TW200815026A - Treatment of ischemic diseases using erythropoietin - Google Patents
Treatment of ischemic diseases using erythropoietin Download PDFInfo
- Publication number
- TW200815026A TW200815026A TW096120549A TW96120549A TW200815026A TW 200815026 A TW200815026 A TW 200815026A TW 096120549 A TW096120549 A TW 096120549A TW 96120549 A TW96120549 A TW 96120549A TW 200815026 A TW200815026 A TW 200815026A
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- peripheral blood
- cells
- erythropoietin
- individual
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Description
200815026 (1) 九、發明說明 【發明所屬之技術領域】 < 本發明關於再血管化之方法、治療局部缺血疾病之方 法及用於這些方法中之組成物。 " 【先前技術】 - 週邊血管疾病是一種因週邊動脈血流降低而造成週邊 Φ 組織局部缺血狀態之醫學狀況,週邊動脈血流之降低係因 例如血管腔收縮、血塊形成、血管阻塞、血管炎、血管收 縮或血液黏稠度增加所致。近年來發現,當衍生自骨髓之 單核細胞被移植至局部缺血部位可促使血管新生,且衍生 自骨髓之單核細胞移植被認爲是治療週邊血管疾病之潛在 方法。然而,移植衍生自骨髓之單核細胞需要收集病患的 骨髓,這對病患來說是一大負擔。 有硏究嘗試以衍生自週邊血液之單核細胞取代衍生自 • 骨髓之單核細胞,其目的是爲了減輕病患負擔;然而,這 個方法無法成功地提供有效治療,因爲週邊血液中單核細 胞的數量太少。 ♦ 紅血球生成素(亦稱爲EPO)是一種促進紅血球前驅 v 細胞(erythroid progenitor cells )分化及增生的酸性糖蛋 白荷爾蒙,其主要在腎臟製造。紅血球是血液中含量最豐 富的細胞,在體內工作一段時間後主要在脾臟中被破壞( 在人類平均壽命約爲1 20天)。正常情況下,週邊紅血球 總數藉由骨髓持續供應以持續維持恆定。EP0對於體內紅 200815026 (2) 血球的恒定性扮演關鍵角色。在臨床上,EPO被用於治療 貧血及手術前及手術後之處理。 此外,曾有報告指出EPO具有促進血管新生活性,且 可有效作爲局部缺血疾病之治療劑(Besarab A et al.,The New England Journal of Medicine,3 3 9 ( 9 ) ,5 84-590,( v 1 998 ),Heeschen C et al.,Blood,1 02 ( 4 ) ,1 340- 1 346,( • 2 0 0 3 ),B a h 1 m a η n F H et al.,Blood,103(3),921-926,( 2 0 0 4 ),Smith K J et a 1·,Cardiovascular Research,( 59) 538-548, ( 2 0 0 3 ) , B ahlmann F H et al·,Kidney
International,64,1 648- 1 652,( 2003 ))。亦有報告指出, EPO促使血管內皮前驅細胞動員至週邊血液(Heeschen C et al”Blood,102 ( 4 ),1 3 4 0 1 3 4 6,( 2 0 0 3 ),Bahlmann F H et al.,Blood,103 ( 3 ),9 2 1 - 9 2 6,( 2 0 0 4 ) ) ° 然而,被EPO動員至週邊血液之細胞是否能有效用於 治療局部缺血疾病,諸如週邊血管疾病,則尙不清楚。 【發明內容】 發明摘要 " 本發明人發現藉由投服EPO可促進單核細胞動員至週 - 邊血液,且以此方式被EPO動員之單核細胞對於治療局部 缺血疾病係特別有效的。 本發明提供用於動員單核細胞至週邊血液以治療局部 缺血疾病或刺激再血管化之組成物,其中該組成物包含作 爲活性成分之紅血球生成素。