品系的抗原，如腦膜炎A 、8和C，肺炎鏈球菌、人類乳頭狀瘤病毒、流行性感冒病 毒、嗜血性流行性感冒B(Hib)、愛氏頓病毒（EBV)，或衍生 自細菌性病原者，如沙門桿菌屬、奈瑟球菌屬、螺旋體屬 (Borrelia)(例如OspA或OspB或其衍生物），或是衣形菌屬或博 德氏菌屬，例如P.69、PT和FHA，或衍生自寄生蟲者，如瘧 原蟲或毒漿體（toxoplasma)。 經濟部中央標準局員工消費合作社印製 HSV糖蛋白D(gD)或其衍生物是較佳的疫苗抗原。它位在 病毒膜上，亦在受感染之細胞的細胞質中發現它（Eisenberg R.J.等人；J of Virol 1980拉428-435)。其由393個胺基酸構 成，包括一個信號肽，並具有大約60kD的分子量。大概所 有HSV被膜糖蛋白均具有最佳的特性(Cohen等人J. Virology ㊇157-166)。在活體内，已知其在病毒附著細胞膜時扮演主 要的角色。然而，已經顯示糖蛋白D能夠在活體内謗發中 和抗體，並保護動物免於致命的挑戰。截短形式之gD分子 缺乏C終端的固定區域，並可在哺乳動物細胞中以可溶性 蛋白質之形式產製，再將其輸出到細胞培養基的上清液中 。這類可溶性形式的gD是較佳的。在歐洲專利0,1 3 9，4 1 7 號中描述了截短形式之gD的產製。gD最好是衍生HSV-2 -7- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 515715 A7 B7 五、發明説明（5 ) 。本發明的一個具體實施例爲具有3 0 8個胺基酸的經過截 短之H S V - 2糖蛋白D，其包括含有從1到3 0 6之天然存在的 胺基酸的糖蛋白，並在經過截短、缺乏其膜固定區域之蛋 白質的C終端處帶有額外的天冬醯胺和穀胺醯胺。這種形 式之蛋白質包含了信號肽，將其切開以容許從宿主細胞中 分泌出成熟的可溶性2 8 3胺基酸蛋白質。 在本發明另外的觀點中，Β型肝炎表面抗原也是較佳的疫 苗抗原。 當此處使用ΠΒ型肝炎表面抗原”或"HBsAg”之措辭時，包 括任何HBsAg抗原或其表現出HBV表面抗原之抗原性的片段 。將瞭解到，除了 226個胺基酸序列的HBsAg抗原（參見 Tiollais等人，Nature，317，489(1985)並在此作爲參考）之外 ，如同此文中描述的HBsAg，若需要可含有全部或部份的 在上述參考文獻中和在歐洲專利-A-0 278 940號中描述的-S 前序列。特定而言，HBsAg可包括含有下列胺基酸序列的 多肽，該胺基酸序列包括在ad血清型之B型肝炎病毒上，與 打開密碼有關之HBsAg的L-蛋白質的殘基12-52，隨後是殘 基133-145，再來是殘基175-400(該多肽也叫作L* ;參見歐洲 專利0 414 374號）。在本發明範圍内的HBsAg也可以包含歐 洲專利0 198 474號中描述的-S1-S2-S多肽（Endotronics)及其密 切類似物，如歐洲專利0 304 578號中描述的那些（Me Cormick和Jones)。此處描述之HBsAg也可以適用於突變體， 例如描述於WO91/14703或歐洲專利申請案第0 51 1 855A1號 中的1逃逸突變體’，特別是其中在位置145處有由甘胺酸對 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) ---II-----. 515715 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（6 精胺酸進行胺基酸取代的HBsAg。 HBsAg通常是顆粒形式的。顆粒可能僅含有例如蛋白質 ，或可以是综合的顆粒，例如（L*，S)，其中L*如同上述之 定義，且S代表HBsAgi S_蛋白質。該顆粒以此形式可有利 地在酵母中表現出來。 令人滿意地證明了 B型肝炎表面抗原S-蛋白質的製備。參 見例如 Harford等人（1983)，在 Develop. Biol. Standard 54，第 125 頁中、Gregg等人（1987)，在Biotechnology 5，第 479 頁中、 歐洲專利0 226 846號、歐洲專利0 299 108號，並在此作爲參考。 在本發明範圍中的調配物也可以含有抗-腫瘤的抗原，並 在免疫治療上用來治療癌症。 疫苗製品通常描述於Voller等人編輯的New Trends and Developments in Vaccines，University Park Press，Baltimore ’ Maryland，U.S.A. 1987中。包膠到微脂粒中的作用則由例如 Fullerton描述於美國專利第4,235,877號中。蛋白質對巨分子 的共軏作用則由例如Likhite描述於美國專利第4,372,945號中 ，以及由Armor等人描述於美國專利第4,474，了57號中。 在每個疫苗劑量中蛋白質的用量，係按照在典型免疫反 應中能引起免疫保護反應，但沒有重大不利之副作用的用 量來選擇。這類用量將依據所使用的特定免疫原及其如何 表達來加以改變。通常期望每個劑量將含有卜1 000mCg的 蛋白質，較佳的是2-l〇〇mcg，最好是4_40mcg。特殊疫 苗的最佳用量，可藉著涉及在患者身上觀察適當之免疫反 應的標準研究來探知。在最初的疫苗接種之後’可使患者 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)
