TW200907056A - New method - Google Patents
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- TW200907056A TW200907056A TW097110852A TW97110852A TW200907056A TW 200907056 A TW200907056 A TW 200907056A TW 097110852 A TW097110852 A TW 097110852A TW 97110852 A TW97110852 A TW 97110852A TW 200907056 A TW200907056 A TW 200907056A
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
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- A—HUMAN NECESSITIES
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200907056 九、發明說明： 【發明所屬之技術領域】 本發明係關於融合蛋白及其在酶促治療阿茲海默氏病患 者中之用途。該融合蛋白包含裂解類澱粉β(Αβ)肽之組 份、調節在4聚中之半衰期的另一組份；及視情況連接前 兩種組份之第三組份。 【先前技術】 本發明係關於預防類澱粉斑塊形成及/或生長之方法， V 其係藉由使類澱粉肽與特異性識別類澱粉肽且經由降解或 改質使其失活之酶反應。本發明另外係關於藉由投與具有 改良催化活性及/或選擇性以及在血漿中具延長活性之最 優化類澱粉肽降解沒酶來治療阿茲海默氏病之方法。本發 明亦係關於醫學療法之領域，詳言之係關於神經退化性疾 病之領域，且提供對患有神經退化性疾病（詳言之為阿兹 海默氏病）之患者的腦部類澱粉引發清除機制之方法。此 外’本發明係關於蛋白及肽有效用於引發此等機制之用 C 途。 本發明描述Αβ肽降解分子如何可藉由連接調節穩定性及 在企衆中之半衰期的分子而變成治療相關藥劑。本發明中 所述之Αβ肽降解分子總體而言具有太短之血衆半衰期以致 並不適用作有效治療劑。然而，藉由將此等降解分子與本 發明中所述及例示之調節劑分子組合，則可製造可藉由投 $此等最優化類澱粉肽降解酶融合蛋白而有效用於治療阿 兹海默氏病的功能性藥劑。 I29669.doc 200907056 神經退化性疾病（詳言之阿茲海默氏病（ad))對患者生命 具有強烈的致衰作用。此外，此等疾病構成巨大的健康、 社會及經濟負擔。AD為最常見之年齡相關神經退化性病 況，其影響65歲以上人群之約1 〇%及85歲以上人群之多達 45%(Vickers等人，ZVogre以 k TVeMroWo/og;; 2000，60:139- 1 65)。目前’在美國、歐洲及日本此值總計估計為丨2〇〇萬 病例。此情形將不可避免地隨發達國家老年人數目之人口 統計增加而惡化。在患有AD之個體的腦中出現之神經病 / 理學特點為與異常絲狀結構之出現及神經原纖維纏結之形 成相符的老年斑及深刻細胞支架變化。家族及偶發性病例 兩者均具有細胞外原纖維β類澱粉在腦中沈積作為共同之 病理學特點，咸信其係與神經元功能損傷及神經元損失相 關聯（Younkin S. G., J㈣.Vewro/· 37，287-288, 1995.
Selkoe，D. J.，卿 399, A23_A31，1999; B〇rcheh D R 等 人，17, 1005·1〇13, 1996)。β類澱粉沈積物包含若 干物種之類澱粉β肽（Αβ);尤其Αρη進行性地沈積為類澱 I 粉斑塊。AD為與記憶形成早期不足相關聯之進行性疾病 且取終導致較高級認知功能之完全損壞。AD發病機制之 特有特徵為特定腦區域及神經細胞亞群對退化過程之選擇 哇易知性。4寺定言之，在疾病進展期間，顯葉區及海馬區 早=及更嚴重地受到影響。另一方面，在額葉皮質、枕葉 皮質及小腦中之神經元在很大程度上保持完整且受保護以 免神經退化（Terry等人，▲似& ΜΗ，Μ ία 129669.doc 200907056 遺傳學證據表明在導致家族性AD之許多（若非所有）遺傳 學病況中產生增加量之APWBorchelt D· R.等人，乃 17，1005-1013，1996; Duff K.等人，383，710-713 1996; Scheuner D.等人，Med. 2，864-870, 1996· Citron Μ.等人 ’ D/丨 5，107-1 16, 1998)，表明類 澱粉形成可由Αβο產生增加或降解減少或兩者引起之可能 性（Glabe，C，Mei 6，133-134，2000)。儘管此等為已 歸因於APP、早老素早老素_2基因中之遺 f 傳缺陷的早期發作AD之罕有實例，但晚期發作偶發性AD 之普遍形式迄今具有未知之病因來源。然而，已識別傾向 於使個體發生AD之若干風險因素，其中最顯著者為脂蛋 白元E(AP〇E)之Μ等位基因及胱抑素C(cysutin c)之B等位 基因。神經退化性病症之晚期發作及複雜發病機制對於研 發治療劑造成巨大挑戰。 目前，不存在AD之治癒，甚至不存在診斷具有高機率 之死前AD的方法。然而，β類澱粉已成為用於研發經設計 1 以減少其形成（Vassar，R.等人，286, 735-41，1999) 或以活化加速其自腦部清除之機制的藥物之主要目標。 然而，Schenk 等人（Nature，第 4〇〇 卷，173177, 1999;
Arch. Neurol_，第 57卷，934_936, 2〇〇〇)之第一實驗結果提 出對AD可能之新穎治療策略。過度表現突變人類App(其 中位置717處之胺基酸為苯丙胺酸，而非正常之纈胺酸)之 PDAPP轉殖基因小鼠以年齡及腦區域依賴性方式進行性地 發生AD之彡種神經病理學特點。在ad型神經病變發作之 129669.doc 200907056 别（6週大）或在較大年齡⑴個月）時，#充分確定類殿粉p 沈積及若干後續神經病理學變化時，以♦使轉殖基因動 、免疫彳幼動物之免疫基本上預防發生β類澱粉斑塊形 成、神經炎營養不良及星形膠質細胞增生（astrogliosis)。 治療較大動物亦顯著降低此等AD樣神經病變之程度及進 展。展示Αβ42免疫導致產生抗#抗體且Αβ免疫反應性單 核細胞/微神經膠質細胞在剩餘斑塊區域中顯現。然而， / 活性免疫方法可使人類受檢者承受嚴重副作用及迄今未知 之併發症。
Bard 等人（Nature Medicine，第 6 卷第 8 期， 2〇〇〇)報導外部投與針對類殿粉陳之抗體足以減小類殺粉 負擔。儘管其相對適度之&清含量，但被動投與之抗體能 夠橫穿血腦障壁且進入中樞神經系統，裝飾斑塊且誘導清 除預先存在之類溯;始·。姊、-Τ' 4+ 、 ，、、、'而’甚至針對β肽之被動免疫可 在人類患者中引起不合需要之副作用。 本發明係關於使用重組蛋白以治療阿兹海默氏病患者。 在Αβ肽之新陳代謝中’合成代謝與分解代謝路徑之間的平 衡係微妙的。儘管已將相當大之努力集中在Αβ肽之產生 上，但直到最近對此等肽之清除的強調仍相當少。移除細 胞外Αβ肽似乎經由兩種通用機制來進行；細胞内化及細胞 外降解。本發明描述將補充類殿粉β肽之天然分解代謝過 程的新穎方法。
DeMaUos(舰S 98: 885〇·8855 2〇〇ι)已描述下沈假設 ㈣—-叫’其陳述可藉由降低血聚中之肽濃度而自 129669.doc 200907056 CNS間接地移除Αβ肽。 其使用在血漿中結合Αβ肽之抗體且
已展不有效用於經由在血漿中結合而自CNS移除類澱 粉 β肽。Matsuoka等人（j. Neur〇science，第 23卷：29_33， 2003)已呈現資料，其使用兩種類澱粉p肽結合劑、膠溶素 及GM1，其钳合血漿Αβ且藉此減小或預防腦部澱粉樣變性 移除或消除Αβ肽之另一種方法為使用將類澱粉ρ肽降解 為較小片段而無毒物學作用或具有較低毒物學作用（其更 傾向於清除）之降解酶。Αβ肽之此酶促消化亦將經由下沈 假設機制藉由降低血漿中類澱粉β肽之游離濃度來工作。 然而，亦存在直接清除CNS及/或CSF中之類澱粉β肽的可 能性。此方法將不僅降低Αβ之游離濃度，而且直接清潔來 自全長肽之環境。此方法係有利的，原因在於其將不增加 ν 血漿中Αβ之總（游離及結合）濃度’如在使用諸如抗體之類 澱粉β肽結合劑之病例中所見。存在文獻中所述之在多個 位點降解Αβ肽之酶，例如NEP(Leissring等人，JBC. 278: 37314-37320，2003)。Αβ肽在多個位點之降解將產生易於 自血流清除之小片段。 【發明内容】 本發明之目標為提供能夠降解Αβ肽之融合蛋白。因此， 本％明提供具有式Μ-Α之融合蛋白’其能夠在該類殿粉β 129669.doc -10- 200907056 肽胺基酸序列中之一或多個裂解位點降解 中Μ為延長融合蛋白半衰期 …β肽，其 ^ ^ ^ &、、且伤’且Α為裂解類资 Μ肽之蛋白組份’其中_蛋白組份係、共價連接至A = 組份之N末端部分。 蛋白 在本發明之一態樣中， 酶。 &供融合蛋白，其中A為蛋白
在本發明之另一態樣中，挺# 1 A ^棱供融合蛋白，其中Α為人類 腦啡肽酶（Neprilysin)。 賴 在本發明之另一態樣中，提供融合蛋白，其中A為人類 腦啡肽酶，其中該腦啡肽酶為細胞外腦啡肽酶。 、 在本發明之另一態樣中’提供融合蛋白，其中A為包含 根據SEQlDN〇·卜2、3或4中任一者之胺基酸序列的細 胞外腦啡肽酶。 提供融合蛋白 之Fc部分。在此態樣之一實施例中，該抗體為抗體 在此態樣之另一實施例中，該抗體為IgG2抗體。 在本發明之另一態樣中’提供融合蛋白，其中Μ為來 IgG2抗體之pc部分且a為細胞外腦啡肽酶。 在本發明之另一態樣中 素降解酶。 在本發明之另一態樣中 I 素轉化酶1。 在本發明之另一態樣中 蛋白。 在本發明之另一態樣中 提供融合蛋白’其中A為胰島 提供融合蛋白，其中A為内皮 提供融合蛋白，其中A為支架 其中Μ為抗體 129669.doc 11 200907056 在本發明之另一態樣中，提供包含根據SEQ ID Ν〇 J J 之胺基酸序列的融合蛋白。 在本發明之另一態樣中，提供融合蛋白，其中M為來自 IgG2抗體之Fc部分且A為胰島素降解酶。 在本發明之另一態樣中，提供包含根據SEq id N〇.工2 之胺基酸序列的融合蛋白。 在本發明之另-態樣中’提供融合蛋白，其中M為來自 IgG2抗體之Fc部分且A為内皮素轉化酶ί。 ί 在本發明之另一態樣中，提供力冬扭缺。^ 促贤包含根據SEQ ID NO, 13 之胺基酸序列的融合蛋白。 在本發明之另一態樣中，提供晶ψ八疋二 八丁捉仏嘁合蛋白，其中Μ係選自 聚乙二醇化及糖基化。 其中Μ為 在本發明之另一態樣中，提供融合蛋白 HSA。
提供融合蛋白，其中Μ為HSA 在本發明之另一態樣中 結合域。
在本發明之另一態樣中 結合域。 提供融合蛋白，其中Μ為抗體 其中Μ與Α係 其中L係選自 在本發明之另一態樣中，提供融合蛋白 以連接子L連接在一起。 在本發明之另一態樣中，提供融合蛋白 肽及化學連接子。 種減小類澱粉β肽濃度 明之融合蛋白。在此態 在本發明之另一態樣中，提供一 之方法，該方法包含投與根據本發 129669.doc -12· 200907056 樣=貝把例中’在血衆中實現類澱粉β肽之該減小。在 此態樣之另一實施例中，在CSF中實現類殿粉β肽之該減 小。在此態樣之又一訾# & 士 ^ 霄施例中，在CNS中實現類澱粉β肽 之該減小。 在本發明之另_能接_ + t 心樣中’提供一種能夠降解類澱粉p肽 之醫藥組合物，其g A s 一 "匕s醫樂學上可接受之量的根據本發明 之融合蛋白以及醫筚里 ，、干上可接梵之載劑或賦形劑。 在本發明之另—離槎由 〜、樣中’ k供一種預防及/或治療其中 降解類澱粉β肽為有利夕、法、w i 勹頁和之病況的方法，其包含向需要此預 防及/或治療之哺乳動物f# 孔勒物（包括人類）投與治療有效量之根據 本發明之融合蛋白。 在本發明之另—態樣中， “佚中七供—種預防及/或治療阿茲 海默氏病、全身性殿粉樣變性病或腦類澱粉血管病變之方 法，其包含向需要此預防及/或治療之哺乳動物(包括人類） 投與治療有效量之根據本發明之融合蛋白。 在本發明之另—態樣中，提供-種適用於醫學療法之根 據本發明之融合蛋白。 在本發明之另一態樣中，接供太益^ αη 扠供本發明之融合蛋白在製造
用於預防及/或治療其中降解類澱粉R 艰，奴物P肽為有利的病況之藥 物中的用途。 在本發明之另-態樣中，提供本發明之融合蛋白在製造 用於預防及/或治療阿兹海默氏病、全身性澱粉樣變性病 或腦類澱粉血管病變之藥物中的用诠。—1 4 ^ ^ 丑此態樣之一實施 例中’該藥物減小類澱粉β肽濃度。類 题叙粉β肽之該減小係 129669.doc 200907056 在血漿、CSF及/或CNS中實現。 【實施方式】 除非在特定情況中另外限制，否則在磐個本說明書中所 用之術語係定義如下。 術語”調節劑”係指防止降解 * t 及日加血漿半衰期、減小 :性、減小免疫原性或增加治療性蛋白之生物活性的分 子。例示性調節劑包括Fc域以及線性聚合物（例如’聚乙 一醇（PEG)、聚離胺酸、葡聚糖等）；支鏈聚合物（例如參 見美國專利第4,289,872號、美國專利第5,229,49〇號；w〇 9—3/21259)，脂f ;膽固醇群（諸如類固醇）；碳水化合物或 养聽’或任何天然或合成蛋白、與補救受體結合之多狀或 肽。糖基化亦為經由增加融合蛋白尺寸主要由於清除機制 之改變而可延長企锻半衰期之調節劑的實例。調節劑亦可 包括人類血清白蛋白（脱）結合組份，其藉此延長融合蛋 白之血漿半衰期。 “術δ吾蛋自"或"蛋白組份"係指具有催化活性之分子，其 藉由在胺基酸序列中任何可能位點之蛋白水解裂解來降解 ::截粉(3肽。蛋白之實例包括腦啡肽酶酶以及降解類澱㈣ 之其他催化活性酶。催化抗體亦可用作蛋白部分。蛋白 可為來自任何物種(例如人類、猴、小鼠)之天然存在之變 或使用口理δ又什或分子進化技術設計之變體。蛋白分子 2可為不同多晶型或剪接變體。蛋白分子亦可為來自任何 ，之天然存在變體的改良變體。蛋白尤其可為腦，肽酶 改良變體，其已藉由胺基酸置換而經結構修都以達成改 129669.doc -14- 200907056 改良之選擇性 血漿中的延長 良之特性，諸如對類澱粉β肽增加之活性、 及由於穩疋性增加及/或抑制減小而引起之 活性。 上：D。融口係、指由調節劑分子及蛋白分子組成之分子。 周U可,、知連接至蛋白部分以產生融合蛋白。非共價方 法亦可用以將蛋白連接至調節劑部分。 ' :降解係、指其中將-種起始分子分成兩個或兩個以 上刀子之過私。更特定言之，類澱粉β肽（自胺基酸卜43之 任何尺寸及更小）經裂解以產生與起始分子相比而言較小 之片段。裂解可經由肽鍵水解或將分子分裂為較小部分之 其他類型反應來實現。
術語"原生Fc"係指無論呈單體或多聚體形式之包含由全 抗體/肖化所產生之非抗原結合片段之序列的分子或序列。 原生Fc之原始免疫球蛋白源可為人類來源，且儘管及 IgG2為較佳，但其可為任何免疫球蛋白。原生。係由單體 多肽組成，該等單體多肽可藉由共價（亦即雙硫鍵）及非共 價締合而連接為二聚體或多聚體形式。原生Fc分子之單體 次單位之間的分子間雙硫鍵之數目視類別（例如，、 IgA、IgE)或子類（例如，IgGl、IgG2、IgG3、IgAi、
IgGA2)而介於l至4之範圍内。原生Fc之一種實例為由 之木瓜蛋白酶消化所產生之雙硫鍵接二聚體（參見E1Hs〇n 等人（1982)，iVwc/ez’c 細ι〇: 4〇719)。如本文中所 用之術語"原生Fc"對單體、二聚體及多聚體形式為通用 的0 129669.doc 200907056 術語，，Fc變體”係指自原生Fc經修倚但仍包含補救受體 FcRn之結合位點的分子或序列。公開案w〇 及 WO 96/32478描述例示性Fe變體以及#㈣μ u μ 用，且其係以引用的方式併入本文中。因此，術語"_ 體”包含自非人類原生以人源化之分子或序列。此外，原 生Fc包3可移除之位點，因為其提供本發明之融合分子所 不需要之結構特徵或生物活性。因此，術語"Fc變體，，包含 缺乏一或多個原生Fc位點或殘基之分子或序列，該等位點 f 或殘基影響⑴雙硫鍵形成、（2)與所選宿主細胞之不相容 性、（3)表現於所選宿主細胞中時之N末端非均質性、（4)糖 基化、（5)與補體之相互作用、（6)與Fc受體而非補救受體 之結合或（7)抗體依賴性細胞毒性（Adcc)或涉及於其中。 下文中進一步詳細描述Fc變體。 術語”Fc域”涵蓋如上所定義之原生卜及Fc變體分子及序 列。關於Fc變體及原生Fc ’術語"以域"包括呈單體或多聚 體形式之分子，其無論係自全抗體消化所得或藉由其他方 'v 式而產生。 術語'’藥理學上活性”意謂如此所述之物質經測定具有影 響醫學參數（例如，血壓、血細胞計數、膽固醇含量）或疾 病病況（例如，癌症、自體免疫病症、癡呆）之活性。 術語"類澱粉β肽"或"Αβ肽"意謂與人類Αβ A4蛋白[前驅 體]中之胺基酸序列（一種字母代碼）DAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIAT相關之 任何形式的肽，該胺基酸序列對應於序列中之胺基酸672 129669.doc •16- 200907056 至7 14(胺基酸1 -43)。其亦包括此肽之任何較短形式，諸如 1 -38、1 -40及1 -42，但不侷限於此等形式。此外，類殿粉β 肽具有若干天然存在之形式。將類澱粉β肽之人類形式稱 為Αβ3 9、Αβ40、Αβ41、Αβ42及Αβ43。此等肽之序列及其 與ΑΡΡ前驅體之關係係由Hardy等人，TINS 20，1 55-1 58 (1997)之圖1來說明。舉例而言，Αβ42具有以下序列： H2N-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ue-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-IIe-Ala-OH。Αβ41、Αβ40 及 Αβ39 因自 c末端 分別省略 Ala、Ala-Ile及 Ala-IIe-Val 而不同於 Αβ42。Αβ43 因在C末端存在蘇胺酸殘基而不同於Αβ42。總體而言，類 澱粉β肽意謂涉及於導致阿茲海默氏病之斑塊形成中的肽 形式。 術語”半表期’’係由自血漿移除一半初始濃度之融合蛋白 所用之時間來定義。本發明描述調節血漿中半衰期之方 法。此修飾可產生具有改良藥物動力學特性（例如，活體 内血清半衰期增加)之融合蛋白。延長半衰期意謂自血襞 移除或清除—半初始濃度之融合蛋白耗費更長時間。醫藥 域合物之半衰期係經明確定義且在此項技術中已知。 術”吾連接”意謂在兩個或兩個以上部分之間的丑價或可 :鍵聯。共價鍵聯可(例如)為肽鍵、雙硫鍵、碳碳偶合或 之間共價鍵的任何類型之鍵。可逆鍵聯可（例如） .”、物素-抗生蛋白鏈菌素、抗體-抗原或鍵聯，其歸類為 129669.doc 200907056 此項技術中已知之可逆鍵聯。舉例而言，當以重組形式自 相同質體產生融合蛋白之蛋白部分及調節劑部分時，直接 獲得共價鍵聯，因此在DNA水平上設計連接。 術語，，共價連接，，意謂其間共用電子之兩個原子之間的化 學鍵。共價連接之鍵的實例為肽鍵、雙硫鍵、碳碳偶合。 藉由多肽鍵可將融合蛋白連接在一起，其中可在核糖體上 之轉澤過程期間當產生融合蛋白時實現鍵聯。其他類型之 共價連接組份可由與蛋白上之胺基殘基(例如離胺酸…賈 連接之聚乙二醇化試劑來㈣。化學偶合反應可(例如)為 醯化反應或將兩種組份連接在一起成為融合蛋白之盆他人 適偶合反應。共價連接亦可意謂其中調節劑與蛋白部料 接在一起之兩個位點處的連接子之鍵聯。 術語”裂解位點”意謂肽序列中可由蛋白或酶裂解之特里 性位置/位點。裂解通常係藉由連接兩個胺基酸之狀鍵的 水解而產生。使用翠獨或組合之蛋白或酶，亦可在相同狀 中之多個位點處發生裂解。裂解位點亦可為除肽鍵以外之 其他位點。本發明詳細描述類澱粉P肽之裂解。 術語"結合域"意謂以治療學相關之親和性結合㈣㈣ 肽之=子1。此等分子以大於或等於約106、107、108、
或101GM·】之結合親和力與類殿粉隊結合。i型处人 (但不偈限於）抗體（例如Fab、❿、所有均包括:區I 、單-域）、如在本發明中及文獻中所述之支架蛋白或對類 澱粉β肽具有親和性之合成產生的分子。 術語”蛋白酶”意謂在肽鍵水解中起作用之任何蛋白分 129669.doc -18- 200907056 子。其包括天然存在之蛋白水解酶 益翔突鐵—、〜稽田位點才曰引或 白、蛋白工程方法獲得之其變體、任何蛋 白水解酶片段或包含 或融合蛋白。蛋白酿η 者的任何分子複合物 金屬蛋白酶。 +胱胺酸、天冬胺酸或 ί \
:二文質”或’’肽受質"意謂具有任何胺基酸組成、序列 任何肽、寡肽或蛋白分子，其含有可藉由蛋白酶 式水解之肽鍵。將經水解之肽鍵稱為”裂解位點”。 又據由 Schlechter 及 Berger(Bi〇chem Bi〇physn η· 27 (1967) 157-162)引人之系统進行受質中位置之 編號。將Ν末端鄰近裂解位點之胺基酸殘基編號為Ρ1、 ,Ρ3等’而將c末端鄰近裂解位點之殘基編號為η,、 —Ρ3等。本發明之受質或肽受質為類澱粉^肽。 —術了特異性”意謂蛋白或蛋白酶選擇性地識別及水解特 疋，文質而同時使其他肽受f保持未裂解之能力。特異性 可疋性且疋里地表現。”定性特異性"係指在肽受質之特定 位置$蛋白酶所接受之胺基酸殘基種類。僅接受所有可能 肽又貝中之小部分的蛋白酶具有"高特異性，，。接受幾乎任 何肽又貝之蛋白酶具有”低特異性”。亦將具有極低特異性 之蛋白酶稱為”非特異性蛋白酶，|。 術浯進化蛋白酶（ev〇lved protease)"描述使用無規 PCR、DNA改組或在DNA/RNA水平產生多樣性之其他類型 方法所獲得之任何蛋白酶。描述此等方法之文獻為（例如）
Drummond, B.L. Iverson, G. Georgiou及 F.H. Arnold, 129669.doc 19 200907056
Journal of Molecular Biology 3 50: 806-816 (2005)及 S. McQ 及 D.S. Tawfik，Biochemistry 44: 5444-5452 (2005)。亦在 文獻（例如 Directed Enzyme Evolution: Screening and
Selection Meth〇ds(Meth〇ds ^ M〇lecular 出。丨〇㈣編輯：
Frances H Arnold及 George Georgiou，第 230卷，2003及其 中之參考文獻）中描述在所產生多樣性中進行篩檢及選擇 之各種方法。各種策略均可用以選擇特性，如增加之穩定 ί 性、增加之活性、改良之選擇性及藉由已知及未知抑制劑 而減小之抑制。 術°。經改良蛋白酶"描述若需要則具有較高催化活性之 4何蛋白酶變體。然而，在一些情況下，較低催化活性可 為較佳的。Μ改良蛋白酶亦可意謂與另—受質相比，比原 始蛋白酶更有效地裂解特定受質之變體。經改良意謂更佳 2 !·生諸如催化活性及/或選擇性以獲得更優化之醫藥 化合物。經改良蛋白酶亦可意謂在（例如）血衆血液（活體外 及/或二舌體内)中具有增加之穩定性的變體。經改良蛋白酶 可明在（例如）血漿血液（活體外及/或活體内）中具有減 m h'a活可藉由因改變胺基酸序列 2 =解w減小蛋白酶之蛋白水解降解來實現。減小 修飾蛋由以(例如)聚乙二醇化及7或糖基化 藉ώ、 、 現以保護蛋白以免裂解。減小失活亦可 小未:乂已知或未知抑制劑來減小蛋白酶之抑制來實現。減 漿抑制劑之抑制可藉由“變體以直 減小蛋白酶活性之抑制來實現。 策中 129669.doc -20- 200907056 —術語”人類腦哪肽酶”係指任何天然形式之人類腦。非 酶。此包括天然存在於人類群體中之所有剪接及多晶型變 體本發明中描述多種形式之人類腦啡肽酶（SEQ ID 1 至’Μ。術語亦包括人類腦啡肽酶之片段或擴展變體，以及 如”經改良蛋白酶”中所述之人類腦啡肽酶的改良變體。 術語”支架蛋白”描述結合類澱粉β肽之任何蛋白。支架 蛋白之實例為澱粉酶抑肽（tendamistat)、親和2 (/fibody)、抗運載蛋白（anticaHn)及錨蛋白⑻。此 等支架蛋白通常經設計且係基於剛性核心結構及可經隨機 化以用於識別結合劑之部分、迴路、表面或空腔。文獻中 充分描述此等支架蛋白。 本發明提出投與最優化重組Αβ降解酶藉由減小腦部Αβ 含量來抑制類澱粉斑塊形成之可能性。因此，亦將減小類 殿粉斑塊相關之星形膠質細胞增生。 在本發明之一態樣中，治療性化合物具有完全人類來 源。融合蛋白包含使用具有最低可能免疫原活性之連接子 連接在一起之完全人類蛋白。 與諸如抗體之結合分子相比，使用降解酶之優勢在於： •與結合方法相比，以類澱粉β肽之酶來降解將直接移 除毒性作用，在該結合方法中’若不足夠快速地清除 與類澱粉β肽複合之結合分子’則類厥粉β狀之浪度可 潛在地增加。尤其若類澱粉β肽濃度外部增加，則此 可係有害的。 •催化降解類澱粉β肽將比結合更有效地移除肽。僅催 129669.doc -21 - 200907056 化置之降解酶將為移除足夠類澱粉β肽所必需，而諸 々抗體之、、.α合分子，對於治療作用而言則將需要化學 計量之量。此將對治療性治療所需之量具有重大與 響。 •若結合分子為抗體且橫穿刪，從而使得可與斑塊中 之類殿粉β肽結合，則可能存在有害的電位免疫學反 應另一方面，催化融合蛋白將不與斑塊結合且使用 Fc反應性，但僅減小類澱粉β肽之游離濃度。因此， f 们匕酶將料解游離彙集之類殿粉β肽。如抗體之結 合劑可潛在地進入CNS中且經由Fc活性而溶解斑塊。 若大量類澱粉β肽在斑塊附近釋放，則此可為不利 的，且其對細胞具有毒性。 Αβ刀解代謝中之一種重要酶為腦啡肽酶，其亦稱為中性 内狀酶-24.U 或 NEPDlwaU 等人（ν^γ6 Me — , & 143_ 149，2000)展不經由藉由如經生物化學分析與腦啡肽酶類 似或一致之NEP進行之受限蛋白分解，從而使A(3i42肽經 1 受完全降解。一貫地，NEP抑制劑輸注導致内源性入042在 細中之生物化學及病理學沈積。已發現，此NEp催化之蛋 白分解因此限制Αβ42分解代謝之速率。 ΝΕΡ為94 kD ’與若干生物活性肽之失活相關聯之兩個 膜結合Zn-金屬肽酶類型，該等生物活性肽包括腦啡肽、 速激肽、緩激肽、内皮素及心房利尿鈉肽。NEp存在於 CNS中之肽能神經元中且其在腦中之表現係以細胞特異性 方式來調節（Roques Β· P.等人，以.心v· 45, 87- 129669.doc -22- 200907056 146，1993; Lu B.等人，乂 五Χρ· 181，2271-2275, 1995.
