TW201142024A - Robo1-Fc fusion protein and use thereof in the treatment of tumours - Google Patents

Robo1-Fc fusion protein and use thereof in the treatment of tumours Download PDF

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TW201142024A
TW201142024A TW100113039A TW100113039A TW201142024A TW 201142024 A TW201142024 A TW 201142024A TW 100113039 A TW100113039 A TW 100113039A TW 100113039 A TW100113039 A TW 100113039A TW 201142024 A TW201142024 A TW 201142024A
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Francis Blanche
Beatrice Cameron
Tarik Dabdoubi
Frederique Dol-Gleizes
Pierre Fons
Jean-Pascal Herault
Catherine Prades
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Description

201142024 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種重組蛋白R〇bol-Fc及其治療Slit蛋白 過度表現之疾病、尤其癌症的用途。本發明亦係關於一種 包含該種重組蛋白之組合物。本發明之另一態樣由RoboΙ-ρο分 子作為 偵測患 者體内 Slit家族分 子過度 表現之 診斷工 具的用途組成。 【先前技術】 首先描述了 Slit配位體在神經元發育中阻礙軸突生長之 作用。此後，亦描述了腫瘤血管生成中之Robo/Slit調節路 徑。特定言之，已描述R〇bo4/Slit2路徑抑制内皮細胞對 VEGF之反應（Jones C.A.等人TVai. Med 14, 448-453 (2008))。 藉由Robo/Slit路徑進行之調節使得有可能引起内皮非成熟 新血管或芽體（bud)過度增殖（非生產性血管生成）及使此等 血管成熟。Slit2在轉錄層面上之表現已於若干人類癌細胞 株中證明，尤其來源於結腸癌之HCT116、來源於卵巢癌 之Skov-3、來源於子宮頸癌之HeLa、來源於黑色素瘤之 MDA-MB-435、來源於子宮癌之Hec-ΙΑ，及最後，來源於 腎癌之 769-P(Stella MC 等人，Mol Biol Cell. 2009 第 20 卷，第2期，642-657)。Slit2蛋白之過度表現亦於來源於以 下癌瘤的人類組織上證明：口腔癌（Wang等人，2008, Cancer Sci. 2008年 3月；99(3): 510-7)、前列腺癌（Latil 等 人，2003 Int J Cancer. 2003年 1月 20 日；103(3): 306-15)、 結腸癌（Wang等人，2003, Cancer Cell，第4卷，第1期， 154995.doc 201142024 2003年7月，第19-29頁）及肝癌（Avci等人，2008，BMC Cancer，8: 392)。最近，Slit2蛋白之過度表現已於子宮内 膜異位症之樣品中證明（Shen等人，2009，175 (2): 479) »
Robol蛋白以兩種同功異型物a&b之形式存在。R〇b〇1 蛋白同功異型物b(NP_598334)之細胞外域包含5個免疫球 蛋白域：Igl、Ig2、ig3、lg4及 Ig5。Robo蛋白與 Slit配位 體在Igl及Ig2域層面上相互作用。Liu等人（2004, Mol. Cell
Neurosci，26: 232-240)已證明Ig2域在與Slit相互作用及
Robo之活性中的重要性（化學排斥（chem〇repulsi〇n))。
Robo 1及Slit2蛋白之特異性抗體之用途已描述於申請案 WO 2003/075860中。此等抗體使得有可能抑制腫瘤血管生 成。 然而，提出治療癌症之替代性方法將會是有利的，尤其 能夠抑制Slit2信號傳導路徑之分子。 本發明者已開發出能夠結合Slit配位體且因此能夠抑制 Robo/Slit路徑之細胞内信號傳導的可溶性嵌合R〇b〇1受體 之策略。令人驚舒的是，本發明之R〇b〇l_Fc分子藉由阻止 成熟也管形成而非藉由抑制内皮細胞增殖而具有抗血管生 成作用。 【發明内容】 本發明之一標的為R〇b〇-Fc重組蛋白，其包含R〇b〇l蛋白 同功異型物b之細胞外域或此結構域之一部分、接合區（連 接子）及免疫球蛋白Fc域。 154995.doc 201142024 在一特定實施例中，Robo 1蛋白同功異型物b之細胞外域 由Igl及Ig2域組成。此等結構域對應於由核苷酸序列SEQ ID NO.l編碼之SEQ ID NO.2之肽，或與序列SEQ ID NO.2 序列具有至少80%、85%、90%、95%或99% —致性的序 列。 融合蛋白亦包含接合區，亦稱為「連接子」。在本發明 之上下文中，連接子使得有可能尤其藉由限制活體内裂解 而使重組蛋白具有穩定性。可用於R〇boΙ-Fc分子中之連接 子為例如 GluArgProSerPheVal及 GlyGlyGlyGlySer。熟習此 項技術者具有足夠知識來選擇適於此用途之連接子。 本發明之Robo 1-Fc重組分子之Fc域對應於免疫球蛋白之 可結晶片段。此Fc片段可來自各種免疫球蛋白IgGl、 IgG2、IgG3或IgG4。其負責免疫反應之效應功能（WO 2008/065543) ° 在本發明之一實施例中，Fc域來自IgG4免疫球蛋白。在 一特定實施例中，已將至少一個點突變或缺失引入IgG4 Fc域中以便增加分子之穩定性，尤其藉由穩定由兩個Fc域 構成之较鍵區（Angla等人，1993，Mol. Immunol.，30: 105-108)，以降低或消除IgG4-Fc之殘餘活性，尤其效應活性 (WO 97/09351)，及增加重組蛋白製備期間之均質性。詳 言之，已將至少兩個點突變，較佳三個點突變引入IgG4 Fc域中。在本發明之 Robol-Fc LI、Robol-Fc L2 及 Robol-Fc L3分子中，較佳突變為以下： -S241P(Kabat編號）以便穩定Fc鉸鏈區中之二硫橋鍵； 154995.doc 201142024 -L248E(Kabat編號）以便消除lgG4-Fc域之殘餘效應活 性； -C端離胺酸不存在以便降低蛋白質之異質性。 如上所述，包含Robol同功異型物b之Igi及ig2域、連接 子及犬變沒IgG4域之本發明R〇b〇l-Fc分子為R〇b〇i_Fc LI、Robol-Fc L2及 Robol-Fc L3。
Robol-Fc L1對應於由核苷酸序列SEQ id ΝΟ·3編碼之序 列SEQ ID N0.4之蛋白質。
Robol-Fc L2對應於由核苷酸序列SEq ID 1^〇5編碼之序 列SEQ ID N0.6之蛋白質。
Robol-Fc L1與Robol-Fc L2之不同之處在於連接子之性 質。
Robol-Fc L3對應於由核苷酸序列SEQ m no.23編碼之 序列SEQ ID NO.24之蛋白質。 在本發明之一特定實施例中’已引入一或多個點突變或 缺失以便增加製備期間之均質性。詳言之，已在N端位置 截短一個胺基酸’較佳兩個胺基酸。該種本發明Robo·^ 卩(：分子為11〇13〇14〇1^3分子，其中已截短兩個胺基酸（8以2〇 及Arg21)且其中胺基酸Leu 22已融合至介白素2之信號肽。 如先前所述，亦藉由缺失C端Lys來增加本發明R〇b〇l-FC 分子之均質性。
本發明之一標的亦為蛋白質序列對應於序列SEQ ID
NO.2、SEQ ID NO.4、SEQ ID N0.6 或 SEQ ID NO.24 或與 序列 SEQ ID N0.2、SEQ ID N0.4、SEQ ID N0.6或 SEQ ID 154995.doc 201142024 N0.24具有至少80%、85%、90%、95%或99〇/〇—致性的蛋 白質。此等蛋白質變異體具有與具有序列SEQ ID NO.2、 SEQ ID N0.4、SEQ ID N0.6或 SEQ ID NO_24之蛋白質相 同的生物活性，尤其其與Slit家族之蛋白質相互作用的能 力。 本發明之Robol-Fc蛋白可藉由以下方法產生··將編碼此 等蛋白質之表現質體轉染至適於表現真核重組蛋白之任何 細胞類型中：HEK293、CHO等，及隨後在培養物上清液 中回收並根據習知方法純化。 本發明之 Robol-Fc LI、Robol-Fc L2及 Robol-Fc L3蛋白 之表徵使得有可能證實其具有作為生物治療劑投與所需要 之品質。 本發明之Robol-Fc蛋白具有與Slit家族之蛋白質相互作 用的能力。 本發明之Robol-Fc蛋白特異性識別人類Slitl、Slit2及 Slit3蛋白及鼠類Slit2蛋白，尤其藉由與其D2域相互作用而 識別。其與Slit家族3種成員之親和力類似。 本發明之另一標的對應於編碼本發明之蛋白質的核酸分 子。 因此，本發明之一部分為對應於序列SEQ ID NO. 1、 SEQ ID N0.3、SEQ ID ΝΟ·5 或 SEQ ID N0.23 或與具有序 列 SEQ ID NO.l、SEQ ID N0.3、SEQ ID N0.5 或 SEQ ID N0.23之分子具有至少80%、85%、90%、95%或99%—致 性的核酸分子。 154995.doc 201142024 本發明之另一標的由本發明之R〇bol-Fc蛋白用於治療 Slit家族蛋白質過度表現之疾病的用途組成。 可由本發明之R〇bol-Fc靶向之Slit家族之蛋白質為 Slitl、Slit2或 Slit3。 已顯示Robol可與Slit家族的各種成員相互作用。因此， 宜注意到本發明之Robol-Fc蛋白能夠同時抑制由Siiu、 Slit2及Slit3介導之信號傳導路徑，此使得有可能與僅對此 等路徑之一具特異性的抗體相比拓寬治療範圍。 在另一實施例中，使用Robo 1 -Fc蛋白藉由抑制企管生成 而不抑制内皮細胞增殖來治療Slit家族蛋白質過度表現之 疾病。與血管成熟缺陷有關之此抗血管生成活性稱作「非 生產性jk管生成」。 特定言之，實驗性研究已顯示本發明之R〇b〇1_Fc分子能 夠抑制小管形成而不抑制内皮細胞增殖。其使得有可能極 顯著地減小肺癌之鼠類模型中之腫瘤體積。 在一較佳實施例中，可用於治療SHt蛋白過度表現之疾 病的 Robol-Fc蛋白為 Robol-Fc LI ' R〇bol_Fc L2及 R〇b〇1_
Fc L3，及由其獲得之分子，尤其包括旨在增加製備期間 之均質性而不顯著改變此等分子之生物性質的點突變或缺 失。 -般而f ’可用本發明之Robo小Fc蛋白治療之疾病為 抑制Slit路徑可具有治療效果之所有疾病尤其8川家族之 蛋白質過度表現之疾病，且尤其Slit2過度表現之疾病。 因為本發明之RoboUe分子特異性結合犯2分子，所以 154995.doc 201142024 有趣的是注意到該等分子能夠同時抑制涉及服之兩個路 徑，亦即Robol/Slit2 及 R〇b〇4/Slit2 路徑。 因 癌、 癌、 癌、 此本發明之蛋白可用於治療癌症，尤其縢臟 結腸癌、伴有或不伴有淋巴轉移之結腸直腸癌、乳 肺癌及肺癌轉移、印巢癌、子宮頸癌、黑色素瘤 '腎 口腔癌、前列腺癌、肝癌等。 在一特定實施例中 癌轉移。 使用Robo-Fc蛋白來治療肺癌及肺 本發明之Robo 1 -Fc分子亦可竹氐1 “ 刀卞刀J作為現盯療法之替代物或補 充物來用作抗癌藥物。 詳言之，此等分子可與抗癌化合物組合（視情況同時）投 與。 本發明之另-標的係關於一種組合物，#包含如上文所 定義之Robol-Fc蛋白及一或多種醫藥學上可接受之賦形 劑。 可考慮到局部、經口、非經腸、鼻内、靜脈内、肌肉 内、皮下、眼内等投藥方式而將本發明之R〇b〇1_Fc蛋白調 配於醫藥組合物中。較佳地，f藥乡且合物含有用於可注射 調配物的醫藥學上可接受之媒劑。其尤其可為等張無菌鹽 水溶液（磷酸二氫鈉或磷酸氫二鈉、氣化鈉、氣化鉀、氣 ㈣或氯化鎂等’或該等鹽之混合物）或乾燥組合物，特 定言之冷凍乾燥組合物，其在適當時藉由添加無菌水或生 理鹽水而允許形成可注射溶質。 本發明之另一態樣由Rob〇l-Fc分子用作偵測患者體内 154995.doc 201142024
Slit家族分子之過度表現之診斷工具的用途組成。此係由 於已顯示Silt路徑牽涉於許多癌症中。提供評估Slit信號傳 導路徑之干擾的測試非常適用於選擇能夠對基於投與 Robol-Fc分子之治療作出反應之患者的目的。 此診斷工具可呈即用套組之形式，其包含呈適合與來自 有可能顯示Slit分子過度表現之患者之生物樣品（血液、 尿、腫瘤活組織檢查）接觸之形式的R〇b〇1_Fc分子 〇 Robo_
Fc分子可視情況經預先標記，且偵測尺心心以與SUt之組合 以便評估與對照樣品相比生物樣品中Siit蛋白表現之增 加。此套組可例如呈ELISA套組之形式。 【實施方式】 實例 實例1 :製備R〇bol-Fc蛋白 a.允許表現用作化學治療劑之R〇b〇1_Fc重組蛋白的構築 體。
Robol-Fc重組蛋白由人類R〇b〇1蛋白同功異型物 b(NP一598334)之前兩個免疫球蛋白域（igi ig2)與人類免疫 球蛋白 G4 之 Fc 域（hIgG4-Fc，SwissPr〇t IGHG4—HUMAN)之 間的融合體組成。 為獲#Robol-Fc L1構築體，使用人類胎兒心臟cDNA文 庫（參考 HL5042T，Cl〇ntech)藉由 pCR擴增 cDNA(SEQ ID N0.1)中對應於此蛋白質（seq ID N0.2)之免疫球蛋白（ig) 域]^1及1§2之片段後接〇111八^?1*〇80『？1^\^1連接子。隨後 將此擴增片段選殖至真核表現載體pXL4904(圖1中所述） 154995.doc •10· 201142024 中，使得Robol之兩個Ig域表現為在C端位置具有人類IgG4 之Fc域的融合體。將3個點突變引入IgG4-Fc域中以便獲得 以下特徵：S241P(Kabat編號），以便穩定Fc鉸鏈區中之二 硫橋鍵；L248E，以便消除IgG4-Fc域之殘餘效應活性；C 端離胺酸不存在，以便降低蛋白質之異質性。用於表現此 重組蛋白之cDNA序列對應於序列SEQ ID N0.3。所獲得之 重組蛋白稱為R〇bol-Fc L1且對應於蛋白質序列SEQ ID ΝΟ·4。 為獲得Robol-Fc L2構築體，將對應於Igl-Ig2域但無所 提及之連接子之相同cDNA選殖至真核表現載體 pXL4909(圖1中所述）中，其允許此等Ig域表現為與含有構 建Robol-Fc L1中所述之3個點突變的IgG4之相同Fc域的融 合體，但此次在Fc域之上游引入GlyGlyGlyGlySer連接 子。用於表現此重組蛋白之cDNA序列對應於序列SEQ ID N0.5。所獲得之重組蛋白稱為Robol-Fc L2且對應於蛋白 質序列 SEQ ID N0.6。 b.構建用作對照之Robol-Fc蛋白 為獲得Robol-Fc Slit2-(Robol-Fc Slit2-minus)構築體， 藉由PCR修飾先前選殖進至pXL4904質體中之cDNA以便引 入允許將位置38處之白胺酸取代為麩醯胺酸且將位置89處 之苯丙胺酸取代為酪胺酸的點突變。用於表現此重組蛋白 之cDNA序列對應於序列SEQ ID N0.7。所獲得之重組蛋白 稱作11〇1?〇1-卩〇8山2-且對應於蛋白質序列8£(5 1〇]^0.8。 為獲得 R〇bol-Fc肝素 _(Robol-Fc heparin-minus)構築體， 154995.doc 201142024 藉由PCR修飾選殖至pXL4904質體中之cDNA以便引入允許 將位置97處之精胺酸取代為苯胺且將位置98處之離胺酸取 代為丙胺酸的點突變。用於表現此重組蛋白之cDNA序列 對應於序列SEQ ID N0.9。所獲得之重組蛋白稱作Robol-Fc肝素·且對應於蛋白質序列SEQ ID NO. 10。 c. 製備各種Robol-Fc蛋白 分別使用PXL4904及pXL4909質體以及允許表現兩種N-聚糖糖基化酶（亦即α-2,3-唾液酸基轉移酶及β· 1,4-半乳糖 苷基轉移酶）之輔助質體PXL4544及pXL4551(如申請案WO 2008/065543中已描述）藉由短暫轉染於HEK293細胞株 (FreeStyle 293-F細胞，參考 51-0029，Invitrogen，根據供 應商建議）中產生兩種蛋白質R〇b〇l-Fc L1及Robol-Fc L2。 亦分別使用PXL4904及pXL4909質體藉由轉染於CHO細胞 株（CHO-S細胞，參考11619-012，Invitrogen，根據供應商 建議）中來產生此等蛋白質。 利用蛋白質A親和管柱（MabSelect參考17-5 199-02 ’ Amersham Biosciences)藉由層析法純化表現於HEK293細 胞之培養物漂浮物（culture natant)中的Robol-Fc L1及 Robol-Fc L2蛋白且在20 mM NaCl/100 mM乙酸緩衝液中 溶離，且隨後調配於PBS緩衝液中（參考Ml90-094， Invitrogen) 0 以相同方式製備及純化R〇bol-Fc Slit2·及Robol-Fc肝素· 重組蛋白。 d. Robol-Fc重組蛋白之物理化學表徵 I54995.doc 201142024 SDS-PAGE及凝膠滲透分析使得有可能顯示該等蛋白質 為二聚的且純度高於96%。質譜分析使得有可能證明此等 蛋白質之身分’去糖基化蛋白質之量測重量完全符合經由 電腦方法§十鼻之重量。如Saddic等人2002(Methods Mol. Biol. 194: 23-36及 Anumula 等人，1998. Glycobiology 8: 685-694)所述分析單醣組成及定量N_聚糖唾液酸使得有可 能證明該等蛋白質在極高程度上經唾液酸化。結果提供於 表1中。注意到Robol-Fc L1及Robol-Fc L2分子之N端分析 顯示此等經純化蛋白質含有可變比例至4〇%)的前2個殘 基（Ser20及Arg21)經截短之形式。 表1 : Robol-Fc蛋白身分
Robol-Fc L1 Robol-Fc L2 重量(SDS-PAGE 還原條件） 56kDa 55 kDa 重量(SEC，HPLC) 180 kDa 180 kDa 重量(去糖基化之後的 LC/MS) 48812 Da 48410 Da N-聚糖概況(HPLC) 高度唾液酸化 21.4%脫唾液酸聚糖 (asialoglycan) 高度唾液酸化 20.1%脫唾液酸聚糖 單醣組成(HPLC) 複雜N-聚糖 完全海藻糖化 無0-聚糖 複雜N-聚糖 完全海藻糖化 無0-聚糖 實例2 ··製備用作配位體之siit蛋白 編碼人類Slit2蛋白之cDNa對應於參考蛋白質 NP一0〇4778。使用人腦 cdna文庫（參考 6393〇〇，Clontech)藉 由PCR擴增此cDNA之片段。 154995.doc 201142024 將對應於D2域之cDNA選殖至真核表現載體pXL4911中 以便表現在C端位置含有His標籤之此結構域。用於表現此 重組蛋白之cDNA序列對應於序列SEQ ID NO.ll。所獲得 之重組蛋白稱作S1U2-D2且對應於蛋白質序列SEQ ID N0.12。 將對應於D1-D2域之cDNA選殖至真核表現載體pxl4912 中以便表現在C端位置含有His標籤的此兩個結構域。用於 表現此重組蛋白之cDNA序列對應於序列SEQ ID NO. 13。 所獲得之重組蛋白稱作Slit2-D1D2且對應於蛋白質序列 SEQ ID N0.14。 將對應於Slit2蛋白之細胞外部分（Nt)之cDNA選殖至真 核表現載體PXL5033中以便表現在C端位置具有His標籤的 此蛋白質。用於表現此重組蛋白之cDNA序列對應於序列 SEQ ID N0.15。所獲得之重組蛋白稱作Slit2-N且對應於蛋 白質序列SEQ ID N0.16。
自選殖至PXL4911質體中之cDNA獲得編碼鼠類Slit2蛋 白之D2域及對應於所述參考蛋白質NP_848919之D2域的 cDNA。以pXL4911為模板藉由PCR產生使得有可能產生5 個點突變之4個片段，且隨後將此等片段用作模板藉由連 續PCR來擴增編碼完全D2域之cDNA。該蛋白質帶有 Thr311Ser、Lys313Arg、Ile329Leu、Ile411Val 及 Pro418Ala 突變，從而使其與鼠類Slit2蛋白之D2域一致。此質體使得 有可能表現在C端位置具有His標籤的鼠類Slit2蛋白之D2 域。用於表現此重組蛋白之cDNA序列對應於序列SEQ ID 154995.doc 14 201142024 ΝΟ·17。所獲得之重組蛋白稱作mSlit2-D2且對應於蛋白質 序列 SEQ ID N0.18。 編碼人類Slitl蛋白之cDNA對應於所述參考蛋白質 NP_003052。使用人腦 cDNA文庫（參考 639300，Clontech) 藉由PCR擴增此cDNA之片段。將對應於D2域之cDNA選殖 至真核表現載體PXL5020中以便表現在C端位置含有His標 籤之此結構域。用於表現此重組蛋白之cDNA序列對應於 序列SEQ ID N0.19。所獲得之重組蛋白稱作Slitl-D2且對 應於蛋白質序列SEQ ID NO.20。 編碼人類Slit3蛋白之cDNA對應於所述參考蛋白質 NP_003053 。使用人月甾 cDNA文庫（參考 639300 ， Clontech) 藉由PCR擴增此cDNA之片段。將對應於D2域之cDNA選殖 至真核表現載體pXL5021中以便表現在C端位置含有His標 籤之此結構域。用於表現此重組蛋白之cDNA序列對應於 序列SEQ ID N0.21。所獲得之重組蛋白稱作Slit3-D2且對 應於蛋白質序列SEQ ID NO.22。 使用pXL4911質體（分別為pXL4912或pXL5033)藉由短暫 轉染於HEK293·細胞株（Freestyle 293-F細胞，根據供應商 建議，Invitrogen)中來產生稱為 Slit2-D2、Slit2-D1D2 及 Slit2-N之三種蛋白質。 利用Ni螯合瓊脂糖凝膠管柱（參考17-0409-03，Amersham Biosciences)藉由層析法純化表現於HEK293細胞之培養物 上清液中的Slit2-D2及Slit2-D1D2蛋白且在咪唑緩衝液中 溶離，且隨後調配於調節至1 M NaCl之PBS緩衝液中（參考 154995.doc -15- 201142024 14190-094，Invitrogen)。質譜分析（LC/MS)使得有可能證 明此等蛋白質之身分。 以類似方式製備、純化及表徵稱為mSlit2-D2、Slitl-D2 及Slit3-D2之三種蛋白質。 實例3:藉助於三種方法：ELISA、SPR及FACS來研究 Robol-Fc重組蛋白對Slit蛋白及肝素之親和力 a. Robol-Fc蛋白對肝素之親和力 為測定Robo 1 -Fc構築體對肝素之親和力，將2 mg經純化 且調配於10 mM磷酸鹽（pH 7.0)中之R〇bol-Fc蛋白藉由以0 至1.5 Μ之NaCl線性梯度溶離利用肝素管柱（1 mL HiTrap肝 素-瓊脂糖凝勝HP，GE Heathcare)進行層析。 表2指示如文獻中所述，溶離R〇b〇l-Fc L1蛋白需要NaCl 濃度為 448 mM(Fukuhara，N.等人，2008 J. Biol. Chem. 283，第 16226-16234頁” 表2 : Robol-Fc蛋白對肝素之親和力
Robol-Fc構築體 自肝素管柱分離之【NaC丨】，mM Robol-Fc L1 448 Robol-Fc 肝素· 無結合 此等結果顯示RobobFc肝素-蛋白未保留在此管柱上， 且因此其對肝素不再具有任何親和力。因此，此蛋白質為 肝素陰性突變體。 b.估Robol-Fc蛋白變異體與人類siit2蛋白之D2域的相 互作用 I54995.doc -16· 201142024 此實例描述藉由ELISA檢定測定稱為Robol-Fc L1及 Robol-Fc L2之兩種變異體與其天然配位體（在此實驗中為 人類Slit2之D2域）的相互作用。 使人類Slit2-D2蛋白結合至Immulon-4酶聯結板上（VWR Scientific Inc. Swedesboro，NJ)。添加一定濃度範圍（20 pg/mL 至 0.02 pg/mL)之 Robol-Fc L1 及 Robol-Fc L2 變異 體，且隨後藉助於過氧化酶結合之山羊抗人類1gG抗體 (Sigma ;參考A0170，稀釋至1:50000)來偵測。利用TMB_ H2〇2受質（Interchim ;參考UP664780)進行觀測且用板讀取 器在4 5 0 nm下進行量測。結果報導於圖2中。其顯示兩種 變異體Robol-Fc L1及L2與人類Slit2蛋白（尤其與D2域）特 異性相互作用。 c.估Robol-Fc蛋白與Slit家族之人類變異體（亦即slitlA Slit3)的相互作用 此實例描述藉由ELISA檢定測定Robol-Fc L1融合蛋白與 Slitl-D2、Slit2-D2及Slit3-D2變異體的相互作用。 使人類Slit變異體之D2域結合至Immulon-4酶聯結板上 (VWR Scientific Inc. Swedesboro, NJ)。添加一定濃度範圍 (1 pg/mL 至 0.001 pg/mL)之 Robol-Fc L1 融合蛋白’且隨後 使用過氧化酶結合之山羊抗人類IgG抗體（Sigma ;參考 A0170，稀釋至1:50000)來偵測。利用TMB-H2〇2受質 (Interchim ;參考UP664780)進行觀測且用板讀取器在450 nm下進行量測。類似地，在與如上所述相同之條件下藉由 ELISA檢定根據濃度範圍（20 pg/mL至0.02 pg/mL)評估在 154995.doc -17- 201142024
Slit2結合位點層面上突變的R〇bol-Fc Slit2_變異體。結果 報導於下表3中。 表3 : Robol-Fc對Slit蛋白之人類變異體的親和力