經濟部中央標準局員工消費合作社印製 515715 A7 __— —____B7 五、發明説明（7 ) 接雙一或數次保持適當間隔的補強免疫作用。 本發明之調配物或許可用於預防和治療兩種目的中。 根據更進一步的觀點，因此本發明提供本發明之疫苗在 治療人類患者方面的用途。本發明提供一種治療方法，其 包括對患者投予有效量的本發明之疫苗。特定而言，本發 明提供一種治療病毒、細菌、寄生蟲感染或癌症的方法， 其包括對患者投予有效量的本發明之疫苗。 以下列實例和數據解釋本發明。 實例 1.1製備微脂粒的方法： 在眞空下（或另外在惰性氣體的蒸氣下），使在有機溶劑 中的脂質（諸如得自卵黃或合成的磷脂醯膽鹼）與膽固醇的混 合物脱水。然後加入含水的溶液（如磷酸緩衝的生理鹽水）， 並搖動容器，直到所有的脂質均懸浮爲止。然後使該懸浮 液微流體化，直到微脂粒的大小減少到1 00毫微米爲止，並 通過0.2微米之濾紙進行無菌過濾。擠壓或聲波振盪可取代 此一步驟。 通常膽固醇：磷脂醯膽鹼的比例爲1 : 4(重量/重量），益 加入含水的溶液，而獲得5到50毫克/毫升的終膽固醇濃度 。如果在含有脂質的有機溶液中，加入在有機溶液中的 MPL ’則最後的微脂粒在膜中會含有]VIPL(稱爲MPL在内）。 具有100毫微米之限定大小的微脂粒，被稱爲SUV(小的單層 囊泡）。若重複冷凍並融解該溶液，囊泡合會融合而形成的 大的多層結構（MLV)，其具有從500毫微米到15微米之大小 -10-
________________^^J 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) -----_---訂-----▲ 515715 A7 B7 五、發明説明（8 ) 經濟部中央標準局員工消費合作社印製 。微脂粒本身對於時間而言是穩定的，且沒有融合的能力 〇 1·2調配物程序： 在微脂粒中加入在含水之溶液中的QS21。然後將該混合 物加至抗原溶液中，如果需要其可含有以1〇〇亳微米顆粒之 形式存在的MPL。 1 · 3藉著含有膽固醇的微脂粒，抑制QS21的溶解活性 當將QS21加至紅血球中時，紅血球溶解而釋出紅血素。 每種溶解活性也可以利用在其膜内含有膽固醇的微脂粒和 被捕捉的螢光染料，羧基螢光素來測定之―當微脂粒被溶 解而釋放出可由螢光光譜監視的染料。若螢光微脂粒在其 膜中未含有膽固醇，則沒有觀察到微脂粒的溶解作用。八 如果在將QS21加至紅血球之前，先將㈨幻與含有膽固醇 的微脂粒一起培養，則紅血球的溶解會隨著膽固醇對qs21 之比例而減少。若使用〗：Ϊ之比例，則檢測不到溶解活性 。若微脂粒不含膽固醇，則抑制溶解作用需要超過卜 1000倍過量的磷脂。 同樣適用於使用螢光微脂粒來測定溶解活性。在下圖中 ，以螢光來測定經利用缺乏膽固醇（每赛 _ 回 、巧Γ毛升含1耄克的卵黃 卵磷脂）或含有膽固醇（每毫升含1毫克卵磕 、 ^ I ,脂和500微克膽固 醇）之微脂粒處理過的4微克QS2!之溶解、、舌座 (請先閱讀背面之注意事項再填寫本頁) 訂 -11 - 各紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 515715 A7 _ B7 五、發明説明（1G) (請先閲讀背面之注意事項再填寫本頁) 著在逆相HPLC上測量符合QS21之峰値的減少來監視之。例 如，下圖顯示在pH値9和溫度37°C，90%的QS21會在16小時 内水解。如果以2 : 1之比例（膽固醇：QS21重量/重量）在 QS21中加入含有膽固醇的微脂粒，則在同樣的條件下未檢 測出QS21的水解。如果該比例爲1 : 1，則有10%的QS21會 降解。 在37°C下在含有膽固醇之SUV的存在下，在 pH値9下培養2〇微克QS21 16小時
經濟部中央標準局員工消費合作社印製 結論是當QS21與含有膽固醇之微脂粒連結時，它會變的 較不易受到鹼-調節之水解作用的影響。當以非經腸方式給 予時，水解產物被描述爲不具佐劑活性，因此含有QS21的 疫苗必須在酸性的p Η値下調製，並存放在4 °C下來保護佐 劑組合物。而微脂粒的使用可以克服此一需求。 1 . 5反應原性之研究： -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 515715 A7 B7 五、發明説明（11 ) 在老鼠脛骨肌中注射5微克QS21(或毛地黃皂甞），加上漸 增量的微脂粒（以換算成膽固醇的微克量來表示之）。以相 當於QS21的微克量來表示溶解活性，其意指達到與試樣相 同的溶血所需的QS21量。 在肌肉注射部位的發紅、壞死和毒性，在犧牲老鼠之後 以目視記錄之。 調配物 溶解活性微克 發紅 壞死 毒性 QS21+PBS 5 +++ 士 +++ QS21+1微克膽固醇(SUV) 4 -H-+ + ++++ QS21 +5微克膽固醇(SUV) 0 麵 士 QS21 +25微克膽固醇(SUV) 0 土 + 僅有SUV 0 画 一 一 毛地黃皂甞 5 讀 土 PBS 0 一 麵 幢 數據顯示，當藉著添加含有膽固醇的微脂粒而廢除了溶 解活性時，因QS21而引起之毒性也被廢除了。 經濟部中央標準局員工消費合作社印製 1 . 6在兔子身上以肌肉内注射時的反應原性 U.I./L中的値 -14- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 515715