Lu B.等人 ’ d㈣5W. 780, 156-163, 1996)。儘 管2型NEP轉錄在CNS中不存在，但丨型及3型轉錄分別在神 經元中及胼胝體之寡樹突神經膠質細胞中局部化（Li c•等 人 ’ Jj/o/. C/2㈣.270, 5723-5728, 1995)。蛋白酶及内肽 酶之腦啡肽酶家族包含結構或功能同源之NEp成員，諸如 最近所述之NEP II基因及其同功異型物（〇uimet τ.等人，
Biochem. Biophys. Res. Commun. 271.565-570，2QQ0),其 以與NEP互補之模式表現於CNS中。此家族之另一成員為 NL-1(腦啡肽酶狀1)，其係藉由NEP抑制劑鱗阿米酮 (phosphoramidon)得以有效抑制之可溶性蛋白（Ghaddar G 等人，价oc/zem. 347: 419-429，2000)。 亦已描述已知分解代謝Αβ之其他酶。鋅金屬肽酶胰島素 降解酶（IDE，EC. 3.4.22.11)將八01-4()及八01_42裂解為似乎為 無害產物之物質。IDE為真肽酶；其並不水解蛋白。該酶 活體外裂解有限數目之肽’包括胰島素及胰島素相關肽、 β内啡肽及Αβ肽。IDE已表明為生理學Αβ代謝酶之一種（w. Q. Qui 等人（1998) «/ _βζ’ο/. C/zem. 273, 32730-32738)。 Kurichkin及 Goto(I. V. Kurochkin 及 S. Gato (1994)
Leii. 345，33-37)首先報導胰島素降解酶可水解Αβ,，。此 發現在兩個獨立研究中得到證實（W. Q. Qui等人（1998) J. Biol. Ch&m. 273, 32730-32738 » R. McDermotts A. M Gibson (1997) 22，49-56)。此外，最近識 別為Αβ降解酶之金屬蛋白酶24.1 5( Yam in R.等人J, 5 129669.doc -23- 200907056 27么18777-18784，1999)亦反應於Αβ注射而不改 變。血管收縮素轉化酶（ACE)(—種無關神經元ζη金屬内肽 酶）亦已作為可能之Αβ肽降解酶而提及（Barnes Ν. Μ.等 人，五wr. 乂 200，289-292，1991; Alvarez R.等 人，J. Neurol. Neurosurg. Psychiatry 67, 733-736, 1999;
Amouyel P,等人，从 r· Id. *SW. 903，437-441, 2000)，其對Αβ無已知之親和性（McDermott J. R.及Gibson A· M.，.心义 22，49-56，1997)。組織蛋白酶 B(C at B)亦已展示為降解Αβ肽（Neuron· 2006年9月21曰； 51(6):703-14)。 所用來自腦啡肽酶之序列可為蛋白之細胞外部分。將細 胞外部分定義為腦啡肽酶之部分，其經定義係位於膜區以 外。本發明亦包括腦啡肽酶之完整序列作為類澱粉p肽降 解組份之用途。本發明亦包含腦啡肽酶之較小片段，只要 保持針對類澱粉β肽之催化活性即可。本發明亦包含腦排 肽酶之任何多態型變體及剪接變體。本發明亦包含腦啡肽 酶之任何改良變體。 本發明描述在Αβ肽形成類澱粉斑塊之前水解Αβ肽或至 少預防現存斑塊進一步發展之新穎及替代性策略。亦可能 藉由水解與游離Αβ肽平衡之任何斑塊衍生Αρ肽來移除^ 存斑塊。 本發明之另一實施例係指包含以高親和性結合類澱粉β 肽之一部分的分子。此親和性在結合親和性中係低於微莫 耳。類澱粉β肽之結合親和性在結合親和性中較佳為奈莫 129669.doc -24- 200907056 耳。與類澱粉β肽之相互作用中所涉及之另一部分為在類 殿粉β肽結構中之-或多個位點處裂解類殿粉ρ肽之活性& 份。組合與催化活性部分連接在一起之結合部分(兩者均 識別類殿粉β肽)之原因在於結合部分結合類殿粉β肽且藉 ㈣加局《度結合部分與催化部分）與解離形式之類 歲粉β肽結合。一些與解離形式特異性結合而不與聚集形 式結合。一些與聚集及解離形式均結合。一些此等抗體與 類殺粉β肽之天然、存在之短形式⑽結合（亦即以共價方式或 以另-方式連接在-起）以藉由因雙官能分子中所設計之 鍵聯而局部圍繞之活性部分來裂解。類殿粉眯結合組份 與類澱粉Ρ肽降解組份之間的鍵聯較佳由具有或不具有連 接子組份之血漿半衰期調節劑組份來介導。
V 本毛月之些實施例中’治療劑包括與類澱粉障或 類殿：斑塊之其他組份特異性結合之融合蛋白。此化合物 °為單株抗體或多株抗體或任何其他類澱粉ρ肽結合劑之 一部=。此等化合物以大於或等於約ι〇6、ίο?、1〇8、1〇9 或ίο1。Μ-丨之結合親和力與類澱粉ρ肽結合。此等結合組份 車父佳與類澱粉β肽降解組份連接。 本發明之-態樣係關於抗體之,％域”與融合蛋白中之類 殿粉β肽降解組份的組合。抗體包含兩個功能上獨立之部 分，稱為” Μ"之可變域’其結合抗原，及稱為"Fc"之怪定 其與諸如補體活化及㈣細胞攻擊之效應功能相關 聯。Fc具有長血清半㈣，而—短命㈣⑽等人㈣外 337· 525-3 1)。當與治療性蛋白一起構築時，以域 129669.doc -25- 200907056 可提供較長之半衰期或併人諸如卜受體結合、蛋白A結 合、補體固定及或許甚至胎盤轉移之功能。 根據本發明之較佳分子為Fc連接之類澱粉^肽降解蛋 白，諸如NEP相關蛋白。 在標題為”M〇dified Peptides as ⑽㈣仏 Agents”（w〇 99/25044)之公開案中詳細論述蛋白治療劑藉由與抗體之& 域融《之有用修飾。該公開案論述與諸如pEG、葡聚糖或 FC區之’'媒劑，，鍵聯。文獻中已描述與Fc域之C端部分連接 為一種可能之方法（Pr〇tein Eng 1998 ιι:495_ 5⑼）。此許 可N端鍵聯於融合蛋白之蛋白部分上。本發明描述此方法 及使用此策略獲得具有活體内功效最優化特性的融合蛋白 之有利作用。
IgG分子與對於IgG類抗體具有特異性之三類Fc受體 (FcR)(亦即FcryRI、FcyRII及FcyRm)相互作用。在較佳實 施例中，融合蛋白之免疫球蛋白（Ig)組份具有一種IgG之恆 定區的至少一部分，該1gG對於Fc^RI、FqRII或FcyRln中 之至y —者具有低結合親和性。在本發明之一態樣中，藉 由使用重鏈同種型作為對細胞上之Fc受體具有減小結合親 和性之融合搭配物，從而減小融合蛋白對Fc受體之結合親 矛〖生舉例而言，人類IgG 1及IgG3均已報導為以高親和性 與FcRyI結合，而IgG4結合要差1〇倍，且IgG2完全不結 。已報導〗gG與Fc受體結合之重要序列位於ch2域中。 因此，在較佳實施例中，藉由將IgG2*IgG4之至少CH2域 連接至第二非免疫球蛋白蛋白來獲得具有增強活體内循環 129669.doc • 26 - 200907056 半哀期之基於抗體的融合蛋白。對於四種已知之igG同種 型舉例而言，已知IgG1(CYl)及IgG3(CY3)以高親和性結合 ，而IgG4(CY4)具有低1〇倍之結合親和性，且
IgG2(Cy2)並不與FcRyl結合。 在一實施例中，融合蛋白之A(3肽降解組份為酶。本文中 使用術語"酶”以描述蛋白、其類似物及其片段，其具有作 為蛋白酶或肽酶之活性。酶較佳包括絲胺酸蛋白酶、天冬 胺酸蛋白_、金屬蛋白酶及半胱胺酸蛋白酶。本發明之融 合蛋白較佳顯示酶促生物活性。 在另一實施例中，免疫球蛋白域係選自由IgG2Fc域、 IgG之重鏈及IgG之輕鏈組成之群。在另一實施例中，融合 蛋白中之抗體的恆定區將具有人類來源，且屬於衍生自 IgG類免疫球蛋白（詳言之來自IgG1、工仰、工仰或邮4 類，杈佳來自IgG2或IgG4類）之免疫球蛋白家族。亦或者 可能使用屬於來自其他哺乳動物，詳言之來自齧齒動物或 靈長類動物之IgG類的免疫球蛋白之恆定區；然而根據本 發明亦可能使用免疫球蛋白類IgD、IgM、IgA或邮之怪定 區。存在於根據本發明之構築體中的抗體片段通常將包含 Fc域CH3或其部分，及]^域（；^2之至少一部分區段。或者 亦可能設想根據本發明之融合構築體，其含有CH3域及鉸 鏈區作為組份（A)以用於二聚化作用。 然而，亦可能使用見於原生狀態之免疫球蛋白序列的衍 生物，詳言之為含有置換、缺失及/或插入中至少一者之 彼等變體(本文統稱為術語"變體”）。此等變體通常與原生 129669.doc •27· 200907056 序列具有至少90。/。’較佳至少95%且更佳至少98%之序列 一致性。在此上下文中尤其較佳之變體為置換變體，其與 各別原生序列相比通常含有小於1 〇個，較佳小於5個，且 極尤其較佳小於3個置換。注意以下較佳之置換可能性： 以 Met、Val、Leu、lie、Phe、His 或 Tyr 置換 Trp，或反之 亦然；以Ser、Thr、Gly、Va卜lie或Leu置換Ala，或反之 亦然；以Gin、Asp或Asn置換Glu，或反之亦然；以giu、 Gin或Asn置換Asp’或反之亦然；以Lys置換Arg，或反之 亦然’·以Thr、Ala ' Val或Cys置換Ser，或反之亦然；以 His、Phe或Trp置換Tyr ’或反之亦然；以其他19個原生胺 基酸中之一者置換Gly或Pro，或反之亦然。 可溶性受體IgG融合蛋白為常見之免疫學試劑且此項技 術中已知其構築方法（例如參見美國專利第5,225,538號）。 功能性類澱粉β肽降解域可與衍生自免疫球蛋白類或子類 之免疫球蛋白Fc域融合。屬於不同lg類或子類之抗體的Fc 域可活化各種次級效應功能。當藉由同源Fc受體結合卜域 時’發生活化。次級效應功能包括活化補體系統以橫穿胎 盤且結合各種微生物蛋白之能力。在R〇itt等人， Immunology, p. 4.8(Mosby-Year Book Europe Ltd.，第 3 版’ 1 993)中描述不同類及子類免疫球蛋白之特性。抗原 結合IgGl、IgG3及IgM抗體之Fc域可活化補體酶級聯。 IgG2之Fc域似乎有效性較小’且以〇4、IgA、IgD及IgE之 Fc域在活化補體時為無效的。因此可基於Fc域之相關次級 效應功能是否為特定免疫反應或以類澱粉β肽降解Fc融合 129669.doc -28- 200907056 蛋白治療之疾病所需來選擇Fc域。若損害或殺死目標細胞 將為有利的，則可選擇尤其活性之以域（1§(}1)以製造類澱 粉β肽降解^融合蛋白。或者，若需要產生類澱粉p肽降解 Fc融合而不觸發補體系統，則可選擇非活性Fc域。 本發明描述具有連接至以部分之催化組份而非直接結合組 份的融合蛋白。此意謂來自Fc之作用及活性將受限，因為 。午夕Fc作用均得、經由結合來介導。舉例而言，補體活化係 視結合及網路形成而定。 / 免疫球蛋白片段之C末端，根據本發明之融合構築體通 常（但非必要）在催化部分與調節劑部& t間含有過渡區， 該過渡區X可含有連接子序列，此連接子序魏佳為狀序 列。此肽序列可具有H@與至多7G個胺基酸之間的長度， 適當時甚至更多胺基酸，較佳10至5〇個胺基酸，且尤其較 佳為12與30個之間的胺基酸。過渡序列之連接區可由盆他 可（例如）對應於DNA限制裂解位點之短肽序列側接。熟習 此項技術者自分子生物學所熟悉之任何限制裂解位點均可 用於此連接。合適之連接子序龍佳為人造序列，直含有 高數目之脯胺酸殘基(例如在連接區中之每隔一個位置卜 且除此之外，較佳具有總體親水性特徵 酸殘基組成之連接子序列為較佳的。親水性特徵較佳可_ ::至少-個胺基酸來達成，該胺基酸具有正電荷(例： 離胺酸或精胺酸）或負雷；^ (也丨』* ’次員電何(例如天冬胺酸或麩胺酸）。納體 而言’連接區因此亦較佳含有高數目之甘胺酸及/或脯 酸殘基以賦予連接區以必要之可撓性及/或剛性。 129669.doc •29- 200907056 ^而，例如安置於細胞外但立即起作用（亦即在細胞臈 之耵）之屬於NEP家族之配位體的彼等片段之原生序列適當 %亦在置換、缺失或插入原生區段之後適合用作連接子。 此等片段較佳為細胞外跟隨於跨臈區後之5〇 AA，或為此 等第一 50 AA之次片段。然而，較佳為與相應天然人類序 列具有至少85%序列—致性之此等區段，尤其極佳為至少 95%序列一致性且尤其較佳為至少99%序列一致性，以限 制此等連接區在根據本發明之融合蛋白中的免疫原性且不 引發任何内在體液性防禦反應。在本發明之上下文中，連 接區應較佳不具有任何免疫原性。 然而，作為與類澱粉β肽降解組份及血漿半衰期調節劑 組份連接之肽序列的替代，藉由醯胺狀鍵，亦可能使用具 有非肽或假肽性質或基於非共價鍵之化合物。就此而論可 提及之實例詳言之為Ν_羥基琥珀醯亞胺酯及雜雙官能連接 子，諸如Ν-琥珀醯亞胺基_3_(2_吡啶基二_硫基）丙酸酯 (SPDP)或類似交聯劑。 調節血漿半衰期之其他方法為使用聚乙二醇化或增加分 子量之其他類型修飾，諸如糖基化。 如上所述，亦可使用聚合物調節劑。目前可得用於連接 適用作調節劑之化學部分的各種方式，例如參見標題為 "N-Terminally Chemically Modified Protein Compositions and Methods，’’之專利申請案w〇 96/1 1953，其係以全文引 用的方式併入本文中。除其他事物以外，此PCT公開案揭 示水溶性聚合物與蛋白之N末端的選擇性連接。 129669.doc 30- 200907056 較佳聚合物調節劑為聚乙二醇(PEG)。PEG基團可具有 任何便利之分子量且可為線性或支鍵。咖之平均分子量 將較佳介於約2千道爾頓⑽”）至約i〇〇 kDa，更佳約$心 ^約50 kDa，最佳約5 kDa至約1〇咖之範圍内。咖美團 一般將經由經PEG部分上之反應性基團（例如，㉒㈣、 ^醇或醋基）與化合物上之反應性基團（例如，駿、„或 西曰基）酸化或還原性燒基化而連接至本發明之化合物。 適用於蛋白之聚乙二醇化的策略係由經由在溶液中形成 宜、輕鍵來組合各自帶有對其他者具相互反應性之特定官能 =的蛋白與咖部分而組成。蛋白可以習知重組表現技術 來I備。在特異性位點以適當官能基將蛋白”預活化”。純 化且充分表徵前驅體’隨後使其與pEG部分反應。蛋白與 PEG之連接通t發生於水相中且可易於藉由逆相分析型 LC來皿’則。聚乙二醇化蛋白可易於藉由製備型HPLC純 由刀析型HPLC、胺基酸分析及雷射解吸附質 來表徵。 多畴聚合物為可用於蛋白修飾之另一類型水溶性聚合 物 '葡聚糖為由主要由α1_6鍵連接之葡萄糖的個別次單位 組成之多醣聚合物。葡聚糖本身以許多分子量範圍可得， 2心約之分子量可得。葡聚糖為料 發月中獨立或與另-調節劑(例如FC)組合用作調節劑 之合適水溶性¥人 Α 。物’例如參見w〇 96/1 1953及WO 96/05309。已起道办、， 導與治療或診斷性免疫球蛋白共軛之葡聚 ’用途’例如參見歐洲專利公開案ΕΡ 〇 315 456,其以 129669.doc 200907056 弓I用的方式併入本文中。當使用葡聚糖作為根據本發明之 媒劑時，具有約1 kD至約20 kD之葡聚糖為較佳的。 碳水化合物（寡醣）基團可便利地連接至已知為蛋白中之 糖基化位點的位點。一般而言，〇連接之寡醣連接至絲胺 酸（Ser)或蘇胺酸（Thr)殘基，而N連接之寡醣連接至天冬醯 胺（Asn)殘基，此係當該等殘基為序列Asn_x_Ser/Thr之部 分時，其中X可為除脯胺酸以外之任何胺基酸。X較佳為 除脯胺酸以外之19個天然存在之胺基酸中的一者。n連接 ( 及〇連接寡醣及見於各類型中之糖殘基的結構係不同的。 通常見於兩者中之一種類型的糖為N_乙醯神經胺糖酸⑺-acetylneuraminic acid)(稱為唾液酸）。唾液酸通常為N連接 及〇連接寡醣之末端殘基，且由於其負電荷，因此其可賦 予糖基化化合物以酸性特性。此（等）位點可併入本發明化 合物之連接子中且較佳在多肽化合物（例如在諸如Ch〇、 BHK、COS之哺乳動物細胞中）之重組產生期間藉由細胞來 糖基化。然而，此等位點可藉由此項技術中已知之合成或 ^ 半合成程序而進一步糖基化。適用於糖基化之胺基酸可併 入調節劑及蛋白部分中之特異性位點中。用於設計此等特 異性胺基酸之較佳技術為定點突變或類似方法。其他可能 之修部包括脯胺酸及離胺酸之羥基化；絲胺醯基或蘇胺醯 基殘基之輕基之碟酸化；Cys中之硫原子之氧化；離胺 酸、精胺酸及組胺酸側鏈之〇^胺基之曱基化。Creighton， Proteins. Structure and Molecule Properties (W. H.