Slit蛋白（配位體） Robol-Fc 蛋白 EC50(pg/mL) CV(%) Slit2-D2 Robol-Fc LI 1.32 E-01 3.3 Slitl-D2 Robol-Fc LI 7.88 E-02 3.9 Slit3-D2 Robol-Fc LI 2.60 E-01 12 Slit2-D2 Robol-Fc Slit2* 1.78 E+01 18 此等結果顯示R〇bol-Fc蛋白與該家族之三種蛋白質 Slitl、Slit2及Slit3(尤其與其D2域）特異性相互作用。 此外，Robol-Fc Slit2_蛋白對肝素不再具有親和力且因 此其為肝素陰性突變體。 d.估Robol-Fc蛋白與鼠類Slit2蛋白的相互作用 此實例描述藉由ELISA檢定測定Robol-Fc L1融合蛋白與 鼠類蛋白質mSlit2-D2的相互作用。 使鼠類蛋白質mSlit2-D2結合至Immulon-4酶聯結板上 (VWR Scientific Inc. Swedesboro，NJ)。添加一定濃度範圍 (2 pg/mL 至 0.002 pg/mL)之 Robol-Fc L1 融合蛋白，且隨後 使用過氧化酶結合之山羊抗人類IgG抗體（Sigma ;參考 A0170 ’稀釋至1:50000)來4貞測。利用TMB-H2O2受質 (Interchim;參考UP664780)進行觀測且用板讀取器在450 nm 下進行量測。結果報導於下表4中。 表4 : Rob〇i»Fc對鼠類slit2蛋白的親和力 所研究- EC50 (Mg/mL) CV (%) mSlit2-D2 2.21 E-01 18 154995.doc • 18- 201142024 此等結果顯示Robol-Fc蛋白與鼠類Slit2蛋白特異性相互 作用。 e.藉由SPR量測之Robol-Fc對Slit蛋白的親和力 此實例描述藉由SPR(表面電漿子共振；BIAcore 2000)測 定Robol-Fc L1融合蛋白與人類Slit2蛋白（在此實驗中為 Slit2-D2)之親和力常數。在使Robol-Fc融合蛋白結合至 CM5晶片之後分析Robol-Fc蛋白與人類Slit2蛋白之間的相 互作用。根據Canziani等人之方案（2004. Anal. Biochem. 325: 3(Π-307)進行動力學量測。 表5 :藉由SPR測得之Robo-Fc L1與人類Slit2-D2之親和力， 常數（穩態分析） 蛋白質 Κ〇(ηΜ) Robol-Fc L1 32 在使S1U2-D2蛋白結合至CM5晶片之後分析第二方法， 該方法在於測定Robol-Fc L1融合蛋白與人類Slit2蛋白之 間的親和力常數。根據具有兩個不等效結合位點之模型使 用史卡查方法（Scatchard method)根據Canziani等人之方案 (2004. Anal. Biochem. 325: 301-307)進行動力學量測。 表6:根據兩相史卡查模型（two-phase Scatchard model)藉 由SPR測得之Robo-Fc與人類Slit2-D2之親和力常數
Robol-Fc LI Κ〇(ηΜ) 南親和力位點 KD1 ： 1.5 低親和力位點 KD2 : 160 f.藉由FACS量測之Robol-Fc對Slit的親和力 154995.doc -19- 201142024 此實例描述Robol-Fc蛋白對表現Slit2之HEK293哺乳動 物細胞之親和力〇 在實例1中描述及使用之ΗΕΚ293細胞用以下質體轉染： 不具有在哺乳動物細胞中編碼之cDNA的壓載質體（ballast plasmid) ’或編碼Slit2-D2蛋白之PXL4911質體，或編碼 Slit2-D1D2蛋白之PXL4912質體，或編碼Slit2-N蛋白之 pXL5 033 ’如實例2中所述。在轉染後48小時將該等細胞 分配至96孔板中’且在4°C下添加濃度範圍為0.01至3 mg/L 的Robol-Fc蛋白持續30分鐘。Robol-Fc蛋白為Robol-Fc L1生物治療劑，或R〇bol-Fc Slit2_突變體，或R〇bol-Fc肝 素 '突變體。洗滌細胞且在4°C下培育經Alexa 488(參考： A-11013，Invitrogen)標記之抗人類Fc抗體30分鐘。隨後藉 由FACS定量經標記之HEK293細胞（Geomean)。 圖3描述在不存在Slit2表現下經由藉由FACS量測之螢光 測得的HEK293細胞與R〇bol-Fc蛋白之結合。R〇bol-Fc蛋 白以及Robol-Fc Slit2·突變體結合至HEK293細胞，而 Robol-Fc肝素_突變體未結合。因此在〇.3至〇.〇3 mg/L之低 Robol-Fc濃度下R〇bol-Fc經由肝素結合部分結合至 HEK293細胞。 圖4描述當Slit2-N藉由短暫轉染來表現時，經由藉由 FACS量測之螢光測得的HEK293細胞與Robol-Fc蛋白之結 合。僅Robol-Fc蛋白結合至表現Slit2-N之HEK293細胞。 相較於生物治療性Robol-Fc L1蛋白，Robol-Fc Slit2·及 Robol-Fc肝素突變體在R〇bol-Fc濃度範圍為3.0至0.3 154995.doc -20- 201142024 mg/L時不結合（或幾乎不結合）。 表7描述當Slit2-N、Slit2-D1D2或Slit2-D2蛋白表現於 HEK293細胞株中時，藉由FACS量測之R〇b〇KFcs白的親 和力常數。 表7 :藉由FACS量測之R〇bol-Fc對細胞上Slit2蛋白的親和力 配位體Robol-Fc 短暫表現於HEK293中之蛋白質 一 Robol-Fc LI Slit2-N Slit2-D1D2 ___0.98 Slit2-D2 ---—- 極弱姑合 Robol-Fc肝素- Slit2-N ____ 43 Slit2-D1D2 41 Robol-Fc SlitJ Slit2-N 無結合 如先前實例中所述，Robol-Fc Slit2_突變體證明為Slit2 陰性且Robol-Fc肝素-突變體相較於生物治療性蛋白質對 S1U2具有較弱親和力。
Robol-Fc以類似親和力結合至由HEK293細胞表現之 Slit2-N及Slit2-D1D2，該等親和力優於與Slit2-D2之親和 力。 實例4 : Robol-Fc L1及Robol-Fc L2蛋白之藥物動力學性質 此實例描述於小鼠體内靜脈内（iv)注射一次之R〇bol-Fc 蛋白之藥物動力學概況及血漿濃度。 三隻Balb/C小鼠（每次）經由尾靜脈以比例1〇〇 KL/l〇 g(約 25 mg/kg)注射2.5 mg/mL之各Robol-Fc蛋白。在預定時間 (投與後0.5、1、6、24、48及72小時）麻醉小鼠，並取血樣 且收集於含有1〇 μΐ^檸檬酸鹽（CPD-A，C-4431 Sigma)及2 μί蛋白酶抑制劑（完全蛋白酶抑制劑混合液（Complete 154995.doc -21 · 201142024
Protease Inhibitor Mix)，Roche Molecular Biochemical)之 管中。將該等管離心且收集血漿樣品並冷凍於-2〇t：下。 用Slit2蛋白（Slit2-D2)塗佈96孔板之孔，且在37°C下使 稀釋至1/5000及1/20000之血漿樣品接觸1小時。隨後培育 過氧化酶結合之抗人類Fc抗體（參考31413，Pierce)，且接 著利用 TMB-H2〇2(參考 UP664780，Interchim)進行觀測， 且在450 nm下讀取吸光度。對於各經純化之Robol-Fc蛋白 均制定校正範圍。
Robol-Fc L1與Robol-Fc L2蛋白之血漿濃度提供於圖5 中。藥物動力學參數描述於下表8中且顯示蛋白質在注射 於小鼠體内之後穩定。 表8 :靜脈内注射於小鼠體内後RobohFc蛋白之藥物動力 學參數 25 mg/kg 之蛋白質 C〇 μ^ιηί Tl/2 h AUC(0-最後） μ&ΐι/ηιί! AUC(0-24h) Cl mL/H/1^ Vdss mL/kg Robol-Fc L1 203 158 3655 1879 2.2 470 Robol-Fc L2 198 142 3973 2042 2.2 417 實例5:描述關於N端位置處之均質性獲得改良的Robol-Fc 生物治療性蛋白質 此實例描述另一 Robol-Fc蛋白（稱為Robol-Fc L3)之表現 質體、製備及物理化學表徵，該蛋白質與R〇bol-Fc L1蛋 白之不同之處在於不存在前兩個殘基Ser20及Arg21。 藉由PCR修飾選殖至pXL4904質體中之cDNA以便消除 Ser20及Arg21密碼子，並使下一密碼子（Leu22)融合至介白 154995.doc •22· 201142024 素2之肽信號的編碼序列。隨後產生pXL5004表現質體， 參見圖1。用於表現此重組蛋白之cDNA序列對應於序列 SEQ ID N0.23。 如實例1中所述製備、純化及表徵Robol-Fc L3蛋白。N 端分析顯示此經純化蛋白質為完全均質的。所獲得之重組 蛋白稱為Robol-Fc L3且對應於蛋白質序列SEQ ID N0.24。 實例6 :評估Robol-Fc L3蛋白與人類Slit2蛋白之相互作用 此實例描述藉由ELISA檢定測定Robol-Fc L3融合蛋白與 人類Slit2蛋白（Slit2-D2)的相互作用。 使人類Slit2-D2蛋白結合至Immulon-4酶聯結板上（VWR Scientific Inc. Swedesboro，NJ)。添加一定濃度範圍（1 pg/mL 至0.001 pg/mL)之Robol-Fc L3融合蛋白，且隨後藉助於過 氧化酶結合之山羊抗人類IgG抗體（Sigma ;參考A0170，稀 釋至1:50000)來偵測。利用TMB-H202受質（Interchim ;參 考UP664780)進行觀測且用板讀取器在450 nm下進行量 測。所獲得之結果報導於下表9中。 表9 : Robol-Fc L3蛋白對Slit2蛋白之親和力-與Robol-Fc L 1蛋白相比較 所研究之蛋白質 EC50 (Mg/ml) CV (%) Robol-Fc L1 0.13 3.3 Robol-Fc L3 0.17 4.4 此等結果顯示兩種變異體Robol-Fc L1及Robol-Fc L3對 S1H2-D2蛋白之親和力類似。 154995.doc -23· 201142024 實例7 :評估Robo-Fc蛋白對新血管生成之活性 a.活體外内皮細胞及纖維母細胞共培養物模型：Robol-Fc L1分子之比活性 活體外血管生成模型對應於人類皮膚纖維母細胞單層上 人類靜脈内皮細胞之重排。簡言之，以於1 ml培養基中 40000個細胞/孔之密度將纖維母細胞（L〇nza)接種於24孔板 (Becton Dickinson)中》增殖3天後（D3)，以於500 μΐ EGM® 培養基（内皮基本培養基，Lonza) + 2% FCS(胎牛血 清-Lonza)+10 pg/ml hEGF(重組人類上皮生長因子-Lonza) 中10 000個細胞/孔之密度將人類靜脈内皮細胞（huvec-Lonza)接種於纖維母細胞單層上。用30 ng/mL VEGF(R&D Systems)連同 R〇bol-Fc L1 分子或連同 R〇bol-Fc Slit2-陰性 對照以500 pg/ml濃度刺激該等細胞（D3至D9)。3天後，置 換培養基且根據實驗條件來刺激該等孔。 2天後’用乙醇固定該等細胞且用HUVEC特異性抗CD31 抗體進行標記’隨後用抗鹼性磷酸酶抗體標記，且隨後用 鹼性磷酸酶受質進行觀測（Dl 1)。藉助於在顯微鏡（4倍物 鏡）下擷取影像進行經抗CD31抗體標記之小管的定量，且 使用影像分析軟體（Biocom Visiolab 2000軟體）分析偽小管 之長度（圖6)。 在此活體外血管生成檢定中，R〇b〇l-Fc Ll(500 pg/mL) 顯示對由HUVEC形成之小管的形成的抑制活性。此抑制 總計達到82%且相較於用R〇bol-Fc Slit2·分子（陰性對照）獲 得之效果’其在統計上顯著。 154995.doc 24 - 201142024 b.離體小鼠主動脈環模型：Robol-Fc L1分子之比活性 在小氣主動脈環模型中評估Robol-Fc L1分子。簡言 之移除小鼠主動脈並清洗，並切割成1 mm之切片（D〇)。 在 1〇 ng/mi VEGF存在下、在5〇〇 Μ—濃度之R〇b〇i Fc li 刀子存在下或在500 Mg/ml濃度之R〇b〇l-Fc Slit2·陰性對照 存在下將此等環嵌埋於大鼠膠原蛋白中。小管將由該等環 形成’從而在活體外模擬新血管之形成。6天後，藉助於 在顯微鏡（3倍物鏡）下擷取影像進行經標記之小管的定量 (圖）且使用影像分析軟體（Biocom Visiolab軟體2000) 分析偽小管之長度（圖7)。 在此等實驗條件下，與用作陰性對照的R〇b〇1_Fc SHt2· 刀子相比，Robol-Fc Ll(500 pg/mi)顯示對所形成之小管 的形成具有強抑制活性。 此等結果表明R〇bol-Fc L1能夠抑制新血管形成而不抑 制内皮細胞增殖。與血管成熟缺陷有關之此抗血管生成活 性稱作「非生產性血管生成」。 實例8 :評估小鼠體内肺腫瘤模型中之R〇b〇i Fe Μ蛋白 在C57/B16小鼠體内在肺癌腫瘤模型中評估R〇b〇1_Fc L1 分子。 a.鼠類肺腫瘤模型 為建立鼠類肺腫瘤模型，麻醉8週齡之雌性小 弟J掉小鼠左肩狎骨位置處之區域並消毒。在肩狎骨上 方製造一1 cm切口。 欲主射之細胞來源於Lewis肺癌腫瘤細胞株（ATCC， 154995.doc -25- 201142024 CRL-1642)。將細胞與Matrigei®# !體積 MatrigeUt(4體積細 胞之比率混合。細胞濃度為每毫升62500個細胞。以每隻 小鼠20 μΐ之比率將細胞注射至肺中，並隨後縫合創口。 23天後，對小鼠實施安樂死。打開胸腔，且移除左肺及 縱隔淋巴結。使用電子卡尺量測左肺上存在之腫瘤以便根 據下式測定腫瘤體積：12xLx〇.52。將縱隔淋巴結稱重。 結果表示為平均值±與平均值的標準差。藉助於參數史都 登氏檢驗（parametric Student's test)進行統計分析。 b.用Robol-Fc重組蛋白處理負載肺腫瘤之小鼠 使用Robol-Fc蛋白如下進行處理：在注射腫瘤細胞後 D10、D14、D17及D21時以每天25 mg/kg之劑量靜脈内注 射含有Robo 1 -Fc蛋白之製劑。對照組注射pbs緩衝液（J 〇 ml/kg) 〇 c ·結果 在D23，用R〇bo 1 -Fc重組蛋白處理之組中獲得之腫瘤平 均體積為2 1 ·45±2.16 mm3 ;對照組中獲得之腫瘤平均體積 為39.93±8_41 mm3。用Robol-Fc蛋白處理之動物中腫瘤體 積減少46%。此差異在統計上顯著（p<0.05)。用R〇bol-Fc 蛋白處理之組中獲得之縱隔淋巴結（轉移性淋巴結）的平均 重量為12.50±1 ·26 mg。對照組中獲得之縱隔淋巴結之平均 重量為30·67±7·69 mg。用Robol-Fc蛋白處理之組中縱隔淋 巴結重量在顯著性極限下（ρ=0·07)減少59%。 【圖式簡單說明】 圓1 . Robol-Fc LI、Robol-Fc L2及 R〇bol-Fc L3蛋白之 154995.doc • 26· 201142024 表現質體； 圖2 :藉由ELISA評估R〇bol-Fc融合蛋白變異體與sm2 蛋白之相互作用； 圖3 .藉由FACS量測之R〇bol-Fc對於不表現8出2之 HEK293細胞之親和力； • 圖4 :藉由FACS量測之R〇bol-Fc對於表現Siit2之 HEK293細胞之親和力； 圖5 :小鼠體内靜脈内注射後…心^以蛋白之藥物動力 學概況。A.投與 Robol-Fc LI，B.投與 R〇bol-Fc L2 ; 圖6 : Robol-Fc L1分子在利用内皮細胞及間葉細胞之共 培養物測試中的作用。A. Robo 1 -Fc L1抑制培養物中之小 管形成。B. Robol-Fc L1顯著抑制VEGF-誘導之偽小管 (pseudotubule)形成；及 圖7 .評估Robo 1 -Fc L1分子對小鼠中離體主動脈環模型 之影響。A ·描述製備主動脈環及量測小管之方案。b : a. 對照組；b. Robol-Fc Slit2· 500 pg/mL+VEGF 1〇 ng/mL ; c. Robol-Fc LI 500 pg/mL+VEGF l〇 ng/mL。 154995.doc -27· 201142024 序 列表 <11〇>法商赛諾菲_安萬特公司 <120> Robol-Fc融合蛋白及其治療腫瘤之用途
<130> FR2009-116PCT <140〉 100113039 <141> 2011-04-14 <150> 1052829 <151> 2010-04-14 <160> 24 <170> Patentln version 3.3 <210> 1 <211> 660 <212> DNA <213> 智人 <220>
<221> CDS <222> (1)..(660) <400> 1 atg att geg gag ccc get cac ttt tac ctg ttt gga tta ata tgt etc 48 Met lie Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu lie cys Leu 1 5 10 15 tgt tea ggc tee cgt ett cgt cag gaa gat ttt cca cct ege att gtt 96 cys Ser Gly Ser Arg Leu Arg Gin Glu Asp Phe Pro Pro Arg lie Val 20 25 30 gaa cac cct tea gac ctg att gtc tea aaa gga gaa cct gca act ttg 144 Glu His Pro Ser Asp Leu lie Val Ser Lys Gly Glu pro Ala Thr Leu 35 40 45 aac tgc aaa 9« gaa ggc ege ccc aca ccc act att gaa tgg tac aaa 192 Asn cys Lys Ala Glu Gly Arg Pro Thr Pro Thr He Glu Trp Tyr Lys 50 55 60 ggg ύν 99¾ gag Gly Glu aga Arg gtg val gag Glu 70 aca Thr gac Asp aaa Lys gat Asp gac Asp 75 cct Pro ege Arg tea ser cac His ega Arg 80 240 atg ttg ctg ccg agt gga tet tta ttt ttc tta cgt ata gta cat gga 288 Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg lie val His Gly 85 90 95 egg aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat 336 Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr val cys Val Ala Arg Asn 100 105 110 tac Tyr ett Leu gga Gly gag Glu age Ser cac His aat Asn gca Ala teg ser ctg Leu gaa gta gee Glu val Ala ata lie 384 115 120 125 ett egg gat gac ttc aga caa aac cct teg gat gtc atg gtt gca gta 432 Leu Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp val Met Val Ala val 130 135 140 m gG?gu cct Pro gca Ala gta val atg Met gaa Glu tgc Cys caa Gin cct Pro cca Pro ega gac cat Arg Gly His cct Pro gag Glu 480 145 150 155 160 ccc acc att tea tgg aag aaa gat ggc tet cca ctg gat gat aaa gat 528 Pro Thr lie Ser Trp 165 Lys Lys Asp Gly Ser 170 Pro Leu Asp Asp i?I Asp 154995-序列表.doc 201142024 gaa aga ata act ata cga gga gaa aag
Glu Arg lie Thr lie Arg Gly Glv lvs 180 1&5 aaa agt gac get ggc aaa tat gtt tgt
Lys Ser Asp Ala Gly Lys Tyr Val cys 195 200 gaa cgt gag agt gaa gta gee gag ctg
Glu Arg Glu Ser Glu Val Ala Glu Leu 210 215 etc atg ate act tac acc cgt 576 Leu Met lie Thr Tyr 190 Thr Arg gtt ggt acc aat atg gtt ggg 624 val Gly Thr Asn Met val Gly 205 act gtc tta 660 Thr val Leu 220 <210> 2 <211> 220 <212> PRT <213> 智人 <400> 2
Leu Phe Gly Leu lie Cys Leu 10 IS
Met lie Ala Glu Pro Ala His Phe Tyr
Cys Ser Gly ser Arg Leu Arg Gin Glu Asp Phe Pro Pro Arg lie val 20 25 30
Glu His Pro ser Asp Leu lie Val ser Lys Gly Glu Pro Ala Thr Leu 35 40 45
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lys 50 55 60
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg 65 70 75 80
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg lie Val His Gly 85 90 95
Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr val cys Val Ala Arg Asn 100 105 110
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala lie 115 120 125
Leu Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp Val Met Val Ala Val 130 135 140
Gly Glu Pro Ala val Met Glu Cys Gin Pro Pro Arg Gly His Pro Glu 145 150 155 160
Pro Thr lie Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175
Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190 154995-序列表.doc 201142024
Lys ser Asp Ala cly Lys Tyr val cys Val Cly Thr Asn Met val cly
Glu Arg Glu Ser Glu val Ala Glu Leu Thr val Leu 210 215 220 <210> 3 <211> 1365 <212> DNA <213>智人 <220> <221> CDS <222> (1)..(1365) <400> 3 atg att gcg gag ccc get cac ttt tac ctg ttt gga tta ata tgt etc Met lie Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu lie Cys Leu 1 5 10 15 tgt tea ggc tcc cgt ett cgt cag gaa gat ttt cca cct ege att gtt Cys ser Gly Ser Arg Leu Arg Gin Glu Asp Phe Pro Pro Arg lie val 20 25 30 gaa cac cct tea gac ctg att gtc tea aaa gga gaa cct Glu His Pro Ser Asp Leu lie Val ser Lys Gly Glu Pro 35 40 45 gca Ala act ttg Thr Leu aac tgc aaa get gaa ggc ege ccc aca ccc act att gaa tgg tac aaa Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lys 50 55 60 gag gga gag Gly Gly Glu 65 aga gtg gag Val Glu