7 B 五、發明説明（12 ) 經濟部中央標準局員工消費合作社印製 實驗 調配物 第0天 溶血 第1天 溶血 第3天 溶血 兔子編號1 1078 + 8650 1523 兔子編號2 1116 4648 1435 兔子編號3 QS21 50微克 660 4819 684 兔子編號4 592 5662 684 兔子編號5 3400 7528 1736 平均値 1369 6261 1212 標準差 1160 1757 495 實驗 調配物 第0天 溶血 第1天 溶血 第3天 溶血 兔子編號6 596 1670 460 兔子编號7 QS21 50微克 540 602 594 兔子編號8 在SUV中的膽 611 1873 803 兔子編號9 固醇50微克 521 507 616 兔子編號10 (1:1) 1092 + 787 555 平均値 672 1088 606 標準差 238 636 125 (請先閲讀背面之注意事項再填寫本頁) -15-本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 515715 A7 B7五、發明説明（13 ) 實驗 調配物 第0天 溶血 第1天 溶血 第3天 溶血 兔子編號11 332 344 387 兔子編號12 QS21 50微克 831 662 694 兔子編號13 在SUV中的膽 464 356 519 兔子編號14 固醇150微克 528 720 614 兔子編號15 (1:3) 1027 568 849 平均値 637 530 613 標準差 285 173 175 經濟部中央標準局員工消費合作社印製 實驗 調配物 第0天 溶血 第1天 溶血 第3天 溶血 兔子編號16 540 769 745 兔子編號17 QS21 50微克 498 404 471 兔子編號18 在SUV中的膽 442 717 (4535) 兔子編號19 固醇250微克 822 801 925 兔子編號20 (1:5) 3182 土 2410 960 平均値 1097 1020 775 (1527) 標準差 1175 793 224 (1692) -16- (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（210X297公釐） 515715 A7 B7 五、發明説明（14 ) 實驗 調配物 第0天 溶血 第1天 溶血 第3天 溶血 兔子編號21 321 290 378 兔子編號22 660 535 755 兔子編號23 PBS 650 603 473 兔子編號24 1395 (3545) (5749) 兔子編號25 429 土 323 263 平均値 691 438 (1059) 467 (1523) 標準差 419 155 (1396) 210 (2369) (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 數據顯示，在調配物中添加含有膽固醇的微脂粒，明顯 地減少了由QS21所引之CPK(磷酸肌酸酶）的高度。因爲 CPK增加是肌肉損傷的程度，這表示降低了肌肉的損傷， 並藉著组織病理學來證實。 1。7微脂粒-QS21複合物對明礬的結合。 將QS21與含有過量膽固醇和具放射線活性之膽固醇的中 性微脂粒一起培養，然後與在PBS中的明礬（A1(0H)3)—起培 養。當單獨的時候，中性的微脂粒或QS21皆不與P B S中的 明礬結合，而只有帶負電荷的微脂粒與之結合。然而當同 時在一起時，QS21和中性微脂粒均與明礬結合。上清液中 不含QS21(藉著地衣酚試驗來分析），也不含具放射線活性 的膽固醇。 這顯示QS21已經與微脂粒結合，並允許微脂粒-QS21的組 合與明礬結合。這可能起因於QS21將負電荷加在微脂粒上 -17- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 515715 A7 B7 五、發明説明（15 ) ，或是暴露出微脂粒上的忌水性區域。結果也暗示QS21未 從膜中引出膽固醇。 (請先閲讀背面之注意事項再填寫本頁) 這表示本發明之組合物可被用在以明礬爲基礎的疫苗中 〇 1.8就抗體和CMI的謗導，比較微脂粒之QS21/MPL和自由的 QS21+MPL藉著壓擠來製備SUV (EYPC :膽固醇：MPL 20 : 5 : 1)。 關於MPL在外，製備不含MPL的微脂粒，再加入100毫微 米之顆粒大小的MPL。 在加入抗原之前先加入QS21。膽固醇：QS21=5 : 1 (重量 /重量）。 藉著在加入抗原之前，先將SUV冷凍-融解三次，來製造 MLV。 爲了要使抗原被捕捉，在冷凍-融解之前先加入抗原，並 在冷凍-融解之後再加入QS21。抗原包膠作用=5%在内， 95%在外。 經濟部中央標準局員工消費合作社印製 -在老鼠的腳蟄中注射兩次（關於gD使用balb/c品系的老鼠， 關於RTSs則使用B10BR品系的老鼠）。gD爲得自單純疱疹病 毒的糖蛋白D。RTSs爲以基因方式修改的B型肝炎表面抗原 (HBsAg)，而使其含有來自鐮狀癔原蟲（Plasmodiium falciparum)種蟲的抗原決定位。 -18- 本紙張尺度適用中國國家標準（CNS ) A4規格（210'〆297公釐） 515715
A B 五、發明説明（16) 經濟部中央榡準局員Η消費合作衽印製
Ag(抗原)=1〇微克RTSs 抗HBsAg力價 在補強之後15天 調配物 IgGl IgG2a IgG2b SUV/QS+MPL(在外） +Ag 1175 10114 71753 MLV/QS+MPL(在外） +Ag 2247 11170 41755 MLV/QS+MPL(在内） +Ag 969 7073 18827 MLV/QS+MPL(在内)/Ag(在内)+Ag 1812 2853 9393 QS+MPL +Ag 372 9294 44457 Ag <100 <100 <100 SUV/QS+MPL (在外） <100 <100 <100 MLV/QS/MPL (在内） <100 <100 <100