該動員之單核細胞係適宜地 -6- 200815026 (3) 自個體中收集且之後被投服至該個體。 本發明之組成物係適宜地於收集個體週邊血液前自3 至1 2天投服給該個體。 本發明亦提供用於治療局部缺血疾病之組成物及用於 刺激再血管化之組成物,彼等包含自先前已投服紅血球生 v 成素之個體的週邊血液中分離之活性成分單核細胞。在這 - 類組成物中,該紅血球生成素較佳在收集週邊血液之前3 _ 至1 2天投服。 本發明亦提供一種用於動員CD34陽性細胞至週邊血 液以治療局部缺血疾病或刺激再血管化之組成物,該組成: 物包含作爲活性成分之紅血球生成素。 在其他態樣中,本發明提供一種製備用於刺激再血管 化及用於治療局部缺血疾病之單核細胞的方法,該方法包. 含自先前已投服紅血球生成素之個體的週邊血液分離單梭 細胞。 φ 在其他態樣中,本發明提供一種用於個體以治療局部 缺血疾病或刺激再血管化之方法,該方法包含下列步驟: (a )投服紅血球生成素至個體; " (b )自該個體收集週邊血液單核細胞;及 " (e )投服該收集之週邊血液單核細胞至該個體之目 標部位。 本發明之詳細說明 紅血球生成素動員週邊血液單核細胞 200815026 (4) 本發明之一個態樣關於一種用於動員單核細胞至週邊 血液以治療局部缺血疾病或刺激再血管化之組成物,其中 該組成物包含作爲活性成分之紅血球生成素。「動員」單 核細胞一詞代表刺激存在多種器官中之多能幹細胞( multipotent stem cells)的分化及增生,並釋放包含多能 幹細胞之單核細胞至血液中。以此方式動員之單核細胞可 ,收集自個體之週邊血液中且可被投服至個體以治療局部缺 _ 血疾病或刺激再血管化。較佳之該個體爲罹患局部缺血疾 病之病患或需要再血管化治療之病患。 本發明對於在收集週邊血液單核細胞之前投服紅血取 生成素至個體之劑量數並無特殊限制,但通常介於.1至3 劑。在投服3劑之案例中,舉例來說,第1劑紅血球生成 素係於收集週邊血液單核細胞之前約2週經全身(例如皮 下或靜脈注射)投服至個體。大約1週後,第2劑紅血球. 生成素係於供血(抽血)後經全身投服。再經過1週後, # 第3劑紅血球生成素係經局部投服,然後所欲之週邊單核 細胞可自個體之週邊血液中收集。在投服2劑之案例中, 舉例來說,第1劑紅血球生成素係於收集週邊血液單核細 胞之前約1週經全身投服至個體,且第2劑紅血球生成素 ^ 係於大約1週後經局部投服,然後所欲之週邊單核細胞可 自週邊血液中收集。在投服單劑之案例中,舉例來說,紅 血球生成素係經全身投服至個體,所欲之週邊單核細胞可 於大約1週後收集。 一單位劑量之紅血球生成素通常包含1 000單位/個體 200815026 (5) 至1 00000單位/個體且較佳爲3000單位/個體至1 2000單 位/個體(例如6000單位/個體)。各別個體所需之劑量將 由主治醫師考慮例如個體之年齢、體重及狀況與投服途徑 來決定。因此,本發明之紅血球生成素之劑量並不限於上 述劑量。 e 紅血球生成素通常經由非經腸途徑投服,舉例來說其 •可以注射劑(例如皮下、靜脈、肌肉、腹腔注射)或以經 φ 皮、經黏膜、經鼻或經肺途徑投服。口服亦可。 週邊血液單核細胞係存在於週邊血液中之單核細胞。 單核細胞(亦稱爲單核球)爲主要存在於血液中及存在於 巨噬細胞類細胞分化階段中之細胞。造血幹細胞在骨髓中 分化成原單核細胞(monoblasts )及幼單核細胞( p r 〇 m ο η q c y t e s ),然後分化成單核細胞以釋放至血液中。 遷移至組織中之單核細胞分化成例如巨噬細胞、樹突細胞 及組織細胞(histiocytes)。 φ 有關利用EPO動員單核細胞至週邊血液方面,過去認 爲在投服EPO之後需要2週以令單核細胞動員至週邊血液 (Bahlmann F H e t a 1 ·,B 1 ο o d,1 0 3 ( 3 ),9 2 1 - 9 2 6,( 2 0 0 4 ) 、 )。然而,根據本發明之發現,在投服EPO之後大約1週 * 將有足以用於治療局部缺血疾病或刺激再血管化之數量的 單核細胞被動員至週邊血液。 因此,本發明關於一種取得或製備用於移植之單核細 胞之方法,該方法包含下列步驟: (a )投服紅血球生成素至個體;及 -9- 200815026 (6) (b )於投服紅血球生成素後約1週自該個體收集週 邊血液單核細胞。 在本發明中,「大約1週」係槪指自3至12天,且 較佳爲自5至9天(例如自6至8天,或7天)。 