Freeman & Co.，San Francisco)，第 79-86 頁（1983)。因此， 129669.doc -32- 200907056 可設計類殿粉β肽降解組份中之糖基化位點。舉例而言， 修飾較佳位於腦啡肽酶結構表面上之殘基以允許糖基化。 腦啡肽酶之三維結構為已知的且可用以選擇合適胺基酸置 換以引入糖基化及聚乙二醇化位點。例如使用Asn_x_ Ser/Thr序列來引人糖基化位點。對於聚乙二醇化而言，例 如將合適表面暴露之胺基酸置換為胱胺酸殘基以特異性且 有效偶合聚乙二醇化組份。 本發明之化合物亦可在DNA水平上改變。化合物之任何 部分的DNA序列可改變為與所選宿主細胞更相容之密碼 子。對於作為較佳宿主細胞之大腸桿菌（五⑺⑺而言，此 項技術中已知最優化之密碼子。密碼子可經取代以消除限 制位點或包括沉默限制位點，其可有助於所選宿主細胞中 之DNA處理。可修飾媒劑、連接子及肽DNA序列以包括前 述序列改變中之任一者。 v 連接子：任何"連接子”基團均為可選的。當存在時，其 化學結構並不關鍵，因為其主要充當間隔劑。連接子較佳 由藉由肽鍵連接在一起之胺基酸構成。因此，在較佳實施 例中，連接子係由1至20個藉由肽鍵連接之胺基酸組成， 其中胺基酸係選自20個天然存在之胺基酸。如熟習此項技 術者所充分瞭解，可糖基化一些此等胺基酸。在更佳實施 例中’ 1至20個胺基酸係選自甘胺酸、丙胺酸、脯胺酸、 天冬醯胺、麩醯胺酸及離胺酸。甚至更佳地，連接子由無 位阻之大部分胺基酸（諸如甘胺酸及丙胺酸）組成。因此， 較佳連接子為聚甘胺酸（尤其（Gly)4、（Gly)5)、聚（Gly_Ala) 129669.doc -33- 200907056 及聚丙胺酸。 ^白酶之定量特異性在廣泛範圍内變化。存在已知之極 非特異性蛋白酶’諸如裂解所有 白丙胺酸、纈胺酸或 ;胺酸殘基之多肽的木瓜蛋白酶，或裂解所有含有精胺酸 :離胺酸殘基之多狀的騰蛋白酶。另-方面，存在= 向度特異性蛋白酶，諸士禮少结 @ u 僅在早—特異性序列裂解纖溶酶 原之組織型纖溶酶原活化劑_)。具有高受質特里性之 蛋白酶在調節活有機體之蛋白功能中起重要作用。多狀為 質，特：性裂解(例如)活化前驅體蛋白或去活化活性蛋： 或酶错此调即其功能。將具有高受質特異性之若干蛋白 2用於醫學應用中。藉由裂解特異性多肽受質進行活化或 去^匕的醫藥實例為在急性心肌梗塞令應用t_pA，其活化 纖溶酶原以溶解血總祕1 /合解血纖維蛋白凝塊，或在中風中應用安克洛 酶（Ancrod)，其去活化血 見 且增強其運輪原，猎此減小血液黏度 二運輪％力。儘管t_PA為在人類域調節中具有必 而’ A類蛋白酶’但安克洛酶為非人類蛋白酶。其係 自毒蛇馬來亞紅口蝮蛇（々—⑽⑽―中分離， =::::要r，，存在少數具有治_ 由投-举物來…其識別通常具高度偶然性。藉 活化特異性蛋病通常係基於由在患者體内活化或去 源性+、_、、之樂物起始之分子機制，無論其為内 等目標之1感染微生物或病毒之蛋白。儘管化學藥物對此 地_數百^==:解或預測’但蛋白藥物能夠特異性 '、蛋白中之此等目標蛋白6具有識別其他 129669.doc -34- 200907056 蛋白之内在可能性的蛋白 酶。儘管存在巨大數目 =為抗體、受體及蛋白 白酶可用以定址此等目標蛋：：蛋白，但現今僅極少蛋 性，因此蛋白醢 於蛋白酶之蛋白水解活 蛋白_尤其適用於蛋白或 慮人類I白拄, 目心之失活。當僅考 頰蛋白時’潛在目標蛋白之數 人類基因組包的。據估計 編碼不同蛋白。呼多此等;個之間的基因’其每-者 此為，、” +/ 4蛋白或肽係與人類疾病有關且因 ’’’、’曰之醫藥目標。藉由篩檢 呈有牿定—α & 杈大…、刀離物，不可能發現 蛋白Η 之此蛋白酶。因此’需要最優化已知 蛋白扭或包括催化抗體之其他支架蛋白的催化選擇性。 此項技術中已知具有已知特異性之蛋白酶的選擇系統， 自 Smith 等人 ’ Proc· Nat1· Acad. Sci USA，第 88 卷 (991)如例不，該系統包含酵母轉錄因子GAL4作為可選 擇私6己、與TE V蛋白酶結合插入GAL4中之確定及可裂解 序歹丨肩碱解將DNA結合域自轉錄活化域分離且以此 使付轉錄因子失活。可藉由量熱檢定或藉由在自殺受質2_ 氧半乳糖上遥擇來偵測所得細胞代謝半乳糖之表型無能 性。 另外’先前由Harris等人（US 2002/022243)所述，可藉由 使用具有例如基於如ACC之基團之螢光部分的修飾之肽受 質來進行選擇。 可使用相同或類似方法以識別或製造如本發明中所述之 有效類厥粉β肽降解組份。設計此類澱粉β肽降解組份之彼 起始點可為針對類澱粉β肽具有一些活性之酶或完全不具 129669.doc -35 - 200907056 有活性之酶。其他組份可為支架 經隨機化以具有針對類澱粉β肽之活性。：：：性£域係 支架蛋白，其中支架結構之—部分為==獻中描述各種 m ^ 1刀為將Ik機化部分保持於 相對固疋位置以產生結合或活性位 澱粉β肽具有一些活性之酶 〜構。針對類 缺蛋白酶。舉▲為降解類搬粉障之天 =啡=I/藉由基本原理設計或更隨機方法 术·»又。t細啡肽酶以使盆爭古六+从从上 八更有效作為類搬粉β肽降解組份。 =有，改變序列特異性之蛋白水解酶的實 原則^為已知。可藉由其表現及選擇系統將其分類。遺傳 選^明在生物體内產生蛋白酶或任何其他蛋白，該蛋白 扭或任何其他蛋白能夠裂解前驅體蛋白，前驅體蛋白又引 起產生其之生物體之生長行為的改變。可自具有不同蛋白 酶之生物體群體來選擇具有經改變生長行為之彼等生物 體。DaV1S等人（美國專利第號）報導此原理。嗟菌 體系統之產生視嗟菌體蛋白之裂解而定，嗤菌體蛋白在蛋 白水解酶或能夠裂解嗟菌體蛋白之抗體存在下經活化。所 選蛋白水解酶、支架或抗體將具有裂解胺基酸序列以活化 噬菌體產生之能力。 報導產生具有經改變序列特異性之蛋白水解酶與膜結合 蛋白酶之系統。Iv⑽n等人（w〇 98/49描 胞表面上之膜結合蛋白酶的表現系統。實驗設計之= 素為催化反應必須在細胞表面進行，亦即受質及產物必須 保持與在表面上表現酶之細菌缔合。選擇系統之另一實例 為使用 FACS 揀選（Varadarajan等人，proc. Natl Aead % 129669.doc •36- 200907056 USA，第 1〇2卷，6855 (2〇〇5))，直力 其在細胞表面上表現活性 蛋白且棟選含有具有改良特性之變體的細胞。其展示 白酶裂解位點具特異性之三百萬倍改變。 亦已知產生具有經改變序列特異性之蛋白水解酶盥自八 泌蛋白酶之系統。滅等人（W〇 98/11237)描述自分^ /
V 白酶之表現系統。實驗設計之基本要素為催化反應在蛋白 酶本身上起作用，其係藉由膜結合前驅體分子之自體蛋白 水解處理以自細胞膜將成熟蛋白酶釋放至細胞外環产中 等人（獨99/1蘭）揭示適用於改變蛋白酶二異性 之異源細胞系統。該系統包含轉錄因子前驅體，1中轉錄 因子經由蛋白酶裂解位點與臈錯定域相連接。藉由蛋白酶 在蛋白酶裂解位點之裂解釋放轉錄因子，轉錄因子又起始 在各別啟動子控制下之目標基因的表現。改變特異性之‘ 驗設計在於以修飾序列插入蛋白酶裂解位點且使蛋白酶姐 受突變。 、 根據本發明，任何蛋白或肽均可直接使用或作為產生合 適類殿粉β肽降解組份之起始點。舉例而言，根據本發 明，任何蛋白酶均可用作第一蛋白酶。較佳使用具有人類 來源之任何蛋白或肽。若使用通常存在於人體内之天狄蛋 白或肽’則最小可能之改變為較佳的。在一些方法中，同 時投與具有不同結合特異性及/或降解活性之兩種或兩種 乂上心蛋白’在該情況下’所投與之各融合蛋白的劑量 屬於指示範圍内。通常以多時機投與融合蛋白。單次劑量 之間的間隔例如可為每週、每月、每三個月或每年。間隔 129669.doc -37- 200907056 =為不定期的’如藉由量測患者血襞中融合蛋白之血液 含量所指示。在-些方法中，調節劑量以達成卜簡 叫/⑹之灰漿融合蛋白濃度且在―些方法中為25_则 μδ/π^。亦在一些方法中，言周節劑量以達成“麵參R 血漿融合蛋白濃度且在-些方法中為25,0 ng/ml。或 者，融合蛋白可以持續釋放型調配物形式投與，在該情況 下需要較不頻繁之投藥。劑量及頻率視融合蛋白在患者體 内之半衰期而變化。一般而言，具有Fc部分之融合蛋白展 不長半衰期。投藥之劑量及頻率可視治療為預防性或治療 眭而變化。在預防性應用中，歷經長時間段以相對不頻繁 t間隔投與相對低之劑量。—些患者在其餘生中繼續接受 /口療。在治療性應用中，有時需要以相對短間隔之相對高 =直至疾病進展減小或終止’且較佳直至患者展示疾病 二:：部分或完全改善。其後，該專利可作為預防性方案 =。預測可以與諸如抗體之結合劑相比而言較低之劑 里奴/、催化活性之類澱粉P肽降解融合蛋白。 本發明之醫藥組合物中之活性成份的實際劑量水平可改 ’s、、則更在對患者無毒性之情況下獲得對達成特定 組合物及投藥模式之所需治療反應有效的活性成份:曰、 所選劑量水平將視多種藥物動力學因素而$，該等因L 括所用本發明之特定組合物或其醋 4 藥途徑;投藥時間；所用特定化合物之排泄速=落投 續期間；其他與所用特定組合物組合使用之藥物、=持 斗，待b療患者之年齡、性別、重量、病況、一 I29669.doc -38- 200907056 般健康狀況及先前病史及醫學技術中所熟知之類似因素。 本文所引用之所有公開案或專利均以全文引用的方式併 入本文中，因為其展示本發明產生時之技術狀態及/或提 供對本發明之描述及實現。公開案係指任何科學或專利公 開案’或任何其他以任何媒體格式（包括所有記錄、電子 或印刷格式）可得之資訊。以下參考文獻係以全文引用的 方式併入本文中：八旧^以等人編，Current ^
Molecular Biology, j〇hn Wiley & Sons, Inc., NY, N.Y. (1987-2001); Sambrook 等人，Molecular cl〇ning: a
Laboratory Manual，第 2版，c〇ld SpHng Η_〇Γ，N Y (1989); Harlow^Lane, antibodies, a Laboratory Manual, Cold Spring Harbor，N.Y. (1989); C〇lligan等人編，Current
Protocols in Immunology, j〇hn Wiley & Sons, Inc., NY (1994-2001); Colligan等人，Current pr〇t〇c〇is in p⑻如 Science，John Wiley & Sons，Νγ，Νγ，（1997 2〇〇i)。 本發明之-態樣為修飾天然野生型蛋白以在降解類澱粉 β肽t甚至更具選擇性之可能性。定點突變可用以在野生 型序列中引人/置換胺基酸。—種方法為使㈣由研究降 解酶之活性位點的合理設計。潛在地改變選擇性概況(與 其他肽/蛋白相比，類澱粉β肽之降解）之胺基酸可經其他胺 基S夂置換’且可在此項技術巾已知之訪檢定巾測試新顆 支體與其他相關肽相比，對類殺粉β肽具有較高催化降 解活性之變體較佳為適用的。其他相關肽包括(但不限於） 腦《、神經肽γ、Ρ物質、生長抑素（s_statin)及膽囊 129669.doc -39- 200907056 收縮素。 已知月自。非肽酶之三維結構（〇efner等人（2000) J M〇l,
Biol. 296:341-9; Sahli 等人（2005) Helv. chim. Acta. 88:731)。此結構可引導將改變引入結構中之方式以及何部 分最有效改變以製造用於篩檢或選擇之庫。腦啡肽酶之活 性位點極深地埋於結構中，此解釋酶對小受質之偏好，該 小受質如為具有約5000 Da以下分子量之肽片段。活性位 點殘基包括N542、H583、H587、E646&R717。接近於活 性位點之胺基酸殘基亦包括V58〇、F563、F564、M579、 F716> 1718^ Fl〇6^ 1558 ^ F563 .F579 .V580 >H583 ^ V692 ^ W693 ^A543(V〇isin^ Λ(2004) JBC 279:46172- 8"。此等及其他殘基可藉由研究三維結構之基本原理設 計而改變，或在各種庫中隨機改變以獲得腦啡肽酶之改良 變體。 尽贫明之目 、 祕為提供適用於研發針對神經退化性疾病之 治療且適用於識別適用於此等疾病之治療性干預之化合物 的方法及材料。基於經由最優化酶促介導機制可 殿粉之Μ’本發明開始提供如在申請專利範圍部分中展 示且在下文所述之此等方法及㈣。 丨刀中展 本發明提供一種預阮Θ/ 〜、 種預防及治療神經退化性病症之方法，豆 匕3向哺礼動物之周邊系統 八 仆入舲 $ — — 另欢里之取優化酶促活性 “勿。评δ之’酶促活性化合物為其中 性且其他部分調節 彳〃 〃有_活 用於預防及治療諸如阿兹該方法適 丙夂恥部澱粉樣變性病。 129669.doc -40- 200907056 本發明亦提供不同之檢定原理-生物化學原理且詳言之 為用於測試最優化酶促化合物、較佳筛檢複數種化合物、 調節活性及血衆半衰期之細胞檢定。在另一實施例中，檢 定包含在細酶活性之前添加腦啡肽酶家族成員之已知 抑制劑。合適抑制劑例如為磷阿米酮、塞奥芬 ⑽orphan)、賜諾芬（spin〇rphin)或前述物質之官能衍生 物。 f . 、瓜心義而σ，根據本發明之檢定活體外及活體内量 測酶活性及血漿中之半衰期。 人在另一態樣中，本發明提供一種製造藥物之方法，其包 含以下步驟：⑴識別降解Αβ肽之化合物，較佳具高度特異 性且具有高Αβ肽降解活性之化合物，⑼將此⑼肽降解化 合物連接至決定血漿中之半衰期的調節劑化合物。 入可在轉化宿主細胞中使用重組腿技術製造本發明之化 合物。為執行此舉’製備編碼融合蛋白之重組舰分子。 此項技術中熟知製備此等DNA分子之方法。舉例而言，使 ^ 口適限制酶’可使編碼調節劑及蛋白之序列自DNa切 :或者’可使用諸如胺基碌酸醋方法之化學合成技術來 〇成DNA分子。亦可使用此等技術之組合。 本發明亦包括能夠在適當宿主中表現 合物之®舻也 1蜊蛋白或融 〜體。载體包含編碼有效連接至適當表現控制序列 5周郎密丨丨、,
八#、蛋白及/或融合物之DNA分子。熟知在將DNA 2 入載體中之前或之後實現此有效連接 控制戾^ 衣現 匕括啟動子（promoter)、活化子（activat〇r)、強化 129669.doc • 41 · 200907056 子（enhancer)、操作子（operator)、核糖體結合位點、 ^ %始 k號、終止信號、帽信號（cap signal)、多聚腺嘌呤信號及 其他與轉錄或轉譯控制相關之信號。 將其上具有DNA分子之所得載體用以轉化適當宿主。此 轉化可使用此項技術中熟知之方法來進行。大量可得及热 知宿主細胞中之任一者均可用於本發明之實踐中。特定宿 主之選擇視許多由此項技術所識別之因素而定。此等因素 包括（例如）與所選表現载體之相容性、由DNA分子編碼之 f 融合物的毒性、轉化速率、回收融合物之簡易性、表現特 徵、生物安全性及成本。為使此等因素平衡，必須瞭解對 於特疋DNA序列之表現而言並非所有宿主均可同等有效。 在此等通用方針内，適用之微生物宿主包括培養物中之細 i (諸如大腸桿菌屬）、酵母（諸如酵母屬（Sacchar〇m八u sp.))及其他真菌、昆蟲、植物、哺乳動物(包括人類)細 胞’或此項技術中已知之其他宿主。 接著，培養且純化轉化宿主。可在習知醱酵條件下培養 冑主細，以便表現所需化合物。此項技術中熟知此等醱酵 條件最終’藉由此項技術中熟知之方法自培養物純化融 合物。當使用Fc部分作為調節劑時，—種較佳之方法為使 用蛋白A或類似技術來純化融合蛋白。調節劑 '蛋白及融 。物亦可藉由合成法來製造。舉例而言，可使用固相合成 技術。合適技術在此項技術中係熟知的且包括以下文獻中 所述之彼等技術：Merrifield (1973)，c/i_ p咖印―， 第 335_61 頁（KatS〇yannis 及 Panayotis 編）；Merrifield 129669.doc -42· 200907056 (1963)，/· dm· Chw· 85: 2149; Davis 等人（1985)， 10: 394-414; Stewart及 Young (1969)，So/W P/zwe / 美國專利第 3,941，763 號；Finn 等 人（1976)，rk /We/似（第 3版）2: 105-253 ;及 Erickson等人 (1976)，77ie 第 3 版）2: 257-527。固相合成為製造 個別肽或蛋白之較佳技術’因為其為製造小肽或蛋白之最 成本有效方法。 一般而言’本發明之化合物具有由其活體内降解類澱粉 β肽之能力產生之藥理學活性。可藉由此項技術中已知之 檢定來量測此等化合物之活性。對於Fc_nep化合物而言， 在本文實例部分中進一步描述活體内檢定。 一般而言，本發明亦提供使用本發明化合物之醫藥組合 物的可能性。此等醫藥組合物可用於注射投藥，或用於口 服、肺部、經鼻、經皮或其他形式之投藥。一般而言，本 發明涵蓋包含有效量之本發明化合物以及醫藥學上可接受 t稀釋劑、防腐劑、增溶劑、乳化劑、佐劑及/或載劑之 窬藥組合物。此等組合物包括具有各種緩衝劑含量（例 叙TriS HC1、乙酸鹽、磷酸鹽）、pH及離子強度之稀釋 d ’添加劑’諸如清潔劑及助溶劑（例如，Tween 80、聚 ’、醇知8〇)、抗氧化劑（例如，抗壞血酸、偏亞硫酸氫 α j防腐劑（例如，Thimerso卜¥醇）及膨化物質（例如， :糖二甘露糖醇)；將材料併入諸如聚乳酸、聚乙醇酸等 糖=化合物之微粒製劑中或併入脂質體中。亦可使用破 且此可具有促進在循環中持續之持續時間的作 129669.d〇( -43· 200907056 用。此等組合物可影響本發明蛋白及衍生物之物理狀離、 穩定性、活體内釋放速率及活體内清除速率。例如：見 sciences,,18,(199〇5 ^ —gCo.，Easton，Pa 18〇42)_35i7 引用的方式併入本文中。袓人胳π⑹ /、係u 不又τ ' 組合物可製備為液體形式 呈乾燥散劑形式，諸如减乾形式。亦涵蓋可植入式持續釋 放型調配物，如經皮調配物。 ，、’’ 代法。 b員技術中熟知此等投藥替 ， 與用於治療上述病況之方法有關之給藥方㈣由主治醫 師考慮改變藥物作用之各稀囡去 - 串來決定，該等因素例如為 患者之年齡、病況、體重、性 ^ . ^ 久膳艮，任何感染之嚴重 :，技樂時間及其他臨床因素。—般而言， 在0.1-1000微克本發明化合物/ 案應 公斤之範圍内。 彳體重，較佳0.W0微克/ 本發明明確描述類澱粉β __活性且變得特定方式改質以 :揭示係支持本發明。於活體内用途。實驗證據經 在例中，本發明提供—種治療Αβ相關病變之* β類搬粉血管病變，m 群（D〇wns synd觸e)及 身性.—限於）腦類澱粉血管病變、全 症，祛 出血、與認知障礙相關之病 症绪如（但不限於）MCin产@ 病、盥h - & 度w知障礙”）、阿茲海默氏 盥諸如财己隐丧失、注意力不足症狀、 ' 氏病或癡呆（包括處合血管型癡呆及退化 129669.doc • 44 - 200907056 性來源之癡呆)之疾病相關之神經退化、早老性癡呆、老 年癡呆及與帕金森氏病(Parkinson’s disease)相關之癡呆、 進行性核上麻痺或皮質基底退化，該方法包含向哺乳動物 (包括人類）投與治療有效量之根據本發明之融合蛋白。 實例 本文中藉由以下非限制性實例來描述本發明： 實例1 蛋白域之描述 將腦啡肽酶之細胞外域定義為胺基酸5丨_749(排除第一 甲硫胺酸）（SEQ ID NOS 1-4)。存在兩種引起在此域中識別 之胺基酸差異的多態現象，且在SEQ ID N〇 1-4中描述不 同變體之胺基酸序列。 IDE(胰島素降解酶）為長1〇18個胺基酸之蛋白（SEq出 NO 5)。存在IDE之所述剪接變體及多態變體。在一種剪接 變體中，一種外顯子經具有相同尺寸之另一外顯子置換， 該另一外顯子編碼類似於” wt”外顯子（在SEq ID no 6中描 述）之狀序列。已將此變體描述為在降解胰島素及Αβ中之 有效性均較小。在所述IDE基因中亦存在若干多態現象， 其引起在此域中識別之胺基酸差異：D947N、E612K、 L298F及E4〇8G(根據SEQ ID NO 5編號）。此等多態現象之 所有組合亦均有可能。 ECE1之細胞外域（内皮素轉化酶1)(SEQ ID NO 7)為長 681個胺基酸之蛋白，其經定義為全長膜結合ECE1蛋白之 胺基酸90-770。ECE1基因含有若干可能之多態現象，其引 129669.doc -45- 200907056 起胺基酸差異：R665C、W541R、L494Q及T252I。此等多 態現象之所有組合亦均有可能。 使腦啡肽酶、IDE及ECE1之細胞外域融合至人類IgG2 Fc域（包括鉸鏈區）。引入信號序列（SEQ ID NO 8)以使得蛋 白能夠在表現期間分泌於培養基中。將鉸鏈區之序列展示 於SEQ ID NO 9中且將IgG2 Fc域展示於SEQ ID NO 10中。 在SEQ ID NOS 11-13中描述具有對應於SEQ ID NO 1之人 類腦啡肽酶變體、對應於SEQ ID NO 5之IDE及對應於SEQ f ID NO 7之ECE1的完整融合蛋白（排除信號序列）。最終融 合蛋白（排除信號序列）具有211 kDa(呈二聚體之Fc-Nep)、 294 kDa(呈二聚體之Fc-IDE)及206 kDa(呈二聚體之Fc-ECE1)之預測分子量。 實例2 構築編碼融合蛋白Fc-雎啡肽酶之基因的描述 以合成方式製造（GeneArt)如融合至編碼IgG2之Fc域之 基因的編碼腦啡肽酶之細胞外域的基因。將包括信號序列 (之完整基因（編碼Fc腦啡肽酶）自GeneArt載體（pCR-Script、 pGA4或pUC-Kana)轉移至Gateway供體載體。Gateway供體 載體係用以將完整基因引入若干表現載體中。藉由使用 Gateway系統，藉由使用重組代替限制酶，可執行自供胃 載體至表現載體之轉移。所研究之哺乳動物表現載體主& 為 pCEP4、ρΕΑΚΙΟ、pEF5/FRT/V5-DEST 及 pcDNA5/ FRT/TO(Gateway調適）。所有此等表現載體均為基於cmv 啟動子（pCEP4、ρΕΑΚΙΟ 及 pcDNA5/FRT/TO)或 EF-la啟動 I29669.doc -46 - 200907056 子（pEF5/FRT/V5-DEST)之標準哺乳動物表現載體。在所有 選殖步驟之後，對基因進行定序以檢驗DNA序列。 實例3 構築編碼融合蛋白Fc-IDE及Fc-ECEl之基因的描述 以合成方式製造如融合至編碼IgG2之Fc域之基因的編碼 酶IDE及ECE1之基因。將完整基因（編碼包括信號序列之 Fc-IDE及Fc-ECEl融合蛋白）自初始選殖載體（pCR-Script、 pGA4或pUC-Kana)轉移至Gateway供體載體。Gateway供體 載體係用以將完整基因引入若干表現載體中。所研究之哺 乳動物表現載體主要為pCEP4、pEAKlO、pEF5/FRT/V5-DEST及pcDNA5/FRT/TO(Gateway調適）。所有此等表現載 體均為基於CMV啟動子（pCEP4、pEAKlO及pcDNA5/ FRT/TO)或 EF-la啟動子（pEF5/FRT/V5-DEST)之標準哺乳 動物表現載體。在所有選殖步驟之後，對基因進行定序以 檢驗DNA序列。 實例4 腦啡肽酶之細胞外域及融合蛋白Fc-腦啡肽酶在HEK293細 胞中之表現 蛋白腦啡肽酶（僅細胞外域）及Fc-腦啡肽酶（Fc-Nep)經瞬 時表現於懸浮液調適之哺乳動物細胞中。用於製造實驗之 細胞株為源自HEK293(包括HEK293S、HEK293S-T及 HEK293S-EBNA細胞）之細胞株。測試自編碼所關注蛋白 之質體pCEP4及pEAKlO之表現。在約0.5-lxlO6之細胞密度 下且以介於0.3-0.8 pg/ml細胞懸浮液（最終濃度）濃度之質 129669.doc -47- 200907056 體DNA進行轉染。所測試之轉染試劑為2 gg/mi細胞懸浮液 (袁終丨辰度）之聚仲乙基亞胺（p〇lySCjence)。在ml至1000 ml(震盪燒瓶）之細胞培養物體積中及5 [至1〇 l之波生物反 應器（Wave Bioreactor)中進行表現。表現之後，在不同天 數自培養物上清液中取樣且分析細胞密度、細胞生存力、 蛋白表現及酶活性。4至14天之後藉由離心來收集細胞培 養物。將細胞培養基用於蛋白純化實驗中。所有質體濃度 及載體均成功’得到不同含量之產量，其通常在丨_3 mg/L 之範圍内。 實例5 融合蛋白Fc-IDE及FcECEl在HEK293細胞中之表現 蛋白Fc-IDE及Fc-ECEl經瞬時表現於懸浮液調適哺乳動 物細胞中。用於製造實驗之細胞株為源自HEK293(包括 HEK293S、HEK293S-T 及 HEK293S-EBNA 細胞）之細胞株。 測試自編碼所關注蛋白之質體pCEP4及ρΕΑΚΙΟ之表現。在 約0.5-lxlO6之細胞密度下且以介於〇 3_〇 8 μ§/ιηι細胞懸浮 液（最終濃度）濃度之質體DNA進行轉染。所測試之轉染試 劑為2 pg/ml細胞懸浮液（最終濃度）之聚伸乙基亞胺 (Polyscience)。在30 ml至1000 ml(震盪燒瓶）之細胞培養物 體積中及5 L至10 L之波生物反應器中進行表現。表現之 後，在不同天數自培養物上清液中取樣且分析細胞密度、 細胞生存力、蛋白表現及酶活性。4至14天之後藉由離心 來收集細胞培養物。將細胞培養基用於蛋白純化實驗中。 實例6 129669.doc -48· 200907056 滕#肽酶之細胞外域及融合蛋白Fc_腦啡肽酶在CHO-S細 胞中之表現 蛋白腦啡肽酶（僅細胞外域）及Fc_Nep經穩定表現於懸浮 液調適哺乳動物細胞中。用於製造實驗中之宿主細胞為 Flpln CHO細胞（invitrogen)，其已調適以供懸浮液生長。 測試自編碼所關注蛋白之質體pcDNA5/FRT/TO-DEST30及 pEF5/FRT/V5-DEST之表現。表現係由CMV啟動子或EFla 啟動子驅動。在F12介質中以約ιχ1〇6個細胞/毫升之細胞密 度使用濃度為約〇_1 pg/ml(最終濃度）之質體DNA進行轉 染。以0.8 pg/ml之最終濃度共轉染編碼重組酶之輔助質體 p〇G44。使用2 pg/ml細胞懸浮液（最終濃度）之聚伸乙基亞 胺（Polyscience)作為轉染試劑。在震盪燒瓶中之3〇 ml至 1 000 ml細胞培養物體積中進行表現。在不同天數自培養 物上清液中取樣且分析細胞密度、細胞生存力、蛋白表現 及酶活性。4至11天之後藉由離心來收集細胞培養物。最 終，將細胞培養基用於蛋白純化實驗中。所用表現載體在 製造所需蛋白中均成功。製造含量通常在1〇_5〇 mg/L之範 圍内。 實例7 融合蛋白Fc-IDE及Fc-ECEl在CHO-S細胞中之表現 蛋白Fc-IDE及Fc-ECEl經穩定表現於懸浮液調適哺乳動 物細胞中。用於製造實驗中之宿主細胞為Flpln CHO細胞 (Invitrogen)，其已調適以供懸浮液生長。測試自編碼所關 注蛋白之質體 pcDNA5/FRT/TO-DEST30 及 pEF5/FRT/V5- 129669.doc -49· 200907056 DEST之表現。表現係由CMV啟動子或EFltx啟動子驅動。 在F 12介質中以約1X106個細胞/毫升之細胞密度使用濃度為 約0.1 gg/ml(最終濃度）之質體DNA進行轉染。以0.8 pg/mi 之最終濃度共轉染編碼重組酶之輔助質體POG44。使用2 pg/ml細胞懸浮液（最終濃度）之聚伸乙基亞胺（P〇lyscience) 作為轉染試劑。在震盪燒瓶中之30 ml至1000 ml細胞培養 物體積中進行表現。在不同天數自培養物上清液中取樣且 分析細胞密度、細胞生存力、蛋白表現及酶活性。4至11 天之後藉由離心來收集細胞培養物。 實例8 藉由親和性層析法純化經表現之Fc-腦啡肽酶蛋白 使用來自哺乳動物細胞中之表現的細胞培養基來進行融 合蛋白之純化。藉由親和性層析法（蛋白A)，接著進行低 pH值〉谷離來進行純化’且純化係在ΑκΤΑ層析系統（探測器
或純化器，GE Healthcare)上進行。使χκ26管柱（GE Healthcare)中之 r 蛋白 A 瓊脂糖 FF(rProtein A Sepharose FF)(GE Hea 丨 thcare)與 10 管柱體積（CV)之 PBS(27 mM KCl、138mMNaCl、1.5mMKH2P〇4、8mMNa2HP〇4- 7H20、PH 6.7-7.0, Invitrogen)平衡。將具有表現融合蛋白 (Fc-腦啡肽酶）之細胞培養基塗覆於管柱上。以2〇 cv pBs 洗蘇管柱’之後以溶離缓衝劑（(K1 “甘胺酸，pH 3·0)溶離 結合蛋白。藉由添加50 μΐ之1M Tris Base至1 ml溶離蛋白 中來立即中和經純化之溶離份。彙集經純化之溶離份且使 用PD10管柱（GE HeaUhcare)將緩衝液交換為5〇爪河 129669.doc -50- 200907056 HCl，pH 7.5，150 mM NaCl。在 SDS-PAGE上分析純化蛋 白，且發現其為約90%純。 實例9 藉由親和性層析法純化經表現之Fc-IDE及Fc-ECEl 使用來自哺乳動物細胞中之表現的細胞培養基來進行融 合蛋白之純化。使XK26管柱（GE Healthcare)中之r蛋白A瓊 脂糖 FF(GE Healthcare)與 10管柱體積（CV)之 PBS(2.7 mM KC1 ' 138 mM NaCl ' 1.5 mM KH2P04 ' 8 mM Na2HP04-7H20、pH 6.7-7·0，Invitrogen)平衡。將具有經表現融合蛋 白（Fc-IDE或Fc-ECEl)之細胞培養基塗覆於管柱上。以2〇 CV PBS洗滌管柱，之後以溶離緩衝劑（〇1 胺酸，pH 3.0)溶離結合蛋白。藉由添加5〇 μΐ之1 μ Tris Base至1 ml 溶離蛋白中來立即中和經純化之溶離份。彙集經純化之溶 離份且使用PD10管柱（GE Healthcare)將緩衝液交換為50 mM Tris-HCM，pH 7.5，150 mM NaC 卜 實例10
Fe-滕啡肽酶表現之SDS_PAGE及西方墨點（B1〇t)分析 使用西方墨點法分析哺乳動物細胞表現之細胞培養基。 將20 μΐ、,.田胞培養基稀釋於包括樣品還原劑（inVitr〇gen)之 LDS樣品緩衝液（invitrogen)中。將樣品加熱至95。〇歷時$ 分鐘’裝載於SDS-PAGE凝勝（4-12°/()梯度凝膠，lO孔（l mm)，Invitrogen)上。使用 MES緩衝液作為運R(running) 缓衝液。凝膠在2 0 0 V下運行3 5分鐘。在3 〇 V進行電墨點 (Electro blotting)歷時1小時以將蛋白轉移至pVDF膜。將 129669.doc •51 · 200907056
臈於包括 5% BSA 之 TBST(TBS(20 mM Tris、500 mM
NaCl、pH 7.5(BioRad))加 0.05% Tween-20)中阻斷隔夜，之 後其與3 0 μΐ初級抗體（經生物素標記之山羊抗人類腦啡肽 酶抗體 ’ 50 pg/ml(R&D Systems))於 15 ml TBST 中培育。 膜在室溫培育兩小時，以TBST洗三次，與抗生蛋白鏈菌
素-辣根（horseradish)過氧化物酶共軛物（GE Healthcare， 稀釋1:10000(1.5 μΐ於15 ml TBST中））培育一小時。膜以 TBST洗三次且以水洗三次，之後使用ECL加試劑（GE
Healthcare)及 ECL 薄膜（GE Healthcare)使各帶呈現。SDS- PAGE顯示純化之蛋白具有正確大小及約9〇%純度。西方墨 點法驗證腦啡狀酶域之一致性。 實例11 腦啡肽酶酶活性FRET檢定 在螢光共振能量轉移（FRET)檢定中測定腦啡肽酶酶活 性。將重組人類腦啡肽酶（r&D Systems)，腦β非肽酶或Fc-月自啡肽柄產生細胞（AZ S5dertalje)之培養基或純化之腦弓卜 肽酶或Fc-腦啡肽酶添加至含有1〇 螢光肽受質V-Mca-
Arg-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH(R&D Systems) 之96孔板中◎對照重組人類腦啡肽酶之最終濃度為〇」 pg/ml或0.25 pg/ml。將1〇 腦啡肽酶抑制劑磷阿米酮 (BIOMOL)添加至—些孔中以控制檢定中信號之特異性且 檢驗特異腦哪肽酶活性。在所有組份添加至孔中之後，立 即將板置於瑩光板讀取器（Ascent)中且在激發34〇 nrn及發 射405 nm每分鐘記錄信號歷時2〇分鐘。藉由計算反應速 129669.doc -52- 200907056 度-斜率係數=2>RFUMt來評估酶之活性。為比較商用重 組腦啡肽酶及Fc-腦啡肽酶融合蛋白之比活性，引入比活 性係數’其係根據此式來計算：比活性=斜率係數/檢定中 腦啡狀酶或單體Fc-腦啡肽酶之pm〇i。 實例12 IDE及ECE1酶活性FRET檢定 在螢光共振能量轉移（FRET)檢定中測定酶活性。將無fc 域之重组酶（商用或内部製造），培養基（來自Fc_IDE或Fc_ ECE1產生細胞）或經純化蛋白（Fc_ide*Fc_ece1)添加至含 有 1〇 μΜ螢光肽受質 V_Mca_Arg_Pr〇_Gly_phe_Ser_Ala_phe_ Lys(Dnp)-〇H(R&D Systems)之96孔板中。在將所有組份均 添加至孔中之後’立即將板置於螢光板讀取器（Ascent)中 且在激發340 nm及發射405 nm處每分鐘記錄信號歷時2〇分 I里。藉由計算反應速度-斜率係數=ZARFU/At來評估酶之 活性。為比較對照物（商用重組酶）之比活性，根據此式來 計算比活性係數：比活性=斜率係數/檢定中酶促域之 pmol ° 實例13 細胞培養物上清液中之腦啡肽酶及FC_雎啡肽酶濃度之 量測 使用Gyros'™ Bi〇affyTM CD微實驗室方法及Gyrolab Workstation LIF設備（Gyros AB，Sweden)來量測細胞培養 物上清液中之腦啡肽酶濃度。將來自不同細胞培養物之樣 品稀釋於標準稀釋劑（Gyr〇s AB)中且置於Therm〇_Fast© 96 129669.doc -53- 200907056 孔PCR板（Abgene，UK)中。使用單株小鼠生物素標記之抗 人類腦啡肽酶抗體（Ser〇tec)作為捕獲試劑（最終濃度〇 〇5 mg/ml)且使以Alexa Fiuor 647染料（分子探針）標記之多株 山羊抗人類腦啡肽酶抗體（R&D Systems)充當偵測抗體（最 終濃度100 nM)以量測腦啡肽酶濃度。使用商用重組腦啡 肽酶（R&D Systems)作為濃度在1〇 ng/mi至1〇〇〇〇吨/^^範 圍内之標準物以構築標準曲線。使用多株生物素標記之抗 人類腦啡肽酶抗體（R&D Systems)作為捕獲抗體，而使用 以Alexa Fluor 647染料（分子探針）標記之多株山羊抗人類 IgG抗體（分子探針）作為偵測抗體以供Fc_腦啡肽酶構築偵 測。使内部產生且經純化之Fc_腦啡肽酶融合蛋白充當濃 度在10 ng/ml至10000 ng/mi範圍内之標準物。將標準物、 捕獲抗體及彳貞測抗體置於Thermo-Fast© 96孔PCR板 (Abgene)上。將板以及 Gyrolab Bioaffy™ CD 均置於 Gyrolab Workstation LIF儀器中’且根據製造商協定使用 Gyrolab Bioaffy™套裝軟體i 8版（(}>^〇3 AB)來進行濃度量 測。 實例14 細胞培養物上清液中之IDE、ECE1、Fc-IDE及Fc-ECEl泼 度之量測 使用Gyr〇s™ Bioaffy™ CD微實驗室方法及Gyr〇lab Workstati.on LIF設備（Gyros AB，Sweden)來量測細胞培養 物上清液中之蛋白濃度。將來自不同細胞培養條件之樣品 稀釋於才示準稀釋劑（Gyros AB)中且置於Thermo-Fast© 96孔 129669.doc -54- 200907056 PCR板（Abgene，UK)中。使用經生物素標記2IDE4ECE1 特異性抗體作為捕獲试劑且使用以IDe或ece 1特異性抗體 標記之Alexa Fluor 647染料（分子探針）作為偵測抗體。將 商用或内部產生之重組IDE及ECE1用以構築標準曲線。當 量測FC-IDE或Fc_ECE1濃度時，差異在於使用以Aiexa Fluor 647染料（分子探針）標記之多株山羊抗人類IgG抗體 (分子探針）作為偵測抗體。將標準物 '捕獲抗體及偵測抗 體置於Thermo-Fast© 96孔PCR板（Abgene)上。將板以及
Gyrolab Bioaffy™ CD均置於 Gyrolab Workstation LIF儀器 中’且根據製造商協定使用Gyrolab Bioaffy™套裝軟體1.8 版（Gyros AB)來進行濃度量測。 實例15 藉由緩衝液中之Fc-腦啡肽酶及雎啡肽酶來降解類澱粉p肽 此實驗之目標在於證明Fc-腦啡肽酶能夠降解類澱粉β j _ 40肽。檢定為在將類澱粉βΐ_4〇肽（Bachem)在具有或不具 有腦啡肽酶抑制劑之腦啡肽酶（r&D Systems)或Fc-腦啡肽 酶存在下培育之後量測其剩餘濃度。在圓底96孔聚丙烯板 中在37°C下將含有類澱粉β1-40肽（最終濃度300 ' 30或3 ηΜ)及/或腦啡肽酶（2.4 pg/ml)及/或Fc-腦啡肽酶構築體（2.4 pg/ml)及/或鱗阿米酮（1〇 μΜ)之1〇〇 μΐ反應混合物培育2,5 小時。培育之後，將1 〇 μΐ反應混合物轉移至含有丨〇 μ1標 準稀釋劑（Gyros ΑΒ)之 Thermo-Fast© 96 孔 PCR 板（Abgene， UK)中。使用Gyrolab Workstation LIF系統來測定類殿粉 β1-40濃度。使用經生物素標記之抗類澱粉β抗體（6El〇 ; 129669.doc -55- 200907056 最終濃度50 w/ml ; Signet)作為捕獲抗體且使用以Αΐ_ F— 647染料(分子探針)標記之多株抗人類酸粉β抗體 (44-348 ; Biosource)作為偵測抗體。根據製造者協定使用