Ag(抗原)=20微克gD 抗gD CMI 調配物 IgG IFN-，96 小時 (微微克/毫升） IL2 48小時 (微微克/毫升） SUV/QS+MPL(在外） +Ag 2347 1572 960 SUV/QS+MPL(在内） +Ag 2036 1113 15 MLV/QS+MPL(在外） +Ag 1578 863 15 MLV/QS+MPL(在内） +Ag 676 373 15 MLV/QS+MPL(在内)/Ag(在内)+Ag 1064 715 15 QS+MPL +Ag 1177 764 15 Ag <100 567 44 SUV/QS+MPL (在外） <100 181 15 MLV/QS/MPL (在内） <100 814 105 (請先閲讀背面之注意事項再填寫本頁) -19-本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 515715 A7 B7 五、發明説明（17) (請先閱讀背面之注意事項再填寫本頁) 該數據顯示SUV/QS+MPL(在外），謗導出至少像qS21+mPL 一樣好的高抗體力價，以及謗導出細胞調節免疫的標記 IL 2，同時譽抑了 QS21的反應原性。 另外的結果顯示於下’遠結果係得自balb/c老鼠身上，以 HSV gD作爲抗原，比較QS21與在膽固醇（SUV)存在下的 QS21 : 同型第II次之後7天 調酉嫩 ίηΜ 第欠嫌天 (GMT) 第1D欠之後14天 (GMT) IgGl 微嫌斤 % IgG2a 微綠斤 % IgG2b % SUV/QS21+MPL 在外 gp&m 20290 16343 331 26 716 56 222 17 SUV/QS21/MPL 在内 gD(5f敗克) 12566 10731 418 44 412 44 111 12 QS21+MPL gD»克) 10504 10168 200 34 285 48 107 18 SUV/QS21+MPL 在外 無 0 0 0 0 0 0 0 0 QS21 gD(5f版克) 3468 4132 156 66 67 28 14 6 SUV/QS21 gD (滅) 11253 11589 484 57 304 36 65 8 1.9比較gpl20加微脂粒的MPL/QS21與自由的MPL/QS21 微脂粒=SUV在膜中含有MPL 膽固醇：QS21=6 : 1 在一次免疫接種之後兩週測試其反應 經濟部中央標準局員工消費合作社印製 調配物 增殖 IFN-g 毫微克/毫升 IL2 微微克/毫升 IL5 微微克/毫升 SUV/MPL/QS21+Ag 12606 16.6 59 476 MPL+QS21+Ag 16726 15.8 60 404 -20- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X297公釐） 經濟部中央標準局員工消費合作社印製 515715 A7 B7 五、發明説明（19 ) 這證實僅有QS21可謗導出CTL活性，而在含有膽固醇之微 脂粒的存在下，QS21謗導出至少和僅有QS21—樣好或更好 的CTL活性。 2 .疫苗 2.1 HBsAg L*，S顆粒的調配物 可依照下列方式來調製HBsAgL*，S顆粒： 在室溫下，在攪動之下培養10微克HBsAg L*，S顆粒/劑量1小 時。利用注射用水和PBS溶液來調整體積，達到帶有QS21水 溶液（10微克/劑量）的70微升/劑量之終體積。pH値保持在7土 0.5 〇 可利用1和5 0微克HBsAg L*，S來製備類似的調配物，亦使 用HBsAg S4元原。 可在Woodchuck代用品治療模式中測試這些調配物，利用 Woodchuck HBV抗原作爲模型。
Woodchuck 模式 可在Woodchuck治療模式中測試DQ QS21(也就是QS21/膽固 醇或受到壓抑的QS21)，在其中以病毒慢性地感染動物。可 加入特定的Woodchuck肝炎病毒疫苗，與QS21本身，或是帶 有或不帶有MPL的DQ混合，並每個月投予動物一共6個月。 可經由病毒DNA清除作用來評估疫苗的效力。 2.2天竺鼠模式（HSV) 2.2.1預防模式 一組1 2隻雌性的Hartley天竺鼠，在第0天和第28天肌肉内 注射下列的調配物： -22- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁)