在其他態樣中,本發明關於一種用於動員CD34陽性 K 細胞至週邊血液以治療局部缺血疾病或刺激再血管化之組 * 成物,該組成物包含作爲活性成分之紅血球生成素。 φ CD34是一種血液幹細胞抗原。其表現於血液幹細胞 上,也表現於例如血管內皮細胞、血管內皮祖細胞( vascular endothelial progenitor cells )及基質細胞( s t Γ o m a 1 c e 11 s )中。由於已知C D 3 4陽性細胞(諸如血管 內皮祖細胞)與血管新生有關,因此在移植之單核細胞族 群中提高CD34陽性細胞之比例係合乎期望,以達到治療 局部缺血疾病之較佳效果或較好之再血管化功效。根據本 發明之方法被動員至週邊血液之單核細胞族群通常具有足 • 以達成局部缺血疾病治療效果或再血管化功效之CD34陽 性細胞力價。在以治療局部缺血疾病或刺激再血管化爲目 標之移植中,自本發明之方法所得到之單核細胞族群中單 ^ 離或濃縮CD34陽性細胞可特別有效地增加CD34陽性細 ^ 胞之比例。 在本發明中,單核細胞中高比例之CD34陽性細胞係 指CD34陽性細胞佔單核細胞之至少1%、較佳爲至少2% 及更佳爲至少3 %。單核細胞中CD34陽性細胞之比例上 限可爲例如99.99%、99.9%或99%及理論上爲100%。 -10- 200815026 (7) 存在於根據本發明所得到之單核細胞中之CD34陽性 細胞亦可爲CD45陽性。CD4 5係白血球共同抗原,其爲造 血類細胞重要的膜糖蛋白。 週邊血液單核細胞可以常用之方法自個體收集。舉例 來說,可藉血液分離術直接收集源自血液之單核細胞、視 k 需要以離心移除大部分之紅血球、顆粒球及血小板以捕捉 - 週邊血液白血球,及之後藉例如離心清洗該得到之週邊血 φ 液白血球以取得單核細胞。 以此方式取得之週邊血液單核細胞可選擇性地藉由添 加、分離或純化之方式被進一步處理。舉例來說,所欲之 細胞(例如CD34陽性細胞及/或血管內皮祖細胞)可進一 步自該收集到之週邊血液單核細胞中被濃縮或分離以供投 月艮。實質上純的CD34陽性細胞可利用標準技術製備。舉 例來說,令週邊血液單核細胞與抗CD34抗體反應,接著 CD34陽性細胞將附著至帶有抗鼠IgG抗體之磁性珠。利 • 用磁片收集與磁性珠結合之CD34陽性抗體,之後利用酵 素處理以使CD34陽性細胞自磁性珠釋放。或者,令CD34 陽性細胞與標示螢光染料之抗CD34抗體結合及利用螢光 ^ 細胞分選儀收集。 治療局部缺血疾病及再血管化 根據本發明所製備之週邊血液單核細胞可被投服至個 體以用於治療局部缺血疾病。因此,本發明之另一態樣關 於一種用於個體以治療局部缺血疾病之方法,該法包含下 -11 - 200815026 (8) 列步驟: (a )投服紅血球生成素至個體; (b )自該個體收集週邊血液單核細胞;及 (c )投服該收集之週邊血液單核細胞至個體之目標 部位。 ‘ 局部缺血疾病是一種由於血管中血流減少而令組織處 ^ 於缺血狀態之醫學狀況,其中血流減少可由許多因素造成 φ ,諸如血管腔收縮、血塊形成、血管阻塞、血管炎、血管 收縮或血液黏稠度增加。局部缺血疾病包括週邊血管疾病 、局部缺血心臟病(例如局部缺血心肌病、心肌梗塞、局 部缺血心衰竭)、局部缺血腦血管疾病、局部缺血腎臟病 、局部缺血肺臟病及與傳染病有關之局部缺血疾病。 週邊血管疾病是一種由於週邊動脈血流減少而令週邊 組織處於缺血狀態之醫學狀況,其中血流減少可由例如血.. 管腔收縮、血塊形成、血管阻塞、血管炎、血管收縮或血 Φ 液黏稠度增加造成。與週邊血管疾病有關之疾病包括慢性 動脈阻塞疾病諸如動脈硬化閉塞症及柏格氏病(Buerger’s disease )及進行性全身硬化症、全身性紅斑性狼瘡、雷諾 ^ 氏病(Raynaud’s disease )、振動症候群、動脈瘤及血管 - 炎。週邊血管疾病是本發明之治療劑較佳的目標疾病,以 動脈硬化閉塞症及柏格氏病爲特別適宜之目標。 此外,根據本發明所製備之週邊血液單核細胞可被投 服至個體以用於刺激再血管化。因此,本發明之另一態樣 關於一種用於個體以剌激再血管化之方法,該法包含下列 -12- 200815026 (9) 步驟: (a )投服紅血球生成素至個體; (b )自該個體收集週邊血液單核細胞;及 (c )投服該收集之週邊血液單核細胞至個體之目標 部位。 如本發明之用法,再血管化代表刺激血管新生及/或 血管之生長及發育。