Gyrolab Bioaffy™套裝軟體丨.8版（Gyr〇s AB)來進行類澱粉 β1-40肽濃度量測。將藉由腦。非肽酶之類殺粉βι_條降解 計算為與不存在腦啡肽酶時類澱粉01_4〇肽之濃度相比， 在腦啡肽酶存在下培育後所留下之類澱粉^_4〇肽之百分 比。 ( 濃度為2.4 Pg/ml之重組人類腦啡肽酶在37〇c下培育2 5小 時之後降解64%之類澱粉pi_40肽（3〇〇 nM)。具有大致相同 濃度（2.4 pg/rnl)之内部產生Fc_腦啡肽酶構築體降解類澱粉 β 1-40肽（300 nM)之 50%(第 1批）及 42%(第 2批）。在 1〇 μΜ磷 阿米酮存在下，特定腦啡肽酶活性幾乎完全消除（圖丨）。此 實例展示Fc-腦啡肽酶有效降解類澱粉(3卜扣肽。 實例16 藉由緩衝液中之IDE、ECE1、Fc-IDE及Fc-ECEl來降解類 I 溉粉P肽 此實驗之目標在於證明Fc-IDE及Fc-ECEl能夠降解類殿 粉β1-40肽。檢定為在將類澱粉βΐ_4〇肽（Bachem)在酶（Fc-IDE或Fc-ECEl)存在下培育之後量測其剩餘濃度。在3Γ(： 下將含有類澱粉β1-40肽（最終濃度300、3〇或3 nM)、Fc-IDE或Fc-ECEl之100 μΐ反應混合物培育2.5小時。培育之 後，將10 μΐ反應混合物轉移至含有1〇 μ1標準稀釋劑（Gyr〇s AB)之 Thermo-Fast© 96 孔 PCR 板（Abgene，UK)中。使用 129669.doc -56- 200907056
Gyfolab Workstation LIF系統來測定類澱粉pi_4〇濃度。使 用絰生物素標記之抗類澱粉β抗體（6E10 ;最終濃度5〇
Pg/ml ’ Signet)作為捕獲抗體且使用以AUxa Fiuor 647染料 (/刀子彳木針）標記之多株抗人類類澱粉p抗體04 — 348 ; Bl〇S〇UrCe)作為偵測抗體。將藉由腦啡肽酶之類澱粉β 1 -40 狀降解計算為與不存在酶時之類澱粉βι_4〇肽濃度相比， 在酶存在下培育後所留下之類澱粉β 1 -40肽之百分比。 實例17 藉由Fc-腦却肽來降解豚鼠血漿中之類澱粉0肽14〇及類救 粉β肽1-42 使用來自重250-300 g之雄性Dunkin Hartley豚鼠 (HBLidkdping ka)之肝素化血漿來研究藉由腦啡肽酶對類 澱粉β肽1-40(Αβ40)及類澱粉β肽ι_42(Αβ42)之降解。藉由 心牙刺術自麻醉豚鼠抽取血液。將血液收集至預冷肝素金 漿管中且在20分鐘之取樣時間内在4°C下以3000xg離心1 〇 分鐘。將血漿樣品轉移至預冷聚丙烯管中且立即在乾冰上 冷凍且在使用之前儲存於-7(TC。在來自七個豚鼠之血漿 池上進行實驗。在37T：下在存在或不存在10 μΜ磷阿米酮 (BIOMOL)之情況下以血漿池將具有相應媒劑（50 mM Tris-HC卜 150 mM NaCl pH 7.5 或 25 mM Tris-HC卜 0.1 M NaCl pH 8.0)之 His-Fc-Nep(6 pg/ml 或 208 pg/ml)或 5 pg/ml 重組人 類腦啡肽酶（R&D Systems)培育0及4 h。將最終濃度為4.7 mM之EDTA添加至管中，之後使用由Biosource(Api-40)或 Innogenetics(Api-42)獲得之商用ELISA套組來分析Αβ40及 129669.doc -57- 200907056 Αβ42之量。 與媒劑相比’在37°C下以豚鼠血漿及6 gg/ml或208 pg/ml His-Fc-Nep離體（£χ_νζ·νο)培育4小時導致Αβ4〇分別減 少26°/。及51%。與媒劑相比，商用人類重組腦啡肽酶（5
Kg/ml)使Α|340降解49¾。添加10 磷阿米酮之後，Αβ40 含量未受影響（圖2)。
當以 208 pg/ml His-Fc-Nep 或 5 pg/ml 腦啡肽酶（R&D
Systems)培育時，與媒劑相比，豚鼠血漿中之Aj342含量減 小57%以上。當與208 pg/ml His-Fc-Nep組合時，磷阿米酮 並不抑制Αβ42之減小。以低濃度His_Fc-Nep不存在Αβ42之 降解（圖3)。 實例18 藉由Fc-腦啡肽酶來降解人類血漿中之類澱粉0肽14〇 在保健中心（AstraZeneca)在兩個不同時間點將來自八隻 個體（5隻雌性及3隻雄性）之血液收集於預冷肝素灰漿管 中。藉由在30分鐘之取樣時間内在4。〇下以25OOxg離心20 分鐘來製備血漿。將血漿樣品轉移至預冷聚丙烯管中且立 即冷凍且在使用之前儲存於_7〇t：下。在37°C下在存在或不 存在1 0 μΜ構阿米酮之情況下以血漿池將具有相應媒劑（5〇 mMTris-HCM、150mMNaClpH7.5 4 25niMTris-Ha、 o.l M NaCl pH 8.0)之His-Fc-Nep(6 pg/ml)或 5 pg/ml重組人 類腦啡肽酶（R&D Systems)培育0及4 h。將最終濃度為47 mM之EDTA添加至管中，之後使用由Biosource獲得之商用 ELISA套組來分析Αβ40之量。與在37°C培育4小時後之媒 129669.doc *58- 200907056 劑相比，His-Fc-Nep(6 pg/ml)及商用人類重組腦啡肽酶（5 pg/ml)分別使Αβ40降解33%及70%。添加1〇 μΜ磷阿米_之 後，Αβ40含量未受影響（圖4)。 實例19 藉由内部產生之Fc-Nep來降解豚鼠血漿中之類澱粉0肽1_ 40及類澱粉p肽1-42(活體内研究） 進行脉鼠中之活體内研究以測試内部產生之Fc_Nep的活 體内功效。讀數為血漿Αβ含量及血漿藥物濃度。使用γ分 泌酶抑制劑、ΑΖ10420130(Μ55(M26)作為參考物（用於減小 血漿Αβ含量之陽性對照）。 將勝鼠（雄性Dunkin Hartley豚鼠，250-300 g)稱重且經 靜脈内投與單次劑量。目標在於劑量應在終止時得到血漿 暴露〇、5及20 pg/ml。在整個實驗期間對動物健康狀況進 订觀察。各時間點中包括8個動物且各時間點具有其自身 之媒劑組。以異氟烷使動物麻醉且藉由心穿刺術進行血液 取樣。關於血液樣品處理及分析Αβ1_4〇或Αβ1_42之資訊 (參見實例23)。所有血漿樣品均將送以pKw究以測定藥物 暴露（關於方法描述，參見實例2〇)。 實例20 僅Fc-Nep及腦啡肽酶之藥物動力學 :發Fc-Nep融合蛋白以改良具有特異性目標之腦啡肽酶 的樂物動力學實體，以減少清除且改良半衰期。為測試 此，吾人已向小鼠投與i mg/kg商用腦啡肽酶或^或 者5 mg/kg内部產生Fc_Nep之單次靜脈内劑量。給藥後在 129669.doc -59- 200907056 設定時間自尾靜脈抽取血液樣品或在終止時藉由心穿刺術 柚取血液樣品。一旦取樣至含有EDTA之管中，即將等分 試樣置於冰上。藉由在15分鐘之取樣時間内離心（通常在 4 C下以1500 g歷時1〇 min)來製備血漿且立即冷凍。經由 免疫檢定使用商用腦啡肽酶之抗Nep或Fc_Nep之抗人類igG 作為捕獲抗體來測定Fc_Nep及腦啡肽酶之血漿濃度，而兩 種物虞均k由抗Nep抗體來偵測。使用套裝軟體 (WinNonlin，Pharsight c〇rp〇rati〇n，USA)來計算藥物動力 學參數且在此實例實驗中，計算半衰期已自Nep之約5分鐘 增加至Fc-Nep之約20小時。結果展示於圖5中。 實例21 使用酶活性FRET檢定來比較滕难肽梅_!^與Fc膜啡肽酶 在細胞培養基中之酶活性 為比較Fc之C末端融合至腦啡肽酶與以之N末端融合至 腦啡肽酶，根據實例4來製造兩種蛋白（Fc_腦啡肽酶及腦啡 肽酶-Fc)且如實例8中所述加以純化。在螢光共振能量轉移 (FRET)檢定中測定細胞培養基中之蛋白的酶活性。將重組 人類腦啡肽酶（R&D Systems)，來自Fc_腦啡肽酶產生細胞 及來自腦啡肽酶-Fc產生細胞之培養基，添加至含有1〇 μΜ 螢光肽受質 V-MCa-Arg-Pr〇-Gly-Phe-Ser-Ala-Phe-LyS(Dnp)_ 〇Η(ΙΙ&ΐ) Systems)之96孔板中。對照重組人類腦啡肽酶之 最終濃度為0.1 pg/mbH〇.25 w/ml。在將所有組份均添加 至孔中之後，立即將板置於螢光板讀取器（Ascent)中且在 激發340 nm及發射405 nm處每分鐘記錄信號歷時2〇分鐘。 129669.doc -60· 200907056 藉由計算反應速度-斜率係數=ΣΔ1ιη；/Μ來評估酶之活 性。為比較商用重組腦啡肽酶、腦啡肽酶_Fc融合蛋白及 &腦啡肽酶融合蛋白之比活性，引入比活性係：，其係 根據此式來計算：比活性=斜率係數/檢定中㈣肽酶或單 體融合蛋白之結果（圖6中所示）展示脚如之表現 產生極低比活性（對於以pCEP4載體表現而言為〇ι且對於 以P職1〇載體表S而言為〇.55)，但Fc_Nep之表現產生高 得多之此活性（對於以pCEP4载體而言為13 4且對於以 f PEAK10載體表現而言為15.2)。 實例22 使用酶活性FRET檢定來比較經純化腦啡肽酶_^^與Fc腦 啡肽酶之酶活性 為比較Fc之C末端融合至腦啡肽酶與Fc之N末端融合至 腦啡肽酶，根據實例4來製造兩種蛋白腦啡肽酶及腦啡 肽酶-Fc)且如實例8中所述加以純化。在螢光共振能量轉移 ((FRET)檢定中測定腦啡肽酶之酶活性。將重組人類腦啡肽 i 酶（R&D Systems)，經純化腦啡肽酶蛋白及經純化腦 啡肽酶，添加至含有10μΜ螢光肽受質v_Mca_Arg_Pr〇_Giy_
Phe-Ser-Ala-Phe-LyS(Dnp)-〇H(R&D Systems)之 96 孔板 中。在將所有組份均添加至孔中之後，立即將板置於螢光 板讀取器（Ascent)中且在激發34〇 nm及發射4〇5 nm處每分 鐘記錄信號歷時20分鐘。藉由計算反應速度_斜率係數 -ZARFU/At來評估酶之活性。為比較商用重組腦啡肽酶、 腦啡肽酶-Fc融合蛋白及]^-腦啡肽酶融合蛋白之比活性， 129669.doc •61- 200907056 引入比活性係數， ’ ”係根據此式來計算：比活性=斜率係
數/檢定中腦啡M 轉或單體腦°非肽酶_Fc之pmol。結果（圖9 中所示）展+ '、、、！純化融合蛋白Nep-Fc之比活性極低 (0.001)，而絰姑儿 、也化融合蛋白Fc-Nep之比活性要高得多 (14.1)。 實例23 、SWE轉殖基因小鼠血漿中可溶性Αβ含量之Fc-腦啡肽 酶進行處理 , 此研九之目的為評估急性靜脈内處理之後Fc—Nep在雌性 APPSWE-tg小鼠血衆中之時間及劑量反應作用。特定目的 在於發見對jk聚Αβ4〇及Αβ42之作用。包括γ分泌酶抑制劑 Μ-550426作為參考化合物。 使25-31週大之雌性APPswe轉殖基因小鼠（丨〇隻小鼠/組） 接收1 mg/kg或5 mg/kg呈單次靜脈内注射形式之媒劑或Fc_ Nep。使用300 pm〇i/kg γ分泌酶抑制劑m_55〇426作為參考 化合物且在3小時内處理此等動物（4隻小鼠）。在研究中亦 、 包括空白組（4隻未處理小鼠）。給藥後1.5及3小時自媒劑處 理及化合物處理動物進行血液取樣。藉由心穿刺術自麻醉 小鼠將血液抽取至含有EDTA之預冷微量管中。立即將血 液樣品置於冰上，之後進行離心。藉由自取樣之2〇分鐘内 在+4°C下以約3000xg離心10分鐘來製備血漿。血液取樣之 後，終止小鼠。藉由分別自Biosource及Innogenetics獲得 之商用ELISA套組來分析血襞中之Αβ40及Αβ42含量。 根據實例2〇中所述之程序來檢定血漿及調配物中之Fc- 129669.doc -62- 200907056
Nep濃度。在來自未處理動物（空白）之樣品中及來自經 M550426處理之動物的樣品中分析血漿中之暴露。 結果 與1 mg/kg或5 mg/kg靜脈内注射劑量之後1.5小時，但非 在APPswe轉瘦基因小鼠中給藥3小時後血装中之媒劑 (Ρ<0·05)相比，Fc-Nep使可溶性Αβ40之含量顯著降低約 20%。以1 mg/kg及5 mg/kg在1.5小時時Fc-Nep的平均血漿 暴露分別為 9_8 pg/ml及 33.6 pg/ml。儘管 1 mg/kg及 5 mg/kg 下之Fc-Nep血漿暴露分別為7.6 gg/ml及27.3 pg/m卜但3小 時之後未見Αβ40之顯著變化。如預期’在以陽性對照，γ 分泌酶抑制劑Μ550426處理之後，觀察到血漿中Αβ40含量 減小。在接收300 μηιοΐ/kg之小鼠中，給藥後3小時之 Μ5 5 0426的平均血漿暴露為33·5 μΜ(圖7)。 與媒劑（Ρ<0.05)相比’以5 mg/kg Fc-Nep處理1·5小時之 後血漿中之Αβ42含量減少約20%。在投藥i mg/kg之h5小 時後未見顯著變化。儘管1 mg/kg及5 mg/kg之Fc-Nep血聚 暴露分別為7·6 pg/ml及27.3 pg/ml’但3小時之後在任何劑 量中均未見Αβ42之顯著變化。在以陽性對照，γ分泌酶抑 制劑Μ550426處理之後，觀察到血漿中Αβ42含量減小。在 接收300 μηιοΐ/kg之小鼠中，給藥後3小時之Μ55〇426的平 均血漿暴露為33,5 μΜ(圖8)。 實例24 以hFc-Nep之處理及對C57BL/6小鼠血漿中之可溶性Αρ含 量的作用（時間及劑量反應研究：及3小時） 129669.doc -63 · 200907056 研九之目的為5平估急性處理之後hFc-Nep在雌性 C5 7BL/6小鼠A漿中之時間及劑量反應作用。特定目的在 於發現對血漿Αβ4〇之作用且使此作用與血漿中2hFc_N邛 暴路含量相關聯。包括γ分泌酶抑制劑厘_55〇426作為陽性 對照。13週大之雌性C57BL/6小鼠〇〇隻小鼠/組）接收i mg/kg或5 mg/kg呈單次靜脈内注射形式之媒劑或沾卜 Nep在、、止之刖3小時，以300 μηιοΐ/kg經口投與 5 50426。研究中亦包括空白組。給藥後15及3小時自媒劑 處理及化合物處理之動物進行血液取樣。藉由心穿刺術自 麻醉小鼠將血液抽取至含有EDTA2預冷微量管中。立即 將血液樣品置於冰上，之後進行離心。藉由自取樣之2〇分 鐘内在+4 C下以約30〇〇xg離心1 〇分鐘來製備血漿。血液取 樣之後’終止小鼠。在整個實驗期間對動物健康狀況進行 觀察，揭示無明顯不良作用。藉由自Biosoinxe獲得之商用 ELISA套組來分析血漿中之小鼠a(340含量。根據實例27中 所述之程序來檢定血漿及調配物中之Fc_Nep濃度。 結果 結果展示藉由在C57BL/6小鼠中1.5小時及3小時後以劑 量依賴性方式以hFc-Nep處理，使得小鼠Αβ40顯著減小。 1.5小時之後，與媒劑相比，在1 mg/kg劑量（ρ=0·163 8)下可 見Αβ40減小17°/。且在5 mg/kg劑量（ρ<〇.〇〇〇ι)下可見Αβ4〇減 小76%。以1 mg/kg及5 mg/kg在1.5小時時hFc-Nep之平岣 血漿暴露分別為14 pg/ml及89 pg/ml。3小時之後，與媒劑 129669.doc -64- 200907056 相比’在1 mg/kg劑量（p<0.005)下Αβ40顯著減小％%且在5 mg/kg 劑量（ρ<0.0001)下 Αβ40顯著減小 72%。以 1 mg/kg 及 5 mg/kg在3小時時Fc-Nep之平均血漿暴露分別為丨7吨化丨及 78 ng/ml。如預期，在以陽性對照，γ分泌酶抑制劑 Μ5 50426處理之後，亦觀察到血漿中之八04〇含量減小。在 接收300 μιηοΐ/kg之小鼠中，給藥後3小時時Μ_55〇426之平 均血漿暴露為42 μΜ(圖10)。 實例25 使用以#次劑量形式給藥 '、經由靜脈内注射至⑸肌^小 鼠之hFc-Nep的時間-反應關係。 此研究之目的為評估單次劑量之後hFc_Nep在雌性 C57BL/6小鼠血t中之時間_反應關係。衫目的在於發現 hFc-Nep在血衆中之減小作i維持多長時間，且使此作用 與血衆中測試化合物之暴露含量相關聯。包括丫分泌酶抑 制劑M-550426作為陽性化合物。 使週大之雌性C57BL/6小鼠(8隻小鼠/組)接收5 mg/kg呈單次靜脈内注射形式之媒劑或响·一，且注射後 在不同時間點(在⑴68小時之間，亦即至多⑷分析 • 0。Μ 口給予，泌酶抑制劑m_55〇426且將動物處理3 ]寺研九中亦包括空白組。在整個實驗期間對動物之健 康狀況進行觀察示無明顯不良作用。血液收集、血漿 處理及血漿中小鼠Αβ4〇含量之量測基本上係如實例^中所 述0 結果 129669.doc -65- 200907056 結果（圖11)展示當hFc_Nep#單次靜脈内注射形式給藥至 C57BL/6小鼠而處理15_168小時之後，血渡顯著減 小。在所有時間點（1.5、6、12、24、36、72及168小時）， Αβ40減小均為持續性的（與媒劑相比，在67%_8〇%之間）。 5 mg/kg下hFC_NeP之平均血漿暴露在丨5小時時為 87 pg/ml 且在1週（168小時）後緩慢減少至38 μ§/ηι1之含量。此等資 料展示小鼠中Fc_Nep之半衰期相當長。如預期，在以陽性 對照，γ分泌酶抑制劑M550426處理之後，觀察到血漿中 Αβ40各里減小。在接收3〇〇 gm〇1/kg之小鼠中給藥後3小 時之M-550426的平均血漿暴露為34 μΜ(圖u)。 實例26 使用以單次劑量形式給藥、經由靜脈内注射至AppswE_tg 小鼠及C57BL/6之小鼠Fc-Nep的時間-反應關係 此研究之目的為評估單次劑量後雌性ApPswE_tg小鼠及 C5 78176小乳血漿中之小鼠版本Fc_Nep(mpc_Nep，SEQ ID N〇14)的時間_反應關係。特定目的在於發現mFc_Nep對 Αβ之減小作用在血漿中維持多長時間，且使此作用與血漿 中測試化合物之暴露含量相關聯。包括γ分泌酶抑制劑Μ-550426作為陽性化合物。 使21 23週大之雌性APPSWE_tg小鼠及24週大之雌性 C5 7BL/6小鼠（6隻小鼠/組）接收5 mg/kg或25 mg/kg呈單次 靜脈内注射形式之媒劑或mFc_Nep，且注射後在不同時間 點（在1.5-336小時之間，亦即至多2週）分析Ap4〇。在終止 之3小時’以3〇〇 Mm〇i/kg經口投與m-550426。對於兩種 I29669.doc -66- 200907056 小鼠模型，APPSWE-tg及C57BL/6，均包括陽性對照及空白 組。對於APPSWE-tg小鼠而言’包括以下組：25 mg/kg : 1.5、 72、168及 336小時；5 mg/kg) : 336 小時（2週）。對於 C57BL/6小鼠而言·· 25 mg/kg : 168及 336小時；5 mg/kg) · 1.5、 1 68及336小時。在整個實驗期間對動物健康狀況進 行觀察，揭示無明顯不良作用。血液收集及血漿處理基本 上係如實例25中所述。C57BL6小鼠血漿中之小鼠Αβ40含 量分析係如實例25中所述。APPSWE-tg小鼠血漿中之人類 Αβ40及Αβ42含量分析係如實例25中所述（如最近APP-tg研 究中所述）。 結果 在APPSWE轉殖基因小鼠中，單次投與25 mg/kg之後，在 所有時間點mFc-Nep均顯著減小血漿中之人類Αβ40及 Αβ42(圖1 2，a及b)。1.5小時之後，當與媒劑相比時，對於 Αβ40及Αβ42而言Αβ含量分別為91%及87%，且當暴露減小 時Αβ含量逐漸增加。兩週（336小時）之後，當與媒劑相比 時’對於Αβ40及Αβ42而言Αβ含量分別為58%及44%。兩週 之後，單次靜脈内注射25 mg/ml mFc-Nep後之暴露已自 299 pg/ml(i.5 小時）降低至 6〇 pg/ml(336 小時）（圖 12，c)。 對於168及3 36小時，使用以5 mg/kg給藥之額外動物組。 如圖12 ’ a及b中所示，對於Αβ4〇及Αβ42而言，Αβ均以劑 里依賴性方式在彼等時間點降解。Ap4〇及八042之血漿功 效作用均與mFc-Nep之血漿暴露反向關聯（圖13)。此等結 果表明關於mFc-Nep之Αβ降解作用，Ap4〇比Ap42大。 129669.doc -67- 200907056 在C57BL/6小鼠中，以5 mg/kgA 25 mg/kg，在所有時間 點（1.5、108及336小時），mFc_Nep均顯著減小血漿中之小 鼠 Αβ40(Κ14)。在168及 336小時，分析 5 mg/kg&25 mg/kg 且Αβ40作用展示具劑量依賴性。2週之後，與媒劑相比， 25 mg/kg mFc-Nep之單次注射（336小時）使血漿中之小鼠 Αβ40含量顯著減小73°/。。此時間點之血漿暴露為48 gg/ml 且mFc-Nep藉此展示具有長血漿半衰期。 實例27
Fc-Nep及内部產生腦啡肽酶之藥物動力學 使用不同批次之Fc-Nepa及Nep來重複藥物動力學研究且 獲付不同PK概況。最重要的為包括igG之Fc部分的化合物 之血衆半衷期顯著延長。 研發Fc-Nep融合蛋白以改良具有特異性目標之腦啡肽酶 的藥物動力學實體’以減少清除且改良半衰期。為測試 此，已向小鼠投與10或50 nmol酶/kg體重腦啡肽酶（Nep)或 Fc-Nep(l mg/kg及5 mg/kg)之單次靜脈内劑量。給藥後在 設定時間自尾靜脈抽取血液樣品或在終止時藉由心穿刺術 抽取血液樣品。一旦取樣至含有EDTA之管中，即將等分 試樣置於冰上。藉由在15分鐘之取樣時間内離心（通常在 4°C下1500 g歷時1〇 min)來製備血漿且立即冷凍。經由免 疫檢定使用Nep之抗Nep或Fc-Nep之抗人類IgG作為捕獲抗 體來測定Nep及Fc-Nep之血漿濃度，而兩種物質均經由抗 Nep抗體來债測。使用套裝軟體（winN〇nUn， Corporation, USA)來計算藥物動力學參數且在此實例實驗 129669.doc -68· 200907056 中，所計算之半衰期已自Nep之約！天增加至Fc_Nep之約 2.5週。結果展示於圖15中。 實例28 藉由人類或小鼠Fc-腦啡肽酶來降解人類及Appswe tg小鼠 血漿中之類澱粉P肽1-40、1-42 在保健中心（AstraZeneca)在三個不同時間點將來自十二 隻個體（6隻雌性及6隻雄性）之血液收集至預冷肝素血漿管 中。藉由在4°C下以2500Xg離心20分鐘來製備血漿。收集 血漿樣品且將其轉移至預冷聚丙烯管中且立即冷來且在使 用之前儲存於- 70C下。就在實驗之前將來自12隻個體之 血漿解凍且彙集。血漿池中之八01_4〇及1_42經具有相應媒 劑（50 mM Tris-HCM、150 mM NaCl pH 7.5)之人類？〇仏卩 或小鼠Fc-Nep降解。使用以下最終濃度之Fc_Nep構築體： 100、32、10、3.2、1、0.3、0.1及 〇 pg/m丨且在室溫下降解 發生1小時，同時在回轉式震盪器上震盪。藉由添加磷阿 米酮（1 0 μΜ最終濃度）來終止酶促反應。使用ELISA套組 (Biosource ; KHB3481)根據製造商說明書來量測人類血漿 池中類澱粉βΐ-40之濃度。 將最終濃度為4.7 mM之EDTA添加至管中，之後使用 ELISA 套組 Innotest® β類澱粉]42(Inn〇genetics，第 177462 批，第80177號參考）根據製造商說明書來分析Αβ42之濃 度。 與未經Fc-Nep處理之血漿相比，最高濃度（1〇〇 之 人類Fc-Nep及小鼠Fc-Nep使人類血漿類澱粉卩卜扣分別降 129669.doc -69- 200907056 解66/。及71 /〇，且使Αβ1-42分別降解28%及。藉由人類 Fc-Nep及小鼠Fc-Nep降解iECs()值對於人類Αβ1_4〇而言分 別為0.58 μΜ及〇.4〇 μΜ，且對於Αβ142而言分別為〇 25 μΜ及0.18 μΜ。結果概括於圖μ中。 將自9隻動物收集之小鼠血漿儲存在_7(rc下。就在實驗 之岫將血漿解凍且彙集。血漿池中之八…扣及丨-^經具有 相應媒劑（50 mM Tris-Ηα、150 mM NaCl pH 7.5)之人類
Fc-Nep或小鼠Fc-Nep降解。使用以下最終濃度之以屮邛構 築體.100、32、10、3.2、1、0.3、0.1 及 〇 pg/ ml且在室 溫下降解發生1小時，同時在回轉式震盪器上震盪。藉由 添加磷阿米酮（10 μΜ最終濃度）來終止酶促反應。 降解之後’在使用ELISA套組（Biosource; ΚΗΒ348 1)量 測tg小鼠血漿池中之類澱粉^^训濃度之前，根據製造商說 明書將血漿樣品於標準稀釋劑緩衝液中稀釋2〇倍。 降解之後’將最終濃度為4· 7 mM之EDTA添加至tg小氣 血t管中，且將血漿樣品於樣品稀釋劑中稀釋3倍，之後 使用ELISA套組Innotest® β類澱粉，第 177462批，弟801 77號參考）根據製造商說明書來分析Αβ42 ί辰度 與未經Fc-Nep處理之血浆相比，最高濃度（1 〇〇 pg/ml)之人類Fc-Nep及小鼠Fc-Nep使人類血漿類殿粉βι_4〇 分別降解71%及77% ’且使Αβί-42分別降解34%及^%。藉 由人類Fc-Nep及小鼠Fc-Nep降解之EC50值對於人類Api_4〇 而吕分別為0.47 μΜ及0.34 μΜ，且對於Αβ1-42而言分別為 1·3 μΜ及0.82 μΜ。結果概括於圖16中。 129669.doc ^70- 200907056 序列表 SEQ ID NO 1 腦啡肽酶之細胞外域的胺基酸序列，版本1
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DILRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDI
YGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVI
H1DQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLPIDENQLALEMN
KVMELEKE1ANATAKPEDRNDPMLLYNKMTLAQIQNNFSLEINGKPFSWLNFTNEI
MSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMDLVSSLSRT
YKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAFAGESKHV
VEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERIGYPDDIVSNDNKLNN
EYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVNAFYSSGR
NQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKDGDLVDW
WTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAY
RAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSP
GNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW SEQ ID NO 2
腦啡肽酶之細胞外域的胺基酸序列，版本2 YDDGICKSSDCIKSAARLIQNMDATTEPCRDFFKYACGGWLKRNVIPETSSRYGNF DILRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDI YGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVI HIDQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLP1DENQLALEMN KVMELEKEIANATAKPEDRNDPMLLYNKMTLAQIQNNFSLEINGKPFSWLNFTNEI MSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMDLVSSLSRT YKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAFAGESKHV VEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERIGYPDDIVSNDNKLNN EYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVNAFYSSGR NQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKDGDLVDW WTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENiADNGGLGQAY RAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSP GNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW 129669.doc -71 - 200907056 SEQ ID NO 3 腦啡肽酶之細胞外域的胺基酸序列，版本3
YDDG1CKSSDCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNV1PETSSRYGMF
DiLRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDI
YGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVI
HIDQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLPIDENQLALEMN
KVMELEKEIANATAKPEDRNDPMLLYNKMRLAQIQNNFSLEINGKPFSWLNFTNEI
MSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMDLVSSLSRT
YKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAFAGESKHV
VEDL1AQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERIGYPDDIVSNDNKLNM
EYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVNAFYSSGR
NQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKDGDLVDW
WTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGEN1ADNGGLGQAY
RAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSP
GNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW SEQ ID NO 4
腦啡肽酶之細胞外域的胺基酸序列，版本4 YDDGICKSSDCIKSAARLIQNMDATTEPCRDFFKYACGGWLKRNVIPETSSRYGNF DILRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDI YGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHV1 HiDQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLPIDENQLALEMN 1 KVMELEKE1ANATAKPEDRNDPMLLYNKMRLAQIQNNFSLEINGKPFSWLNFTNEI
MSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMDLVSSLSRT YKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAFAGESKHV VEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERIGYPDDIVSNDNKLNN EYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVNAFYSSGR NQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKDGDLVDW WTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAY RAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSfKTDVHSP GNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW SEQ ID NO 5 129669.doc -72- 200907056 IDE之胺基酸序列（胰島素降解酶）
MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITK
SPEDKREYRGLELANGIKVLLMSDPTTDKSSAALDVHIGSLSDPPNIAGLSHFCEH
MLFLGTKKYPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQ
FFLCPLFDESCKDREVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTG
NKYTLETRPNQEGIDVRQELLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFS
EVENKNVPLPEFPEHPFQEEHLKQLYKIVPIKDIRNLYVTFPIPDLQKYYKSNPGHY
LGHLIGHEGPGSLLSELKSKGWVNTLVGGQKEGARGFMFFIINVDLTEEGLLHVED
IILHMFQYIQKLRAEGPQEWVFQECKDLNAVAFRFKDKERPRGYTSKIAGILHYYP
LEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAIVSKSFEGKTDRTEEWYGTQYK
QEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPLEKEATPYPALIKDTVMSK
LWFKQDDKKKKPKACLNFEFFSPFAYVDPLHCNMAYLYLELLKDSLNEYAYAAE
LAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFEIIKEAYMRS
LNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLLSRL
H1EALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFV
YQQRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFS
GPRRANGIQSLRFilQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRR
LDKPKKLSAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDA
PRRHKVSVHVLAREMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPL
FPLVKPHINFMAAKL SEQ ID NO 6 IDE之胺基酸序列（胰島素降解酶）（剪接變體）
MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITK
SPEDKREYRGLELANGIKVLLISDPTTDKSSAALDVHIGSLSDPPN1AGLSHFCEHM
LFLGTKKYPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQFF
LCPLFDESCKDREVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTGNK
YTLETRPNQEGIDVRQELLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFSEV
ENKNVPLPEFPEHPFQEEHLKQLYKIVPIKDIRNLYVTFP1PDLQKYYKSNPGHYLG
HLIGHEGPGSLLSELKSKOWVNTLVGGQKEGARGFMFFIINVDLTEEGLLHVEDIIL
HMFQYiQKLRAEGPQGWVFQECKDLNAVAFRFKDKERPRGYTSKIAGILHYYPLE
EVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAIVSKSFEGKTDRTEEWYGTQYKQE