515715 A7 B7 五、發明説明（2G ) 第一個實驗： (請先閲讀背面之注意事項再填寫本頁) gD 5微克+QS21 50微克+含有50微克膽固醇的SUV gD 5微克+QS21 100微克+含有100微克膽固醇的SUV gD 5微克+QS21 50微克+含有250微克膽固醇的SUV gD 5微克+QS21 50微克 第二個實驗： §0 5微克+1^1?1^12.5微克+(^2112.5微克+含有62.5微克膽固 醇的SUV，或保留不加以處理。 在第二次免疫接種後第14和28天時將動物放血，並對其 gD-特異性之ELISA抗體力價進行血清測試。 然後利用1〇5 pfu個HSV-2MS品系，以陰道内之方式來挑戰 這些動物。從4到12天，每天對主要痕療病變的評估計分。 計分方式如下·· 陰道病變： -出血=0.5 -發紅一或兩天，但未出血=0.5 -發紅且出血一天=1 -發紅但未出血，持續3天=1 外部的疱疹水泡： 經濟部中央標準局員工消費合作社印製 -<4個小水泡=2 ->=4個小水泡或一個大水泡=4，>=4個大的病變=8，匯合的 大病變=16 •在整個外生殖器區域均有匯合的大病變=32。 結果顯示於下表中： -23- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 515715 A7 B7 五、發明説明（21 經濟部中央標準局員工消費合作社印製 Η-^ 1—A H-A ^ Η-A μ to to Ν> 一 bJ VI crq ciq 〇Q oq ^ σ σ σ σ 才、、' W % χ /Ο Ο /Ο /Ο E3 X GO CO OD 〇 ύ§ cn cn Ln cri t ??i > ^ ^ > Ο Ο Λ nr sr g. a a 〇 K ^ S ^ 沒有病變 的動物之 百分比 ° 〇 〇〇 i 陰道病變 發生率的 百分比 ui ^ 〇 SS ^ ^卜部病變 發生率的 百分比 馋2 * ,sgss 對對照組 的降低率 1__ 1.50 2.50 0.75 55.00 病變嚴 ,......_ 中間値 v〇 〇\ » as iirttli VW 口 * 物 丨+m 颯 s XTL < %% (請先閲讀背面之注意事項再填寫本頁) ----：---Ϊ1Τ------- -24- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 515715 A7 B7 五、發明説明（22 ) 經濟部中央標準局員工消費合作社印製 * 私韌淞菸4^12^3:孰飧茸今容箨命(^<%麵涔斜孰)«容》參)0 孰濰孳今”龄孰飧(0二醪麻孰飧(0.5涔1了岑者泠鉍夭浚(2-4“8^16) ** 澳淞鈦犛=翁命(鄭斤今»:ix(lf^^%)；3ii=0-0.5 1r2 4 4 -S16 —· to to 、 3 is〜 < 調配物 Ϊ 47006 <400 EL] 第Π次之後 第14天 抗體力價;（GMT) 31574 <400 SA 第Π次之核 第28天 ί 八廿 U\ 4^ 〇 VO • %% t ^ h* c1^ 58,33 16.67 刮~择 今梦斜 ~ s m 1 1 33.33 8.33 . 陰道病變 發生率的 百分比 国1 8.33 75.00 外部病變 發生率的 百分比 • 1 37.50 丨 587.50 ‘ PI 指數# 主要疾病 94% 對對照組 的降低率 1.00 11.50 病變嚴i 中間値 〇 ^ 3 贪 * 碲棼2 -25» (請先閱讀背面之注意事項再填寫本頁)
木紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 515715 A7 B7 五、發明説明（23 ) 表和圖表顯示，在預防模式中，當以gD/MPL/QS21/SUV免 疫接種時，對主要疾病诱導出非常南程度的保護作用。外 部病變的發生率和病變嚴重性上，在以gD/MPL/QS21/SUV免 疫接種的動物組中顯示出高度的減少。 、2.2.2治療模式 在治療模式中，第一次以1〇5 pfu個HSVdMS品系挑戰雌性 的Hartley天竺鼠。然後將有痕療病變的動物隨機分成16隻 一組0 在第2 1天和第4 2天，以下列調配物其中一種來免疫牠們 -gD+MPL 50微克+QS21 50微克+含有250微克膽固醇的SUV， -gD+Al(OH)3+MPL 50微克+QS21 50微克+含有250微克膽固醇 的SUV或保留不加以處理。 從第22到75天，每天監視評估再發性疾病。計分方式按 照預防模式之描述。結果顯示於下表和圖表中： (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 -26- 本紙張尺度適用中國國家標準（CNs ) A4規格（210 X 297公釐） 515715 A7 B7 五、發明説明（24 ) 治療模式： η 調配物 嚴， 中間値 f性* 對對照組 降低的％ 期Η 中間値 對對照組 降低的％ 偶發事利 中間値 卜數目*** 對對照組 降低的％ 16 gD+MPL+QS21 9.00 43% 7.00 18% 3.00 14% +SUV 15 gD+Al(OH)3 + 8.50 46% 7.00 18% 3.00 14% MPL+QS21+SUV 16 未處理 15.75 8.50 3.50 * 感染後第22到75天的病變計分之總合。 (請先閱讀背面之注意事項再填寫本頁) ** 在感染後第22到75天，動物體驗到再發性疾病的總曰數 ***在感染後第22到75天，再發性偶發事件的數目。一個偶 發事件先發生，之後一天沒有病變，且其特徵爲出現 紅斑至少兩天（分數=0.5)，或是出現外邵水泡一天（分數 >=2) 〇 在第21和42天時進行免疫治療的處理。 經濟部中央標準局員工消費合作社印製 結果顯示，在HSV-2感染的治療模式中也謗導出良好程度 的保護。以帶有或不帶有明礬的gD/MPL/QSZl/SUVf^疫，對 中間嚴重性的再發性疾病有明顯的效果。也稍微減少了偶 發事件的數量和期間（參見表中）。 -27- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） .