本發明之方法可用於刺激任何種類之 血管的新生、生長及發育,尤其是動脈,且特別以週邊動 脈爲佳。再血管化可以熟習該項技術者所知之技術監測, 舉例來說,利用鹼性磷酸酶染料測量微血管之密度。 如本發明之用法,目標部位一般係指發生缺血之部位 及期望再血管化之部位。在移植週邊血液單核細胞至其他 部位導致期望再血管化之部位再血管化的情況中,目標部 位係指該其他部位。局部投服部位之特定實例包括下肢骨 骼肌、上肢骨骼肌及心臟(心肌)。 投服或移植至目標部位之該收集的單核細胞數量並無 特殊限制’但通常介於1 ·0χ1 07至1 .0x1 012個細胞,且較 佳爲l.OxlO9至l.OxlO11個細胞。 局部投服是一種可有效投服細胞至受影響區域之位置 ,而不造成顯著全身影響的方法。局部投服可利用例如一 般針筒、針頭或局部細針進行。 在投服該收集之單核細胞至目標部位時,該單核細胞 可被單獨投服或與其它物質組合投服。與單核細胞組合投 服之物質並無特別限制,但以可促進再血管化活性之物質 -13- 200815026 (10) 爲佳。 紅血球生成素 任何種類之EPO均可被用於本發明,但以高純度之 EPO爲佳,及與哺乳類之EPO (特別是人類EPO )具有實 質上相同生物活性者亦佳。 本發明所使用之EPO可以任何方法製備;舉例來說, 其可爲自人類來源萃取物純化得到之天然人類EPO (參見 例如日本經審查專利公開說明書1_3 8 8 00 )或其可爲以基 因工程技術於大腸桿菌、酵母菌、中國倉鼠卵巢細胞( CHO細胞)、C127細胞、COS細胞、骨髓瘤細胞、BHK 細胞或昆蟲細胞中產生,然後以任何各種方法萃取、分離 及純化之人類EPO。本發明所使用之EPO以基因工程技術 所產生之EPO爲佳,及於哺乳類細胞中(特別是CHO紐 胞)所生產之EPO爲佳(參見例如日本經審查專利公開說 明書 1-44317,Kenneth Jacob s et a 1·,Nature,31 3,80 6-81 0 ( 1985) ) 〇 以基因重組技術取得之EPO可與天然來源之EPO具 有相同之胺基酸序列,或可與天然來源之EPO具有相同之 生物活性但具有刪除、取代或增加一或多個胺基酸之胺基 酸序列。胺基酸刪除、取代或增加可藉該領域已知之方法 進行。舉例來說,熟習該項技術者可利用定點突變在EPO 之胺基酸序列中導入適當之突變以製備功能相等於EP0之 多肽(Gotoh,T.et al. ( 1 995 ) Gene 1 52,27 1 - -14- 200815026 (11) 2 7 5 ; Ζ ο 11 e r 9 Μ . J . and Smith,M· ( 1 9 8 3 ) Methods E n z y m o L 1 0 0,4 6 8 - 5 0 0 ; K r a m e r,W · e t a L ( 1 9 8 4 ) Nucleic Acids Res.12,9441-9456 ;Kramer,W. and Fritz,H.J. ( 1987 ) Methods Enzymol. 154,3 5 0-36 7;Kvinkel,T.A. ( 1985) P roc.Natl.Acad.Sci.USA. 82,488- 492;Kunkel ( 1 9 8 8 )
Methods Enzy mo 1.8 5 ?2 763 -2 76 6 )。胺基酸突變亦可自行 發生。一般來說,胺基酸殘基以被其他具有類似性質之胺 基酸側鏈的胺基酸殘基取代爲佳。胺基酸側鏈之性質包括 例如疏水性胺基酸(A、I、L、Μ、F、P、W、Y、V )、 親水性胺基酸(R、D、Ν、C、Ε、Q、G、Η、Κ、S、Τ ) 、具有脂肪族側鏈之胺基酸(G、A、V、L、I、P )、具 有羥基官能基側鏈之胺基酸(S、Τ、Y )、具有含硫側鏈 之胺基酸(C、M)、具有羧酸或含醯胺側鏈之胺基酸(D 、N、E、Q)、具有含鹼性基團側鏈之胺基酸(R、K、H )及具有芳香性側鏈之胺基酸(Η、F、Y、W )(括弧中 爲胺基酸之英文字母代號)。已知具有由刪除、增加或取 代一或多個胺基酸殘基所造成之改質胺基酸序列之多肽仍 保留其生物活性(M a r k,D . F . e t a 1 ·,P r 〇 c · N a 11. A c a d · S c i · U S A (1 9 8 4 ) 8 1,5662-5666;Zoller,M. J· & Smith,M.Nucleic