Arg 70 aca gac aaa gat gac cct ege tea cac ega Thr Asp Lys Asp Asp Pro Arg Ser His Arg 75 80 atg ttg ctg ccg agt gga tet tta ttt ttc tta cgt ata gta cat gga Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg lie val His Gly 85 90 95 egg aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn 100 105 110 tac ett gga gag get gtg age cac aat gca teg ctg gaa gta gee ata Tyr Leu Gly Glu Ala val Ser His Asn Ala Ser Leu Glu val Ala lie 115 120 125 ett egg gat gac ttc aga caa aac cct teg gat gtc atg gtt gca gta Leu Arg Asp Asp Phe Arg Gin Asn Pro ser Asp Val Met val Ala val 130 135 140 cct gca gta atg gaa tgc caa cct cca ega ggc cat cct gag Pro Ala Val Met Glu Cys Gin Pro Pro Arg Gly His Pro Glu 150 155 160 ccc acc att tea tgg aag aaa gat ggc tet cca ctg gat gat aaa gat Pro Thr lie Ser Trp Lys Lys Asp Gly ser Pro Leu Asp Asp Lys Asp 165 170 175 gaa aga ata act ata ega gga gga aag etc atg ate act tac acc cgt Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190 aaa agt gac get ggc aaa tat gtt tgt gtt ggt acc aat atg gtt ggg 48 96 144 192 240 288 336 384 432 480 528 576 624 154995·序列表.doc 672201142024
Lys ser Asp Ala Gly 195 Lys Tyr val 200 cys val Gly Thr Asn 205 Met Val Gly gaa Glu cgt Arg 210 agt Ser gaa gta gcc gag Glu val Ala Glu 215 ctg Leu act Thr tta Leu 220 gag Glu aga Arg cca Pro tea Ser ttt Phe 225 tcc Ser aag Lys tac Tyr 230 ggc Gly cct Pro cct Pro tgc cys cct Pro 235 ccc Pro tgc cys cct Pro cct Pro 240 gag Glu ttc gag ggc gga Phe Glu Gly Gly 245 cct Pro age Ser gtg val ttc Phe ctg Leu 250 ttc Phe cct Pro cct Pro aag Lys cct Pro 255 aag Lys gac Asp acc Thr ctg Leu atg Met 260 ate lie tcc Ser egg acc Arg Thr cct Pro 265 §?9U acc Thr tgt cys gtg gtg gtg val val val 270 gac Asp gtg val tcc Ser 275 cag Gin gag Glu gac Asp cct Pro gag Glu 280 ttc Phe aac tgg tac Asn Trp Tyr 285 gac Asp ggc gtg gag gtg cac Gly val Glu VaT His 290 aac Asn 9cc Ala 295 aag Lys acc Thr aag Lys cct pro egg Arg 300 gag gag cag Glu Glu Gin ttc Phe aat Asn 305 tcc Ser acc Thr tac egg Tyr Arg gtg gtg val val 310 tet Ser gtg val ctg Leu acc Thr 315 gtg val ctg Leu cac His cag Gin gac Asp 320 tgg Trp ctg Leu aac Asn ggc Gly aaa Lys 325 gaa Glu tac Tyr aag Lys tgt cys aag Lys 330 tcc ser aac Asn aag Lys ggc Gly 335 ctg Leu ccc Pro tcc Ser tcc ser ate lie 340 gag Glu aaa Lys acc Thr ate lie tcc Ser 345 aag Lys aag Lys ggc Gly cag Gin 350 cct agg Pro Arg gag Glu cct Pro cag gtg Gin val 355 tac Tyr acc Thr ctg Leu cct Pro 360 cct Pro age Ser cag gaa Gin Glu gag Glu 365 atg Met acc Thr aag Lys aac Asn cag gtg Gin val 370 tcc ser ctg Leu acc Thr tgt cys 375 ctg Leu aag Lys ggc Gly ttc tac Phe Tyr 380 cct Pro tcc Ser gac Asp ate lie 385 gec gtg Ala VaT gag tgg Glu Trp gag 6lu 390 tcc Ser aac Asn ggc Gly cag Gin cct Pro 395 gag Glu aac Asn aac tac Asn Tyr aag Lys 400 acc Thr acc Thr cct Pro cct Pro a 405 ctg Leu gac tcc gac Asp ser Asp ggc Gly 410 tcc Ser ttc Phe ttc Phe ctg Leu tac Tyr 415 tcc Ser agg Arg ctg Leu acc Thr 420 gac Asp aag Lys tcc Ser egg Arg tgg Trp 425 ggc Gly aac Asn 430 ttt Phe tcc ser tgc cys tcc ser Ώ 435 atg Met cac His gag gcc Glu Ala ctg Leu 440 cac His aac Asn cac His tac Tyr acc Thr 445 cag Gin aag Lys tcc ser ctg Leu tcc Ser 450 ctg Leu tet Ser ctg ggc Leu Gly tga 720 768 816 864 912 960 1008 1056 1104 1152 1200 1248 1296 1344 154995·序列表.doc -4- 1365 201142024 <210> 4 <211> 454 <212> PRT <213> 智人 <400> 4
Met lie Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu lie cys Leu IS 10 15 cys Ser Gly ser Arg Leu Arg Gin Glu Asp Phe Pro Pro Arg lie Val 20 25 30
Glu His Pro ser Asp Leu lie Val Ser Lys Gly Glu Pro Ala Thr Leu 35 40 45
Asn cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lys 50 55 60
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg 65 70 75 80
Met Leu Leu pro ser Gly Ser Leu Phe Phe Leu Arg lie val His Gly 85 90 95
Arg Lys ser Arg Pro Asp Glu Gly Val Tyr Val cys Val Ala Arg Asn 100 105 110
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala lie 115 120 125
Leu Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp Val Met Val Ala Val 130 135 140
Gly Glu Pro Ala val Met Glu cys Gin Pro Pro Arg Gly His Pro Glu 145 ISO 155 160
Pro Thr lie Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175
Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190
Lys ser Asp Ala Gly Lys Tyr val Cys val Gly Thr Asn Met Val Gly 195 200 205
Glu Arg clu ser Glu Val Ala Glu Leu Thr val Leu Glu Arg Pro ser
Phe Val Glu ser Lys Tyr Gly Pro Pro Cys Pro Pro cys Pro Ala Pro 225 230 235 240
Glu Phe Glu Gly Gly Pro ser Val Phe Leu Phe Pro Pro Lys Pro Lys 154995-序列表.doc 201142024 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr val Asp 275 280 285
Gly Val Glu val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 290 295 300
Asn Ser Thr Tyr Arg val val ser val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 325 330 335
Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin val Tyr Thr Leu Pro Pro ser Gin Glu Glu Met Thr Lys 355 360 365
Asn Gin val Ser Leu Thr Cys Leu val Lys Gly Phe Tyr pro Ser Asp 370 375 380 lie Ala val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp ser Asp Gly ser Phe Phe Leu Tyr ser 405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn val Phe ser 420 425 430 cys Ser val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys ser 435 440 445
Leu Ser Leu ser Leu Gly 450 <210> 5 <211> 1362 <212> DNA <213>智人 <220> <221> CDS <222> (1)..(1362) <400> 5 atg att gcg gag ccc get cac ttt tac ctg ttt gga tta ata tgt etc Met lie Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu lie Cys Leu 154995-序列表.doc 201142024 1 5 10 15 tgt tea ggc tee cgt ett cgt cag gaa gat ttt cca cct ege att gtt 96 Cys Ser Gly ser Arg Leu Arg Gin Glu Asp Phe pro Pro Arg lie val 20 25 30 gaa Glu cac His cct Pro 35 tea Ser gac Asp ctg Leu att lie gtc val 40 tea Ser aaa gaa Lys Gly gaa Glu cct Pro 45 gca Ala act Thr ttg Leu 144 aac tgc aaa get gaa ggc ege ccc aca ccc act att gaa tgg tac aaa 192 Asn cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lys 50 55 60 ggg gga gag aga gtg gag aca gac aaa gat gac cct ege tea cac ega 240 Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg 65 70 75 80 atg ttg ctg ccg agt gga tet tta ttt ttc tta cgt ata gta cat gga 288 Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg lie val His Gly 85 90 95 egg aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat 336 Arg Lys Ser Arg Pro Asp Glu Gly val Tyr val Cys val Ala Arg Asn 100 105 110 tac ett gga gag get gtg age cac aat gca teg ctg gaa gta gee ata 384 Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala lie 115 120 125 ett egg gat gac ttc aga caa aac cct teg gat gtc atg gtt gca gta 432 Leu Arg Asp Asp Phe Arg Gin Asn Pro ser Asp Val Met val Ala val 130 1B5 140 gga gag cct gca gta atg gaa tgc caa cct cca ega ggc cat cct gag 480 Gly Glu Pro Ala Val Met Glu cys Gin ΡΓΟ Pro Arg Gly His Pro Glu 145 ISO 155 160 ccc acc att tea tgg aag aaa gat ggc tet cca ctg gat gat aaa gat 528 Pro Thr lie ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175 gaa aga ata act ata ega gga gga aag etc atg ate act tac acc cgt 576 Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190 aaa agt gac get ggc aaa tat gtt tgt g« ggt acc aat atg g« ggg 624 Lys Ser Asp Ala Gly Lys Tyr Val cys Val Gly Thr Asn Met Val Gly 195 200 205 gaa cgt gag agt gaa gta gee gag ctg act gtc tta gga ggc gga gga 672 Glu Arg Glu ser Glu val Ala Glu Leu Thr val Leu Gly Gly Gly Gly 210 215 220 tee gag tee aag tac ggc cct cct tgc cct ccc tgc cct gee cct gag 720 Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 ttc Phe gag Glu ggc gga Gly Gly cct Pro 245 age ser gtg val ttc Phe ctg Leu ttc Phe 250 cct Pro cct Pro aag Lys cct Pro aag Lys 255 gac Asp 768 acc Thr ctg Leu atg Met ate lie tee Ser egg Arg acc Thr cct Pro gag Glu acc Thr tgt Cys Ώ Ώ gac Asp 816 260 265 270 tee Ser cag Gin gag Glu gac Asp cct Pro gag Glu gtc val cag Gin ttc Phe aac Asn tgg Trp tac Tyr gac Asp ggc Gly 864 154995·序列表.doc 912201142024 275 gag Glu 290 tcc acc tac Ser Thr Tyr 305 ctg aac ggc Leu Asn Gly tcc tcc ate Ser Ser lie cct Pro cag gtg Gin val 355 cag gtg Gin Val tcc ser 370 9cc Ala gta val gag Glu 385 acc cct cct Thr Pro Pro ctg Leu acc Thr tcc ser gtg Val atg Met 435 tcc ctg tct Ser Leu Ser 450 280 cac aac gcc aag acc His Asn Ala Lys Thr 295 egg gta gtg tct gtg Arg val val ser val 310 aaa gaa tac aag tgt Lys Glu Tyr Lys Cys 325 gag aaa acc ate tcc Glu Lys Thr lie Ser 340 tac acc ctg cct cct Tyr Thr Leu pro Pro 360 ctg acc tgt ctg gtg Leu Thr cys Leu val 375 tgg gag tcc aac gac Trp Glu Ser Asn Gly 390 ctg gac tcc gac Leu Asp Ser Asp 405 gac aag tcc egg tgg Asp Lys Ser Arg Trp 420 cac gag gcc ctg cac His Glu Ala Leu His 440 ctg gac tga Leu Gly to c Γ c p 9S ay
cm i cm CM c* c* I c Γ cf 5 cl Γ c c* Γ 5 c Γ t 6ayay 4 9 eay'a'l Qgr- &Ί 2as CL a L a L3 B s a L c G 9g c 64 B A c s 9 s aiay 9G c HaL 9UO 9U c n alo t e as 9G3 CL a A 9 9 οΐ 5 c Γ 9 Γ t a 1 c e
9n el c G 5 9 u 8 SI
9n al c G c y 91 9G 9 s ay t s a L CIO c a t a3 cl 9V 3 9A 9n c y too a'l QT c Γ 5
t n 9PO Co 9 u as 9 Γ 2 c Γ al a A t T3 CP 9g c e CP 9U5 9 9 t h as te3 9 r t p gA,c L 3aA
as tl a A a I 9 s CP ay as a L 9a c Γ etch c e a T t s 9t 5 to t e6 c r a M3 CP 9U c ΓΟ al a y8 9G t T3 a u a<l 9G 9n al c G
c e th t p c y 9— 9G ay t T c n 9U as t e a A CL c n c e as t h a A t p 9U5 c e al9 th 9G3 t p to c r o c Γ cel CP t S4 aaLy cel t 54 c r taTy acTh40agAr
9y t c c r c e t s t eo t h3 t P4 cl t a 9V c n as a A c y 9Ί 9G 9U al 9G
t e c L c r c e t s 9 s lay a L 9 n 5 314 c G4 c r ch a T c r ay tics ai c H 960 1008 1056 1104 1152 1200 1248 1296 1344 1362 <210> 6 <211> 453 <212> PRT <213> 智人 <400> 6 Met lie Ala
Glu Pro Ala His Phe
Gl e ph u eo LI Γ Ty 8
Cys Ser Gly ser Arg Leu Arg Gin 20 G125 he 9 ΓΟ A3
Glu His Pro 35
Ser Asp Leu lie Val 40
Th a A1 o Γ 5 p 4 u G1 y G1 s Ly
Asn Cys Lys 50
Ala Glu Gly Arg Pro 55
Th
Th i60
Ly r Ty rp Tr u G1 154995-序列表.doc 201142024
Civ Cly Clu Arg val Clu Thr ASP Lys Asp ΛξΡ Pro Arg Sen His Arg
Met Leu Leu Pro Sen Cly Ser Leu Phe Phe Leu Arg He Val His Gly
Arg Lys ser Arg Pro Asp Glu Gly Tyr val Cys Val Ala Arg Asn 100 l〇5 110
Tyr Leu Gly Glu Ala val ser His Asn Ala ser Leu Glu Val Ala lie 115 120 125
Leu Arg Asp Asp Phe Arg Gin asn Pro Ser Asp val Met Val Ala Val 130 135 140
Gly Glu Pro Ala val Met Glu cys Gin Pro Pro Arg Gly His Pro Glu 145 150 155 160
Pro Thr lie Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175
Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190
Lys Ser Asp Ala Gly Lys Tyr val Cys Val Gly Thr Asn Met val Gly 195 200 205
Glu Arg Glu ser Glu val Ala Glu Leu Thr val Leu Gly Gly Gly Gly 210 215 220 ser Glu ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240
Phe Glu Gly Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255
Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270
Val ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 275 280 285
Val Glu val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 290 295 300 ser Thr Tyr Arg va! Val ser Val Leu Thr Val Leu His Cln Asp T.p
Leu Asn Gly Lys Glu Tyr Lys cys Lys val ser Asn Lys Gly Leu Pro 325 330 335 154995-序列表.doc 201142024
Ser ser lie
Glu Lys Thr lie ser Lys Ala Lys Gly Gin Pro Ara Glu 340 345 350
Pro Gin val 355
Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lvs Asn 360 365
Gin val ser 370
Leu Thr cys Leu val Lys Gly Phe Tyr Pro Ser asd lie 375 380
Ala val Glu 385
Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 390 395 400
Thr Pro Pro
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ara 405 410 415
Leu Thr Val
Asp Lys ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys 420 425 430
Ser Val Met 435
His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 440 445 ser Leu ser 450