AIPDEV1KKWQNADLNGKFKLPTKNEFIPTNFEILPLEKEATPYPALIKDTAMSKLW 129669.doc -73 - 200907056
FKQDDKFFLPKACLNFEFFSRYIYADPLHCNMTYLFIRLLKDDLKEYTYAARLSGL
SYGIASGMNAILLSVKGYNDKQPILLKKIIEKMATFEIDEKRFEIIKEAYMRSLNNFR
AEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLLSRLHIEALL
HGN1TKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFVYQQRNE
VHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFSGPRRAN
GIQGLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRRLDKPKK
LSAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDAPRRHKV
SVHVLAREMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPLFPLVKP
HINFMAAKL SEQ ID NO 7 ECE1之胺基酸序列（内皮素轉化酶1)
QYQTRSPSVCLSEACVSVTSSILSSMDPTVDPCHDFFSYACGGWIKANPVPDGHSR
WGTFSNLWEHMQAIIKHLLENSTASVSEAERKAQVYYRACMNETRIEELRAKPLM
ELIERLGGWNITGPWAKDNFQDTLQVVTAHYRTSPFFSVYVSADSKNSNSNVIQV
DQSGLGLPSRDYYLNKTENEKVLTGYLNYMVQLGKLLGGGDEEAIRPQMQQILD
FETALANITIPQEKRRDEELIYHKVTAAELQTLAPAINWLPFLNTIFYPVEINESEP1V
VYDKEYLEQISTLINTTDRCLLNNYM1WNLVRKTSSFLDQRFQDADEKFMEVMYG
TKKTCLPRWKFCVSDTENNLGFALGPMFVKATFAEDSKSIATEHLEIKKAFEESLS
TLKWMDEETRKSAKEKADAIYNMIGYPNFIMDPKELDKVFNDYTAVPDLYFENA
MRFFNFSWRVTADQLRKAPNRDQWSMTPPMVNAYYSPTKNEIVFPAGILQAPFYT
RSSPKALNFGGIGVVVGHELTHAFDDQGREYDKDGNLRPWWKNSSVEAFKRQTE
CMVEQYSNYSVNGEPVNGRHTLGENIADNGGLKAAYRAYQNWVKKNGAEHSLP
TLGLTNNQLFFLGFAQVWCSVRTPESSHEGLITDPHSPSRFRVIGSLSNSKEFSEHFR
CPPGSPMNPPHKCEVW SEQ ID NO 8 用於表現構築體之信號肽的胺基酸序列
METDTLLLWVLLLWVPGSTGD SEQ ID NO 9
鉸鏈區（來自IgG2)之胺基酸序列 BRKCCVECPPCP 129669.doc -74- 200907056 SEQ ID NO 10
Fc域（來自IgG2)之胺基酸序列
APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN
AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKG
QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPP
MLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO 11 完整融合蛋白Fc-腦啡肽酶之胺基酸序列
ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQF
NWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGL f PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG
QPENMYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKYDDGICKSSDC1KSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPE TSSRYGNFDILRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEP
LLKLLPDIYGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDK
NSVNHVIHIDQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLPIDEN
QLALEMNKVMELEKEIANATAKPEDRNDPMLLYNKMTLAQIQNNFSLEINGKPFS
WLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMD
LVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAF
AGESKHVVEDHAQ1REVF1QTLDDLTWMDAETKKRAEEKALA1KER1GYPDD1VS
NDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVN
AFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNG
GLGQAYRAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSI
KTDVHSPGNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW SEQ ID NO 12 完整融合蛋白Fc-IDE之胺基酸序列
ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQF
NWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGL
PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG
QPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK 129669.doc -75- 200907056
SLSLSPGKMRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIK
RIGNHITKSPEDKREYRGLELANGIKVLLMSDPTTDKSSAALDVHIGSLSDPPNIAG
LSHFCEHMLFLGTKKYPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEG
ALDRFAQFFLCPLFDESCKDREVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHP
FSKFGTGNKYTLETRPNQEGIDVRQELLKFHSAYYSSNLMAVCVLGRESLDDLTN
LVVKLFSEVENKNVPLPEFPEHPFQEEHLKQLYKIVPIKDIRNLYVTFPIPDLQKYY
KSNPGHYLGHLIGHEGPGSLLSELKSKGWVNTLVGGQKEGARGFMFFIINVDLTEE
GLLHVEDI1LHMFQYIQKLRAEGPQEWVFQECKDLNAVAFRFKDKERPRGYTSKIA
GILHYYPLEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAIVSKSFEGKTDRTEE
WYGTQYKQEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPLEKEATPYPALI
KDTVMSKLWFKQDDKKKKPKACLNFEFFSPFAYVDPLHCNMAYLYLELLKDSLN
EYAYAAELAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFEII
KEAYMRSLNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFI
PQLLSRLHIEALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLP
DRGWFVYQQRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQ
LGYIVFSGPRRANGIQSLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQ
ALAIRRLDKPKKLSAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEM
LAVDAPRRHKVSVHVLAREMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEF
KRGLPLFPLVKPH1NFMAAKL SEQ ID NO 13 完整融合蛋白Fc-ECEl之胺基酸序列
ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQF
NWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGL
PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG
QPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGKQYQTRSPSVCLSEACVSVTSSILSSMDPTVDPCHDFFSYACGGWIKANP
VPDGHSRWGTFSNLWEHNQAIIKHLLENSTASVSEAERKAQVYYRACMNETRIEE
LRAKPLMELIERLGGWNITGPWAKDNFQDTLQVVTAHYRTSPFFSVYVSADSKNS
NSNVIQVDQSGLGLPSRDYYLNKTENEKVLTGYLNYMVQLGKLLGGGDEEAIRPQ MQQILDFETALANITIPQEKRRDEELIYHKVTAAELQTLAPAINWLPFLNTIFYPVE1
NESEPIVVYDKEYLEQISTLINTTDRCLLNNYM1WNLVRKTSSFLDQRFQDADEKF
MEVMYGTKKTCLPRWKFCVSDTENNLGFALGPMFVKATFAEDSKSIATEIILEIKK
AFEESLSTLKWMDEETRKSAKEKADAIYNMIGYPNFIMDPKELDKVFNDYTAVPD 129669.doc -76- 200907056
LYFENAMRFFNFSWRVTADQLRKAPNRDQWSMTPPMVNAYYSPTKNEIVFPAGIL
QAPFYTRSSPKALNFGGIGVVVGHELTHAFDDQGREYDKDGNLRPWWKNSSVEA
FKRQTECMVEQYSNYSVNGEPVNGRHTLGENIADNGGLKAAYRAYQNWVKKNG
AEHSLPTLGLTNNQLFFLGFAQVWCSVRTPESSHEGLITDPHSPSRFRVIGSLSNSKE
FSEHFRCPPGSPMNPPHKCEVW SEQ ID NO 14 完整鼠科動物融合蛋白Fc-腦啡肽酶之胺基酸序列
METDTLLLWVLLLWVPGSTGDVPRDCGCKPCICTVPPVSSVFIFPPKPKDVLTITLT
PKVTCVVVAISKDDPEVQFSWFVDDVEVHTAQTQPREEQFASTFRSVSELPIMHQD
WLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYT1PPPKEQMAKDKVSLTCM
ITDFFPEDITVEWQWNGQPAENYKNTQPIMNTNGSYFVYSKLNVQKSNWEAGNTF
TCSVLHEGLHNHHTEKSLSHSPGKYDDGICKSSDCIKSAARLIQNMDASVEPCTDF
FKYACGGWLKRNVIPETSSRYSNFDILRDELEVILKDVLQEPKTEDIVAVQKAKTL
YRSCINESAIDSRGGQPLLKLLPDIYGWPVASDNWDQTYGTSWTAEKSIAQLNSKY
GKKVLINFFVGTDDKNSTQHIIHFDQPRLGLPSRDYYECTGIYKEACTAYVDFMIS
VARLIRQEQSLPIDENQLSLEMNKVMELEKEIANATTKPEDRNDPMLLYNKMTLA
KLQNNFSLEVNGKSFSWSNFTNEIMSTVN1N1QNEEEVVVYAPEYLTKLKPILTKYS
PRDLQNLMSWRFIMDLVSSLSRNYKESRNAFRKALYGTTSETATWRRCANYVNG
NMENAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKKAEE
KALAIKERIGYPDDI1SNENKLNNEYLELNYREDEYFENIIQNLKFSQSKQLKKLRE
KVDKDEWISGAAVVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGH
EITHGFDDNGRNFNKDGDLVDWWTQQSANNFKDQSQCMVYQYGNFSWDLAGG
QHLNGINTLGENIADNGGIGQAYRAYQNYVKKNGEEKLLPGLDLNHKQLFFLNFA
QVWCGTYRPEYAVNSIKTDVHSPGNFRIIGTLQNSAEFADAFHCRKNSYMNPERK
CRVW SEQ ID NO 15 人類類澱粉β肽1-3 8之胺基酸序列 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGG SEQ ID NO 16 人類類澱粉β肽1 -39之胺基酸序列
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGV 129669.doc -77- 200907056 SEQ ID NO 17 人類類澱粉β肽1 -40之胺基酸序列 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV SEQ ID NO 18
人類類澱粉β肽卜4 1之胺基酸序列 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVI SEQ ID NO 19
人類類澱粉β肽1 -42之胺基酸序列 f DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA SEQ ID NO 20
人類類澱粉β肽1 -43之胺基酸序列 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIAT 【圖式簡單說明】 圊1 藉由緩衝液中之市售腦啡肽酶（Neprilysin)(2.4 pg/ml)或 Fc-腦啡肽酶融合蛋白（2.4 pg/ml)降解類澱粉βΐ -40肽（最終 V 濃度 300 ηΜ)。 圖2 藉由豚鼠血漿中之His-Fc-Nep(SPL061 128)及腦啡肽酶 (R&D Systems)降解 Αβ40。使用兩種濃度之 His-Fc-Nep， 且4小時之後量測Αβ40含量。使用市售腦啡肽酶作為陽性 對照，且使用麟阿米酮（phosphoramidon)作為腦啡肽酶特 異性抑制劑。 圖3 129669.doc -78- 200907056 藉由豚鼠血漿中之HiS-FC-NeP(SPL061 128)及腦啡肽酶 (R&D Systems)降解 Αβ42。使用兩種濃度之 His_Fc_Nep， 且4小時之後量測Αβ42含量。使用市售腦啡肽酶作為陽性 對照，且使用磷阿米酮作為腦啡肽酶特異性抑制劑。 圓4 藉由人類血漿中之His-Fc-Nep(SPL061128)及腦啡肽酶 (R&D Systems)降解 Αβ40。使用兩種濃度之 His_Fc_Nep , 且4小時之後量測Αβ40含量。使用市售腦啡肽酶作為陽性 : 對照，且使用碟阿米酮作為腦啡肽酶特異性抑制劑。 囷5 與市售腦啡肽酶相比，Fc_Nep融合蛋白之ρκ概況（隨時 間流逝之血漿濃度）。對小鼠投與i mg/kg之市售腦啡肽酶 或1 mg/kg或者5 mg/kg内部產生之pc_Nep。 圖6 與腦啡肽酶-Fc(Fc之C末端融合）相比，來自Fc_腦啡肽酶 (Fc之N末端融合）之表現的細胞培養基中之酶活性。描 V 述：PCEP4GW_NeP-Fc :由PCEP4質體表現之腦啡肽酶_ Fc ; PEAKIOGW-Nep-Fc :由ρΕΑΚΙΟ質體表現之腦啡肽酶_ Fc ; com.Nep :陽性對照，市售腦啡肽酶；pCEp4Gw_Fe_ Nep ··由PCEP4質體表現之Fc_腦啡肽酶；pEAK1〇GW_Fc_ Nep:由ρΕΑΚΙΟ質體表現之Fc-腦啡肽酶。 圖7 在以Fc-Nep急性處理以及以陽性對照，γ分泌酶抑制劑 Μ550426處理之後，雌性APPsWE_tg小鼠血漿中之可溶性 129669.doc •79- 200907056 Αβ40含量。 圖8 在以Fc-Nep急性處理以及以陽性對照，γ分泌酶抑制劑 Μ55〇426處理之後，雌性APPsWE_tg小鼠血漿中之可溶二 Αβ42含量。 丨 圓9 與腦啡肽酶-Fc(Fc之C末端融合）相比，經純化蛋白Fc_腦 啡肽酶（Fc之N末端融合）之酶活性。 描述·· Nep-Fc :在腦啡肽酶之c末端部分融合至Fc之腦 啡肽酶；Fc-Nep :在腦啡肽酶之;^末端部分融合至Fc之腦 啡肽酶。 圖10 在以hFc-Nep急性處理以及以陽性對照，γ分泌酶抑制劑 Μ55〇426處理之後，雌性C57bl/6小氣血聚中之小鼠〇 含量。 圖11 向雌性C57BL6小鼠單
八/工巧ilJTC 士 後，不同q 甜 日守血毁中之Αβ4〇含量。百分比展示與媒劑相比之減小。 ㈣邛之暴露展示於圖中之各處理條上。以红色展示以 陽性對照，7分泌酶抑制劑Μ550426^里之作肖。l〇q線展 示檢定中之定量限制。 圖12 在向雌性APP 不同時間點（自 SWE 轉殖基因小鼠單a a & 乳早-人注射mFc_Nep之後， I.5小時直至336小時、 4听）時血漿中之平均 129669.doc 200907056 Αβ40(Α)及Αβ42含量（B)。百分比展示與媒劑相比之減小。 表（C)展示各別群之血聚暴露。以紅色展示以陽性對照，丫 分泌酶抑制劑Μ55〇426處理之作用。L〇q條展示檢定中之 定量限制。使用ANOVA模型中之兩側t測試（two-sided U tests)以時間及劑量作為固定因素來分析資料; **P<0.01 及 ***ρ<〇.〇〇1 且 n.s.非顯著）。 圖13 藥物動力學及藥力學圖’其分別展示作為所有時間點 f (1.5-336小時）之媒劑百分比的Αβ40及Αβ42之血漿功效作 用，以及mFc-Nep之相應血漿暴露。各別圖中之線展示預 測暴露及作用。 在C57BL/6小鼠中，以5 mg/kg及25 mg/kg，在所有時間 點（1.5、168及336小時），mFc_Nep均顯著減少血漿中之小 鼠Αβ40(圖i 4)。在！ 68及336小時’分析5及25 mg/kg 且Αβ40作用經展示具劑量依賴性。2週後，與媒劑相比，
25 mg/kg mFc-Nep之單次注射（336小時）使血漿_之小氣 Αβ40含量顯著減少73% 且mFc-Nep藉此展示具有長的血漿半衰期 囷14 此時間點之金漿暴露為48 pg/mi 在向雌性C57BL6小鼠單次靜脈内注射mFe_Nep之後，不 同時間點（1.5、168及336小時）時血漿中之平均寧〇含量。 百分比展示與媒劑相比之減小。右表展示各別群之血衆暴 露。以紅色展示以陽性對照’ 丫分泌酶抑制劑他⑽處 理之作用。LQQ條展示檢定巾^量_。使用則輝 I29669.doc -8!- 200907056 型中之兩側t測試以時門β节丨丨曰& A门 了間及劑置作為固定因素來分析資料 (*p<0.05 ; "p<0 〇1 ; * 圖15 ρ<0·001 且 n_s·非顯著）。 與左内部產生之腦啡肽酶相比，Fc-Nep融合蛋白之Ρκ概 /兄（Ik時間流逝之血漿濃度）。向小鼠以或nm〇1酶/kg 體重腦非肽酶（NeP)4Fc-Nep(l mg/kg及5 mg/kg)之單次靜 脈内劑量投與小鼠。 圖16 f 描述在人類血漿或APPswe-tg小鼠血漿中藉由人類或小氣 Fc-腦啡肽酶降解類澱粉β肽1-40或1-42之表。在最高（1 〇〇 pg/mL)濃度之人類或小鼠Fc-腦啡狀酶下之降解， Ε(：5〇(μΜ)及降解結果係基於2-3個獨立實驗。 129669.doc -82- 200907056 <110:»瑞典商阿斯特捷利康公司 序列表 <120;» 新方法 <130> 102706-1 <140> 097110852 <141> 2008-03-26 <150> US 60/908471 <151> 2007-03-28 <160> 20 <170> Patentln version 3.5 <210> 1 <211> 699 <212< PRT <213> 智人 <400> 1
Tyr Asp Asp Gly lie cys Lys ser Ser Asp cys lie Lys Ser Ala Ala 1 5 10 15
Arg Leu lie Gin Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe 2〇 25 30
Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val lie Pro Glu 35 40 45
Thr Ser ser Arg Tyr Gly Asn Phe Asp lie Leu Arg Asp Glu Leu Glu 5〇 55 60
Val Val Leu Lys Asp Val Leu Gin Glu Pro Lys Thr Glu Asp lie val 65 70 75 80
Ala Val Gin Lys Ala Lys Ala Leu Tyr Arg Ser Cys lie Asn Glu Ser 85 90 95
Ala lie Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp 100 105 110 lie Tyr Gly Trp pro Val Ala Thr Glu Asn Trp Glu Gin Lys Tyr Gly 115 120 125
Ala ser Trp Thr Ala Glu Lys Ala lie Ala Gin Leu Asn ser Lys Tyr 130 135 140
Gly Lys Lys Val Leu lie Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 145 150 155 160
Ser Val Asn His Val lie His lie Asp Gin Pro Arg Leu Gly Leu Pro 165 170 175
Ser Arg Asp Tyr Tyr Glu cys Thr Gly lie Tyr Lys Glu Ala Cys Thr 180 185 190 129669-序列表.doc 200907056
Ala Tyr Val Asp Phe Met lie ser val Ala Arg Leu He Ara Gin Glu 195 200 205
Glu Arg Leu Pro He Asp Glu Asn Gin Leu Ala Leu Glu Met Asn Lvs 210 215 220
Val Met Glu Leu Glu Lys Glu lie Ala Asn Ala Thr Ala Lvs Pro Glu 225 230 235 240
Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gin 245 250 255
lie Gin Asn Asn Phe Ser Leu Glu lie Asn Gly Lys Pro phe Ser TrD 260 265 270
Leu Asn Phe Thr Asn Glu lie Met Ser Thr Val Asn lie Ser lie Thr 275 280 285
Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lvs Leu 290 295 300
Lys Pro lie Leu Thr Lys Tyr ser Ala Arg Asp Leu Gin Asn Leu Met 305 310 315 320
Ser Trp Arg Phe lie Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr 325 330 335
Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr ser 340 345 350
Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met 355 360 365
Glu Asn Ala val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu 370 375 380
Ser Lys His val val Glu Asp Leu lie Ala Gin lie Arg Glu val Phe 385 390 395 400 lie Gin Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys 405 410 415
Arg Ala Glu Glu Lys Ala Leu Ala lie Lys Glu Arg lie Gly Tyr Pro 420 425 430
Asp Asp lie Val ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 435 440 445
Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn lie lie Gin Asn Leu 450 455 460 12%69-序列表.doc -2- 200907056
Lys Phe ser Gin Ser Lys Gin Leu Lys Lys Leu Arg Glu Lvs Val Asp 465 470 475 480
Lys Asp Glu Trp lie Ser Gly Ala Ala Val Val Asn Ala Phe Tyr ser 485 490 495 ser Gly Arg Asn Gin lie Val Phe Pro Ala Gly lie Leu Gin pro Pro 500 505 5i〇
Phe Phe Ser Ala Gin Gin Ser Asn ser Leu Asn Tyr Gly Gly lie Gly 515 520
Met Val lie Gly His Glu lie Thr His Gly Phe Asp asd Asn Glv Ara 530 535 540 7
Asn Phe Asn Lys Asp Gly Asp Leu val Asp Trp Trp Thr Gin Gin Ser 545 550 555 560
Ala ser Asn Phe Lys Glu Gin Ser Gin Cys Met val Tyr Gin Tyr Gly 565 570 575
Asn Phe Ser Trp Asp Leu Ala Gly Gly Gin His Leu Asn Gly lie Asn 580 585 590
Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Gly Gin Ala Tyr 595 600 605
Arg Ala Tyr Gin Asn Tyr lie Lys Lys Asn Gly Glu Glu Lys Leu Leu 610 615 620
Pro Gly Leu Asp Leu Asn His Lys Gin Leu Phe Phe Leu Asn Phe Ala 625 630 635 640
Gin Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn ser lie 645 650 655
Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg lie lie Gly Thr Leu 660 665 670
Gin Asn Ser Ala Glu Phe ser Glu Ala phe His Cys Arg Lys Asn Ser 675 680 685
Tyr Met Asn Pro Glu Lys Lys cys Arg Val Trp 690 695 <210> 2 <211> 699 <212> PRT <213> 智人 <400> 2 129669-序列表.doc 200907056
Tyr Asp Asp Gly lie cys Lys Ser ser Asp cys lie Lys Ser Ala Ala 15 10 15
Arg Leu lie Gin Asn Met Asp Ala Thr Thr Glu Pro cys Arg asd Phe 20 25 30
Phe Lys Tyr Ala cys Gly Gly Trp Leu Lys Arg Asn Val lie Pro Glu 35 40 45
Thr ser Ser Arg Tyr Gly Asn Phe Asp lie Leu Arg Asp Glu Leu Glu 50 55 60
Val Val Leu Lys Asp Val Leu Gin Glu Pro Lys Thr Glu Asp lie Val 65 70 75 80
Ala val Gin Lys Ala Lys Ala Leu Tyr Arg Ser cys lie Asn Glu ser 85 90 95
Ala lie Asp ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp 100 105 110 lie Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gin Lys Tyr Gly 115 120 125
Ala ser Trp Thr Ala Glu Lys Ala lie Ala Gin Leu Asn Ser Lys Tyr 130 135 140
Gly Lys Lys Val Leu lie Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 14B 150 155 160 ser Val Asn His Val lie His lie Asp Gin pro Arg Leu Gly Leu Pro 165 170 175
Ser Arg Asp Tyr Tyr Glu Cys Thr Gly lie Tyr Lys Glu Ala Cys Thr 180 185 190 、 Ala Tyr Val Asp Phe Met lie Ser Val Ala Arg Leu lie Arg Gin Glu 195 200 205
Glu Arg Leu Pro lie Asp Glu Asn Gin Leu Ala Leu Glu Met Asn Lys 210 215 220 val Met Glu Leu Glu Lys Glu lie Ala Asn Ala Thr Ala Lys Pro Glu 225 230 235 240
Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gin 245 250 255 lie Gin Asn Asn Phe ser Leu Glu lie Asn Gly Lys Pro Phe Ser Trp 260 265 270 -4- 129669-序列表.doc 200907056
Leu Asn Phe Thr Asn Glu lie Met Ser Thr val Asn lie Ser lie Thr 275 280 285
Asn Glu Glu Asp Val val Val Ty「 Ala Pro Glu Tyr Leu Thr lvs Leu 290 295 BOO y
Lys Pro He Leu Thr Lys Tyr ser Ala Arg Asp Leu Gin Asn Leu Met 305 310 315 320
Ser Trp Arg Phe lie Met Asp Leu Val Ser ser Leu Ser Ara Thr Tvr
325 330 335 V
Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr ser 340 345 350
Glu Thr Ala Thr Trp Arg Arg cys Ala Asn Tyr Val Asn Gly Asn Met 355 360 365
Glu Asn Ala val Gly Arg Leu Tyr Val Glu Ala Ala phe Ala Glv Glu 370 375 380
Ser Lys His Val Val Glu Asp Leu lie Ala Gin lie Arg Glu Val Phe 385 390 395 4〇〇 lie Gin Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr ivc i v«：
405 410 S
Arg Ala Glu Glu Lys Ala Leu Ala lie Lys Glu Arg lie Gly Tyr Pro 420 425 430 y
Asp Asp lie Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 435 440 445
Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn lie lie Gin Asn Leu 450 455 460
Lys Phe ser Gin Ser Lys Gin Leu Lys Lys Leu Arg Glu Lys Val Asp 470 475 480
Lys Asp Glu Trp lie Ser Gly Ala Ala Val Val Asn Ala Phe Tvr ςρτ 485 490 说
Ser Gly Arg Asn Gin lie Val Phe Pro Ala Gly lie Leu Gin Pro Prn 500 505 5i〇
Phe Phe Ser Ala Gin Gin Ser Asn Ser Leu Asn Tyr Gly Gly He Gly 520 525
Met Val lie Gly His Glu lie Thr His Gly Phe Asp asd Asn κίν &rn 530 535 Pwwy Arg 129669-序列表.doc 200907056
Asn Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gin Gin ser 545 550 555 560
Ala ser Asn Phe Lys Glu Gin se「 Gin Cys Met val Tyr Gin Tyr Gly 565 570 575
Asn Phe ser Trp Asp Leu Ala cly Gln His Leu Asn Cly He Asn
Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Gly Gin Ala Tyr 595 600 605
Arg Ala Tyr Gin Asn Tyr lie Lys Lys Asn cly Glu Glu Lys Leu Leu
Pro Gly Leu Asp Leu Asn His Lys Gin Leu Phe Phe Leu Asn Phe Ala 625 630 635 640