Acids Research ( 1 982 ) 1 0 9 6 4 8 7 - 6 5 0 0; W an g ? A . e t al·,Science 224,1431-1433;Dalbadie-McFarland, G.et al.,Proc.Natl.Acad.Sci.USA ( 1 982 ) 79,6409_6413)。 亦可使用EPO與其他蛋白質之融合蛋白。融合蛋白之 構建可藉由例如順框連接編碼EPO之DNA與編碼其它蛋 -15- 200815026 (12) 白質之DNA ;插入該DN A至表現載體;接著於宿主中表 現該載體。與本發明之EPO融合之其他蛋白質並無特殊限 制。 化學改質之EPO亦可用於本發明。化學改質之^〇 包括與無機或有機化合物(例如聚乙二醇或維他命B 1 2 ) ~ 連接之EPO。用於本發明之EPO亦可爲EPO衍生物。 -如本發明之用法,EPO衍生物係指EPO分子中之胺基 φ 酸經改質之EPO,或EPO分子中之糖鏈經改質之ΕΡΌ。 EPO分子中之糖鏈改質包括增加、取代或刪除糖鏈。本發 明中較佳之糖鏈改質係自EPO分子中刪除唾液酸。 藉重組動物細胞產生之EPO或源自尿液之EPO通常 以包含各種具有不同糖鏈結構之EPO S的EPO組成物之 形式獲得。EPO組成物中與EPO分子連接之唾液酸數目將 視EPO分子而有所不同,但各別之EPO分子通常與介於 11至 15個唾液酸連接。去唾液酸EPO(asialo-EPO)可 • 藉由移除唾液酸製備。去唾液酸化處理之移除的唾液酸數 量並無特殊限制;可移除所有唾液酸,或可移除1、2、3 、4、5、6、7、8、9、10、11、12、13 或 14 個唾液酸。 • 本發明所使用之去唾液酸EPO以不超過10個唾液酸與該 - EPO分子連接爲佳,更適宜者不超過5個,及特別適宜者 不超過2個。本發明所提及之唾液酸數量係指EPO組成物 中所包含之EPO分子上的唾液酸平均數量。每個分子之平 均唾液酸可由熟習該項技術者利用已知之方法測定(參見 例如 EP 0428267)。 -16- (13) (13)200815026 唾液酸已被移除之EPO (去唾液酸EPO)可利用熟習 該項技術者已知之方法生產。舉例來說,可利用酵素諸如 唾液酸酶處理EPO來製備。商用之唾液酸酶可用於此目的 (參見例如 N a t i ο n a 1 P u b Π c a t i 〇 n 〇 f T r a n s 1 a t e d V e r s i 〇 n N o . 2 0 0 5 - 5 0 7 4 2 6 ; N o b u ο I m a i e t a 1.5 E u r. J . B i o c h e m. 1 9 4,457-462 ( 1 990 ))。 EPO分子中胺基酸改質之實例包括胺基甲醯化、生物 素化、眯基化(amidination)、乙醯化及胍基化( guanidination )。胺基甲醯化係本發明中較佳之胺基酸改 質。 被改質之胺基酸殘基並無特殊限制,且可包括離胺酸 、精胺酸、麩胺酸及色胺酸。在本發明中以改質離胺酸爲 佳。 因此,含胺基甲醯化離胺酸之EPO係本發明中改質胺 基酸EPO之特別適宜的實施態樣(參見例如Marcel L.et al·,Derivatives of erythropoietin that are tissue protective but not erythropoietic· Science,2004;3 05:23 9;Fiordaliso E. et al.?A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury.PNAS,2005; 102: 20 46)。胺基甲醯化 EPO 之方 法包括例如與氰酸根離子反應之胺基甲醯化、與烷基異氰 酸反應之烷基胺基甲醯化及與芳基異氰酸反應之芳基胺基 甲醯化。 •17- 200815026 (14) 醫藥調合物 ΕΡΌ可根據該領域熟習之技術藉由適當添加例如懸浮 劑、增溶劑、穩定劑、等張劑、保存劑、吸附抑制劑、界 面活性劑、稀釋劑、賦形劑、ρ Η調整劑、緩解劑.、.緩衝 劑、含硫還原劑、氧化抑制劑等以調合。 ~ 懸浮劑包含甲基纖維素、聚山梨酯80、羥基乙基纖維 - 素、阿拉伯膠、黃耆膠粉、羧甲基纖維素鈉及聚氧乙烯去 φ 水山梨醇單月桂酸酯。 增溶劑包括聚氧乙烯氫化蓖麻油、聚山梨酯8 0、菸鹼 胺、聚氧乙烯去水山梨醇單月桂酸酯、聚乙二醇及蓖麻油 脂肪酸之乙酯。 穩定劑包括右旋糖酐40、甲基纖維素、明膠、硫化鈉 及偏亞硫酸鈉。 