Leu Gly <210> 7 <211> 1365 <212> DNA <213> 智人 (1365) tgt tea ggc Cys ser Gly gag Glu ccc Pro 5 cac His ttt Phe tac Tyr ctg Leu 10 ttt Phe gga Gly tta Leu ata lie tgt cys 15 etc Leu 48 tcc Ser 20 cgt Arg ett cgt Leu Arg cag gaa Gin Glu 25 gat Asp ttt Phe cca Pro cct Pro ege Arg 30 att lie 96 tea Ser gac Asp cag Gin att lie gtc Val 40 tea Ser aaa Lys gga Gly gaa Glu cct Pro 45 gca Ala act Thr ttg Leu 144 沉 gaa Glu ggc ege Gly Arg 55 ccc Pro aca Thr ccc Pro act Thr att lie 60 gaa Glu tgg tac Trp Tyr aaa Lys 192 aga Arg gtg gag val Glu 70 aca gac Thr Asp aaa Lys gat gac Asp Asp 75 cct ege Pro Arg tea Ser cac His ega Arg 80 240 ccg Pro agt Ser 85 tet Ser tta Leu tat Tyr ttc Phe 90 tta cgt Leu Arg ata gta lie Val cat His 95 gga Gly 288 <220> <221> CDS <222> (1). <400> 7 atg att gcg Met lie Ala gaa cac cct Glu His Pro 35 aac tgc aaa Asn Cys Lys 50 gag gga gag Gly Gly Glu 65 atg ttg ctg Met Leu Leu 154995·序列表.doc -10· 201142024 egg Arg aaa Lys agt Ser aga Arg 100 cct Pro gat Asp gaa Glu gga Gly 3¾ 105 tat Tyr tgt Cys gta gca val Ala 110 agg Arg aat Asn 336 tac Tyr ett Leu gga Gly 115 gag Glu get Ala 緦 age Ser cac His 120 aat Asn gca Ala teg Ser ctg Leu gaa Glu 125 gta Val ata lie 384 ett Leu egg Arg 130 gat Asp gac Asp ttc Phe aga Arg caa Gin 135 aac Asn cct Pro teg ser gat ASP 9tc Val 140 atg Met gtt gca gta val Ala Val 432 gga gag Gly Glu 145 cct Pro gca gta Ala Val atg Met ISO gaa tgc Glu Cys caa Gin cct Pro cca Pro 155 ega Arg ggc Gly cat His cct Pro gag Glu 160 480 ccc Pro acc Thr att lie tea ser tgg Trp 165 aag Lys aaa gat Lys Asp ggc Gly tet Ser 170 cca Pro ctg Leu gat gat Asp Asp aaa Lys 175 gat Asp 528 gaa Glu aga Arg ata lie act Thr 180 ata lie eg a Arg gga Gly gga Gly aag Lys 185 etc Leu atg Met ate He act tac Thr Tyr 190 acc Thr cgt Arg 576 aaa Lys agt Ser gac Asp 195 aaa Lys tat Tyr 200 tgt cys 9« Val ggt Gly acc Thr aat Asn 205 atg Met ggg Gly 624 gaa Glu cgt Arg 210 gag Glu agt Ser gaa Glu gta val gee Ala 215 gag Glu ctg Leu act Thr gt:〒 val tta Leu 220 gag Glu aga Arg cca Pro tea Ser 672 ttt Phe 225 gtg gag Val Glu tee Ser aag Lys tac Tyr 230 ggc Gly cct Pro cct Pro tgc cys cct Pro 235 ccc Pro tgc cys cct Pro ISt cct Pro 240 720 gag Glu ttc Phe gag Glu ggc Gly gga Gly 245 cct Pro age Ser gtg val ttc Phe ctg Leu 250 ttc Phe cct Pro cct Pro aag *-ys cct Pro 255 aag Lys 768 gac Asp acc Thr ctg Leu atg Met 260 ate lie tee Ser egg acc Arg Thr cct Pro 265 gag gtg Glu val acc Thr tgt cys gtg gtg gtg Val Val Val 270 816 gac Asp tee Ser 275 cag gag Gin Glu gac Asp cct Pro gag gtc Glu Val 280 cag Gin ttc Phe aac Asn tgg tac gtg Trp Tyr Val 285 gac Asp 864 ggc gtg gag gtg Gly Val Glu Val 290 cac His aac Asn 冗 295 aag Lys acc Thr aag Lys cct Pro egg Arg 300 gag gag cag Glu Glu Gin ttc Phe 912 aat Asn 305 tee Ser acc Thr tac egg gtg Tyr Arg Val 310 gtg Val tet Ser ctg Leu acc Thr 315 gtg Val ctg Leu cac His cag Gin gac Asp 320 960 tgg Trp ctg Leu aac Asn ggc Gly aaa Lys 325 gaa Glu tac Tyr aag Lys tgt cys aag Lys 330 tee Ser aac Asn aag Lys ggc Gly 335 ctg Leu 1008 ccc pro tee ser tee ser ate lie 340 gag Glu aaa Lys acc Thr ate lie tee ser 345 aag Lys aag Lys ggc Gly cag Gin 350 cct Pro agg Arg 1056 gag Gl u cct Pro cag Gin gtg val tac Tyr acc Thr ctg Leu cct Pro cct Pro age ser cag gaa gag Gin Glu Glu atg Met acc Thr aag Lys 1104 355 360 365 -11 - 154995·序列表.doc 201142024 aac As η cag gtg Gin Val 370 tcc ser ctg acc tgt Leu Thr Cys 375 ctg Leu aag Lys ggc Gly ttc Phe 380 tac Tyr cct Pro tcc gac Ser Asp 1152 ate lie 385 tgg Trp gag Glu 390 tcc Ser aac Asn ggc Gly cag Gin cct Pro 395 gag Glu aac Asn aac Asn tac Tyr aag Lys 400 1200 acc Thr acc cct Thr Pro cct Pro gtg Val 405 ctg Leu gac Asp tcc Ser gac Asp ggc Gly 410 tcc ser ttc Phe ttc Phe ctg Leu tac Tyr 415 tcc Ser 1248 agg Arg ctg acc Leu Thr 420 gac Asp aag Lys tcc Ser egg Arg tgg Trp 425 cag gag Gin Glu ggc Gly aac Asn 沿 430 ttt Phe tcc Ser 1296 tgc Cys tcc gtg ser val 435 atg Met cac His gag Glu 9cc Ala ctg Leu 440 cac His aac Asn cac His tac acc Tyr Thr 445 cag Gin aag Lys tcc Ser 1344 ctg Leu tcc ctg Ser Leu 450 tet Ser ctg Leu ggc Gly tga 1365 <210> 8 <211> 454 <212> PRT <213> 智人 <400> 8 Met 1 lie Ala Glu Pro 5 Ala His Phe Tyr Leu 10 Phe Gly Leu lie if Leu cys ser Gly Ser 20 Arg Leu Arg Gin Glu Asp 25 Phe Pro Pro Arg 30 lie val Glu His Pro 35 Ser ASp Gin lie Val 40 ser Lys Gly Glu Pro Ala Thr 45 Leu Asn Cys Lys 50 Ala Glu Gly Arg 55 Pro Thr Pro Thr lie 60 Glu Trp Tyr Lys Gly Gly Glu Arg Val 65 Glu 70 Thr Asp Lys Asp Asp 75 Pro Arg Ser His Arg 80 Met Leu Leu Pro ser Gly 85 Ser Leu Tyr Phe 90 Leu Arg lie val His Gly 95 Arg Lys ser Arg 100 ΡΓΟ Asp Glu Gly Val 105 Tyr val Cys val Ala Arg 110 Asn Tyr Leu Gly Glu 115 Ala Val Ser His 120 Asn Ala Ser Leu Glu 125 Val Ala lie Leu Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp val Met Val Ala Val 130 135 140 -12- 154995·序列表.doc 201142024
Gly Glu Pro Ala val Met Glu Cys Gin Pro Pro Arg Gly His Pro Glu 145 ISO 155 160
Pro Thr lie Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175
Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190
Lys ser Asp Ala Gly Lys Tyr val cys val Gly Thr Asn Met val cly
Glu Arg Glu ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser
Phe Val Glu ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 22S 230 235 240
Glu Phe Glu Gly Gly Pro ser val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met He Ser Arg Thr Pro Glu val Thr cys Val val val 260 265 270
Asp Val ser Gin Glu Asp Pro Glu val Gin Phe Asn Trp Tyr val asd 275 280 285 G"*y βΐ Glu Va"* H1'S Asn Ala Lys Thr Lys Pro Ar9 Glu Glu Gin Phe 290 295 B00 今sn ser Thr Tyr Arg Val val ser val Leu Thr val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys cys Lys val ser Asn Lys Glv Leu 325 330 335
Pro Ser ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Ara 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lvs 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser asd 370 375 B80 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tvr Lvs 385 390 395 Y 400
Thr Thr Pro Pro val Leu Asp ser Asp Gly ser Phe Phe Leu Tvr ser 405 410 415 -13- 154995-序列表.doc 201142024
Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser 420 425 430
Cys ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu ser Leu ser Leu Gly 450 <210> 9 <211> 1365 <212> DNA <213> 智人 <220> <221> CDS <222> (1)..(1365) <400> 9 atg att geg gag ccc get cac ttt tac Met 1 lie Ala Glu Pro S Ala His Phe Tyr tgt tea ggc tcc cgt ett cgt cag gaa cys Ser Gly Ser Arg Leu Arg Gin Glu 20 25 gaa cac cct tea gac ctg att gtc tea Glu His Pro Ser Asp Leu lie val ser 35 40 aac tgc aaa get gaa ggc ege ccc aca Asn cys Lys Ala Glu Gly Arg Pro Thr 50 55 ggg Gly 65 gga Gly gag Glu aga Arg gag Glu 70 aca Thr gac Asp aaa Lys atg ttg ctg ccg agt gga tet tta ttt Met Leu Leu Pro Ser 85 Gly Ser Leu Phe 9cc Ala agt Ser aga Arg cct Pro gat Asp gaa Glu gga Gly 100 105 tac Tyr ett Leu gga Gly gag Glu 9« Ala 辦 age Ser cac His aat Asn 115 120 ett egg gat gac ttc aga caa aac cct Leu Arg Asp Asp Phe Arg Gin Asn Pro 130 135 gga gag cct gca gta atg gaa tgc caa Gly Glu Pro Ala val Met Glu cys Gin 145 150 ccc acc att tea tgg aag aaa gat ggc Pro Thr lie ser Trp Lys Lys Asp Gly 165 ctg ttt gaa tta ata tgt etc 48
Leu Phe Gly Leu lie Cys Leu 10 15 gat ttt cca cct ege att gtt 96
Asp Phe Pro pro Arg lie val 30 aaa gga gaa cct gca act ttg 144
Lys Gly Glu Pro Ala Thr Leu 45 ccc act att gaa tgg tac aaa 192 Pro Thr lie Glu Trp Tyr Lys 60 gat gac cct ege tea cac ega 240 Asp Asp Pro Arg Ser His Arg 75 80 ttc tta cgt ata gta cat gga 288 Phe Leu Arg lie Val His Gly 90 95 tat gtc tgt gta gca agg aat 336
Tyr val Cys val Ala Arg Asn 110 gca teg ctg gaa gta gcc ata 384 Ala Ser Leu Glu Val Ala lie 125 teg gat gtc atg gtt gca gta 432 Ser Asp val Met val Ala Val 140 cct cca ega ggc cat cct gag 480 Pro Pro Arg Gly His Pro Glu 155 160 tet cca ctg gat gat aaa gat 528 ser Pro Leu Asp Asp Lys Asp 170 175 • 14· 154995-序列表.doc 201142024 gaa Glu aga Arg ata lie act Thr 180 ata ega lie Arg gga gga Gly Gly aag Lys 185 etc Leu atg Met ate lie act Thr tac Tyr 190 acc Thr cgt Arg 576 aaa Lys agt ser gac Asp 195 aaa Lys tat gtt Tyr Val 200 tgt gtt cys Val ggt Gly acc Thr aat Asn 205 atg Met 9« val ggg Gly 624 gaa cgt Glu Arg 210 gag Glu agt gaa gta ser Glu val 215 gag Glu ctg Leu act Thr gti val tta Leu 220 gag Glu aga Arg cca Pro tea ser 672 ttt Phe 225 gtg val gag Glu tcc ser aag Lys tac Tyr 230 ggc Gly cct Pro cct Pro tgc cys cct Pro 235 ccc pro tgc cys cct Pro 沉 cct Pro 240 720 gag Glu ttc gag ggc gga Phe Glu Gly Gly 245 cct ΡΓΟ age gtg ser val ttc Phe ctg Leu 250 ttc Phe cct pro cct Pro aag Lys cct Pro 255 aag Lys 768 gac acc Asp Thr ctg Leu atg Met 260 ate He tcc Ser egg acc Arg Thr cct Pro 265 gag gtq Glu Val acc Thr tgt Cys gtg gtg val Val 270 gtg val 816 gac Asp tcc Ser 275 cag Gin gag Glu gac Asp cct Pro gag Glu 280 gtc cag val Gin ttc Phe aac tgg tac Asn Trp Tyr 285 gtg val gac Asp 864 ggc gtg Gly Val 290 gag Glu SS? cac His aac Asn gcc Ala 295 aag Lys acc Thr aag Lys cct Pro egg Arg 300 gag Glu gag Glu cag Gin ttc Phe 912 aat Asn 305 tcc Ser acc Thr tac Tyr egg Arg gtg gtg Val Val B10 tet Ser gtg val ctg Leu acc Thr 315 gtg Val ctg Leu cac His cag Gin gac Asp 320 960 tgg Trp ctg Leu aac Asn ggc Gly aaa Lys 325 gaa Glu tac Tyr aag Lys tgt cys aag Lys 330 gtc val tcc Ser aac Asn aag Lys ggc Gly 335 ctg Leu 1008 ccc Pro tcc Ser tcc Ser ate He 340 gag Glu aaa Lys acc Thr ate lie tcc Ser 345 aag Lys gcc aag ggc cag Ala Lys Gly Gin 350 cct Pro agg Arg 1056 gag Glu cct Pro cag Gin 355 緦 tac acc Tyr Thr ctg Leu cct Pro 360 cct Pro age Ser cag Gin gaa gag Glu Glu 365 atg Met acc Thr aag Lys 1104 aac Asn cag Gin 370 gtg val tcc Ser ctg Leu acc Thr tgt cys 375 ctg Leu gtg val aag Lys ggc ttc tac Gly Phe Tyr 380 cct Pro tcc gac ser Asp 1152 ate lie 385 gag Glu tgg Trp gag Glu 390 tcc ser aac Asn ggc Gly cag Gin cct Pro 395 gag Glu aac Asn aac tac Asn Tyr aag Lys 400 1200 acc Thr acc Thr cct Pro cct gtg Pro val 405 ctg Leu gac tcc Asp ser gac Asp ggc Gly 410 tcc Ser ttc Phe ttc Phe ctg Leu tac Tyr 415 tcc Ser 1248 agg Arg ctg Leu acc Thr gtg Val 420 gac Asp aag Lys tcc egg ser Arg tgg cag Trp Gin 425 gag Glu ggc Gly aac Asn gtc val 430 ttt Phe tcc Ser 1296 tgc Cys tcc Ser gtg val 435 atg Met cac His gag Glu gcc Ala ctg Leu 440 cac His aac Asn cac His tac acc Tyr Thr 445 cag Gin aag Lys tcc Ser 1344 -15- 154995·序列表.doc 1365 201142024 ctg tcc ctg tct ctg ggc tga Leu ser Leu Ser Leu Gly 450 <210> 10 <2U> 454 <212> PRT <213> 智人 <400> 10
Met lie Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu lie cys Leu 15 10 15 cys Ser Gly Ser Arg Leu Arg Gin Glu Asp Phe Pro Pro Arg lie val 20 25 30
Glu His Pro ser Asp Leu He val Ser Lys Gly Glu Pro Ala Thr Leu 35 40 45
Asn cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lvs 50 55 60
Gly Gly Glu Arg val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg 65 70 75 80
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg lie Val His Gly 85 90 95
Ala Ala ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn 100 105 110
Tyr Leu Gly Glu Ala Val ser His Asn Ala Ser Leu Glu val Ala lie 115 120 125
Leu Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp Val Met Val Ala Val 130 135 140
Gly Glu Pro Ala Val Met Glu Cys Gin Pro Pro Arg Gly His Pro Glu 145 150 155 160
Pro Thr lie Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp 165 170 175
Glu Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg 180 185 190