公%. r _ 1，一 ，本 +請曰期 85.4.23 案 號 085104841 類 別 (以上各欄由本局填註） 修丨 A4, C4 中文說明書修正頁(91年f月）515715 || ^專利説明書 中 文 、爹明 新型 名稱 英 文 姓 名 國 籍 具有免疫活性QS21之疫苗組合物 VACCINE COMPOSITIONS HAVING IMMUNOLOGICALLY ACTIVE QS21 1·納沙力·馬力-約瑟·克勞德·加肯 2·馬丁·佛萊德 發明 創作 人 住、居所 國 籍 1.法國 2,英國 均比利時利克森沙特市第一學院路89號 裝· 三、申請人 住、居所 (事務所) 比利時商史密斯克萊美占生物公司 比利時 比利時利克森吵特市弟一學院路89號 詹恩·史帝芬 本紙張尺度適财S國家鲜(CNS) Μ規格⑽χ 297公爱) 515715 第085104841號專利申請案 中文說明書修正頁(91年|月） 修ill丨 五、發明説明（ ） 1 本發明係關於新穎的疫苗調配物·、其產製方法，及其在 醫學上的用途。特定而言，本發明係關於疫苗，其包括抗 原或抗原性組合物免疫活性之QS21，以犮固醇。 在此項技藝中，已知具有佐劑活性並具有免疫活性的皂 角嘗部份，係衍生自南美樹Quillaja Saponaria Molina的樹皮 。例如，QS21，也叫作 QA21，為一種從 Quillaja Saponaria Molina樹中，經Hplc純化的部份，及其產製方法，均揭示於 美國專利第5,057,540號（叫作QS21)。亦曾由Scott等人，Int. Archs. Allergy Appl. Immun·，1985，77，409揭示了皂樹可作 為佐劑。然而，使用QS21作為佐劑，與某種不利有關。例 如，當把自由分子之形式的QS21注射到哺乳動物體内時， 已經觀察到壞死，也就是說，在注射部位發生局部的組織 死亡。 現在已經意外地發現，藉著使用含有QS21與固醇混合的 調配物，可避免注射部位的壞死。較佳的固醇包括/3 -麥胚 脂醇、豆脂醇、麥角留醇、麥角鈣化留醇和膽固醇。這些 固醇類為此項技藝中已熟知的，例如膽固醇被揭示於Merck Index，第11版，341頁，被發現是一種天然存在於動物脂質 中的固醇。 因此本發明的主要觀點是提供一種疫苗組合物，其包括 抗原、具有.免疫活性的皂角苷部份和固醇。本發明之組合 物較好是包含大體上為純粹形式的皂角甞部份。最好是本 發明之組合物含有大體上為純粹形式之QS21，也就是說， 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
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515715 第85104841號專利申請案 I ~ 中文說明書修正頁(90年1〇月） Α7
QS，純度至少為90%，較佳的是純度至少為95%,而最佳 的疋純度至少為98% °其他可使用於本發明組合物中， 免後活性的m部份包括QA17/QS17。含有讲21和膽固醇 的本發明組合物，當與缺乏膽固醇之組合物相比較時，顯 π出降低的反應原性，同時乃保留佐劑效力。除此之外， 已知(^21在？11值約為7或更高的驗性條件下會降解。本發明 化合物具有更多的優點，就是在含有膽固醇的調配物中， 促進了 QS21對驗-調節之水解作用的穩定性。 本發明中較佳的組合物是形成微脂粒結構的那些。 QS21 :固醇的比例，通常將按照以重量計丨：1〇〇到1 ··工的 順序。較佳的是出現過量的固醇，QS21 :固醇之比例至少 為1 · 2的重量/重量。代表性對人類投藥用的1和固醇， 在疫苗中將以每個劑量出現大約丨微克到大約100微克之間 ’幸父佳的是大約10微克到大約50微克之間。 微脂粒最好是含有中性的脂質，例如磷脂醯膽鹼，最好 疋在室溫下無結晶的，例如卵黃磷脂醯膽鹼、二油醯磷脂 酿膽驗或二月桂基磷脂醯膽驗。微脂粒也可以含有帶電荷 的脂質，其增加微脂粒-QS2U#構對於由飽和脂質構成之微 脂粒的穩定性。在這些案例中，帶電荷脂質的量，較佳的 是1-20%重量/重量，最好是5··1〇%。而固醇對磷脂的比例為 1-50%(莫耳/莫耳），最好是20-25%。 本發明中較佳的組合物含有MPL(3-脫醯基化的單-磷酸脂 ___ -5- 本纸張尺度適用中國國家標準⑴!^^ A4規格(21〇χ 297公釐）
裝* % 515715 第85104841號專利申請案 中文説明書修正頁(87年9月） A7 B7
五、發明説明（9) 比較以含有或缺乏膽固 醇之微脂粒壓抑的QS21
Γ (窆贫鋈轻)J
微脂粒的微升量
(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 數據顯示，以特定方式與在膜中之膽固醇連結的QS21， 因此而引起（細胞或螢光微脂粒）的溶解。 若先使QS21與膽固醇在微脂粒中連結，則其不再使細胞 或其他微脂粒溶解。所需要的最低比例爲0.5 : 1的膽固醇： QS21(重量/重量）。 膽固醇在含水的溶液中是不可溶的，且不會形成穩定的 懸浮液。當磷脂存在時，膽固醇存在於鱗脂雙層之中，可 形成穩定的囊泡懸浮液，稱作微脂粒。要避免加入鱗1脂的 需求，嘗試可溶性的衍生物。多氧乙烯基膽固醇癸二酸酯 能夠以60毫克/毫升之濃度而溶於水中，然而即使其超過 QS21的2000倍過量（重量/重量），也不能檢測到QS21溶解活 性的減少。 1.4藉著含有膽固醇之微脂粒來增加QS21的穩定性。 QS21在pH値高於7時是非常容易水解的。