特定胺基酸亦可被添加以作爲穩定劑(參見例如日本 專利早期公開號1 0- 1 8248 1 )。可被添加作爲穩定劑之胺 φ 基酸包括例如游離胺基酸及其鹽類諸如鈉鹽、鉀鹽及氯化 氫。可添加單一胺基酸或二或多個胺基酸之組合。對於添 加作爲穩定劑之胺基酸並無特殊限制,但在這方面較佳之 ^ 胺基酸爲例如白胺酸、色胺酸、絲胺酸、麩胺酸、精胺酸 - 、組胺酸及離胺酸。 等張劑包括D-甘露醇及山梨醇。 保存劑包括對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、 山梨酸、酚類、甲酚及氯甲酚。 吸附抑制劑包括人類血清白蛋白、卵磷脂、右旋糖酐 -18 - 200815026 (15) 、環氧乙烷、環氧丙烷共聚合物、羥丙基纖維素、甲基纖 維素、聚氧乙烯氫化蓖麻油及聚乙二醇。 界面活性劑之代表性實例爲非離子界面活性劑,例如 HLB値介於6至1 8之間之非離子界面活性劑,例如去水 山梨醇糖脂肪酸酯(諸如去水山梨醇單辛酸酯、去水山梨 ^ 醇單月桂酸酯及去水山梨醇單棕櫚酸酯);甘油之脂肪酸 , 酯(諸如甘油單辛酸酯、甘油單肉宣蔻酸酯及甘油單硬脂 φ 酸酯):聚甘油之脂肪酸酯(諸如十聚甘油單硬脂酸酯、 十聚甘油雙硬脂酸酯及十聚甘油單亞油酸酯);聚氧乙烯 去水山梨醇脂肪酸酯(諸如聚氧乙烯去水山梨醇單月桂酸 酯、聚氧乙烯去水山梨醇單油酸酯、聚氧乙烯去水山梨醇 單硬脂酸酯、聚氧乙烯去水山梨醇單棕櫚酸酯、聚氧乙烯 去水山梨醇三油酸酯及聚氧乙烯去水山梨醇三硬脂酸酯) :聚氧乙烯山梨醇脂肪酸酯(諸如聚氧乙烯山梨醇四硬脂 酸酯及聚氧乙烯山梨醇四油酸酯);聚氧乙烯甘油脂肪酸 # 酯(諸如聚氧乙烯甘油單硬脂酸酯);聚乙烯甘油脂肪酸 酯(諸如聚乙烯甘油雙硬脂酸酯);聚氧乙烯烷基醚(諸 如聚氧乙烯月桂醚);聚氧乙烯-聚氧丙烯烷基醚(諸如 聚氧乙烯-聚氧丙烯二醇、聚氧乙烯-聚氧丙烯丙基醚及聚 " 氧乙靖·聚氧丙烯十六烷基醚)·,聚氧乙烯烷基苯基醚( 諸如聚氧乙烯壬基苯基醚);聚氧乙烯蓖麻油及聚氧乙烯 硬化蓖麻油(聚氧乙烯氫化蓖麻油):聚氧乙烯/蜂蠟衍 生物(諸如聚氧乙烯山梨醇蜂蠟);聚氧乙烯/羊毛脂衍 生物(諸如聚氧乙烯羊毛脂);及聚氧乙烯脂肪酸醯胺( -19- 200815026 (16) 諸如聚氧乙烯硬脂醯胺)。界面活性劑之其它代表性實例 爲陰離子界面活性劑,例如具有C1()-18烷基之烷基硫酸鹽 (諸如十六烷基硫酸鈉、十二烷基硫酸鈉及十八烯基硫酸 鈉);具有平均2至4莫耳之環氧乙烷加成物及C1Q_18院^ 基之聚氧乙烯烷基醚硫酸鹽(諸如聚氧乙烯十二烷基硫酸 ’ 鈉);及具有C8.18烷基之烷基磺琥珀酸酯鹽(諸如十二 > 烷基磺琥珀酸鈉)。其它界面活性劑之代表性實例爲天然 φ 界面活性劑,例如卵磷脂、甘油磷脂、鞘磷脂(諸如神經 鞘磷脂)及具有C!2_18脂肪酸之蔗糖脂肪酸酯。單一界面 活性劑或二或多種界面活性劑之組合可被添加至本發明之 調合物中。聚氧乙烯去水山梨醇脂肪酸酯(諸如聚山梨醇 酯20、40、6 0及80 )爲較佳之界面活性劑,且聚山梨醇 酯20及80係特別適宜。聚氧乙烯-聚氧丙烯甘油諸如泊 洛沙姆(poloxamer )(例如普流尼克 F-68 ( Pluronic F-68)(註冊商標))亦爲適宜。 φ 含硫還原劑包括含氫硫基之還原劑,諸如N -乙醯半 胱胺酸、N·乙醯同半胱胺酸、硫代乳酸、二乙醇硫醚、硫 代乙醇胺、硫甘油、硫山梨醇、硫乙醇酸及其鹽類、硫代 ^ 硫酸鈉、谷胱甘肽及Ci-7硫代直鏈烷酸。 - 氧化抑制劑包括異維生素C、二丁基羥基甲苯、丁基 羥苯基甲基醚、生育酚、生育酚醋酸鹽、L -抗壞血酸 及其鹽類、L-抗壞血酸棕櫚酸酯、L-抗壞血酸硬脂酸酯、 亞硫酸氫鈉、亞硫酸鈉、沒食子酸三戊酯及沒食子酸丙酯 及螯合劑諸如伸乙二胺四乙酸二鈉(EDTA )、焦磷酸鈉 -20- 200815026 (17) 及偏磷酸鈉。 可視需要添加之成份亦包括無機鹽類(諸如氯化鈉、 氯化鉀、氯化鈣、磷酸鈉、磷酸鉀及碳酸氫鈉)及有機鹽 類(諸如檸檬酸鈉、檸檬酸鉀及乙酸鈉)。 本申請案之說明書中明白引用之所有專利及參考文獻 的內容以參照方式整體納入本發明。此外,日本專利申請 . 案2006-1 58998之說明書及圖式內容(其係本申請案主張 A 優先權之基礎)以參照方式整體納入本發明。 【實施方式】 本發明藉下面實施例詳細說明,但不限於這些實施例 實施例1 以EPO動員造血細胞 皮下注射重組人類EPO ( Epogin (註冊商標),活性成 分··倍他促紅血球生成素)至鼠(C57BL/6,9週齢)每天 1次共4天,劑量爲100微克/公斤/天。