Lys Ser Asp Ala Gly Lys Tyr val cys val Gly Thr Asn Met val Gly 195 200 205
Glu Arg Glu Ser Glu val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser 210 215 220 -16· 154995·序列表.doc 201142024
Phe val Glu ser Lys Tyr Gly Pro 225 230
Pro cys Pro Pro cys Pro Ala Pro 235 240
Glu Phe Glu Gly Gly Pro ser Val
Phe Leu Phe Pro Pro Lys pro Lys 250 255
Asp Thr Leu Met lie Ser Arg Thr 260
Pro Glu Val Thr cys Val Val Val 265 270
Asp Val ser Gin Glu Asp Pro Glu 275 280
Val Gin Phe Asn Trp Tyr Val Asp 285
Gly Val Glu val His Asn Ala Lys 290 295
Thr Lys Pro Arg Glu Glu Gin Phe 300
Asn ser Thr Tyr Arg Val val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Cly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys cly Leu
Pro ser ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Ara 340 345 350
Glu Pro Gin val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr lvs 355 360 365
Asn Gin val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser asd B70 375 380 μ
lie Ala val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tvr Lvs 385 390 395 Y
Thr Thr Pro Pro val Leu Asp Ser Asp Gly ser Phe Phe Leu Tvr spt 405 410 4i5
Arg Leu Thr val Asp Lys ser Arg Trp Gin Glu Gly Asn Val phe qpt 420 425 430
Cys ser val Met His Glu Ala Leu His Asn His Tyr Th「 Gin Lvs ςρΓ
435 440 445 Y
Leu ser Leu ser Leu Glv 450 <210> 11 <211> 717 <212> DNA <213>智人 <220>
<221> CDS 17- 154995·序列表.doc 201142024 <222> (1)..(717) <400> 11 atg tac agg Met Tyr Arg 1 atg Met caa Gin 5 etc Leu ctg Leu tet Ser tgc cys att lie 10 gca Ala eta Leu agt Ser ett Leu gca Ala 15 ett Leu 48 耑 aat Asn tea Ser 20 ttg Leu cac His tgc Cys cct Pro gee gee Ala Ala 25 tgt cys acc Thr tgt age Cys Ser 30 aac Asn aat Asn 96 ate lie gta Val gac Asp 35 tgt Cys cgt Arg ggg Gly aaa Lys ggt Gly 40 etc Leu act Thr gag Glu ate lie ccc Pro 45 aca Thr aat Asn ett Leu 144 cca Pro gag Glu 50 acc Thr ate lie aca Thr gaa Glu ata lie 55 cgt Arg ttg Leu gaa cag Glu Gin aac Asn 60 aca Thr ate lie aaa Lys 猎 192 ate lie 65 cct Pro cct Pro gga Gly 沉 ttc Phe 70 tea ser cca Pro tat Tyr aaa Lys aag Lys 75 ett Leu aga Arg ega Arg att lie gac Asp 80 240 ctg Leu age Ser aat Asn aat Asn cag Gin 85 ate lie tet ser gaa Gl u ett Leu gca Ala 90 cca Pro gat get Asp Ala ttc caa Phe Gin 95 gga Gly 288 eta ege Leu Arg tet Ser ctg Leu 100 aat Asn tea ser ett Leu etc Leu 105 tat Tyr gga Gly aat Asn aaa Lys ate lie 110 aca Thr gaa Glu BB6 etc Leu ccc Pro aaa Lys 115 agt Ser tta Leu ttt Phe gaa gga Glu Gly 120 ctg Leu ttt Phe tee Ser tta Leu cag Gin 125 etc Leu eta Leu tta Leu 384 ttg Leu aat Asn 130 9« Ala aac Asn aag Lys ata lie aac Asn 135 tgc cys ett egg Leu Arg gta val gat Asp 140 K ttt Phe cag Gin gat Asp 432 etc Leu 145 cac His aac Asn ttg Leu aac Asn ett Leu 150 etc Leu tee Ser eta Leu tat gac aac Tyr Asp Asn 155 aag Lys ett Leu cag Gin acc Thr 160 480 ate lie ISl aag Lys ggg Gly acc Thr 165 ttt Phe tea ser cct pro ett egg Leu Arg 170 att lie caa Gin act Thr atg Met 175 cat His 528 ttg Leu cag Gin aac Asn 180 ccc Pro ttt Phe att lie tgt gac tgc cys Asp Cys 185 cat His etc Leu aag tgg Lys Trp 190 eta Leu geg Ala 576 gat tat Asp Tyr etc Leu 195 cat His acc Thr aac Asn ccg Pro att lie 200 ifu acc Thr agt Ser ggt gee cgt Gly Ala Arg 205 tgc cys acc Thr 624 age ser ccc ege Pro Arg 210 ege Arg ctg Leu gca Ala aac Asn 215 aaa aga Lys Arg att lie gga Gly cag Gin 220 ate lie aaa Lys age Ser aag Lys 672 aaa Lys 225 ttc cgt Phe Arg tgt cys tea Ser ggt Gly 230 age ser cat His cac His cat His 235 cat His cat His cac His tga 717 <210> 12 <211> 238 <212> PRT <213> 智人 154995-序列表.doc · 18· 201142024 <400> 12
Met Tyr Arg Met Gin Leu Leu ser cys lie Ala Leu ser Leu Ala Leu IS 10 15
Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr cys ser Asn Asn 20 25 30 lie Val Asp Cys Arg Gly Lys Gly Leu Thr Glu lie Pro Thr Asn Leu 35 40 45
Pro Glu Thr lie Thr Glu lie Arg Leu Glu Gin Asn Thr lie Lys Val 50 55 60 lie Pro Pro Gly Ala Phe ser Pro Tyr Lys Lys Leu Arg Arg lie Asp 65 70 75 80
Leu Ser Asn Asn Gin lie Ser Glu Leu Ala Pro Asp Ala Phe Gin Gly 85 90 95
Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys lie Thr Glu 100 105 HO
Leu Pro Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gin Leu Leu Leu 115 120 125
Leu Asn Ala Asn Lys lie Asn Cys Leu Arg Val Asp Ala Phe Gin Asp 130 135 140
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gin Thr 145 150 155 160 lie Ala Lys Gly Thr Phe ser Pro Leu Arg Ala lie Gin Thr Met His 165 170 175
Leu Ala Gin Asn Pro Phe lie Cys Asp cys His Leu Lys Trp Leu Ala 180 185 190
Asp Tyr Leu His Thr Asn Pro lie Glu Thr Ser Gly Ala Ara Cvs Thr 195 200 205
Ser Pro Arg Arg Leu Ala Asn Lys Arg lie Gly Gin lie Lys Ser Lys 210 215 220
Lys Phe Arg Cys Ser Gly ser Ala His His His His His His 225 230 235 <210> 13 <211> 1467 <212> DNA <213> 智人 19· 154995-序列表.doc 201142024 <220> <221> CDS <222> (1)..(1467) <400> 13 atg ege ggc gtt ggc tgg cag atg ctg tee ctg teg ctg ggg tta gtg 48 Met Arg Gly val Gly Trp Gin Met Leu Ser Leu Ser Leu Gly Leu val 1 5 10 15 ctg geg ate ctg aac aag gtg gca ccg cag geg tgc ccg geg cag tgc 96 Leu Ala lie Leu Asn Lys val Ala Pro Gin Ala cys Pro Ala Gin cys 20 25 30 tct tgc teg ggc age aca gtg gac tgt cac ggg ctg geg ctg ege age 144 Ser cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser 35 40 45 gtg ccc agg aat ate ccc ege aac acc gag aga ctg gat tta aat gga 192 val Pro Arg Asn lie Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly 50 55 60 aat aac ate aca aga att aeg aag aca gat ttt get ggt ett aga cat 240 Asn Asn lie Thr Arg lie Thr Lys Thr Asp Phe Ala Gly Leu Arg His 65 70 75 80 eta aga gtt ett cag ett atg gag aat aag att age acc att gaa aga 288 Leu Arg Val Leu Gin 85 Leu Met Glu Asn Lys 90 lie Ser Thr lie Glu 95 Arg gga gca ttc cag gat ett aaa gaa eta gag aga ctg cgt tta aac aga 336 Gly Ala Phe Gin Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg 100 105 110 aat cac ett cag ctg ttt cct gag ttg ctg ttt ett ggg act geg aag 384 Asn His Leu Gin Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys 115 120 125 eta tac agg ett gat etc agt gaa aac caa att cag gca ate cca agg 432 Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gin lie Gin Ala lie Pro Arg 130 135 140 aaa get ttc cgt ggg gca gtt gac ata aaa aat ttg caa ctg gat tac 480 Lys Ala Phe Arg Gly Ala val Asp lie Lys Asn Leu Gin Leu Asp Tyr 145 150 155 160 aac cag ate age tgt att gaa gat ggg gca ttc agg get etc egg gac 528 Asn Gin lie ser cys lie Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp 165 170 175 ctg gaa gtg etc act etc aac aat aac aac att act aga ett tct gtg 576 Leu Glu Val Leu Thr Leu Asn Asn Asn Asn lie Thr Arg Leu Ser Val 180 185 190 gca agt ttc aac cat atg cct aaa ett agg act ttt ega ctg cat tea 624 Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser 195 200 205 aac aac ctg tat tgt gac tgc cac ctg gee tgg etc tee gac tgg ett 672 Asn Asn Leu Tyr cys Asp cys His Leu Ala Trp Leu Ser Asp Trp Leu 210 215 220 ege caa agg cct egg gtt ggt ctg tac act cag tgt atg ggc ccc tee 720 Arg Gin Arg Pro Arg Val Gly Leu Tyr Thr Gin cys Met Gly Pro Ser 225 230 235 240 cac His ctg Leu aga Arg ggc Gly cat His aat Asn gta gee val Ala gag Glu 9« val caa Gin aaa Lys ega Arg gaa Glu ttt Phe gti Val 768 •20· 154995·序列表.doc 201142024 245 250 255 tgc Cys agt Ser ggt Gly cac His 260 cag Gin tea ser ttt Phe atg Met get Ala 265 cct Pro tet Ser agt Ser 270 ttg ueu cac His 816 tgc Cys cct Pro gee Ala 275 gee Ala tgt cys acc Thr tgt cys age Ser 280 aac Asn aat Asn ate lie gta gac tgt cgt val Asp cys Arg 285 ggg Gly 864 aaa Lys ggt Gly 290 etc Leu act Thr gag Glu ate lie ccc aca Pro Thr 295 aat Asn ett Leu cca Pro gag Glu 300 acc Thr ate lie aca Thr gaa Glu 912 ata cgt lie Arg 305 ttg Leu gaa Glu cag Gin aac Asn 310 aca Thr ate lie aaa gtc Lys val ate lie 315 cct Pro cct gga get Pro Gly Ala ttc Phe 320 960 tea Ser cca tat Pro Tyr aaa Lys aag Lys 325 ett aga ega Leu Arg Arg att gac lie Asp 330 ctg Leu age Ser aat Asn aat Asn cag Gin 335 ate lie 1008 tet Ser gaa Glu ett Leu gca Ala 340 cca Pro gat get Asp Ala ttc Phe caa gga Gin Gly 345 eta ege Leu Arg tet ser ctg Leu 350 aat Asn tea Ser 1056 ett Leu gtc Val etc Leu 355 tat Tyr gga Gly aat Asn aaa Lys ate lie 360 aca Thr gaa Glu etc Leu ccc Pro aaa Lys 365 agt Ser tta Leu ttt Phe 1104 gaa Glu gga Gly 370 ctg Leu ttt Phe tee Ser tta Leu cag Gin 375 etc Leu eta Leu tta Leu ttg Leu aat Asn 380 gee aac Ala Asn aag Lys ata lie 1152 aac Asn 385 tgc cys ett Leu egg Arg gta Val gat get Asp Ala 390 ttt Phe cag gat Gin Asp etc Leu 395 cac His aac Asn ttg Leu aac Asn ett Leu 400 1200 etc Leu tee Ser eta Leu tat Tyr gac aac Asp Asn 405 aag Lys ett Leu cag Gin acc Thr 410 ate lie 9cc Ala aag Lys ggg Gly acc Thr 415 ttt Phe 1248 tea ser cct Pro ett Leu egg Arg 420 Ala att lie caa Gin act Thr atg Met 425 cat His ttg Leu gee Ala cag aac Gin Asn 430 ccc Pro ttt Phe 1296 att lie tgt cys gac Asp 435 tgc Cys cat His etc Leu aag Lys tgg Trp 440 eta Leu geg Ala gat tat Asp Tyr etc Leu 445 cat His acc Thr aac Asn 1344 ccg Pro att lie 450 gag Glu acc Thr agt Ser ggt Gly gee cgt tgc Ala Arg cys 455 acc Thr age Ser ccc ege ege Pro Arg Arg 460 ctg Leu gca Ala 1392 aac Asn 465 aaa Lys aga Arg att gga cag lie Gly Gin 470 ate lie aaa Lys age Ser aag Lys aaa Lys 475 ttc cgt tgt Phe Arg Cys tea Ser ggt Gly 480 1440 age get Ser Ala cat His cac His cat His cat His cat His cac His tga 1467 485 <210> 14 <211> 488 <212> PRT <213> 智人 •21 - 154995·序列表.doc 201142024 <400> 14
Met Arg Gly val Gly Trp Gin Met Leu Ser Leu Ser Leu Gly Leu val 1 5 10 15
Leu Ala lie Leu Asn Lys val Ala Pro Gin Ala Cys Pro Ala Gin cys 20 25 30
Ser cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg ser 35 40 45
Val Pro Arg Asn lie Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly 50 55 60
Asn Asn lie Thr Arg lie Thr Lys Thr Asp Phe Ala Gly Leu Arg His 65 70 75 80
Leu Arg val Leu Gin Leu Met Glu Asn Lys lie Ser Thr lie Glu Arg 85 90 95
Gly Ala Phe Gin Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg 100 105 110
Asn His Leu Gin Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys 115 120 125
Leu Tyr Arg Leu Asp Leu ser Glu Asn Gin lie Gin Ala lie Pro Arg 130 135 140
Lys Ala Phe Arg Gly Ala Val Asp lie Lys Asn Leu Gin Leu Asp Tyr 145 150 155 160
Asn Gin lie Ser Cys lie Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp 165 170 175
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn lie Thr Arg Leu Ser Val 180 185 190
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser 195 200 205
Asn Asn Leu Tyr Cys Asp cys His Leu Ala Trp Leu Ser Asp Trp Leu
Arg Gin Arg Pro Arg Val Gly Leu Tyr Thr Gin Cys Met Gly Pro Ser 225 230 235 240
His Leu Arg Cly His Asn val Ala clu val Gln Lys Arg Glu Phe Val
Cys Ser Gly His Gin Ser Phe Met Ala Pro Ser Cys ser val Leu His 260 265 270 •22- 154995-序列表.doc 201142024 cys Pro Ala Ala cys Thr cys Ser Asn Asn lie Val Asp cys Arg Gly 275 280 285
Lys Gly Leu Thr Glu lie Pro Thr Asn Leu Pro Glu Thr lie Thr Glu 290 295 300 lie Arg Leu Glu Gin Asn Thr lie Lys Val lie Pro Pro Gly Ala Phe 305 B10 315 320
Ser Pro Tyr Lys Lys Leu Arg Arg lie Asp Leu ser Asn Asn Gin lie 325 330 335
Ser Glu Leu Ala Pro Asp Ala Phe Gin Gly Leu Arg ser Leu Asn Ser 340 345 350
Leu val Leu Tyr Gly Asn Lys lie Thr Glu Leu Pro Lys ser Leu Phe 355 360 365
Glu Gly Leu Phe ser Leu Gin Leu Leu Leu Leu Asn Ala Asn Lys lie 370 375 380
Asn Cys Leu Arg val Asp Ala Phe Gin Asp Leu His Asn Leu Asn Leu 385 390 395 400
Leu ser Leu Tyr Asp Asn Lys Leu Gin Thr lie Ala Lys Gly Thr Phe 405 410 415