Gin Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser lie 645 650 655
Lys Thr Asp Val His ser Pro Gly Asn Phe Arg lie lie Gly Thr Leu 660 665 670
Gin Asn ser Ala Glu phe Ser Glu Ala Phe His cys Arg Lys Asn Ser 675 680 685
Tyr Met Asn Pro Glu Lys Lys cys Arg Val Trp 690 695 <210> 3 <211> 699 <212> PRT <213> 智人 <400> 3
Tyr Asp Asp Gly lie cys Lys ser Ser Asp cys He Lys Ser Ala Ala 1 5 10 15
Arg Leu lie Gin Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe 20 25 30
Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val lie Pro Glu 35 40 45
Thr Ser ser Arg Tyr Gly Asn Phe Asp lie Leu Arg Asp Glu Leu Glu 50 55 60
Val val Leu Lys Asp Val Leu Gin Glu Pro Lys Thr Glu Asp lie Val 65 70 75 80 -6- 129669-序列表.doc 200907056
Ala Val Gin Lys Ala Lys Ala Leu Tyr Arg ser Cys lie Asn Glu Ser 85 90 95
Ala He Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp 100 105 no lie Ty「 Gly T「P Pro Val Ala Thr Glu Asn Trp Glu Gin Lys Tyr Gly 115 120 125
Ala Ser Trp Th「 Ala Glu Lys Ala lie Ala Gin Leu Asn Ser Lys Tyr 130 135 140
Gly Lys Lys Val Leu He Asn Leu Phe val Gly Thr Asp Asp Lys Asn 145 150 155 160
Ser Val Asn His val lie His lie Asp Gin Pro Arg Leu Glv Leu Pro 165 170 175 / se「 Arg Asp Tyr Tyr Glu cys Thr Gly lie Tyr Lys Glu Ala Cys Thr k 180 185 i9〇
Ala Tyr Val Asp Phe Met lie Ser Val Ala Arg Leu lie Arq Gin Glu 195 200 205
Glu Arg Leu Pro lie Asp Glu Asn Gin Leu Ala Leu Glu Met Asn Lys 210 215 220
Val Met Glu Leu Glu Lys Glu lie Ala Asn Ala Thr Ala Lys Pro Glu 225 230 235 240
Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Arq Leu Ala Gin 245 250 255 lie Gin Asn Asn Phe Ser Leu Glu lie Asn Gly Lys Pro Phe ser Trp 260 265 270
Leu Asn Phe Thr Asn Glu lie Met ser Thr val Asn lie ser lie Thr 275 280 285
Asn Glu gTu Asp Val Val val Tyr Ala Pro Glu Tyr Leu Th「Lys Leu 290 295 300
Lys Pro lie Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gin Asn Leu Met 305 310 315 320
Se厂 T「p A「g phe lie Met Asp Leu Val Se「 Se「 Leu Ser A「q Thr Tv「 325 330 335
Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Glv Thr Thr ser 340 345 350 129669-序列表.doc 200907056
Clu Thr Ala Th, Trp Arg Arg cys Ala Asn Tyr Val Asn cly Asn Met
Clu Asn Ala Val Gly Ang Leu Tyn val Glu Ala Ala Phe Ala cly clu ser Lys His val Val ,lu Asp Leu Ile Ala Cjn Xle Arg clu val Phe lie Gin Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys 405 410 415
Arg Ala Glu Glu Lys Ala Leu Ala lie Lys Glu Arg lie Gly Tyr Pro 420 425 430
Asp Asp lie Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 435 440 445
Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn lie lie Gin Asn Leu 450 455 460
Lys Phe ser Gin Se「 Lys Gin Leu Lys Lys Leu Arg Glu Lys Val Asp 465 470 475 480
Lys Asp Glu Trp lie ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser 485 490 495
Ser Gly Arg Asn Gin lie Val Phe Pro Ala Gly lie Leu Gin Pro Pro 500 505 510
Phe Phe Ser Ala Gin Gin Ser Asn Ser Leu Asn Tyr Gly Gly lie Gly 515 520 525
Met Val lie Gly His Glu lie Thr His Gly Phe Asp Asp Asn Gly Arg 530 535 540
Asn Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gin Gin Ser 545 550 555 560
Ala ser Asn Phe Lvs Glu Gin Ser Gin Cys Met Val Tyr Gin Tyr Gly 565 570 575
Asn Phe Se「丁rp Asp Leu Ala Gly Gly Gin His Leu Asn Gly lie Asn 580 585 590
Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Gly Gin Ala Tyr 595 600 605
Arg Ala Tyr Gin Asn Tyr lie Lys Lys Asn Gly Glu Glu Lys Leu Leu 610 615 620 129669-序列表.doc 200907056
Pro Gly Leu Asp Leu Asn His Lys Gin Leu Phe Phe Leu Asn Phe Ala 625 630 635 640
Gin Val Trp cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser lie 645 650 655
Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg lie lie Gly Thr Leu 660 665 670
Gin Asn Ser Ala Glu Phe ser Glu Ala Phe His cys Arg Lys Asn Ser 675 680 685
Tyr Met Asn Pro Glu Lys Lys cys Arg Val Trp 690 695 <210> 4 <211> 699 <212> PRT <213> 智人 <400> 4
Tyr Asp Asp Gly lie Cys Lys ser ser Asp Cys lie Lys Ser Ala Ala 15 10 15
Arg Leu lie Gin Asn Met Asp Ala Thr Thr Glu Pro cys Arq asd Phe 20 25 30
Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val He Pro Glu 35 40 45
Thr ser ser Arg Tyr Gly Asn Phe Asp lie Leu Arg Asp Glu Leu Glu 50 55 60
Val Val Leu Lys Asp Val Leu Gin Glu Pro Lys Thr Glu Asp lie Val 65 70 75 80
Ala Val Gin Lys Ala Lys Ala Leu Tyr Arg Ser cys lie Asn Glu ser 85 90 95
Ala He Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro asd 100 105 110 lie Tyr cly Trp Pro val Ala Thr Glu Asn Trp Glu Gin Lys Tyr Gly
Ala ser Tnp Thr Ala clu Lys Ala He Ala Cln Leu Asn Ser Lys Tyr
Gly Lys Lys val Leu lie Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 145 150 155 160 ser Val Asn His Val lie His He Asp Gin Pro Arg Leu Gly Leu Pro -9- 129669-序列表.doc 200907056 165 170 175
Ser Arg Asp Tyr Tyr Glu cys Thr Gly lie Tyr Lys Glu Ala cys Thr 180 185 190
Ala Tyr Val Asp Phe Met lie Ser Val Ala Arg Leu lie Arg Gin Glu 195 200 205
Glu Arg Leu Pro lie Asp Glu Asn Gin Leu Ala Leu Glu Met Asn Lys 210 215 220 val Met Glu Leu Glu Lys Glu lie Ala Asn Ala Thr Ala Lys Pro Glu 225 230 235 240
Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Arg Leu Ala Gin 245 250 255 lie Gin Asn Asn Phe Ser Leu Glu lie Asn Gly Lys pro Phe ser Trp 260 265 270
Leu Asn Phe Thr Asn Glu lie Met Ser Thr Val Asn lie ser lie Thr 275 280 285
Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lvs Leu 290 295 300
Lys Pro lie Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gin Asn Leu Met 305 310 315 32〇
Ser Trp Arg Phe lie Met Asp Leu Val Ser ser Leu Ser Arg Thr Tyr 325 330 335
Lys Glu ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr ser 340 345 350
Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr val Asn Gly Asn Met 355 360 365
Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu lie Arg Glu Val phe 400 ser Lys His val val Glu Asp Leu lie Ala Gin 385 390 395
Asp Ala Glu Thr Lys Lys 415 lie Gin Thr Leu Asp Asp Leu Thr Trp Met 405 410
Arg Ala Glu
Glu 420
Lys Ala
Leu Ala lie 425
Lys Glu Arg lie
Gly 430
Tyr Pro
Asp Asp lie val ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu -10· 129669-序列表.doc 200907056 435 440 445
Leu Asn Tyr Lys Glu Asp Glu Tyr phe Glu Asn lie lie Gin Asn Leu 450 455 460
Lys Phe Ser Gin Ser Lys Gin Leu Lys Lys Leu Arg Glu Lys Val Asp 465 470 475 480
Lys Asp Glu Trp lie ser Gly Ala Ala val Val Asn Ala Phe Tyr Ser 485 490 495
Ser Gly Arg Asn Gin lie val Phe Pro Ala Gly lie Leu Gin Pro Pro 500 505 510
Phe Phe Ser Ala Gin Gin se「 Asn Ser Leu Asn Tyr Gly Gly lie Gly 515 520 525
Met Val lie Gly His Glu lie Thr His Gly Phe Asp Asp Asn Gly Arg 530 535 540
Asn Phe Asn Lys Asp Gly Asp Leu Val Asd Trp Trp Thr Gin Gin Ser 545 550 555 560
Ala Ser Asn Phe Lys Glu Gin ser Gin cys Met Val Tyr Gin Tyr Gly 565 570 575
Asn Phe ser Trp Asp Leu Ala Gly Gly Gin His Leu Asn Gly lie Asn 580 585 590
Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Gly Gin Ala Tyr 595 600 605
Arg Ala Tyr Gin Asn Tyr He Lys Lys Asn Gly Glu Glu Lys Leu Leu 610 615 620
Pro Gly Leu Asp Leu Asn His Lys Gin Leu Phe Phe Leu Asn Phe Ala 625 630 635 640
Gin Val Trp cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn ser lie 645 650 655
Lys Thr Asp Val His Ser Pr〇 Gly Asn Phe Arg lie lie Gly Th「 Leu 660 665 670
Gin Asn Ser Ala Glu Phe ser Glu Ala Phe His Cys Arg Lys Asn ser 675 680 685
Tyr Met Asn Pro Glu Lys Lys cys Arg Val Trp 〇90 695 <210> 5 -11 - 129669-序列表 doc 200907056 <211> 1019 <212> PRT <213> 智人 <400> 5
Met Arg Tyr Arg Leu Ala Trp Leu Leu His Pro Ala Leu Pro ser Thr 15 10 15
Phe Arg ser Val Leu Gly Ala Arg Leu Pro p「o Pro Glu Arg Leu cys 20 25 30
Gly phe Gin Lys Lys Thr Tyr ser Lys Met Asn Asn Pro Ala lie Lvs 35 40 45
Arg lie Gly Asn His lie Thr Lys ser Pro Glu Asp Lys Arg Glu Tyr 50 55 60
Arg Gly Leu Glu Leu Ala Asn Gly lie Lys Val Leu Leu Met Ser Asp 65 70 75 80
Pro Thr Thr Asp Lys Ser ser Ala Ala Leu Asp val His lie Gly Ser 85 90 95
Leu Ser Asp Pro Pro Asn lie Ala Gly Leu Ser His Phe cys Glu His 100 105 110
Met Leu Phe Leu Gly Thr Lys Lys Tyr Pro Lys Glu Asn Glu Tyr Ser 115 120 125
Gin Phe Leu Ser Glu His Ala Gly Ser Ser Asn Ala Phe Thr Ser Gly 130 135 140
Glu His Thr Asn Tyr Tyr Phe Asp Val ser His Glu His Leu Glu Gly 145 150 155 160
Ala Leu Asp Arg Phe Ala Gin Phe Phe Leu cys Pro Leu Phe Asp Glu 165 170 175
Ser cys Lys Asp Arg Glu Val Asn Ala val Asp ser Glu His Glu Lys 180 185 190
Asn Val Met Asn Asp Ala Trp Arg Leu Phe Gin Leu Glu Lys Ala Thr 195 200 205
Gly Asn Pro Lys His Pro Phe ser Lys Phe Gly Thr Gly Asn Lvs Tvr 210 215 220
Thr Leu Glu Thr Arg Pro Asn Gin Glu Gly lie Asp val Arg Gin Glu 225 230 235 240
Leu Leu Lys Phe His ser Ala Tyr Tyr Ser Ser Asn Leu Met Ala Val 245 250 255 -12- 129669-序列表.doc 200907056
Cys val Leu Gly Arg Glu Ser Leu Asp Asp Leu Thr Asn Leu val Val 260 265 270
Lys Leu Phe Ser Glu Val Glu Asn Lys Asn Val Pro Leu Pro Glu Phe 275 280 285
Pro Glu His Pro Phe Gin Glu Glu His Leu Lys Gin Leu Tyr Lys lie 290 295 300
Val Pro lie Lys Asp lie Arg Asn Leu Tyr Val Thr Phe Pro lie Pro 305 310 315 320
Asp Leu Gin Lys Tyr Tyr Lys Ser Asn Pro Gly His Tyr Leu Gly His 325 330 335
Leu lie Gly His Glu Gly Pro Gly Ser Leu Leu ser Glu Leu Lys ser 340 345 350
Lys Gly Trp Val Asn Thr Leu Val Gly Gly Gin Lys Glu Gly Ala Arg 355 360 365
Gly Phe Met Phe Phe lie lie Asn Val Asp Leu Thr Glu Glu Gly Leu 370 375 380
Leu His Val Glu Asp lie lie Leu His Met Phe Gin Tyr lie Gin Lys 385 390 395 400
Leu Arg Ala Glu Gly Pro Gin Glu Trp Val Phe Gin Glu Cys Lys Asp 405 410 415
Leu Asn Ala Val Ala Phe Arg Phe Lys Asp Lys Glu Arg Pro Arg Gly 420 425 430
Tyr Thr ser Lys lie Ala Gly lie Leu His Tyr Tyr Pro Leu Glu Glu 435 440 445 val Leu Thr Ala Glu Tyr Leu Leu Glu Glu Phe Arg Pro Asp Leu lie 450 455 460
Glu Met Val Leu Asp Lys Leu Arg Pro Glu Asn val Arg val Ala lie 465 470 475 480
Val Ser Lys Ser Phe Glu Gly Lys Thr Asp Arg Thr Glu Glu Trp Tyr 485 490 495
Gly Thr Gin Tyr Lys Gin Glu Ala lie Pro Asp Glu Val lie Lys Lys 500 505 510
Trp Gin Asn Ala Asp Leu Asn Gly Lys Phe Lys Leu Pro Thr Lys Asn 515 520 525 -13- 129669-序列表.doc 200907056
Glu Phe He pr〇 yhr Asn Phe Glu lie Leu Pro Leu Glu Lys Glu Ala 530 535 540
Thr Pro Tyr pr〇 Ala Leu lie Lys Asp Thr Val Met Ser Lys Leu Trp 545 550 555 560
Phe Lys Gin Asp Asp Lys Lys Lys Lys Pro Lys Ala cys Leu Asn Phe 565 570 575
Glu phe Phe Ser Pro Phe Ala Tyr Val Asp Pro Leu His Cys Asn Met 580 585 590
Ala Tyr Leu Tyr Leu Glu Leu Leu Lys Asp ser Leu Asn Glu Tyr Ala 595 600 605
Tyr Ala Ala clu Leu Ala cly Leu Ser Tyr Asp Leu cln Asn Thr He
Tyr Gly Met Tyr Leu ser Val LyS Gly Tyr jsn Asp Lys cln Pro lie
Leu Leu Lys Lys He lie Glu Lys Met Ala Thr Phe Glu lie Asp Glu 645 650 655
Lys Arg Phe Glu He lie Lys Glu Ala Tyr Met Arg ser Leu Asn Asn 660 665 670
Phs Arg Ala Glu Gin Pro His Gin His Ala Met Tvr Tvr Leu Aro Leu 675 680 y 685
Leu Thr Glu Val Ala Trp Thr Lys Asp Glu Leu Lys Glu Ala Leu 690 695 700
Asp Asp val Thr Leu Pro Arg Leu Lys Ala Phe xle Pno Cln Leu Leu
Ser Arg Leu His lie Glu Ala Leu Leu His Gly Asn lie Th「Lvs Gin 725 730 735
Ala Ala Leu Gly lie Met Gin Met Val Glu Asp Thr Leu lie Glu His 740 745 750
Ala His Thr Lys Pro Leu Leu Pro Ser Gin Leu val Arg Tyr Arg Glu 755 760 765 val Gin Leu Pro Asp Arg Gly Trp Phe Val Tyr Gln Gin Arg Asn Glu 770 775 780 val His Asn Asn cys Cly xle cl, xle Tyr Gln Thr Asp Met ,,, 14- 129669-序列表.doc 200907056
Ser Thr Ser Glu Asn Met Phe 805
Leu Glu Leu Phe cys Gin lie lie ser 810 815
Glu Pro cys Phe Asn Thr Leu 820
Arg Thr Lys Glu Gin Leu Gly Tyr lie 825 830 val Phe ser GTy Pro Arg Arg 835
Ala Asn Gly lie Gin ser Leu Arg phe 840 845 lie lie Gin Ser Glu Lys Pro 850 855
Pro His Tyr Leu Glu ser Arg Val Glu 860
Ala Phe Leu lie Thr Met Glu 865 870
Lys Ser lie Glu Asp Met Thr Glu Glu 875 880
Ala Phe Gin Lys His lie Gin 885
Ala Leu Ala lie Arg Arg Leu Asp Lys 890 895
Pro Lys Lys Leu Ser Ala Glu 900 cys Ala Lys Tyr Trp Gly Glu lie lie 905 910
Ser Gin Gin Tyr Asn Phe Asp Arg Asp Asn Thr Glu Val Ala Tyr Leu 915 920 925
Lys Thr Leu Thr Lys Glu Asp lie lie Lys Phe Tyr Lys Glu Met Leu 930 935 940
Ala Val Asp Ala Pro Arg Arg His Lys Val Ser Val His Val Leu Ala 945 950 955 960
Arg Glu Met Asp Ser Cys Pro Val Val Gly Glu Phe Pro Cys Gin Asn 965 970 975
Asp lie Asn Leu Ser Gin Ala Pro Ala Leu Pro Gin Pro Glu Val lie 980 985 990 Gin Asn Met Thr Glu Phe Lys Arg Gly Leu Pro Leu Phe Pro Leu Val 995 1000 1005 Lys Pro His lie Asn Phe Met Ala Ala Lys Leu 1010 1015 <210> 6 <2U> 1019 <212> PRT <213> 智人 <400> 6
Met Arg Tyr Arg Leu Ala Trp Leu Leu His Pro Ala Leu Pro 1 5 10 ser Thr 15 129669-序列表.d〇c -15 - 200907056
Phe Arg ser Val Leu Gly Ala Arg Leu Pro Pro Pro Glu Arg Leu cys 20 25 30
Gly Phe Lys Lys Thr Tyr ser Lys Met Asn Asn Pro Ala lie Lys 35 40 45
Arg Qe Gly Asn His ile Thr Lys ser Pro Glu Asp Lys Arg Glu Tyr 55 60
Arg Gly Leu Glu Leu Ala Asn Gly lie Lys Val Leu Leu lie Ser Asp bb 70 75 80
Pro Th「Thr Asp gs Ser ser Ala Ala Leu Asp Val His lie Gly Ser 85 90 95
Leu Ser Asp Pro Pro Asn lie Ala Gly Leu Ser His Phe cys Glu His 105 110
Met Leu 盌 Leu Gly Thr Lys 说 Ty「 pr。 Lys Glu 错 Glu Tyr ser
GlnLeu Ser G]u His Gly Ser Ser Asn Ala Phe Thr Ser Gly 135 140
His Thr Asn Tyr phe ASp val ser His Glu His Leu Glu Gly
ISO 155 160
Ala Leu Asp Arg Phe Ala Gin Phe Phe Leu Cys pro Leu Phe Asp Glu 1β5 170 175 ser cys Lys Asp Arg Glu val Asn Ala Val Asp ser Glu His Glu Lys 180 185 190
Asn Val Met Asn Asp Ala Trp Arg Leu Phe Gin Leu Glu Lys Ala Thr 195 200 205 、 Gly Asn Pro Lys His Pro phe ser Lys Phe Gly Thr Gly Asn Lys Tyr 210 215 220
Thr Leu Glu Thr Arg Pro Asn Gin Glu Gly lie Asp Val Arg Gin Glu 225 230 235 240
Leu Leu Lys Phe His Ser Ala Tyr Tyr Ser ser Asn Leu Met Ala val 245 250 255
Cys Val Leu Gly Arg Glu Ser Leu Asp Asp Leu Thr Asn Leu Val Val 260 265 270
Lys Leu Phe ser Glu Val Glu Asn Lys Asn Val Pro Leu Pro Glu Phe 275 280 285 U9669·序列表.doc -16 - 200907056
Pro Glu His Pro phe Gin Glu Glu His Leu Lys Gin Leu Tyr Lys lie 290 295 300
Val Pro lie Lys Asp lie Arg Asn Leu Tyr Val Thr Phe Pro lie Pro 305 310 315 320
Asp Leu Gin Lys Tyr Tyr Lys Ser Asn Fro Gly His Tyr Leu Gly His 325 330 335
Leu lie Gly His Glu Gly Pro Gly ser Leu Leu Ser Glu Leu Lys Ser 340 345 350
Lys Gly Trp Val Asn Thr Leu Val Gly Gly Gin Lys Glu Gly Ala Arg 355 360 365
Gly Phe Met Phe Phe lie lie Asn Val Asp Leu Thr Glu Glu Gly Leu 370 375 380
Leu His Val Glu Asp lie lie Leu His Met Phe Gin Tyr lie Gin Lys 385 390 395 400
Leu Arg Ala Glu Gly Pro Gin Gly Trp Val Phe Gin Glu Cys Lys Asp 405 410 415
Leu Asn Ala Val Ala Phe Arg Phe Lys Asp Lys Glu Arg Pro Arg Gly 420 425 430
Tyr Thr ser Lys lie Ala Gly lie Leu His Tyr Tyr Pro Leu Glu Glu 435 440 445
Val Leu Thr Ala Glu Tyr Leu Leu Glu Glu Phe Arg Pro Asp Leu lie 450 455 460
Glu Met Val Leu Asp Lys Leu Arg Pro Glu Asn Val Arg Val Ala lie 465 470 475 480
Val Ser Lys Ser Phe Glu Gly Lys Thr Asp Arg Thr Glu Glu Trp Tyr 485 490 495
Gly Thr Gin Tyr Lys Gin Glu Ala lie Pro Asp Glu val lie Lys Lys 500 505 510
Trp Gin Asn Ala Asp Leu Asn Gly Lys Phe Lys Leu Pro Thr Lys Asn 515 520 525
Glu Phe lie Pro Thr Asn Phe Glu lie Leu Pro Leu Glu Lys Glu Ala 530 535 540
Thr Pro Tyr Pro Ala Leu lie Lys Asp Thr Ala Met Ser Lys Leu Trp 545 550 555 560 -17· 129669·序列表.doc 200907056
Phe Lys Gin Asp Asp Lys Phe Phe Leu Pro Lys Ala cys Leu Asn Phe 565 570 575
Glu Phe Phe Ser Arg Tyr lie Tyr Ala Asp Pro Leu His cys Asn Met 580 585 590
Thr Tyr Leu Phe lie Arg Leu Leu Lys Asp Asp Leu Lys Glu Tyr Thr 595 600 605
Tyr Ala Ala Arg Leu Ser Gly Leu ser Tyr Gly lie Ala ser Gly Met 610 615 620
Asn Ala lie Leu Leu ser vaT Lys Gly Tyr Asn Asp Lys Gin Pro lie 625 630 635 640
Leu Leu Lys Lys lie lie Glu Lys Met Ala Thr Phe Glu lie Asp Glu 645 650 655 /" Lys Arg Phe Glu lie lie Lys Glu Ala Tyr Met Arg ser Leu Asn Asn I 660 665 670
Phe Arg Ala Glu Gin Pro His Gin His Ala Met Tyr Tyr Leu Arg Leu 675 680 685
Leu Met Thr Glu val Ala Trp Thr Lys Asp Glu Leu Lys Glu Ala Leu 690 695 700
Asp Asp Val Thr Leu Pro Arg Leu Lys Ala Phe lie pro Gin Leu Leu 705 710 715 720 ser Arg Leu His lie Glu Ala Leu Leu His Gly Asn lie Thr Lys Gin 725 730 735
Ala Ala Leu Gly lie Met Gin Met val Glu Asp Thr Leu lie Glu His 740 745 750
Ala His Thr Lys Pro Leu Leu Pro Ser Gin Leu val Arg Tyr Arg Glu 755 760 765 val Gin Leu Pro Asp Arg Gly Trp Phe Val Tyr Gin Gin Arg Asn Glu 770 775 780
Val His Asn Asn Cys Gly lie Glu lie Tyr Tyr Gin Thr Asp Met Gin 785 790 795 800
Ser Thr Ser Glu Asn Met Phe Leu Glu Leu Phe Cys Gin lie lie Ser 805 810 815