以類似方式皮下 單獨投服載劑至對照鼠。鼠於第5天被殺死並收集週邊血 液細胞(〇 · 6至1毫升)。添加含8 · 3克/升氯化銨之0.0 1 莫耳Tris-HCl緩衝液pH7.5:t〇.2之紅血球溶解緩衝液( SIGMA)以溶血,並令其於室溫下靜置5至10分鐘,隨後以 2% BSF + PBS (-)沖洗。CD16/CD32 ( FcYIII/II 受體)非 專一性反應阻斷抗體(BD-Pharmingen,San Diego,CA)係 -21 - (18) 200815026 以1微克/1 〇6細胞添加,並置於冰上3 0分鐘。FIT C -結合抗 鼠 Sea-1 抗體(BD Pharmingen,San Diego,CA ) 、PE-結合 抗鼠 C D 3 4 抗體、A P C -結合抗 m c · K i t抗體(B D Pharmingen,San Diego,CA)及 APC-Cy7·結合抗鼠 CD3、 CD4、CD 8 a > CD45R/B220、Ly6G ( GR-1 ) 、CDllb (
Mac-1 (x鏈)及Terl 19抗體之混合物被用來作爲系列標記 。細胞經抗體染色後,以 FACSvantage SE ( Becton D i c ki n s ο η,Μ o untai η V i e w,C A )進行分析。 結果顯示於圖1。如圖1中R3所示,投服EPO使c-Kit + Sca-1+Lin·細胞增加約 13 倍。由於 c-Kit + Sca-1+Lin-細 胞爲鼠 CFU-S-Uke 細胞之標誌(參見例如 Blood,1 992Dec.l5;80 ( 1 2 ) :3 044-50 ),上述結果證實投服 EPO可動員CFU-S-like細胞至週邊血液。 CFU-S聚落測試 利用已皮下投服EPO 5天之C57/b6鼠的週邊血液細 胞作爲捐贈者細胞。1〇4至1〇5個細胞/1〇〇至200微升之 捐贈者細胞經尾靜脈被移植至接受者C57/b6鼠中’該鼠 已經放射線暴露儀器(Hitachi Medico)之致死劑量r射 線處理(950 cGy鉋137源)。移植後8或12天切除脾臟, 並利用波音氏(Bonin’s)染色分析脾臟聚落(在脾臟中形 成之聚落數量)。 結果顯示於圖2。與FACS分析之結果相同的是,觀察 到類C FU - S細胞動員至週邊血液。 -22- 200815026 (19) 實施例2 移植週邊血液單核細胞之血管新生療法 此試驗係設計用於探討造血幹細胞是否能藉由投服紅 血球生成素調合物而被動員至5名有嚴重局部缺血肢體疾 病之病患的週邊血液中。同時進行自體移植週邊單核細胞 •之血管新生療法之臨床試驗。該臨床試驗之一般設計採用 ϋ 開放標籤之試驗計劃書。 病患於預定之細胞移植之前2週接受6000單位ΕΡΟ 皮下注射(第1次投服)。在細胞移植前1週,抽取血液 槪 (約400毫升)以用於自體供血之目的並皮下注射6000 單位之ΕΡΟ (第2次投服)。在手術當天早上注射6000 單位之ΕΡΟ (第3次投服),然後以血液分離術自週邊血 液分離約1〇9週邊單核細胞。週邊血液檢體係於投服ΕΡΟ 之前、第2次投服之後及緊接血液分離術之前收集,且進 % 行血液檢測(白血球數、C反應蛋白、肌酸激酶)及 CD34陽性細胞計數。 該分離之週邊單核細胞被注射至50至100個病患局 部缺血肢體之肌肉部位。血管新生療法之療效係於細胞移 - 植前、移植當天、移植後1週、2週、1個月、2個月及6 個月根據下列項目之觀察與測量評估。 QOL:疼痛依目測類比評分表(VAS )評估,0代表無 疼痛而1 〇代表最強烈之疼痛 -23- 200815026 (20) 採集血液 檢測血液 血管造影術 跑步機測試:以2.4公里/小時水平速度測量絕對走動 距離或疼痛出現距離 客觀評估皮膚或潰瘍病灶:踝臂血壓指數(ABPI )、 數位體積描記法、跑步機測試(步行功能)、熱攝影術、 雷射都卜勒血流計(LDPI )及經皮氧氣分壓(TdP02 )測 CD34陽性細胞之變化 表1摘列出各例、移植細胞數及CD3 4陽性細胞數。 以投服紅血球生成素之前的數値當作100%校正後,週邊 血液中CD34陽性細胞之比例於第1次投服紅血球生成素 後1週抽血時顯示增加82至245% (平均158%)。經過 1週緊接於血液分離術之前,增加88至175% (平均139 % )。這些結果顯示在第1次投服紅血球生成素後1週, CD34陽性細胞數(放血時)與2週後(緊接分離術之前 )之細胞數相同或較高。 