該水解作用可藉 12- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 515715 第85104841號專利申請案' A7. 厂杉正 中文説明書修正頁(87年9月)_Β7_1^ 充 五、發明説明（18) 在第二次免疫接種之後： 調配物 增殖 IFN-g IL4 IL5 毫微克/毫升 微微克/毫升 微微克/毫升 SUV/MPL/〇S21+Ae 12606 135 0 250 MPL+QS21+As 16726 60 0 500 (請先閱讀背面之注意事項再填寫本頁) 該數據顯示與含有膽固醇之微脂粒和MPL連結的QS21， 謗導出相當於MPL+QS21的Thl/ThO反應。 以這樣的膽固醇對QS21之比例，QS21對兔子是無毒性的（由 CPK得知）。 在第二個實驗中，在QS21或QS21 +含有膽固醇之SUV的存 在下，利用gpl20以腳塾内注射之方式來免疫balb/c老鼠。·測 量在脾臟細胞中胞毒T-淋巴球的活性。 yp!20 +QS21 經濟部中央標準局員工消費合作社印製 □Kfi—Tf 5 Ό 5 ο 5 2 2 11 ——Ρ815 —〇—Ρ815 + Ε7 gpl20 +QS21 +SUV 0050432020100
——P8) •5 —σ—Ρ81 5 + Β7 〇. C3 ΓΊ 〇 Q CO ^ ” O' 效為物/目標之比例 效應物：蛀標i比例:: -21 - 本紙張尺度適用中國國家標準（CNS)A4規格（210X 297公釐）

Claims (1)

  1. 中文i1^4^41號專利申請案 —專利範圍修正太⑼年^月）申請專利範圍 A8 B8 C8 D8 Π1 % ¥ Η
    種疫苗組合物，包括抗原或抗原性組合物、Q S 2 1和固 醇’特徵在於QS21對固醇之比例為1 ·· 1至1 : 100(w/w) 〇 2 ·根據申請專利範圍第1項之疫苗組合物，其中Q S 2 1對固 醇之比例為1 : 1至1 : 5(w/w)。 3 ·根據申請專利範圍第1項之疫苗組合物，其中Q S 2 1對固 辱之比例為1 : 2 (w / w)。 4 ·根據申請專利範圍第1項之疫苗組合物，其中該固醇為 膽固醇。 5 ·根據申請專利範圍第1項之疫苗組合物，其另含有3去- 〇-酿基化單磷酸酯A (3D-MPL)。 6 ·根據申请專利範圍第1項之疫苗組合物，其另含一載劑 〇 7.根據申請專利範圍第6項之疫苗組合物，其中載劑選自含 油落於水乳劑、明礬、微球體及抗原被包囊顆粒之群組 〇 8 ·根據申請專利範圍第1項之疫苗組合物，其中該Q s 2 i係 呈脂小體結構。 9 ·根據申請專利範圍第8項之疫苗組合物，其中該卩$ 2 1之 純度大於95 %。 ι〇·根據申請專利範圍第9項之疫苗組合物，其中該Qs2ii 純度大於9 8 %。 1 1 .根據申請專利範圍第8項之疫苗組合物， MPL包含於該脂小體中。 ^ 51571f A B c D 、申請專利祀圍 1 2 .根據申請專利範圍第1項之疫苗\组合物，其中該抗原或 抗原性組合物衍生自：任何人類的免疫缺乏病毒、貓的 免疫缺乏病毒、帶狀水痘病毒、單純⑴療病毒1型、單純 ⑴疹病毒2型、人類巨細胞病毒、A、B、C或E型肝炎、 呼吸道融合細胞病毒、人類乳頭狀瘤病毒、流行性感冒 病毒、Hib、腦膜炎病毒、沙門桿菌屬（Salmonella)、奈瑟 球菌屬（Neisseria)、螺旋體屬（Borrelia)、衣形菌屬 (Chlamydia)、博德氏菌屬（Bordetella)、癔原蟲（Plasmodium) 或毒漿體（Toxoplasma)。 1 3 .根據申請專利範圍第1至7項之疫苗組合物，另包括衍生 自腫瘤之抗原。 1 4 .根據申請專利範圍第1至7項之疫苗組合物.，用於醫藥品 〇 1 5 .根據申請專利範圍第1至7項之疫苗組合物，用於病毒、 細菌或寄生蟲感染之預防性治療。 1 6 .根據申請專利範圍第1至7項中任一項之疫苗組合物，用 於癌症之免疫醫療處理。 1 7 . —種使Q S 2 1對於碱引發性水解安定之方法，其包括使 Q S 2 1與含固醇之脂小體混合。 1 8 . —種使Q S 2 1對於碱引發性水解安定之方法，其包括使 Q S 2 1與固醇以1 : 1至1: 1 0 0之重量比混合。 1 9 .根據申請專利範圍第1 7或1 8項之方法，其中該固醇為膽 固醇。 2 0 . —種製備根據申請專利範圍第1項之疫苗組合物之方法， -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)
    515715 8 8 8 8 A BCD 六、申請專利範圍 其包括下列步騾： a) 製備含有固醇之脂質懸浮液； b) 使該脂質懸浮液微流體化，直至脂小體之體積降低至 1 0 0 nm ;及 c) 力π 入 QS21 〇 2 1 . —種製造根據申請專利範圍第1項之疫苗組合物的方法 ，其包括將Q S 2 1和膽固醇，與抗原或抗原性組合物混合 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）
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CA2156525A1 (en) * 1993-02-19 1994-09-01 Susan Dillon Influenza vaccine compositions containing 3-o-deacylated monophosphoryl lipid a