Glu Pro cys Phe Asn Thr Leu Arg Thr Lys Glu Gin Leu Gly Tvr lie 820 825 830 -18 - 129669-序列表.doc 200907056
Val Phe Ser Gly Pro Arg Arg Ala Asn Gly lie Gin Gly Leu Ara Phe 835 840 845 lie lie Gin ser Glu Lys Pro Pro His Tyr Leu Glu ser Arq Val Glu 850 855 860
Ala Phe Leu He Thr Met Glu Lys Ser He Glu Asp Met Thr Glu Glu 865 870 875 880
Ala Phe Gin Lys His lie Gin Ala Leu Ala lie Ara Ara Leu asd lvs 885 890 895
Pro Lys Lys Leu Ser Ala Glu Cys Ala Lys Tyr Trp Gly Glu lie lie 900 905 9i〇
Ser Gin Gin Tyr Asn Phe Asp Arg Asp Asn Thr Glu Val Ala Tvr Leu 915 920 925
Lys Thr Leu Thr Lys Glu Asp lie lie Lys Phe Tyr Lys Glu Met Leu 930 935 940
Ala Val Asp Ala Pro Arg Arg His Lys Val Ser Val His Val Leu Ala 945 950 955 960
Arg Glu Met Asp Ser cys Pro Val Val Gly Glu Phe Pro cys Gin Asn 965 970 975
Asp lie Asn Leu Ser Gin Ala Pro Ala Leu Pro Gin Pro Glu val lie 980 985 990
Gin Asn Met Thr Glu Phe Lys Arg Gly Leu Pro Leu Phe Pro Leu Val 995 1000 1005
Lys Pro His lie Asn Phe Met Ala Ala Lys Leu 1010 1015 v, <210> 7 <211> 681 <212> PRT <213> 智人 <400> 7
Gin Tyr Gin Thr Arg Ser Pro Ser Val cys Leu ser Glu Ala cys val 15 10 15
Ser val Thr ser Ser lie Leu Ser Ser Met Asp Pro Thr val Asp Pro 20 25 30
Cys His Asp Phe Phe Ser Tyr Ala Cys Gly Gly Trp lie Lys Ala Asn 35 40 45 129669-序列表.doc -19- 200907056
Pro val Pro Asp Gly His Ser Arg Trp Gly Thr Phe Ser Asn Leu Trp 50 55 60
Glu His Asn Gin Ala lie lie Lys His Leu Leu Glu Asn Ser Thr Ala 65 70 75 80
Ser Val Ser Glu Ala Glu Arg Lys Ala Gin Val Tyr Tyr Arg Ala Cys 85 90 95
Met Asn Glu Thr Arg lie Glu Glu Leu Arg Ala Lys Pro Leu Met Glu 100 105 110
Leu lie Glu Arg Leu Gly Gly Trp Asn lie Thr Gly Pro Trp Ala Lys 115 120 125
Asp Asn Phe Gin Asp Thr Leu Gin val val Thr Ala His Tyr Arg Thr 130 135 140 ser Pro phe Phe ser val Tyr Val ser Ala Asp ser Lys Asn Ser Asn 145 150 155 160 ser Asn Val He Gin val Asp Gin ser Gly Leu Gly Leu Pro Ser Arg 165 170 175
Asp Tyr Tyr Leu Asn Lys Thr Glu Asn Glu Lys val Leu Thr Gly Tyr 180 185 190
Leu Asn Tyr Met val Gin Leu Gly Lys Leu Leu Gly Gly Gly Asp Glu 195 200 205
Glu Ala lie Arg Pro Gin Met Gin Gin lie Leu Asp Phe Glu Thr Ala 210 215 220
Leu Ala Asn lie Thr lie Pro Gin Glu Lys Arg Arg Asp Glu Glu Leu 225 230 235 240 lie Tyr His Lys val Thr Ala Ala Glu Leu Gin Thr Leu Ala Pro Ala 245 250 255 lie Asn Trp Leu Pro Phe Leu Asn Thr lie Phe Tyr Pro Val Glu lie 260 265 270
Asn Glu Ser Glu Pro lie val Val Tyr Asp Lys Glu Tyr Leu Glu Gin 275 280 285 lie ser Thr Leu lie Asn Thr Thr Asp Arg cys Leu Leu Asn Asn Tyr 290 295 300
Met lie Trp Asn Leu val Arg Lys Thr Ser ser Phe Leu Asp Gin Arg 305 310 315 320 -20- 129669-序列表.d〇l 200907056
Phe Gin Asp Ala Asp Glu Lys Phe Met Glu val Met Tvr Glv Thr Lvs 325 330 335
Lys Thr cys Leu Pro Arg Trp Lys Phe cys Val ser Asp Thr Clu Asn
Asn Leu Cly Phe Ma Leu Cly Pro Met Phe val Lys Ala Thr Phe Ala
Glu Asp ser Lys Ser lie Ala Thr Glu lie lie Leu Glu He Lvs Lvs 370 375 380
Ala Phe Glu Glu Ser Leu Ser Thr Leu Lys Trp Met Asp Glu Glu Thr 385 390 395 400
Arg Lys ser Ala Lys Glu Lys Ala Asp Ala lie Tyr Asn Met lie Gly 405 410 415
Tyr pro Asn Phe lie Met Asp Pro Lys Glu Leu Asp Lys val Phe Asn 420 425 430
Asp Tyr Thr Ala Val Pro Asp Leu Tyr Phe clu Asn Ala Met Arg Phe
Phe Asn Phe Ser Trp Arg Val Thr Ala Asp Gin Leu Arg Lys Ala Pro 450 455 460
Asn Arg Asp Gin Trp Ser Met Thr Pro Pro Met Val Asn Ala Tyr Tyr 465 470 475 480 ser pro Thr Lys Asn Glu lie Val Phe Pro Ala Gly lie Leu Gin Ala 485 490 495
Pro Phe Tyr Thr Arg ser Ser Pro Lys Ala Leu Asn Phe Gly Gly lie 500 505 510
Gly val val val Gly His Glu Leu Thr His Ala Phe Asp Asp Gin Gly 515 520 525
Arg Glu Tyr Asp Lys Asp Gly Asn Leu Arg Pro Trp Trp Lys Asn Ser 530 535 540
Ser Val Glu Ala Phe Lys Arg Gin Thr Glu cys Met val Glu Gin Tyr 545 550 555 560
Ser Asn Tyr Ser val Asn Gly Glu Pro val Asn Gly Arg His Thr Leu 565 570 575
Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Lys Ala Ala Tyr Arg Ala 580 585 590 -21 - 129669-序列表.doc 200907056
Tyr Gin Asn Trp Val Lys Lys Asn Gly Ala Glu His ser Leu Pro Thr 595 600 605
Leu Gly Leu Thr Asn Asn Gin Leu Phe Phe Leu Gly Phe Ala Gin Val 610 615 620
Trp cys ser Val Arg Thr Pro Glu Ser Ser His Glu Gly Leu lie Thr 625 630 635 640
Asp Pro His ser Pro Ser Arg Phe Arg Val lie Gly ser Leu Ser Asn 645 650 655 ser Lys Glu Phe Ser Glu His Phe Arg cys Pro Pro Gly Ser Pro Met 660 665 670
Asn Pro Pro His Lys cys Glu Val Trp 675 680 <210> 8 <211> 21 <212> PRT <Z13> 人造 <220> <223>信號肽 <400> 8
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 15 10 15
Gly Ser Thr Gly Asp 20 <210> 9 <211> 12 <212> PRT <213> 智人 <400> 9
Glu Arg Lys Cys cys val Glu Cys Pro Pro Cys Pro 15 10 <210> 10 <211> 216 <212> PRT <213> 智人 <400> 10
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 15 10 15
Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val val 20 25 30 129669-序列表.doc -22
Val Asp val ser His Glu Asp Pro 35 40 Asp Gly Val Glu Val His Asn Ala 50 55 Phe Asn ser Thr Phe Arg Val Val 65 70 Asp Trp Leu Asn Gly Lys Glu Tyr 85 Leu Pro Ala Pro lie Glu Lys Thr 100 Arg Glu Pro Gin Val Tyr Thr Leu 115 120 Lys Asn Gin val Ser Leu Thr Cys 130 135 Asp lie Ala val Glu Trp Glu Ser 145 150 Lys Thr Thr Pro Pro Met Leu Asp 165 Ser Lys Leu Thr val Asp Lys ser 180 ser cys Ser val Met His Glu Ala 195 200 ser Leu ser Leu ser Pro Gly Lys 210 215 <210> 11 <2U> ' 927 <212> l PRT <213> 人造 <220> <223> ' 融合蛋白 <400> 11 Glu Arg Lys cys Cys Val Glu cys 1 5 Ala Gly pro Ser Val Phe Leu Phe 20 Met lie ser Arg Thr Pro Glu Val 35 40
Glu Val Gin Phe Asn Trp Tyr Val 45
Lys Thr Lys pro Arg Glu Glu Gin 60 ser val Leu Thr Val val His Gin 75 80
Lys Cys Lys Val Ser Asn Lys Gly 90 95 lie Ser Lys Thr Lys Gly Gin Pro 105 110
Pro pro ser Arg Glu Glu Met Thr 125
Leu Val Lys Gly Phe Tyr Pro Ser 140
Asn Gly Gin Pro Glu Asn Asn Tyr 155 160
Ser Asp Gly Ser Phe Phe Leu Tyr 170 175
Arg Trp Gin Gin Gly Asn val Phe 185 190
Leu His Asn His Tyr Thr Gin Lys 205
Pro Pro cys Pro Ala Pro Pro Val 10 15
Pro Pro Lys Pro Lys Asp Thr Leu 25 30
Thr cys val val Val Asp val Ser 45 129669-序列表.doc -23· 200907056
His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn ser Thr 65 70 75 80
Phe Arg val Val ser Val Leu Thr val Val His Gin Asp Trp Leu Asn 85 90 95
Gly Lys Glu Tyr Lys cys Lys val Ser Asn Lys Gly Leu Pro Ala Pro 100 105 HO lie Glu Lys Thr He ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin 115 120 125
Val Ty「 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val 130 135 140
Ser Leu Thr cys Leu val Lys Gly Phe Tyr Pro Ser Asp lie Ala val 145 150 155 160
Glu Trp Glu ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175
Pro Met Leu Asp ser Asp Gly ser Phe Phe Leu Tyr ser Lys Leu Thr 180 185 190 val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser cys ser Val 195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys ser Leu Ser Leu 210 215 220
Ser Pro Gly Lys Tyr Asp Asp Gly He cys Lys ser Ser Asd cvs lie 225 230 235 240
Lys ser Ala Ala Arg Leu lie Gin Asn Met Asp Ala Thr Thr Glu Pro 245 250 255
Cys Thr Asp Phe Phe Lys Tyr Ala cys Gly Gly Trp Leu Lys Arg Asn 260 265 270
Val lie Pro Glu Thr Ser Ser Arg Tyr Gly Asn Phe Asp lie Leu Ara 275 280 285
Asp Glu Leu Glu Val Val Leu Lys Asp Val Leu Gin Glu Pro Lvs Thr 290 295 300 y
Glu Asp lie Val Ala Val Gin Lys Ala Lys Ala Leu Tyr Arg Ser cys 305 310 315 320 -24- 129669-序列表.doc 200907056 lie Asn Glu Ser Ala lie Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys 325 330 335
Leu Leu Pro Asp lie Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu 340 345 350
Gin Lys Tyr Gly Ala ser Trp Thr Ala Glu Lys Ala lie Ala Gin Leu 355 360 B65
Asn ser Lys Tyr Gly Lys Lys Val Leu lie Asn Leu Phe Val Gly Thr 370 375 380
Asp Asp Lys Asn Ser Val Asn His Val lie His lie Asp Gin Pro Arg 385 390 395 400
Leu Gly Leu Pro Ser Arg Asp Tyr Tyr Glu cys Thr Gly lie Tyr Lys 405 410 415
Glu Ala Cys Thr Ala Tyr Val Asp Phe Met lie Ser Val Ala Arg Leu 420 425 430 lie Arg Gin Glu Glu Arg Leu Pro lie Asp Glu Asn Gin Leu Ala Leu 435 440 445
Glu Met Asn Lys Val Met Glu Leu Glu Lys Glu lie Ala Asn Ala Thr 450 455 460
Ala Lys Pro Glu Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met 465 470 475 480
Thr Leu Ala Gin lie Gin Asn Asn Phe ser Leu Glu lie Asn Gly Lys 485 490 495
Pro Phe Ser Trp Leu Asn Phe Thr Asn Glu lie Met Ser Thr val Asn 500 505 510 lie ser lie Thr Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr 515 520 525
Leu Thr Lys Leu Lys pro lie Leu Thr Lys Tyr ser Ala Arg Asp Leu 530 535 540
Gin Asn Leu Met ser Trp Arg Phe lie Met Asp Leu val ser ser Leu 545 550 555 560
Ser Arg Thr Tyr Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tvr 565 570 575
Gly Thr Thr Ser Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val 580 585 590 -25- 129669-序列表.doc 200907056
Asn Gly Asn Met Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala 595 600 605
Phe Ala Gly Glu Ser Lys His Val Val Glu Asp Leu lie Ala Gin He 610 615 620
Arg Glu Val Phe He Gin Thr Leu Asp Asp Leu Thr Trp Met asd Ala 625 630 635 549
Glu Thr Lys Lys Arg Ala Glu Glu Lys Ala Leu Ala lie Lys Glu Ara 645 650 655 lie Gly Tyr Pro Asp Asp lie Val ser Asn Asp Asn Lys Leu Asn Asn 660 665 670
Glu Tyr Leu Glu Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn lie 675 680 685 lie Gin Asn Leu Lys Phe Ser Gin Ser Lys Gin Leu Lys Lys Leu Arg 690 695 700
Glu Lys Val Asp Lys Asp Glu Trp lie Ser Gly Ala Ala Val Val Asn 705 710 715 720
Ala Phe Tyr Ser Ser Gly Arg Asn Gin lie Val Phe Pro Ala Gly lie 725 730 735
Leu Gin Pro Pro Phe Phe Ser Ala Gin Gin ser Asn ser Leu Asn Tyr 740 745 750
Gly Gly lie Gly Met Val lie Gly His Glu lie Thr His Gly Phe Asp 755 760 765
Asp Asn Gly Arg Asn Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp 770 775 780
Thr Gin Gin Ser Ala Ser Asn Phe Lys Glu Gin Ser Gin Cys Met Val 785 790 795 800
Tyr Gin Tyr Gly Asn Phe ser Trp Asp Leu Ala Gly Gly Gin His Leu 805 810 815
Asn Gly lie Asn Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu 820 825 830
Gly Gin Ala Tyr Arg Ala Tyr Gin Asn Tyr lie Lys Lys Asn Gly Glu 835 840 845
Glu Lys Leu Leu Pro Gly Leu Asp Leu Asn His Lys Gin Leu Phe Phe 850 855 860 -26- 129669-序列表.doc 200907056
Leu Asn Phe Ala Gin Val Trp cys Gly Thr Tyr Arg Pro Glu Tyr Ala 865 870 875 880
Val Asn Ser lie Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg lie 885 890 895 lie Gly Thr Leu Gin Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys 900 905 910
Arg Lys Asn Ser Tyr Met Asn Pro Glu Lys Lys Cys Arg Val Trp 915 920 925 <210> 12 <211> 1247 <212> PRT <213> 人造 <220> <223> 融合蛋白 ， <400> 12
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val 1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30
Met lie ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45
His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr 65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn 85 90 95
Gly Lys Glu Tyr Lys Cys Lys val ser Asn Lys Gly Leu Pro Ala Pro 100 105 110 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin 115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val 130 135 140
Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val 145 150 155 160 27- 129669-序列表.doc 200907056
Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175
Pro Met Leu Asp Ser Asp Gly ser Phe Phe Leu Tyr ser Lys Leu Thr 180 185 190 val Asp Lys ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val 195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys ser Leu Ser Leu 210 215 220 ser Pro Gly Lys Met Arg Tyr Arg Leu Ala Trp Leu Leu His Pro Ala 225 230 235 240
Leu Pro ser Thr Phe Arg ser val Leu Gly Ala Arg Leu Pro Pro Pro 245 250 255
Glu Arg Leu cys Gly Phe Gin Lys Lys Thr Tyr Ser Lys Met Asn Asn 260 265 270
Pro Ala lie Lys Arg lie Gly Asn His lie Thr Lys ser Pro Glu Asp 275 280 285
Lys Arg Glu Tyr Arg Gly Leu Glu Leu Ala Asn Gly lie Lys Val Leu 290 295 300
Leu Met ser Asp Pro Thr Thr Asp Lys Ser Ser Ala Ala Leu Asp Val 305 310 315 320
His lie Gly ser Leu ser Asp Pro Pro Asn lie Ala Gly Leu Ser His 325 330 335
Phe Cys Glu His Met Leu Phe Leu Gly Thr Lys Lys Tyr pro Lys Glu 340 345 350
Asn Glu Tyr ser Gin Phe Leu ser Glu His Ala Gly Ser ser Asn Ala 355 360 365
Phe Thr Ser Gly Glu His Thr Asn Tyr Tyr Phe Asp Val ser His Glu 370 375 380
His Leu Glu Gly Ala Leu Asp Arg Phe Ala Gin Phe Phe Leu cys Pro 385 390 395 400
Leu Phe Asp Glu ser Cys Lys Asp Arg Glu val Asn Ala val Asp Ser 405 410 415
Glu His Glu Lys Asn Val Met Asn Asp Ala Trp Arg Leu Phe Gin Leu 420 425 430 -28- 129669-序列表.doc 200907056
Glu Lys Ala Thr Gly Asn Pro Lys His Pro Phe ser Lys Phe Gly Thr 435 440 445
Gly Asn Lys Tyr Thr Leu G"lu Thr Arg Pro Asn Gin Glu Gly lie Asp 450 455 460
Val Arg Gin Glu Leu Leu Lys Phe His Ser Ala Tyr Tyr Ser Ser Asn 465 470 475 480
Leu Met Ala Val cys Val Leu Gly Arg Glu Ser Leu Asp Asp Leu Thr 485 490 495
Asn Leu val Val Lys Leu Phe Ser Glu val Glu Asn Lys Asn Val Pro 500 505 510
Leu pro Glu Phe pro Glu His Pro Phe Gin Glu Glu His Leu Lys Gin 515 520 525
Leu Tyr Lys lie Val Pro lie Lys Asp lie Arg Asn Leu Tyr Val Thr 530 535 540
Phe Pro lie Pro Asp Leu Gin Lys Tyr Tyr Lys Ser Asn Pro Gly His 545 550 555 560
Tyr Leu Gly His Leu lie Gly His Glu Gly Pro Gly ser Leu Leu Ser 565 570 575
Glu Leu Lys Ser Lys Gly Trp val Asn Thr Leu Val Gly Gly Gin Lys 580 585 590
Glu Gly Ala Arg Gly Phe Met Phe Phe lie lie Asn val Asp Leu Thr 595 600 605
Glu Glu Gly Leu Leu His Val Glu Asp lie lie Leu His Met Phe Gin 610 615 620 、 Tyr lie Gin Lys Leu Arg Ala Glu Gly Pro Gin Glu Trp val Phe Gin 625 630 635 640
Glu cys Lys Asp Leu Asn Ala Val Ala Phe Arg Phe Lys Asp Lys Glu 645 650 655
Arg Pro Arg Gly Tyr Thr Ser Lys lie Ala Gly lie Leu His Tyr Tyr 660 665 670
Pro Leu Glu Glu Val Leu Thr Ala Glu Tyr Leu Leu Glu Glu Phe Arg 675 680 685
Pro Asp Leu lie Glu Met Val Leu Asp Lys Leu Arg Pro Glu Asn Val 690 695 700 -29- 129669-序列表,doc 200907056 yg val Ala lie Val Lys ser phe Glu Gly Lys Thr Asp Arg Thr 705 710 715 720
Glu Glu Trp Tyr Gly Thr Gin Tyr Lys Gin Glu Ala lie Pro Asp Glu 725 730 735
Val He LyS 溢 Trp · Asn Ala 错 Leu Asn Gly Lys 郜 Lys Leu
Pro Thr Lys Asn Glu Phe lie Pro Thr Asn Phe Glu lie Leu Pro Leu 755 760 765
Glu Lys Glu Ala Thr Pro Tyr Pro Ala Leu He Lys Asp Thr Val Met
Ser Lys Leu Trp Phe Lys Gin Asp Asp Lys Lys Lys Lys Pro Lys Ala 785 790 795 800
Cys Leu Asn Phe Glu Phe Phe Ser Pro Phe Ala Tyr val Asp Pro Leu 805 810 815
His cys Asn Met Ala Tyr Leu Tyr Leu Glu Leu Leu Lys Asp Ser Leu 820 825 830
Asn Glu Tyr Ala Tyr Ala Ala Glu Leu Ala Gly Leu Ser Tyr Asp Leu 835 840 845
Gin Asn Thr lie Tyr Gly Met Tyr Leu Ser val Lys Gly Tyr Asn Asp 850 855 860
Lys Gin Pro lie Leu Leu Lys Lys lie lie Glu Lys Met Ala Thr Phe 865 870 875 880
Glu He Asp Glu Lys Arg Phe Glu lie lie Lys Glu Ala Tyr Met Arg 885 890 895
Ser Leu Asn Asn Phe Arg Ala Glu Gin Pro His Gin His Ala Met Tyr 900 905 910
Tyr Leu Arg Leu Leu Met Thr Glu Val Ala Trp Thr Lys Asp Glu Leu 915 920 925
Lys Glu Ala Leu Asp Asp val Thr Leu Pro Arg Leu Lys Ala Phe lie 930 935 940
Pro Gin Leu Leu Ser Arg Leu His lie Glu Ala Leu Leu His Gly Asn 945 950 955 960 lie Thr Lys Gin Ala Ala Leu Gly lie Met Gin Met Val Glu Asp Thr 965 970 975 -30- 129669-序列表.doc 200907056
Leu lie Glu His Ala His Thr Lys Pro Leu Leu Pro ser" Gin Leu Val 980 985 990
Arg Tyr Arg Glu val Gin Leu Pro〇 Asp Arg Cly Trp Ph^ Val Tyr cln
Gin Arg Asn Glu VaT His Asn Asn cys Gly lie Glu lie Tyr Tyr 1010 1015 1020
Gin Thr Asp Met Gin Ser Thr Ser Glu Asn Met Phe Leu Glu Leu 1025 1030 1035
Phe Cys Gin lie lie ser Glu Pro Cys Phe Asn Thr Leu Arq Thr 1040 1045 1050
Lys Glu Gin Leu Gly Tyr lie Val Phe ser Gly Pro Arq Arq Ala 1055 1060 1065
Asn Gly lie Gin Ser Leu Arg Phe lie lie Gin Ser Glu Lys Pro 1070 1075 1080
Pro His Tyr Leu Glu ser Arg Val Glu Ala Phe Leu lie Thr Met 1085 1090 1095
Glu Lys Ser lie Glu Asp Met Thr Glu Glu Ala Phe Gin Lys His 1100 1105 1110 lie Gin Ala Leu Ala lie Arg Arg Leu Asp Lys Pro Lys Lys Leu 1115 1120 1125
Ser Ala Glu cys Ala Lys Tyr Trp Gly Glu lie lie Ser Gin Gin 1130 1135 1140
Tyr Asn Phe Asp Arg Asp Asn Thr Glu Val Ala Tyr Leu Lys Thr 1145 1150 1155
Leu Thr Lys Glu Asp lie He Lys Phe Tyr Lys Glu Met Leu Ala 1160 1165 ii7〇
Val Asp Ala Pro Arg Arg His Lys Val ser Val His Val Leu Ala 1175 1180 1185
Arg Glu Met Asp Ser Cys Pro Val Val Gly Glu Phe Pro Cys Gin 1190 1195 1200
Asn Asp lie Asn Leu Ser Gin Ala Pro Ala Leu Pro Gin Pro Glu 1205 1210 1215