CD34陽性細胞佔血液分離術所收集之單核細胞之 0 · 0 2 至 0 · 1 % (平均=0 · 0 6 % )。 -24- 200815026 (21) 表1 病例 性別 年齡 病因 移植部位 總移植細胞數 CD34陽性細胞 1 男性 77 動脈硬化閉塞症 右下肢 0.5x 109 OJx 106 (0·2χ104 細胞/kg) 2 男性 66 動脈硬化閉塞症 左下肢 16.7X109 5.Ox 106 (8χ 104 細胞/kg) 3 男性 48 柏格氏病 左右上肢 9.2x 109 9.2χ 106 (14χ104 細胞/kg) 4 男性 48 柏格氏病 右上肢 6·9χ 109 5.5χ ΙΟ6 (9χ ΙΟ4細胞/kg) 細胞移植之臨床評估 以主觀症狀及血管造影術評估 表2 病例 觀察期 狀況 目測類比評分 Fontatine分級法 血管造影術 1 11個月 麻木 休息時疼痛 7—7 III—II 無改變 2 3個月 麻木 休息時疼痛 2—0 III—II 無改變 3 3個月 潰瘍 6—3 無法分級 — 4 1週 潰瘍 3—1 無法分級 未進行 主觀地來說,4例中有3例觀察到疼痛改善。 此外,移植後1個月在第3例之血管造影中觀察.到再 血管化(圖3 )。 客觀評估 -25- 200815026 (22) 表3 病例 觀察期 踝臂血壓指數 數位體積 描記法 熱攝影術 雷射都人勒血流計 經皮氧氣分壓 1 11個月 0·24—0.4 改善 適度改善 無改變 無變化 2 3f@Fl 0.49-^0.66 改善 無改變 無改變 無變化 3 3個月 未進行 改善 適度改善 適度改善 改善 4 1週 未進行 改善 未進行 未進行 未進行 在一些案例中發現踝臂血壓指數與經皮氧氣分壓之改 • 善。第2例於跑步機測試之走動距離顯示顯著改善,自 160米增加至915米。 上述結果顯示造血幹細胞可藉由投服紅血球生成素而 被動員至週邊血液,且週邊阻塞動脈疾病可藉由將週邊單 核細胞移植至局部缺血骨骼肌之血管新生療法治療。 另外,在第一次投服EPO後1週所收集之週邊血液單 核細胞中之CD34陽性細胞數係等於或高於2週後所收集 之單核細胞中的CD34陽性細胞數,這表示在投服EPO後 • 1週收集到之單核細胞相較於2週後收集到之單核細胞可 提供相等或較高之血管新生治療功效。 產業應用性 ^ 本發明之方法及組成物可用於治療局部缺血疾病,諸 如週邊血管疾病。 【圖式簡單說明】 圖1顯示紅血球生成素動員造血幹細胞之FA C S分析 -26- 200815026 (23) 結果。 圖2顯示投服紅血球生成素所動員之造血幹細胞聚落 數量的測量結果;及 圖3顯示已接受紅血球生成素治療之病患(第3例) 於移植週邊血液單核細胞1個月後之血管造影圖。
-27-
Claims (1)
- 200815026 (1) 十、申請專利範圍 1 · 一種用於動員單核細胞至週邊血液以治療局部缺 血性疾病之組成物,其包含作爲活性成分之紅血球生成素 〇 2. —種用於動員單核細胞至週邊血液以刺激再血管 ^ 化之組成物,其包含作爲活性成分之紅血球生成素。 - 3 ·如申請專利範圍第1或2項之組成物,其中該動 φ 員之單核細胞係自個體中收集且之後被投服至該個體。 4·如申請專利範圍第1或2項之組成物,其係於收 集個體週邊血液前之自3至12天投服給該個體。 5 · —種用於治療局部缺血性疾病之組成物,其包含 作爲活性成分之自先前已投服紅血球生成素之個體的週邊 血液中分離之單核細胞。 6· —種用於刺激再血管化之組成物,其包含作爲活 性成分之自先前已投服紅血球生成素之個體的週邊血液中 φ 分離之單核細胞。, 7·如申請專利範圍第5或6項之組成物,其中該紅 血球生成素係於收集週邊血液前之自3至1 2天投服。 ^ 8· —種用於動員CD34陽性細胞至週邊血液以治療局 ^ 部缺血性疾病之組成物,該組成物包含作爲活性成分之紅 血球生成素。 9. 一種用於動員CD34陽性細胞至週邊血液以刺激再 血管化之組成物,其包含作爲活性成分之紅血球生成素。 10* 一種製備用於移植之單核細胞之方法,該法包含 -28- 200815026 (2) 下列步驟: (a )投服紅血球生成素至個體;及 (b )於紅血球生成素投服後約1週,自該個體收集 週邊血液單核細胞。-29-
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