Ser Pro Leu Arg Ala lie Gin Thr Met His Leu Ala Gin Asn Pro Phe 420 425 430 lie cys Asp cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn 435 440 445
Pro lie Glu Thr Ser Gly Ala Arg cys Thr Ser Pro Arq Ara Leu Ala 450 455 460
Asn Lys Arg He cly cln He Lys Ser Lys Lys Phe Arg cys Sen cly
Ser Ala His His His His His His 485 <210> 15 <211> 3390 <212> DNA <213> 智人 <220> <221> CDS <222> (1)..(3390) -23- 154995·序列表.doc 201142024 <400> 15 atg cgc Met Arg 1 ggc Gly S3 ggc tgg Gly Trp 5 cag Gin atg Met ctg Leu tcc Ser 10 ctg Leu teg ser ctg Leu tta Leu 15 gtg Val 48 ctg Leu ??9a ate lie ctg Leu 20 aac Asn aag gtg gca Lys Val Ala ccg pro 25 cag geg Gin Ala tgc cys ccg Pro geg cag Ala Gin 30 tgc cys 96 tct Ser tgc cys teg Ser 35 ggc Gly age Ser aca Thr gac Asp 40 tgt Cys cac His ggg Gly ctg Leu geg Ala 45 ctg Leu cgc Arg age Ser 144 gtg val ccc Pro 50 agg Arg aat Asn ate lie ccc Pro cgc Arg 55 aac Asn acc Thr gag Glu aga Arg ctg Leu 60 gat Asp tta Leu aat Asn gga Gly 192 aat Asn 65 aac Asn ate lie aca Thr aga Arg att lie 70 aeg Thr aag Lys aca Thr gat Asp ttt Phe 75 ett Leu aga Arg cat His 80 240 eta Leu aga Arg S ett Leu cag Gin 85 ett Leu atg Met gag Glu aat Asn aag Lys 90 att lie age ser acc Thr att lie gaa Glu 95 aga Arg 288 gga gca Gly Ala ttc Phe cag Gin 100 gat Asp ett Leu aaa Lys gaa Glu eta Leu 105 gag Glu aga Arg ctg cgt Leu Arg tta Leu 110 aac aga Asn Arg 336 aat Asn cac His ett Leu 115 cag Gin ctg Leu ttt Phe cct Pro gag Glu 120 ttg Leu ctg Leu ttt Phe ett Leu ggg Gly 125 act Thr aag Lys 384 eta tac Leu Tyr 130 agg Arg ett Leu gat Asp etc Leu agt Ser 135 gaa Glu aac Asn caa Gin att lie cag Gin 140 gca Ala ate lie cca agg Pro Arg 432 aaa Lys 145 9« Ala ttc Phe cgt Arg ggg Gly gca gtt Ala Val 150 gac Asp ata lie aaa Lys aat Asn 155 ttg Leu caa ctg gat tac Gin Leu Asp Tyr 160 480 aac Asn cag Gin ate lie age tgt ser Cys 165 att lie gaa gat ggg gca Glu Asp Gly Ala 170 ttc Phe agg get Arg Ala etc Leu egg Arg 175 gac Asp 528 ctg Leu gaa gtg Glu val etc Leu 180 act Thr etc Leu aac Asn aat Asn aac Asn 185 aac Asn att act aga lie Thr Arg ett Leu 190 tct Ser gtg val 576 gca Ala agt ser ttc Phe 195 aac Asn cat His atg Met cct Pro aaa Lys 200 ett agg Leu Arg act Thr ttt ega ctg Phe Arg Leu 205 cat His tea ser 624 aac Asn aac Asn 210 ctg Leu tat Tyr tgt gac tgc Cys Asp cys 215 cac His ctg gcc tgg Leu Ala Trp etc Leu 220 tcc gac tgg ser Asp Trp ett Leu 672 cgc Arg 225 caa Gin agg Arg cct Pro egg Arg 9« val 230 ggt Gly ctg Leu tac act Tyr Thr cag Gin 235 tgt cys atg Met ggc Gly ccc Pro tcc ser 240 720 cac His ctg Leu aga Arg ggc Gly cat His 245 aat Asn gta val Ala gag Glu val 250 caa Gin aaa Lys ega Arg gaa Glu ttt Phe 255 猎 768 tgc cys agt Ser ggt Gly cac His cag Gin tea Ser ttt Phe atg Met ir, cct Pro tct ser tgt Cys agt Ser ttg Leu cac His 816 260 265 270 -24· 154995-序列表.doc 201142024 tgc cys cct pro gee Ala 275 gee tgt Ala cys acc Thr tgt age cys ser 280 aac Asn aat Asn ate lie gta Val gac tgt cgt Asp cys Arg 285 ggg Gly 864 aaa Lys ggt Gly 290 etc Leu act Thr gag Glu ate lie ccc Pro 295 aca Thr aat Asn ett Leu cca pro gag Glu 300 acc Thr ate aca lie Thr gaa Glu 912 ata lie 305 cgt Arg ttg Leu gaa Glu cag Gin aac Asn 310 aca Thr ate lie aaa Lys ate lie 315 cct Pro cct Pro gga Gly ttc Phe 320 960 tea Ser cca Pro tat Tyr aaa Lys aag Lys 325 ett aga ega Leu Arg Arg att gac lie Asp 330 ctg Leu age Ser aat Asn aat Asn cag Gin 335 ate lie 1008 tet Ser gaa Glu ett Leu gca Ala 340 cca gat Pro Asp ttc Phe caa Gin 345 gga Gly eta ege Leu Arg tet Ser ctg Leu 350 aat Asn tea ser 1056 ett Leu etc Leu 355 tat Tyr gga Gly aat Asn aaa Lys ate lie 360 aca gaa Thr Glu etc Leu ccc Pro aaa Lys 365 agt tta Ser Leu ttt phe 1104 gaa Glu gga Gly 370 ctg Leu ttt Phe tee Ser tta cag Leu Gin 375 etc Leu eta Leu tta Leu ttg Leu aat Asn 380 婼 aac Asn aag Lys ata lie 1152 aac Asn 385 tgc cys ett Leu egg Arg gta Val gat Asp 390 ttt Phe cag gat Gin Asp etc Leu 395 cac His aac Asn ttg Leu aac Asn ett Leu 400 1200 etc Leu tee ser eta Leu tat Tyr gac aac Asp Asn 405 aag Lys ett Leu cag Gin acc Thr 410 ate lie gee Ala aag Lys ggg Gly acc Thr 415 ttt Phe 1248 tea Ser cct Pro ett Leu egg Arg 420 gee Ala att lie caa act Gin Thr atg Met 425 cat His ttg Leu gee cag Ala Gin aac Asn 430 ccc Pro ttt Phe 1296 att lie tgt cys gac Asp 4B5 tgc Cys cat His etc Leu aag tgg Lys Trp 440 eta Leu geg Ala gat tat Asp Tyr etc Leu 445 cat His acc Thr aac Asn 1344 ccg Pro att lie 450 gag Glu acc Thr agt ser ggt Gly ISl 455 cgt Arg tgc cys acc Thr age Ser ccc Pro 460 ege Arg ege Arg ctg Leu lit 1392 aac Asn 465 aaa aga Lys Arg att lie gga cag Gly Gin 470 ate lie aaa Lys age ser aag Lys aaa Lys 475 ttc cgt Phe Arg tgt tea Cys Ser K 480 1440 aaa Lys gaa cag Glu Gin tat Tyr ttc Phe 485 att lie cca Pro ggt Gly aca Thr gaa Glu 490 gat tat ega Asp Tyr Arg tea Ser aaa Lys 495 tta Leu 1488 agt ser gga gac Gly Asp tgc Cys 500 ttt Phe geg Ala gat ctg Asp Leu 505 tgc cys cct Pro gaa Glu aag Lys tgt cys 510 ege Arg tgt cys 1536 gaa Glu gga Gly acc Thr 515 aca gta gat tgc tet Thr val Asp Cys ser 520 aat caa Asn Gin aag Lys etc Leu aac Asn 525 aaa Lys ate lie ccg Pro 1584 gag Glu cac His 530 att lie ccc Pro cag tac act gca Gin Tyr Thr Ala 535 if9U ttg cgt Leu Arg etc Leu 540 aat Asn aat Asn aat Asn gaa Glu 1632 -25- 154995·序列表.doc 201142024 ttt Phe 545 acc Thr ttg Leu gaa Glu Qcc Ala 550 aca Thr gga Gly ate lie ttt Phe aag Lys 555 aaa Lys ett Leu cct Pro caa Gin tta Leu 560 1680 cgt Arg aaa Lys ata lie aac Asn ttt Phe 565 age Ser aac Asn aat Asn aag Lys ate lie 570 aca gat Thr Asp att lie gag gag gaa Glu Glu Gly 575 1728 gca Ala ttt Phe gaa gga Glu Gly 580 gca Ala tct ser ggt Gly gta Val aat Asn 585 gaa Glu ata lie ett Leu ett Leu aeg Thr 590 agt Ser aat Asn 1776 cgt Arg ttg Leu gaa Glu 595 aat Asn 說 cat His aag Lys 600 atg Met ttc Phe aag Lys gga Gly ttg Leu 60S gaa Glu age ser etc Leu 1824 aaa Lys act Thr 610 ttg Leu atg Met ttg Leu aga Arg age ser 615 aat Asn ega Arg ata lie acc Thr tgt cys 620 gtg ggg val Gly aat Asn gac Asp 1872 agt Ser 625 ttc Phe ata lie gga Gly etc Leu agt ser 630 tct ser gtg val cgt Arg ttg Leu ett Leu 635 tct ser ttg tat Leu Tyr gat aat Asp Asn 640 1920 caa Gin att lie act Thr aca Thr gtt Val 645 gca Ala cca Pro ttt Phe 650 gat act Asp Thr etc Leu cat His tct Ser 655 tta Leu 1968 tct Ser act Thr eta Leu aac Asn 660 etc Leu ttg Leu 9« Ala aat Asn cct Pro 665 ttt Phe aac Asn tgt aac tgc Cys Asn cys 670 tac Tyr ctg Leu 2016 tgg Trp ttg Leu 675 gga Gly gag Glu tgg Trp ctg Leu aga Arg 680 aag Lys aag Lys aga Arg att gtc lie val 685 aeg Thr gga Gly aat Asn 2064 cct Pro aga Arg 690 tgt Cys caa Gin aaa Lys cca Pro tac Tyr 695 ttc Phe ctg Leu aaa Lys gaa Glu ata lie 700 ccc Pro ate lie cag Gin gat Asp 2112 gtg gcc vaT Ala 705 att lie cag Gin gac Asp ttc Phe 710 act Thr tgt cys gat gac gaa aat gat gac Asp Asp Gly Asn Asp Asp 715 aat Asn agt ser 720 2160 tgc Cys tcc Ser cca Pro ett Leu tct ser 725 ege Arg tgt cys cct Pro act Thr gaa Glu 730 tgt cys act tgc Thr Cys ttg gat Leu Asp 735 aca Thr 2208 gtc Val ega Arg tgt Cys 740 age Ser aac Asn aag Lys ggt Gly ttg Leu 745 aag Lys 沿 ttg Leu ccg Pro aaa Lys 750 ggt Gly att lie 2256 cca Pro aga Arg gat Asp 755 沿 aca Thr gag Glu ttg Leu tat Tyr 760 ctg gat Leu Asp gga Gly aac Asn caa Gin 765 ttt Phe aca Thr ctg Leu 2304 9« Val ccc Pro 770 aag Lys gaa Glu etc Leu tcc ser aac Asn 775 tac Tyr aaa Lys cat His tta Leu aca Thr 780 ett Leu ata gac lie Asp tta Leu 2352 agt Ser 785 aac Asn aac aga Asn Arg ata lie age Ser 790 aeg Thr ett Leu tct Ser aat Asn cag Gin 795 age ser ttc Phe age ser aac Asn atg Met 800 2400 acc Thr cag Gin etc Leu etc Leu acc Thr 805 tta Leu att lie ett Leu agt tac aac cgt ser Tyr Asn Arg 810 ctg aga tgt Leu Arg Cys 815 att lie 2448 26- 154995·序列表.doc gta ggt gaa Val Gly Glu 1070 cac tgc gac ate His cys Asp lie 1075 201142024 cct cct ege acc ttt gat gga tta aag tct ctt ega tta ctt tct eta Pro Pro Arg Thr Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu 820 825 830 cat His gga Gly aat Asn gac Asp att lie tct Ser gtt gtg Val val cct Pro gaa Glu ggt Gly get Ala ttc Phe aat Asn gat Asp ctt Leu 835 840 845 tct Ser gca Ala tta Leu tea Ser cat His eta Leu gca Ala att lie gga Gly aac Asn cct Pro ctt Leu tac Tyr tgt Cys gat Asp 850 855 860 tgt aac atg cag tgg tta tcc gac tgg gtg aag teg gaa tat aag gag cys Asn Met Gin Trp Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu 865 870 875 880 cct gga att get cgt tgt get ggt cct gga gaa atg gca gat aaa ctt Pro Gly lie Ala Arg cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu 885 890 895 tta etc aca act ccc tcc aaa aaa ttt acc tgt caa ggt cct gtg gat Leu Leu Thr Thr Pro ser Lys Lys Phe Thr cys Gin Gly Pro vaT Asp 900 905 910 gtc aat att eta get aag tgt aac ccc tgc eta tea aat ccg tgt aaa val Asn lie Leu Ala Lys cys Asn Pro cys Leu Ser Asn Pro cys Lys 915 920 925 aat gat ggc aca tgt aat agt gat cca gtt gac ttt tac ega tgc acc Asn Asp Gly Thr Cys Asn Ser Asp Pro val Asp Phe Tyr Arg cys Thr 930 935 940 tgt cca tat ggt ttc aag ggg cag gac tgt gat gtc cca att cat gcc cys Pro Tyr GTy Phe Lys Gly Gin Asp cys Asp val Pro lie His Ala 945 950 955 960 tgc ate agt aac cca tgt aaa cat gga gga act tgc cac tta aag gaa cys lie Ser Asn Pro cys Lys His Gly Gly Thr Cys His Leu Lys Glu 965 970 975 gga Gly gaa Glu gaa Glu gat Asp gga Gly ttc Phe tgg Trp tgt cys att lie tgt cys gat Asp gga Gly ttt Phe gaa Glu gga Gly 980 985 990 gaa aat tgt gaa gtc aac gtt gat gat tgt gaa gat aat gac tgt gaa Glu Asn Cys Glu Val Asn Val Asp Asp cys Glu Asp Asn Asp cys Glu 995 1000 1005 aat aat tct aca tgt gtc gat gac att aat aac tac aca tgc ctt Asn Asn ser Thr cys val Asp Gly lie Asn Asn Tyr Thr cys Leu 1010 1015 1020 tgc cca cct gag tat aca ggt gag ttg tgt gag gag aag ctg gac
Cys Pro Pro Glu Tyr Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp 1025 1030 1035 ttc tgt gcc cag gac ctg aac ccc tgc cag cac gat tea aag tgc
Phe Cys Ala Gin Asp Leu Asn Pro Cys Gin His Asp Ser Lys Cys 1040 1045 1050 ate eta act cca aag gga ttc aaa tgt gac tgc aca cca ggg tac lie Leu Thr Pro Lys Gly Phe Lys Cys Asp Cys Thr Pro Gly Tyr 1055 1060 1065 gat ttt gac gac tgc caa gac aac Asp Phe Asp Asp cys Gin Asp Asn 1080 154995·序列表.doc -27· 2496 2544 2592 2640 2688 2736 2784 2832 2880 2928 2976 3024 3069 3114 3159 3204 3249 201142024 aag tgt aaa aac gga gcc cac tgc aca gat gca gtg aac ggc tat
Lys Cys Lys Asn Gly Ala His Cys Thr Asp Ala val Asn Gly Tyr 1085 1090 1095 acg tgc ata tgc ccc gaa ggt tac agt ggc ttg ttc tgt gag ttt
Thr cys lie Cys Pro Glu Gly Tyr Ser Gly Leu Phe Cys Glu Phe 1100 1105 1110 tct cca ccc atg gtc etc cct cgt age get cat cac cat cat cat ser Pro Pro Met val Leu Pro Arg ser Ala His His His His His 1115 1120 1125 cac tga His <210> 16 <2U> 1129 <212> PRT <213> 智人 <400> 16
Met Arg Gly val Gly Trp Gin Met Leu ser Leu ser Leu Gly Leu val 1 5 10 15
Leu Ala lie Leu Asn Lys Val Ala Pro Gin Ala cys Pro Ala Gin Cys 20 25 30 ser Cys ser Gly ser Thr val Asp Cys His Gly Leu Ala Leu Arg Ser 35 40 45
Val Pro Arg Asn lie Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly 50 55 60
Asn Asn lie Thr Arg lie Thr Lys Thr Asp Phe Ala Gly Leu Arg His 65 70 75 80
Leu Arg val Leu Gin Leu Met Glu Asn Lys lie ser Thr lie Glu Arg 85 90 95
Gly Ala Phe Gin Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Ara 100 105 110
Asn His Leu Gin Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys 115 120 125