Val lie Gin Asn Met Thr Glu Phe Lys Arg Gly Leu Pro Leu Phe 1220 1225 1230 -31 · 129669-序列表.doc 200907056
Pro Leu val Lys Pro His lie Asn Phe Met Ala Ala Lys Leu 1235 1240 1245 <210> 13 <211> 909 <212> PRT <213> 人造 <220> <223> 融合蛋白 <400> 13
Glu Arg Lys cys cys val Glu Cys Pro Pro cys Pro Ala Pro Pro Val 1 5 10 15
Ala Gly Pro ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30
Met lie ser Arg Thr Pro Glu val Thr cys Val val Val Asp Val Ser 35 40 45
His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn ser Thr 65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn 85 90 95
Gly Lys Glu Tyr Lys cys Lys val Ser Asn Lys Gly Leu Pro Ala Pro 100 105 110 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin 115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val 130 135 140
Ser Leu Thr cys Leu val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val 145 150 155 160
Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175
Pro Met Leu Asp ser Asp Gly Ser Phe Phe Leu Tyr ser Lys Leu Thr 180 185 190
Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys ser Val 195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu ser Leu 210 215 220 -32 129669-序列表.doc 200907056
Ser Pro Gly Lys Gin Tyr Gin Thr Arg ser Pro Ser val cys Leu ser 225 230 235 240
Glu Ala Cys Val ser Val Thr Ser Ser lie Leu Ser Ser Met Asp Pro 245 250 255
Thr val Asp Pro cys His Asp Phe Phe ser Tyr Ala cys Gly Gly Trp 260 265 270 lie Lys Ala Asn Pro Val Pro Asp Gly His ser Arg Trp Gly Thr Phe 275 280 285 ser Asn Leu Trp Glu His Asn Gin Ala lie lie Lys His Leu Leu Glu 290 295 300
Asn ser Thr Ala ser Val ser Glu Ala Glu Arg Lys Ala Gin Val Tyr 305 310 315 320
Tyr Arg Ala Cys Met Asn Glu Thr Arg lie Glu Glu Leu Arg Ala Lys 325 330 335
Pro Leu Met Glu Leu lie Glu Arg Leu Gly Gly Trp Asn lie Thr Gly 340 345 350
Pro Trp Ala Lys Asp Asn Phe Gin Asp Thr Leu Gin Val val Thr Ala 355 360 365
His Tyr Arg Thr ser Pro Phe phe Ser Val Tyr val Ser Ala Asp ser 370 37B 380
Lys Asn ser Asn ser Asn Val lie Gin val Asp Gin Ser Gly Leu Gly 385 390 395 400
Leu Pro ser Arg Asp Tyr Tyr Leu Asn Lys Thr Glu Asn Glu Lys Val 405 410 415
Leu Thr Gly Tyr Leu Asn Tyr Met Val Gin Leu cly Lys Leu Leu Gly
Gly Gly Asp Glu Glu Ala lie Arg Pro Gin Met Gin Gin lie Leu Asp 4i5 440 445
Phe Clu Thr Ala Leu Ala Asn He Thr He Pro cln Glu Lys Arg Arg
Asp Glu Glu Leu He Tyr His Lys Val Thr Ala Ala Glu Leu Gin Thr 465 470 475 480
Leu Ala Pro Ala 子y Asn Trp Leu Pro Phe Leu Asn Thr lie phe Tyr 485 490 495 -33 - 12%69-序列表.doc 200907056
Pro Val Glu lie Asn Glu Ser Glu Pro lie Val Val Tyr Asp Lys Glu 500 505 510
Tyr Leu Glu Gin lie ser Th「 Leu lie Asn Thr Thr Asp Arg Cys Leu 515 520 525
Leu Asn Asn Tyr Met lie Trp Asn Leu val Arq Lys Thr ser ser Phe 530 535 540
Leu Asp Gin Arg Phe Gin Asp Ala Asp Glu Lys Phe Met Glu Val Met 545 550 555 560
Tyr Gly Thr Lys Lys Thr cys Leu Pro Arg Trp Lys Phe Cys Val Ser 565 570 575
Asp Thr Glu Asn Asn Leu Gly Phe Ala Leu Gly Pro Met Phe Val Lys 580 585 590
Ala Thr Phe Ala Glu Asp Ser Lys Ser lie Ala Thr Glu lie lie Leu 595 600 605
Glu lie Lys Lys Ala Phe Glu Glu ser Leu Ser Thr Leu Lys Trp Met 610 615 620
Asp Glu Glu Thr Arg Lys Ser Ala Lys Glu Lys Ala Asp Ala lie Tyr 625 630 635 640
Asn Met lie Gly Tyr Pro Asn Phe lie Met Asp Pro Lys Glu Leu Asp 645 650 655
Lys val Phe Asn Asp Tyr Thr Ala Val Pro Asp Leu Tyr Phe Glu Asn 660 665 670
Ala Met Arg Phe Phe Asn Phe Ser Trp Arg Val Thr Ala Asp Gin Leu 675 680 685
Arg Lys Ala Pro Asn Arg Asp Gin Trp Ser Met Thr Pro Pro Met Val 690 695 700
Asn Ala Tyr Tyr ser Pro Thr Lys Asn Glu lie Val Phe Pro Ala Gly 705 710 715 720 lie Leu Gin Ala Pro phe Tyr Thr Arg Ser Ser Pro Lys Ala Leu Asn 725 730 735
Phe Gly Gly lie Gly val Val Val Gly His Glu Leu Thr His Ala Phe 740 745 750
Asp Asp Gin Gly Arg Glu Tyr Asp Lys Asp Gly Asn Leu Arg Pro Trp 755 760 765 -34- 129669-序列表.doc 200907056
Trp Lys Asn Ser ser Val Glu Ala Phe Lys Arg Gin Thr Glu Cys Met 770 775 780
Val Glu Gin Tyr ser Asn Tyr Ser Val Asn Gly Glu Pro Val Asn Gly 785 790 795 800
Arg His Thr Leu Gly Glu Asn lie Ala Asp Asn Gly Gly Leu Lys Ala 805 810 815
Ala Tyr Arg Ala Tyr Gin Asn Trp Val Lys Lys Asn Gly Ala Glu Hi's 820 825 830
Ser Leu Pro Thr Leu Gly Leu Thr Asn Asn Gin Leu Phe Phe Leu Gly 835 840 845
Phe Ala Gin Val Trp Cys ser Val Arg Thr Pro Glu Ser Ser His Glu 8S0 855 860 / Gly Leu lie Thr Asp Pro His Ser Pro Ser Arg Phe Arg val lie Gly 865 870 875 880
Ser Leu ser Asn ser Lys Glu Phe Ser Glu His Phe Arg cys Pro Pro 885 890 895
Gly Ser Pro Met Asn Pro Pro His Lys cys Glu val Trp 900 905 <210> 14 <211> 947 <212> PRT <213> 小鼠 <400> 14
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15
Gly Ser Thr Gly Asp Val Pro Arg Asp Cys Gly Cys Lys Pro Cys lie 20 25 30
Cys Thr Val Pro Pro Val Ser Ser Val Phe lie Phe Pro Pro Lys Pro 35 40 45
Lys Asp Val Leu Thr lie Thr Leu Thr Pro Lys Val Thr Cys Val val 50 55 60
Val Ala lie Ser Lys Asp Asp Pro Glu Val Gin Phe Ser Trp Phe Val 65 70 75 80
Asp Asp Val Glu Val His Thr Ala Gin Thr Gin Pro Arg Glu Glu Gin 85 90 95 -35 - 129669-序列表.doc 200907056
Phe Ala Ser Thr Phe Arg ser Val Ser Glu Leu Pro lie Met His Gin 100 105 HO
Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala 115 120 125
Phe Pro Ala Pro lie Glu Lys Thr lie ser Lys Thr Lys Gly Ara Pro 130 135 140
Lys Ala Pro Gin Val Tyr Thr lie Pro Pro Pro Lys Glu Gin Met Ala 145 150 155 160
Lys Asp Lys Val Ser Leu Thr Cys Met lie Thr Asp Phe Phe Pro Glu 165 170 175
Asp lie Thr Val Glu Trp Gin Trp Asn Gly Gin Pro Ala Glu Asn Tyr 180 185 190
Lys Asn Thr Gin Pro lie Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr 195 200 205
Ser Lys Leu Asn Val Gin Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe 210 215 220
Thr cys ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys 225 230 235 240
Ser Leu Ser His Ser Pro Gly Lys Tyr Asp Asp Gly lie Cys Lys Ser 245 250 255
Ser Asp Cys lie Lys ser Ala Ala Arg Leu lie Gin Asn Met Asp Ala 260 265 270 ser Val Glu Pro Cys Thr Asp Phe Phe Lys Tyr Ala cys Gly Gly Trp 275 280 285
Leu Lys Arg Asn Val lie Pro Glu Thr Ser ser Arg Tyr ser Asn Phe 290 295 300
Asp lie Leu Arg Asp Glu Leu Glu Val lie Leu Lys Asp Val Leu Gin 305 310 315 320
Glu Pro Lys Thr Glu Asp lie Val Ala Val Gin Lys Ala Lys Thr Leu 325 330 335
Tyr Arg Ser Cys lie Asn Glu Ser Ala lie Asp Ser Arg Gly Gly Gin 340 345 350
Pro Leu Leu Lys Leu Leu Pro Asp lie Tyr Gly Trp Pro Val Ala Ser 355 360 365 • 36· 129669-序列表.doc 200907056
Asp Asn Trp Asp Gin Thr Tyr Gly Thr Ser Trp Thr Ala Glu Lys Ser 370 375 380 lie Ala Gin Leu Asn Ser Lys Tyr Gly Lys Lys Val Leu lie Asn Phe 385 390 395 400
Phe Val Gly Thr Asp Asp Lys Asn Ser Thr Gin His lie lie His Phe 405 410 415
Asp Gin Pro Arg Leu Gly Leu Pro Ser Arg Asp Tyr Tyr Glu Cys Thr 420 425 430
Gly lie Tyr Lys Glu Ala Cys Thr Ala Tyr Val Asp Phe Met lie Ser 435 440 445
Val Ala Arg Leu lie Arg Gin Glu Gin ser Leu Pro lie Asp Glu Asn 450 455 460
Gin Leu ser Leu Glu Met Asn Lys Val Met Glu Leu Glu Lys Glu lie 465 470 475 480
Ala Asn Ala Thr Thr Lys Pro Glu Asp Arg Asn Asp pro Met Leu Leu 485 490 495
Tyr Asn Lys Met Thr Leu Ala Lys Leu Gin Asn Asn Phe Ser Leu Glu 500 505 510
Val Asn Gly Lys ser Phe Ser Trp Ser Asn Phe Thr Asn Glu lie Met 51S 520 525
Ser Thr Val Asn lie Asn lie Gin Asn Glu Glu Glu Val Val Val Tyr 530 535 540
Ala Pro Glu Tyr Leu Thr Lys Leu Lys Pro lie Leu Thr Lys Tyr Ser 545 550 555 560
Pro Arg Asp Leu Gin Asn Leu Met Ser Trp Arg Phe lie Met Asp Leu 565 570 575
Val Ser Ser Leu Ser Arg Asn Tyr Lys Glu Ser Arg Asn Ala Phe Arg 580 585 590
Lys Ala Leu Tyr cly Thr Thr Ser clu Thr Ala Thr Trp Arg Arg cys
Ala Asn Tyr Val Asn Gly Asn Met Glu Asn Ala Val Gly Arg Leu Tyr 610 615 620
Val Glu Ala Ala Phe Ala Gly Glu ser Lys His val val Glu Asp Leu 625 630 635 640 -37- 129669-序列表.doc 200907056 lie Ala Gin lie Arg gIu Val Phe lie Gin Thr Leu Asp Asp Leu Thr 645 650 655
Trp Met Asp Ala Glu Th「Lys Lys Lys Ala Glu Glu Lys Ala Leu Ala 660 665 670 lie Lys Glu Arg lie Gly jyr Pro Asp Asp lie lie Ser Asn Glu Asn 675 680 685
Lys Leu Asn Asn Glu Tyr Leu Glu Leu Asn Tyr Arg Glu Asp Glu Tyr 690 695 700
Phe Glu Asn lie lie Gin Asn Leu Lys Phe Ser Gin ser Lys Gin Leu 705 710 715 720
Lys Lys Leu Arg Glu Lys Val Asp Lys Asp Glu Trp lie Ser Gly Ala 725 730 735
Ala Val Val Asn Ala Phe Tyr Ser Ser Gly Arg Asn Gin lie Val Phe 740 745 750
Pro Ala Gly lie Leu Gin Pro Pro Phe Phe Ser Ala Gin Gin Ser Asn 755 760 765 ser Leu Asn Tyr Gly cly ile Cly Met Val He Cly His Glu He Thr
His Gly Phe Asp Asp Asn Gly Arg Asn Phe Asn Lys Asp Gly Asp Leu 785 790 795 800
Val Asp Trp Trp Thr Gin Gin Ser Ala Asn Asn Phe Lys Asp Gin ser 805 810 815
Gin Cys Met Val Tyr Gin Tyr Gly Asn Phe Ser Trp Asp Leu Ala Gly 820 825 830 y I： i. Gly Gin His Leu Asn Gly lie Asn Thr Leu Gly Glu Asn lie Ala Asp 835 840 845
Asn Gly Gly lie Gly Gin Ala Tyr Arg Ala Tyr Gin Asn Tyr Val lvs 850 855 860
Lys Asn Gly Glu Glu Lys Leu Leu Pro Gly Leu Asp Leu Asn His Lys 865 870 875 880
Gin Leu Phe Phe Leu Asn Phe Ala Gin val Trp cys Gly Thr Tyr Arg 885 890 895
Pro Glu Tyr Ala val Asn ser lie Lys Thr Asp Val His Ser Pro gIv 900 905 910 -38- 129669-序列表.doc 200907056
Asn Phe Arg 915 lie lie Gly Thr Leu Gin Asn ser Ala 920
Glu Phe Ala Asp 925 eo h 3 p 9 a Al
His Cys Arg Lys Asn ser Tyr Met Asn Pro Glu Arg Lys cys 935 940
Arg val Trp 945 <210> 15 <211> 38 <212> PRT <213> 智人 <400> 15 \
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val Hi s His Gin 1 5 10 15 Leu Val Phe Phe Ala Gl u Asp Val Gly Ser Asn Lys Gly Al a lie 20 25 30 Gly Leu Met Val Gly Gly 35 <210> 16 <211> 39 <212> PRT <213> 智人 <400> 16 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val Hi s Hi s Gin 1 5 10 15 Leu Val Phe Phe Al a Glu Asp Val Gly ser Asn Lys Gly Al a lie 20 25 30 Gly Leu Met Val Gly Gly val 35 <210> 17 <211> 40 <212> PRT <213> 智人 <400> 17 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gin 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Al a lie 20 25 30
Gly Leu Met Val Gly Gly Val Val 35 40 129669-序列表.doc -39- 200907056 <210> 18 <211> 41 <212> PRT <213> 智人 <400> 18
Asp Ala Glu Phe Arg His Asp ser Gly Tyr Glu Val His His Gin Lys 1 5 10 15
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala lie lie 20 25 30
Gly Leu Met Val Gly Gly Val Val lie 35 40 <210> 19 <211> 42 <212> PRT <213> 智人 <400> 19
Asp Al a Glu Phe Arg His Asp Ser Gly Tyr Glu Val Hi s Hi s Gin Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp val Gly Ser Asn Lys Gly Ala lie lie 20 25 30 Gly Leu Met Val Gly Gly Val Val lie Ala 35 40 <210> 20 <211> 43 <212> PRT <213> 智人 <400> 20 Asp Ala Glu Phe Arg Hi s Asp Ser Gly Tyr Glu Val His Hi s Gin Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Al a lie lie 20 25 30 Gly Leu Met Val Gly Gly Val Val lie Al a Thr 35 40 -40- 129669-序列表.doc
Claims (1)
- 200907056 十、申請專利範圍： 1· 一種具有式Μ-A之融合蛋白，甘At 序列中$ , . , /、此夠在類澱粉β肽胺基酸 汁夕j Τ之一或多個裂解位 延2降解该類澱粉β肽，其中Μ為 延長泫融合蛋白半衰期之 巧 肽之I 伤，Α為裂解該類澱粉β 胀之蛋白組份，苴中兮Μ ρ 蛋白組份共價連接至該Α蛋白 組份之N端部分。 疋㈡ 2·如：求項1之融合蛋白，其中A為蛋白酶。 .月求項2之融合蛋白，其中A為人類腦口非狀酶 名 lysin) 〇 p 之融口蛋白，其中該腦啡肽酶為細胞外腦啡 肽酶。 5. 如。月求項4之融合蛋白，其令該細胞外腦啡肽 據卿出耻1、^或种任-者之胺基酸序列。 6. 如：求項2之融合蛋白’其申a為胰島素降解酶。 7. 如=求項2之融合蛋白，其中a為内皮素轉化酶1。 8. 如明求項1之融合蛋白，其中A為一種支架（scaffold)蛋 白0 9.如請求項1至8中任 部分 項之融合蛋白，其中Μ為抗體之^ 10.如7求項9之融合蛋白，其中該抗體為igG抗體。 11’々叫求項9之融合蛋白，其中該抗體為〖仰抗體。 1 2 ·如請求jg 1人 貝之融5蛋白，其中Μ為IgG2抗體之Fc部分且A 為細胞外腦啡肽酶。 13.如叫求項丨之融合蛋白其包含根據_出Μ II之胺 129669.doc 200907056 14 15. 16. 17. f .. 18. 19.20.21. \. 22· 23. 24. 25. 基酸序列。 如請求項1之融合蛋 皮白其中M為IgG2抗體之Fc部分且A 為騰島素降解酶。 如請求項1之融合蛋白，其包含根 基酸序列。 如請求項1之融合I . 蛋白’其中M為IgG2抗體之Fc部分且A 為内皮素轉化酶1。 月求項1之融合蛋白，其包含根據SEQ ID NO. 13之胺 基酸序歹ij。 據 SEQ ID NO. 12之胺 如請求項1至8中任一 二醇化及糖基化。 如請求項1至8中任— 如請求項1至8中任一 如請求項1至8中任— 如請求項1 一起。 項之融合蛋白，其中Μ係選自聚乙 項之融合蛋白，其中Μ為HS Α。 項之融合蛋白，其申Μ為HSA結合 項之融合蛋白，其中Μ為抗體結合 之融σ蛋白，其中馗與Α係以連接子L連接在 :請求項22之融合蛋白’其中[係選自 肽及化學連接 種成夠降解類殿粉β肽之醫藥組合物，其包含醫藥風 上Γ接受量之如請求項1至23 w項之融合蛋白，'以 及醫藥學上可接受之 種如請求項1至23中任 载劑或賦形劑 項之融合蛋白之用途，其 係 129669.doc 200907056 用於製造用以預防及/或治療降解類靖狀為有益之病 況的藥物。 26. —種如請求項J至23中任—項之融合蛋白之用途，其係 用於製造用以預防及/或治療阿兹海默氏病（Alzheimer，s disease)、全身性澱粉樣變性病或腦類澱粉血管病變之藥 物。 27. 如請求項25或26之用途’其中該藥物滅少類殿粉β肽之 濃度。 (28 ·如請求項27之用途，其中該類澱粉β肽之減少係在血漿 中實現。 29·如請求項27之用途，其中該類澱粉β肽之減少係在CSF中 實現。 30.如請求項27之用途，其中該類殿粉β肽之減少係在CNS中 實現。 \ 129669.doc
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| CN102647998A (zh) * | 2009-06-19 | 2012-08-22 | 医学免疫有限责任公司 | 蛋白酶变体 |
| WO2011161127A1 (en) | 2010-06-21 | 2011-12-29 | Medimmune, Llc | Protease variants of human neprilysin |
| WO2011160732A1 (en) | 2010-06-21 | 2011-12-29 | Medimmune, Llc. | Protease variants of human neprilysin |
| US20140377319A1 (en) * | 2011-04-21 | 2014-12-25 | Washington University | Altering protein concentrations in cerebrospinal fluid and/or brain interstitial fluid |
| CN103529182B (zh) * | 2012-07-06 | 2016-03-16 | 中国科学院上海生命科学研究院 | rbo/Efr3a/Efr3b基因或其蛋白在诊断和治疗阿尔茨海默病中的应用 |
| BR112016001782A2 (pt) * | 2013-08-02 | 2017-08-29 | Hoffmann La Roche | Proteína de fusão terapêutica |
| EP2832854A1 (en) * | 2013-08-02 | 2015-02-04 | F. Hoffmann-La Roche AG | Method for improving the recombinant expression of a polypeptide by C-terminal fusion to human neprilysin |
| CN106574930B (zh) * | 2014-05-22 | 2019-09-03 | 株式会社岛津制作所 | 评价脑内的淀粉样蛋白β肽蓄积状态的替代性生物标记物和其分析方法 |
| CN109071600A (zh) * | 2016-04-14 | 2018-12-21 | 道健康生活医药株式会社 | 淀粉样蛋白球体（aspd）结合抑制肽以及评价和筛选方法 |
| CA3052058A1 (en) * | 2017-01-30 | 2018-08-02 | National Research Council Of Canada | Blood-brain barrier transmigrating compounds and uses thereof |
| AR111341A1 (es) | 2017-03-23 | 2019-07-03 | Hanmi Pharm Ind Co Ltd | Un conjugado del análogo de insulina con afinidad reducida para el receptor de insulina y uso del mismo |
| CN110241128B (zh) * | 2018-03-07 | 2020-10-02 | 上海大学 | 一种含有cbd的融合基因、细胞系、液态ecm与应用 |
| CA3107349A1 (en) | 2018-07-23 | 2020-01-30 | Enclear Therapies, Inc. | Methods of treating neurological disorders |
| CA3107352A1 (en) | 2018-07-23 | 2020-01-30 | Enclear Therapies, Inc. | Methods of treating neurological disorders |
| CN114007665B (zh) | 2019-04-11 | 2024-11-12 | 因柯利尔疗法公司 | 改善脑脊液的方法及其装置和系统 |
| US12337140B2 (en) | 2020-09-29 | 2025-06-24 | Enclear Therapies, Inc. | Subarachnoid fluid management method and system with varying rates |
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| CA2320403A1 (en) * | 1998-02-25 | 1999-09-02 | Lexigen Pharmaceuticals Corporation | Enhancing the circulating half-life of antibody-based fusion proteins |
| US20020086405A1 (en) * | 2000-09-25 | 2002-07-04 | Inmaculada Silos-Santiago | 56638, a novel human neprilysin protease and uses thereof |
| CA2260376A1 (en) * | 1999-02-11 | 2000-08-11 | Universite De Montreal | New metalloproteases of the neprilysin family |
| US20030083277A1 (en) * | 2000-02-24 | 2003-05-01 | Hersh Louis B. | Use of insulin degrading enzyme (IDE) for the treatment of alzheimer's disease in patients |
| EP1390069A1 (en) * | 2001-05-30 | 2004-02-25 | Cornell Research Foundation, Inc. | Endopeptidase/anti-psma antibody fusion proteins for treatment of cancer |
| US20050118632A1 (en) * | 2003-11-06 | 2005-06-02 | Jian Chen | Polynucleotides and polypeptides encoding a novel metalloprotease, Protease-40b |
| CN101321863A (zh) * | 2005-10-03 | 2008-12-10 | 阿斯利康(瑞典)有限公司 | 具有受调控的血浆半衰期的融合蛋白 |
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- 2008-03-27 AR ARP080101265A patent/AR066199A1/es not_active Application Discontinuation
- 2008-03-27 WO PCT/SE2008/050346 patent/WO2008118093A1/en not_active Ceased
- 2008-03-27 CN CN200880010294A patent/CN101668545A/zh active Pending
- 2008-03-27 JP JP2010500877A patent/JP2010522559A/ja not_active Withdrawn
- 2008-03-27 AU AU2008230177A patent/AU2008230177B2/en not_active Ceased
- 2008-03-27 CA CA002681404A patent/CA2681404A1/en not_active Abandoned
- 2008-03-28 CL CL2008000910A patent/CL2008000910A1/es unknown
- 2008-03-28 US US12/057,464 patent/US20080242590A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CA2681404A1 (en) | 2008-10-02 |
| US20080242590A1 (en) | 2008-10-02 |
| JP2010522559A (ja) | 2010-07-08 |
| WO2008118093A1 (en) | 2008-10-02 |
| PE20090225A1 (es) | 2009-04-19 |
| AR066199A1 (es) | 2009-08-05 |
| EP2139525A1 (en) | 2010-01-06 |
| AU2008230177A1 (en) | 2008-10-02 |
| CL2008000910A1 (es) | 2008-11-21 |
| UY30984A1 (es) | 2008-10-31 |
| CN101668545A (zh) | 2010-03-10 |
| AU2008230177B2 (en) | 2012-05-10 |
| EP2139525A4 (en) | 2010-08-18 |
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