PL178578B1 (pl) * 1993-03-23 2000-05-31 Smithkline Beecham Biolog Zawiesina cząstek 3-0-deacylowanego monofosforylolipidu A i sposób jej wytwarzania oraz kompozycja szczepionki zawierającej antygen w połączeniu z 3-0-deacylowanym monofosforylolipidem A i sposób jej wytwarzania
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GB9718901D0 (en) † 1997-09-05 1997-11-12 Smithkline Beecham Biolog Vaccine

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DE69605296D1 (de) 1999-12-30
NO974859L (no) 1997-10-21
SK144297A3 (en) 1998-05-06
MX9708226A (es) 1998-06-30
MA23850A1 (fr) 1996-12-31
IL118004A (en) 1999-11-30
AU6987398A (en) 1998-07-23
NZ305365A (en) 1999-05-28
EA199700272A1 (ru) 1998-04-30
EP0822831B1 (en) 1999-11-24
DE69605296T2 (de) 2000-05-18
EP0884056A1 (en) 1998-12-16
HK1025244A1 (en) 2000-11-10
AP9701123A0 (en) 1997-10-31
CY2588B2 (en) 2009-11-04
HUP9801560A3 (en) 1999-07-28
DE69637254D1 (de) 2007-10-31
BG101995A (en) 1998-11-30
WO1996033739A1 (en) 1996-10-31
TR199701252T1 (xx) 1998-03-21
PT955059E (pt) 2007-11-27
RO119068B1 (ro) 2004-03-30
OA10629A (en) 2002-09-16
CN1111071C (zh) 2003-06-11
EP0822831B2 (en) 2006-08-23
CN1515245A (zh) 2004-07-28
EP0822831A1 (en) 1998-02-11
UA56132C2 (uk) 2003-05-15
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PL184061B1 (pl) 2002-08-30
IL118004A0 (en) 1996-08-04
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KR100463372B1 (ko) 2005-02-28
JP3901731B2 (ja) 2007-04-04
CN1480214A (zh) 2004-03-10
CN1248737C (zh) 2006-04-05
SI0822831T2 (sl) 2006-12-31
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BR9608199A (pt) 1999-05-18
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AR001686A1 (es) 1997-11-26
CZ296216B6 (cs) 2006-02-15
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NO322190B1 (no) 2006-08-28
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CZ337997A3 (cs) 1998-03-18
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HK1009086A1 (en) 1999-05-28
DE69637254T2 (de) 2008-06-19
BR9608199B1 (pt) 2009-05-05
SI0955059T1 (sl) 2008-02-29
ATE186842T1 (de) 1999-12-15
ES2140076T3 (es) 2000-02-16
HUP9801560A1 (hu) 1998-10-28
DZ2026A1 (fr) 2002-07-21
HU227944B1 (en) 2012-06-28
NO974859D0 (no) 1997-10-21
AU693022B2 (en) 1998-06-18
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AU699213B2 (en) 1998-11-26

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