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gin lie Gin Ala lie Pro Arg 130 135 140 y
Lys Ala Phe Arg Gly Ala val Asp lie Lys Asn Leu Gin Leu Asp Tyr 145 150 155 160
Asn Gin lie ser Cys lie Glu Asp Gly Ala Phe Arg Ala Leu Arg Asd 165 170 175 28· 3294 3339 3384 3390
154995·序列表.d0C 201142024
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn lie Thr Arg Leu Ser val 180 185 190
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser 195 200 205
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu 210 215 220
Arg Gin Arg Pro Arg val Gly Leu Tyr Thr Gin Cys Met Gly Pro Ser 225 230 235 240
His Leu Arg Gly His Asn val Ala Glu val Gin Lys Arg Glu Phe val 245 250 255
Cys Ser Gly His Gin Ser Phe Met Ala Pro ser cys ser val Leu His 260 265 270
Cys Pro Ala Ala cys Thr Cys Ser Asn Asn lie val Asp cys Arg Gly 275 280 285
Lys Gly Leu Thr Glu lie Pro Thr Asn Leu Pro Glu Thr lie Thr Glu 290 295 300 lie Arg Leu Glu Gin Asn Thr lie Lys Val lie Pro Pro Gly Ala Phe 305 310 315 320
Ser Pro Tyr Lys Lys Leu Arg Arg He Asp Leu ser Asn Asn Gin lie 325 330 335
Ser Glu Leu Ala Pro Asp Ala Phe Gin Gly Leu Arg Ser Leu Asn Ser 340 B45 350
Leu Val Leu Tyr Gly Asn Lys lie Thr Glu Leu Pro Lys Ser Leu Phe 355 360 B65
Glu Gly Leu Phe Ser Leu Gin Leu Leu Leu Leu Asn Ala Asn Lys lie 370 375 380
Asn Cys Leu Arg Val Asp Ala Phe Gin Asp Leu His Asn Leu Asn Leu 385 390 395 400
Leu Ser Leu Tyr Asp Asn Lys Leu Gin Thr lie Ala Lys Gly Thr Phe 405 410 415
Ser Pro Leu Arg Ala lie Gin Thr Met His Leu Ala Gin Asn Pro Phe 420 425 430 lie Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn 435 440 445 -29- 154995-序列表.doc 201142024
Pro lie Glu Thr Ser Gly Ala Arg Cys Thr ser Pro Arg Arg Leu Ala 450 455 460
Asn Lys Arg lie Gly Gin lie Lys ser Lys Lys Phe Arg Cys Ser Ala 465 470 475 480
Lys Glu Gin Tyr Phe lie Pro Gly Thr Glu Asp Tyr Arg Ser Lys Leu 485 490 495 ser Gly Asp Cys Phe Ala Asp Leu Ala Cys Pro Glu Lys cys Arg Cys 500 505 510
Glu Gly Thr Thr Val Asp cys Ser Asn Gin Lys Leu Asn Lys lie Pro 515 520 525
Glu His lie Pro Gin Tyr Thr Ala Glu Leu Arg Leu Asn Asn Asn Glu 5B0 535 540
Phe Thr val Leu Glu Ala Thr Gly He Phe Lys Lys Leu Pro Gin Leu 545 550 555 560
Arg Lys lie Asn Phe ser Asn Asn Lys lie Thr Asp lie Glu Glu Gly 565 570 575
Ala Phe Glu Gly Ala ser Gly val Asn Glu lie Leu Leu Thr ser Asn 580 585 590
Arg Leu Glu Asn Val Gin His Lys Met Phe Lys Gly Leu Glu Ser Leu 595 600 605
Lys Thr Leu Met Leu Arg Ser Asn Arg lie Thr Cys Val Gly Asn Asp 610 615 620
Ser Phe lie Gly Leu ser ser Val Arg Leu Leu Ser Leu Tyr Asp Asn 625 630 635 640
Gin lie Thr Thr val Ala Pro Gly Ala Phe Asp Thr Leu His Ser Leu 645 650 6S5 ser Thr Leu Asn Leu Leu Ala Asn Pro Phe Asn Cys Asn cys Tyr Leu 660 665 670
Ala Trp Leu Gly Glu Trp Leu Arg Lys Lys Arg lie val Thr Gly Asn 675 680 685
Pro Arq Cys Gin Lys Pro Tyr Phe Leu Lys Glu lie Pro lie Gin Asp 690 695 700
Val Ala lie Gin Asp Phe Thr Cys Asp Asp Gly Asn Asp Asp Asn Ser 70S 710 715 720 •30· 154995·序列表.doc 201142024 cys ser Pro Leu Ser Arg Cys Pro Thr Cys Thr Cys Leu Asp Thr val val Arg cys Sen Asn Lys cly ,eu Lys Val Leu Pro Lys Gly He
Pro Arg Asp val Thr Glu Leu Leu Asp Gly Asn Gin Phe Thr Leu val Pro Lys Clu Leu Ser Asn Tyr Lys His Leu Thr Leu He Asp Leu
Ser Asn Asn Arg lie Ser Thr Leu ser Asn Gin ser Phe ser Asn Met 785 790 795 800
Thr Gin Leu Leu Thr Leu lie Leu ser Tyr Asn Arg Leu Arg cys lie 80S 810 815
Pro Pro Arg Thr Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu ser Leu 820 825 830
His Gly Asn Asp lie Ser Val Val Pro Glu Gly Ala Phe Asn Asp Leu 835 840 845 ser Ala Leu Ser His Leu Ala lie Gly Ala Asn Pro Leu Tyr Cys Asp 850 855 860 cys Asn Met Gin Trp Leu Ser Asp Trp val Lys ser Glu Tyr Lys Glu 865 870 875 880
Pro Gly lie Ala Arg Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu 885 890 895
Leu Leu Thr Thr Pro Ser Lys Lys Phe Thr Cys Gin Gly Pro val Asp 900 90S 910
Val Asn lie Leu Ala Lys cys Asn Pro cys Leu ser Asn Pro cys Lys 915 920 925
Asn Asp Gly Thr Cys Asn ser Asp Pro val Asp Phe Tyr Arg cys Thr 930 935 940
Cys Pro Tyr Gly Phe Lys Gly Gin Asp cys Asp Val Pro lie His Ala 945 950 955 960
Cys lie Ser Asn Pro cys Lys His Gly Gly Thr cys His Leu Lys Glu 965 970 975
Gly Glu Glu Asp Gly Phe Trp cys lie cys Ala Asp Gly Phe Glu Gly 980 985 990 -31· 154995-序列表.doc 201142024
Glu Asn Cys Glu Val Asn Val Asp Asp cys Glu Asp Asn Asp Cys Glu 995 1000 1005
Asn Asn Ser Thr Cys val Asp Gly lie Asn Asn Tyr Thr cys Leu 1010 1015 1020
Cys Pro Pro Glu Tyr Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp 1025 1030 1035
Phe Cys Ala Gin Asp Leu Asn Pro Cys Gin His Asp Ser Lys Cys 1040 1045 1050 lie Leu Thr Pro Lys Gly Phe Lys Cys Asp Cys Thr Pro Gly Tyr 1055 1060 1065
Val Gly Glu His Cys Asp lie Asp Phe Asp Asp Cys Gin Asp Asn 1070 1075 1080
Lys Cys Lys Asn Gly Ala His cys Thr Asp Ala Val Asn Gly Tyr 1085 1090 1095
Thr Cys lie Cys Pro Glu Gly Tyr Ser Gly Leu Phe Cys Glu Phe 1100 1105 1110
Ser Pro Pro Met val Leu Pro Arg ser Ala His His His His His 1115 1120 1125
His <210> 17 <211> 717 <212> DNA <21B> 小家鼠 <220> <221> CDS <222> ⑴"（717〕 <400> 17 atg tac a卯 atg caa etc ctg tet tgc att gca eta agt ett gca ett 48 Met Tyr Arg Met Gin Leu Leu Ser cys lie Ala Leu ser Leu Ala Leu 1 5 10 15 gtc aeg aat tea ttg cac tgc cct gec gcc tgt acc tgt age aac aat 96 Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr cys ser Asn Asn 20 25 30 ate lie gta val gac Asp 35 tgt cys cgt Arg QQ9 Gly aaa Lys ggt Gly 40 etc Leu act Thr gag Glu ate lie ccc Pro 45 aca Thr aat Asn ett Leu 144 cca Pro gag Glu acc Thr ate lie aca Thr gaa Glu ata lie cgt Arg ttg Leu gaa cag Glu Gin aac Asn age ser ate lie aga gtc Arg val 192 50 55 60 32- 154995·序列表.doc 240 201142024 ate cct cct gga get ttc tea cca tat aaa aag ett aga ega ctg gac lie Pro Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Leu Asp 65 70 75 80 ctg age aat aat cag ate tet gaa ett gca cca gat get ttc caa gga
Leu ser Asn Asn Gin lie Ser Glu Leu Ala Pro Asp Ala Phe Gin Gly 85 90 95 eta ege tet ctg aat tea ett gtc etc tat gga aat aaa ate aca gaa
Leu Arg ser Leu Asn ser Leu val Leu Tyr Gly Asn Lys lie Thr Glu 100 105 110 etc ccc aaa agt tta ttt gaa gga ctg ttt tee tta cag etc eta tta
Leu pro Lys Ser Leu Phe Glu Gly Leu Phe ser Leu Gin Leu Leu Leu 115 120 125 ttg aat gee aac aag ata aac tgc ett egg gta gat get ttt cag gat
Leu Asn Ala Asn Lys lie Asn Cys Leu Arg val Asp Ala Phe Gin Asp 130 135 140 etc cac aac ttg aac ett etc tee eta tat gac aac aag ett cag acc
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gin Thr 145 150 155 160 gtc gee aag ggg acc ttt tea get ett egg gee att caa act atg cat val Ala Lys Gly Thr Phe ser Ala Leu Arg Ala lie Gin Thr Met His 165 170 175 ttg gee cag aac ccc ttt att tgt gac tgc cat etc aag tgg eta geg
Leu Ala Gin Asn pro Phe lie Cys Asp Cys His Leu Lys Trp Leu Ala 180 185 190 gat tat etc cat acc aac ccg att gag acc agt ggt gee cgt tgc acc
Asp Tyr Leu His Thr Asn Pro lie Glu Thr Ser Gly Ala Arg cys Thr 195 200 205 age ccc ege ege ctg gca aac aaa aga att gaa cag ate aaa age aag
Ser Pro Arg Arg Leu Ala Asn Lys Arg lie Gly Gin lie Lys Ser Lys 210 215 220 aaa ttc cgt tgt tea ggt age get cat cac cat cat cat cac tga
Lys Phe Arg Cys Ser Gly Ser Ala His His His His His His 225 230 235 <210> 18 <211> 238 <212> PRT <213>小家鼠 <400> 18
Met Tyr Arg Met Gin Leu Leu Ser Cys lie Ala Leu Ser Leu Ala Leu 15 10 15 val Thr Asn ser Leu His cys Pro Ala Ala cys Thr Cys ser Asn Asn 20 25 30 lie Val Asp Cys Arg Gly Lys Gly Leu Thr Glu lie Pro Thr Asn Leu 35 40 45
Pro Glu Thr lie Thr Glu lie Arg Leu Glu Gin Asn Ser lie Arg Val 50 55 60 154995·序列表.doc -33· 288 336 384 432 480 528 576 624 672 717 201142024 lie Pro Pro Gly Ala Phe Ser 65 70
Leu Ser Asn Asn Gin lie Ser 85
Leu Arg ser Leu Asn Ser Leu 100
Leu Pro Lys ser Leu Phe Glu 115
Leu Asn Ala Asn Lys lie Asn 130 135
Leu His Asn Leu Asn Leu Leu 145 150
Val Ala Lys Gly Thr Phe ser 165
Leu Ala Gin Asn Pro Phe lie 180
Asp Tyr Leu His Thr Asn Pro 195
Ser Pro Arg Arg Leu Ala Asn 210 215
Lys Phe Arg Cys Ser Gly ser 225 230 <210> 19 <2U> 726 <212> DNA <213>智人 <220> <221> CDS <222> (1)..(726) <400> 19 atg tac agg atg caa etc ctg Met Tyr Arg Met Gin Leu Leu gtc aeg aat tea ctg tcc tcc Val Thr Asn Ser Leu Ser ser 20 age aat gac ate gtg gac tgt Ser Asn Gly lie val Asp cys 35 gcc aac ctg ccc gag acc atg 154995-序列表.doc
Tyr Lys Lys Leu Arg Arg Leu Asp 75 80 Leu Ala Pro Asp Ala Phe Gin Gly 90 95 Leu Tyr Gly Asn Lys lie Thr Glu 105 110 Leu Phe Ser Leu Gin Leu Leu Leu 125 Leu Arg Val Asp Ala Phe Gin Asp 140 Leu Tyr Asp Asn Lys Leu Gin Thr 155 160 Leu Arg Ala lie Gin Thr Met His 170 175 Asp Cys His Leu Lys Trp Leu Ala 185 190 Glu Thr ser Gly Ala Arg cys Thr 205 Arg lie Gly Gin lie Lys Ser Lys 220 His His His His His His 235 tgc att gca eta agt ett gca ett 48 cys lie Ala Leu Ser Leu Ala Leu 10 15 tcc tgc ccg gcc atg tgc acc tgc 96 Ser Cys Pro Ala Met Cys Thr cys 25 30 gga Gly aaa Lys ggc Gly etc Leu act Thr 婼 ate lie ccg Pro 144 45 gag ata ege ctg gag ctg aac ggc 192 34- 240 201142024
Ala Asn Leu Pro Glu Thr Met Thr 50 55 ate aag tee ate cct cct gga gee lie Lys Ser He Pro Pro Gly Ala 65 70 agg ata gac ctg age aac aat cag Arg lie Asp Leu Ser Asn Asn Gin 85 ttc cag ggc etc ege tee ctg aac Phe Gin Gly Leu 100 Arg Ser Leu Asn ate lie aca Thr gac Asp etc Leu ccc Pro cgt Arg ggt Gly gtg val 115 120 etc ctg etc ctg aat gee aac aag Leu Leu Leu Leu Asn Ala Asn Lys 130 135 ttc cag gac ctg cag aac etc tea Phe Gin Asp Leu Gin Asn Leu Ser 145 150 ate cag age etc gee aag ggc act lie Gin ser Leu Ala Lys Gly Thr 165 act ctg cac ctg gee cag aac cct Thr Leu His Leu Ala Gin Asn Pro 180 tgg ctg gca gac ttc ctg ege acc Trp Leu Ala Asp Phe Leu Arg Thr 195 200 ege tgt gee agt ccc egg ege etc Arg cys Ala Ser Pro Arg Arg Leu 210 215 aag age aag aag ttc egg tgc tea Lys ser Lys Lys Phe Arg cys Ser 225 230 cac tga His
Glu lie Arg Leu Glu Leu Asn Gly 60 ttc tea ccc tac aga aag eta egg
Phe Ser Pro Tyr Arg Lys Leu Arg 75 80 ate get gag att gca ccc gac gee lie Ala Glu lie Ala Pro Asp Ala 90 95 teg ctg gtc etc tat gga aac aag
Ser Leu Val Leu Tyr Gly Asn Lys 105 110 ttt gga ggc eta tac acc eta cag
Phe Gly Gly Leu Tyr Thr Leu Gin 125 ate aac tgc ate egg ccc gat gee lie Asn cys lie Arg Pro Asp Ala 140 ctg etc tee ctg tat gac aac aag
Leu Leu ser Leu Tyr Asp Asn Lys 155 160 ttc acc tee ctg egg gee ate cag
Phe Thr Ser Leu Arg Ala lie Gin 170 175 ttc att tgc gac tgt aac etc aag
Phe lie Cys Asp cys Asn Leu Lys 185 190 aat ccc ate gag aeg agt ggt gee
Asn Pro lie Glu Thr ser Gly Ala 205 gee aac aag ege ate ggg cag ate
Ala Asn Lys Arg lie Gly Gin lie 220 ggt age get cat cac cat cat cat
Gly Ser Ala His His His His His 235 240 288 336 384 432 480 528 576 624 672 720 726 <210> 20 <211> 241 <212> PRT <213> 智人 <400> 20
Met Tyr Arg Met Gin Leu Leu Ser cys lie Ala Leu Ser Leu Ala Leu 1 5 10 15
Val Thr Asn ser Leu ser Ser Gly ser cys Pro Ala Met Cys Thr cys 20 25 30
Ser Asn Gly lie Val Asp cys Arg Gly Lys Gly Leu Thr Ala lie Pro 35- 154995-序列表.doe 201142024 35 40 45
Ala Asn Leu Pro Glu Thr Met Thr Glu lie Arg Leu Glu Leu Asn Glv 50 55 60 lie Lys Ser lie Pro Pro Gly Ala Phe Ser Pro Tyr Arg Lys Leu Ara 65 70 75 80
Arg lie Asp Leu Ser Asn Asn Gin lie Ala Glu lie Ala Pro Asp Ala 85 90 95
Phe Gin Gly Leu Arg Ser Leu Asn Ser Leu val Leu Tyr Gly Asn Lvs 100 105 no lie Thr Asp Leu Pro Arg Gly val Phe Gly Gly Leu Tyr Thr Leu Gin 115 120 125
Leu Leu Leu Leu Asn Ala Asn Lys lie Asn cys lie Arg Pro Asp Ala 130 135 140
Phe Gin Asp Leu Gin Asn Leu Ser Leu Leu ser Leu Tyr Asp Asn Lys 145 150 155 160 lie Gin Ser Leu Ala Lys Gly Thr Phe Thr ser Leu Arg Ala lie Gin 165 170 175
Thr Leu His Leu Ala Gin Asn Pro Phe lie cys Asp cys Asn Leu Lys 180 185 190
Trp Leu Ala Asp Phe Leu Arg Thr Asn Pro lie Glu Thr ser Gly Ala 195 200 205
Arg Cys Ala Ser Pro Arg Arg Leu Ala Asn Lys Arg lie Gly Gin lie 210 215 220
Lys ser Lys Lys Phe Arg cys ser Gly ser Ala His His His His His 225 230 235 240
His <210> 21 <211> 726 <212> DNA <213> 智人 <220> <221> CDS <222> (1)..(726) <400> 21 atg tac agg atg caa etc ctg tet tgc att gca eta agt ett gca ett Met Tyr Arg Met Gin Leu Leu ser Cys lie Ala Leu ser Leu Ala Leu •36· 154995-序列表.doc 201142024 1 5 10 15 9tc aeg aat tea gee aac tee ate tee tgc cct teg ccc tgc aeg tgc 96 val Thr Asn Ser Ala Asn Ser lie Ser Cys Pro ser Pro Cys Thr Cys 20 25 30 age aat aac ate gtg gac tgt ega gga aag ggc ttg atg gag att cct 144 Ser Asn Asn lie Val Asp Cys Arg Gly Lys Gly Leu Met Glu lie Pro 35 40 45 gee aac ttg ccg gag ggc ate gtc gaa ata ege eta gaa cag aac tee 192 Ala Asn Leu Pro Glu Gly lie Val Glu lie Arg Leu Glu Gin Asn ser 50 55 60 ate aaa gee ate cct gca gga gee ttc acc cag tac aag aaa ctg aag 240 He Lys Ala lie Pro Ala Gly Ala Phe Thr Gin Tyr Lys Lys Leu Lys 65 70 75 80 ega ata gac ate age aag aat cag ata teg gat att get cca gat gee 288 Arg lie Asp lie Ser Lys Asn Gin lie Ser Asp lie Ala Pro Asp Ala 85 90 95 ttc cag ggc ctg aaa tea etc aca teg ctg gtc ctg tat ggg aac aag 336 Phe Gin Gly Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys 100 105 110 ate acc gag att gee aag gga ctg ttt gat ggg ctg gtg tee eta cag 384 lie Thr Glu lie Ala Lys Gly Leu Phe Asp Gly Leu val ser Leu Gin 115 120 125 ctg etc etc etc aat gee aac aag ate aac tgc ctg egg gtg aac aeg 432 Leu Leu Leu Leu Asn Ala Asn Lys lie Asn cys Leu Arg val Asn Thr 130 135 140 ttt cag gac ctg cag aac etc aac ttg etc tee ctg tat gac aac aag 480 Phe Gin Asp Leu Gin Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys 145 ISO 155 160 ctg cag acc ate age aag ggg etc ttc gee cct ctg cag tee ate cag 528 Leu Gin Thr lie Ser Lys Gly Leu Phe Ala Pro Leu Gin Ser lie Gin 165 170 175 aca Thr etc Leu cac His tta Leu Ala caa Gin aac Asn cca Pro ttt Phe gtg val tgc Cys gac Asp tgc Cys cac His ttg Leu aag Lys 576 180 185 190 tgg ctg gee gac tac etc cag gac aac ccc ate gag aca age ggg gee 624 Trp Leu Ala Asp Tyr Leu Gin Asp Asn Pro He Glu Thr Ser Gly Ala 195 200 205 ege tgc age age ccg ege ega etc gee aac aag ege ate age cag ate 672 Arg cys Ser Ser Pro Arg Arg Leu Ala Asn Lys Arg lie Ser Gin lie 210 215 220 aag age aag aag ttc egg tgc tea ggt age get cat cac cat cat cat 720 Lys Ser Lys Lys Phe Arg Cys Ser Gly Ser Ala His His His His His 225 230 235 240 cac tga 726 <210> 22 <211> 241 <212> PRT <213> 智人 154995·序列表.doc - 37 - 201142024 <400> 22
Met Tyr Arg Met Gin Leu Leu Ser cys lie Ala Leu ser Leu Ala Leu IS 10 15 val Thr Asn Ser Ala Asn Ser lie ser cys Pro Ser Pro Cvs Thr Cvs 20 25 30 ser Asn Asn lie Val Asp Cys Arg Gly Lys Gly Leu Met Glu lie Pro 35 40 45
Ala Asn Leu Pro Glu Gly lie val Glu lie Arg Leu Glu Gin Asn Ser 50 55 60 lie Lys Ala lie Pro Ala Gly Ala Phe Thr Gin Tyr Lys Lys Leu Lys 65 70 75 80
Arg lie Asp lie Ser Lys Asn Gin lie Ser Asp lie Ala Pro Asp Ala 85 90 95
Phe Gin Gly Leu Lys Ser Leu Thr ser Leu Val Leu Tyr Gly Asn Lys 100 105 HO lie Thr 6lu lie Ala Lys Gly Leu Phe Asp Gly Leu val ser Leu Gin 115 120 125
Leu Leu Leu Leu Asn Ala Asn Lys lie Asn Cys Leu Arg Val Asn Thr 130 135 140
Phe Gin Asp Leu Gin Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys 145 150 155 160
Leu Gin Thr lie Ser Lys Gly Leu phe Ala Pro Leu Gin ser lie Gin 165 170 175
Thr Leu His Leu Ala Gin Asn Pro Phe val cys Asp cys His Leu Lys 180 185 190
Trp Leu Ala Asp Tyr Leu Gin Asp Asn Pro lie Glu Thr ser Gly Ala 195 200 205
Arg Cys Ser Ser Pro Arg Arg Leu Ala Asn Lys Arg lie Ser Gin lie 210 215 220
Lys Ser Lys Lys Phe Arg cys Ser Gly Ser Ala His His His His His 225 230 235 240
His <210> 23 <211> 1362 38- 154995·序列表.doc 201142024 <212> DNA <213>智人 <220> <221> CDS <222> (1)..(1362) <400> 23 atg tac agg Met Tyr Arg 1 atg Met caa Gin 5 etc Leu ctg Leu tet Ser tgc cys att lie 10 gca Ala eta agt Leu Ser ctt Leu gca Ala 15 ctt Leu 48 fh? aat Asn tea Ser 20 ctt Leu cgt Arg cag gaa Gin Glu gat Asp 25 ttt Phe cca Pro cct Pro ege Arg att lie 30 sa gaa Glu 96 cac His cct Pro tea Ser 35 gac Asp ctg Leu att lie tea Ser 40 aaa Lys gga Gly gaa Glu cct Pro gca Ala 45 act Thr ttg Leu aac Asn 144 tgc cys aaa Lys 50 get gaa ggc ege Ala Glu Gly Arg ccc Pro 55 aca Thr ccc Pro act Thr att lie gaa Glu 60 tgg tac Trp Tyr aaa Lys ggg Gly 192 gga gag Gly Glu 65 aga Arg i?gu aca gac Thr Asp 70 aaa Lys gat gac Asp Asp cct ege Pro Arg 75 tea Ser cac His ega Arg atg Met 80 240 ttg Leu ctg Leu ccg Pro agt Ser gga Gly 85 tet Ser tta Leu ttt Phe ttc Phe tta Leu 90 cgt Arg ata lie cat His gga Gly 95 egg Arg 288 aaa Lys agt aga Ser Arg cct Pro 100 gat Asp gaa Glu gga Gly tat Tyr 105 tgt Cys gta gca val Ala agg Arg 110 aat tac Asn Tyr 336 ctt Leu iry gag get gtg Glu Ala val 115 age Ser cac His aat Asn 120 gca teg Ala ser ctg Leu gaa Glu gta val 125 ata lie ctt Leu 384 egg Arg gat gac Asp Asp 130 ttc Phe aga Arg caa Gin aac Asn 135 cct Pro teg gat ser Asp 猎 atg Met 140 gtt val ir, ss m 432 gag Glu 145 cct Pro gca Ala gta Val atg Met gaa Glu 150 tgc Cys caa Gin cct Pro cca Pro ega Arg 155 ggc Gly cat His cct Pro gag Glu ccc Pro 160 480 acc Thr att lie tea Ser tgg Trp aag Lys 165 aaa Lys gat Asp ggc Gly tet Ser cca Pro 170 ctg gat gat aaa Leu Asp Asp Lys gat Asp 175 gaa Glu 528 aga Arg ata act lie Thr ata lie 180 ega Arg gga Gly gga aag Gly Lys etc Leu 185 atg Met ate act tac acc cgt lie Thr Tyr Thr Arg 190 aaa Lys 576 agt Ser gac get ggc Asp Ala Gly 195 aaa Lys tat gtt Tyr val tgt cys 200 fa? m acc Thr aat Asn atg Met 205 gaa Glu 624 cgt Arg gag Glu 210 agt Ser gaa Glu gta gee gag Val Ala Glu 215 ctg Leu act Thr gtc tta gag Val Leu Glu 220 aga Arg cca Pro tea Ser ttt Phe 672 gtg gag VaT Glu 225 tee Ser aag Lys tac Tyr ggc Gly 230 cct Pro cct Pro tgc Cys cct Pro ccc Pro 235 Ss cct Pro cct Pro gag Glu 240 720 -39· 154995-序列表.doc 201142024 ttc Phe gag ggc gga Glu Gly Gly cct Pro 24S age Ser gtg val ttc Phe ctg Leu ttc Phe 250 cct Pro cct Pro aag Lys cct Pro aag Lys 255 gac Asp 768 acc Thr ctg Leu atg Met ate lie 260 tcc Ser egg Arg acc Thr cct Pro gag Glu 265 gtg Val acc tgt Thr Cys gtg gtg gtg val val val 270 gac Asp 816 39 tcc Ser cag gag Gin Glu 275 gac Asp cct Pro gag gtc cag Glu val Gin 280 ttc Phe aac Asn tgg tac gta Trp Tyr Val 285 gac ggc Asp Gly 864 gtg gag gtg Val Glu Val 290 cac His aac Asn aag Lys 295 acc Thr aag Lys cct egg Pro Arg gag gag cag Glu Glu Gin 300 ttc Phe aat Asn 912 tcc Ser 305 acc tac Thr Tyr egg Arg gtg gtg val val 310 tet ser gtg vaT ctg Leu acc Thr 315 ctg Leu cac His cag Gin gac Asp tgg Trp 320 960 ctg Leu aac Asn ggc Gly aaa Lys gaa Glu 325 tac Tyr aag Lys tgt Cys aag Lys 330 tcc Ser aac Asn aag Lys ggc Gly ctg Leu 335 ccc Pro 1008 tcc Ser tcc Ser ate lie gag Glu 340 aaa Lys acc Thr ate lie tcc Ser aag Lys 345 aag Lys ggc Gly cag Gin cct agg Pro Arg 350 gag Glu 1056 cct Pro cag Gin gtg val 355 tac acc Tyr Thr ctg Leu cct Pro cct Pro 360 age Ser cag gaa gag Gin Glu Glu atg Met 365 acc Thr aag aac Lys Asn 1104 cag Gin gtg val 370 tcc Ser ctg Leu acc Thr tgt cys ctg Leu 375 aag Lys ggc Gly ttc tac Phe Tyr 380 cct Pro tcc Ser gac Asp ate lie 1152 gcc Ala 385 tgg Trp gag Glu tcc Ser 390 aac Asn ggc Gly cag Gin cct Pro gag Glu 395 aac Asn aac tac Asn Tyr aag Lys acc Thr 400 1200 acc Thr cct Pro cct Pro ctg Leu 405 gac Asp tcc Ser gac Asp ggc Gly tcc Ser 410 ttc Phe ttc Phe ctg Leu tac Tyr tcc Ser 415 agg Arg 1248 ctg Leu acc Thr gac Asp 420 aag Lys tcc ser egg Arg tgg Trp cag Gin 425 ifu m aac Asn 3活 ttt Phe 430 tcc Ser tgc Cys 1296 tcc Ser gtg val atg Met 435 cac His gag gcc Glu Ala ctg Leu cac His 440 aac Asn cac His tac acc Tyr Thr cag Gin 445 aag Lys tcc Ser ctg Leu 1344 tcc ser ctg Leu tet ser ctg Leu 1% tga 1362 450 <210> 24 <211> 453 <212> PRT <213>智人 <400> 24
Met Tyr Arg Met Gin Leu Leu ser Cys He Ala Leu ser Leu Ala Leu 1 5 10 15 • 40· 154995·序列表.doc 201142024
Val Thr Asn ser Leu Arg Gin Glu Asp Phe Pro Pro Arg lie val Glu 20 25 30
His Pro Ser Asp Leu lie Val Ser Lys Gly Glu Pro Ala Thr Leu Asn 35 40 45
Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr lie Glu Trp Tyr Lys Gly 50 55 60
Gly Glu Arg val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg Met 65 70 75 80
Leu Leu Pro Ser Gly ser Leu Phe Phe Leu Arg lie Val His Gly Arg 85 90 95
Lys ser Arg Pro Asp Glu Gly Val Tyr val Cys val Ala Arg Asn Tyr 100 105 110
Leu Gly Glu Ala val ser His Asn Ala ser Leu Glu val Ala lie Leu 115 120 125
Arg Asp Asp Phe Arg Gin Asn Pro Ser Asp val Met Val Ala val Gly 130 135 140
Glu Pro Ala Val Met Glu Cys Gin Pro Pro Arg Gly His Pro Glu Pro 145 150 155 160
Thr lie ser Trp Lys Lys Asp Gly ser Pro Leu Asp Asp Lys Asp Glu 165 170 175
Arg lie Thr lie Arg Gly Gly Lys Leu Met lie Thr Tyr Thr Arg Lys 180 185 190
Ser Asp Ala Gly Lys Tyr val Cys Val Gly Thr Asn Met Val Gly Glu 195 200 205
Arg Glu ser Glu Val Ala Glu Leu Thr val Leu Glu Arg Pro Ser Phe 210 215 220
Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240
Phe Glu Gly Gly Pro ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255
Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val val Asp 260 265 270
Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 275 280 285 -41 - 154995·序列表.doc 201142024 val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 290 295 300 ser Thr Tyr Arg val Val sen Val Leu Thr Val Leu His cln Asp Trg
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 325 330 335 ser Ser lie Glu Lys Thr lie ser Lys Ala Lys Gly Gin Pro Arg Glu 340 345 350
Pro Gin val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn 355 360 365
Gin val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro ser Asp lie 370 375 380
Ala val Glu Trp Glu ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400
Thr Pro Pro val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr ser Ara 405 410 415 a
Leu Thr Val Asp Lys ser Arg Trp Gin Glu Gly Asn Val Phe ser Cvs 420 425 430 3
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys ser Leu 435 440 445
Ser Leu Ser Leu Gly 450 • 42· 154995·序列表.doc

Claims (1)

  1. 201142024 七、申請專利範圍： 1. 一種Robo-以重組蛋白，其包含尺以〇1蛋白之細胞外域或 此結構域之一部分、連接子及免疫球蛋白Fc域，其中該 細胞外域來自該R〇bo 1蛋白之同功異型物b。 2. 如請求項1之蛋白質，其中該尺〇13〇1之細胞外域包含 及免疫球蛋白域。 3. 如請求項2之蛋白質，其中該R〇b〇1之細胞外域與序列 SEQ ID NO.2具有至少80%之一致性。 4. 如前述請求項中任一項之蛋白質，其中該。域來自人類 免疫球蛋白G4。 5. 如請求項4之蛋白質，其中該以域含有至少一個點突 變，其旨在增加該蛋白質之穩定性及/或消除該以域之殘 餘效應活性及/或增加在其製備期間之均質性。 6. 如請求項5之蛋白質，其中該以域包含3241?及[248£突 變且其中位於C端位置之離胺酸不存在。 7. 如請求項2至4中任一項之蛋白質，其中胺基酸5^2〇及 Arg21已缺失以便增加其製備期間之均質性。 8·如請求項1至4中任一項之蛋白質，其中該序列與序列 SEQ ID N0.4、SEQ ID N0.6 或 SEQ ID N0.24具有至少 8 0 %之一致性。 9. 一種核酸分子’其編碼如請求項1至8中所定義之蛋白質 —— 〇 10. —種核酸分子，其對應於序列SEq ID NO.l、SEQ ID ΝΟ·3、SEQ ID NO.5或SEQ ID NO.23或與具有該序列 154995.doc 201142024 SEQ ID ΝΟ·1、SEQ ID NO.3、SEQ ID ΝΟ·5 或 SEQ ID NO.23之分子具有至少80%之一致性。 11.如請求項1至8中任一項之|1〇13〇1_1^重組蛋白，其係用作 藥物。 12·如請求項丨！所使用之蛋白質，其係用於治療81^家族之 蛋白質過度表現的疾病。 13. 如請求項U所使用之蛋白質，其係用於治療癌症。 14. 如請求項12及13中任一項所#用夕疋&陆 . 哨所便用之蛋白質，其不抑制内 皮細胞增殖。 15.如s奮求項13所使用之蛋白質 轉移。 ，其係用於治療肺癌或肺癌 π π仗用之蛋白質 16.如請求項11至15中任 源於該Robo 1蛋白之同功異型物b 17·:::Γ所使用之蛋白質，此蛋― 18二種醫藥組合物，其包含如請求項！至8中所定義 竭如重組蛋白及至少-種賦形劑。 19· 一種本發明之Robol-Fc分子之用.全^ , 體内sm家族分子之過度表現的診斷工具#用作偵測患 154995.doc • 2 *
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