TW201130511A - Soluble proteins for use as therapeutics - Google Patents
Soluble proteins for use as therapeutics Download PDFInfo
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- TW201130511A TW201130511A TW099145049A TW99145049A TW201130511A TW 201130511 A TW201130511 A TW 201130511A TW 099145049 A TW099145049 A TW 099145049A TW 99145049 A TW99145049 A TW 99145049A TW 201130511 A TW201130511 A TW 201130511A
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Classifications
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- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Description
201130511 六、發明說明: 【發明所屬之技術領域】 本發明係關於用作藥劑,特定言之用於預防或治療自體 免疫及發炎性病症,例如過敏性哮喘及發炎性腸病之藥劑 的可溶性SIRPcx結合蛋白。本發明更特定言之係關於包含 至少兩個二價雜二聚體之複合物的可溶性SIRPcx結合蛋 白,其中各雜二聚體基本上由以下組成: (i) 包含第一 SIRPa結合域融合於抗體重鏈恆定區之N-端部分的第一單價單鏈多肽;及 (ii) 包含第二SIRPa結合域融合於抗體輕鏈恆定區之N-端部分的第二單價單鏈多肽。本發明之一特定實施例由圖 1進一步說明。 【先前技術】 SIRPa(CDl 72a)為一種由包括巨嗔細胞、粒細胞及習知 樹突狀細胞(DC)在内之骨髓系細胞表現以及在神經元細胞 上表現的免疫受體(van den Berg等人2008,Trends in Immunol., 29(5):203-6)。SIRPa為 CD47之低親和力配位體 (Rebres 等人 2001, J.Biol.Chem.; 276(37):34607-16 ;
Hatherley 等人 2007; J.Biol.Chem.; 2 82(19):14567-75 ; Hatherley 等人 2008; Mol. Cell; 3 1 (2) 266-77),且 SIRPa與 CD47之相互作用構成基於黏著及雙向信號傳導控制之細 胞通信系統,其調控免疫及神經元系統中之多種細胞功 能。此等功能包括遷移、細胞成熟、巨噬細胞吞噬作用及 骨髓樹突狀細胞之細胞激素產生(van den Berg等人2008 152818.doc 201130511
Trends in Immunol. 29(5):203-6 ; Sarfati 2009, Curr. Drug. Targets,9(10):852-50)。 來自動物模型之資料表明SIRPa/CD47相互作用可有助 於或甚至控制若干病症之發病機制,該等病症包括自體免 疫性疾病、發炎性疾病(Okuzawa等人2008, BBRC; 371(3):561-6 ; Tomizawa等人 2007, J Immunol; 179(2):869-877);缺血性疾病(Isenberg 等人 2008, Arter.Thromb Vase. Biol., 28(4):615-21 ; Isenberg 2008, Am. J. Pathol., 173(4): 11 00-12)或腫瘤相關性疾病(Chan等人2009, PNAS, 106(33): 14016-14021 ; Majeti等人2009,Cell, 138(2):286-99)。因此調節SIRPa/CD47路徑可能為多種疾病之有希望 的治療選擇。 已提出使用針對CD47、SIRPa之抗體或CD47源性SIRPa 結合多肽作為治療方法(WO 1998/40940、WO 2004/108923、 WO 2007/133811、WO 2009/046541)。此外,結合SIRPa 之 CD47源性融合蛋白在諸如TNBS結腸炎(Fortin等人2009,J Exp Med., 206(9):1995-2011)、蘭氏細胞(Langerhans cell) 遷移(J Immunol. 2004,172: 4091-4099)及關節炎(VLST Inc, 2008, Exp. Opin.Therap. Pat., 18(5): 555-561)之疾病 的動物模型中有效。 此外,提出SIRPa/CD47參與控制吞嗔作用(van den Berg 等人2008,Trends in Immunol·, 29(5):203-6) ’ 且聲稱利用 SIRPa結合多肽進行干預可增強NOD小鼠品系中之人類幹 細胞移植(WO 2009/046541),表明含有CD47細胞外域 152818.doc 201130511 (ECD)之治療劑用於人類幹細胞移植中之潛在益處。 【發明内容】 本發明提供包含第-及第二多肽鏈之雜二聚體的可溶性 結合蛋白,各鏈包含結合部分融合於抗體恆定區序列。該 等可溶性蛋白質係用作治療劑。 本發明另外提供用作治療劑之改良的可溶性潰〜結合 :白。相較於先前技術CD47蛋白質融合&,如本發明中 疋義之SIRPa結合抗體樣蛋白f可提供增加對目標表 現細胞之親合力同時保持極佳可發展性的手段。另外,不 何理,束縛,預期較高親合力可導致較長藥效學半衰 期,從而提供增強之治療功效。此等新穎結果提供靶向 卿表現細胞之新賴治療工具,且代表特定言之用於多 體免疫及發炎性病症 '癌症或幹細胞移植之治療前 因此,在一態樣中 之複合物之可溶性蛋 組成: ’本發明提供包含至少兩個雜二聚體 白質’其中各雜二聚體基本上由以下 3 ·礼動物結合分子之區域融合於抗體重鍵怪定 區的弟一單價單鏈多肽;及 ^ 3相同、,,a合分子之區域融合於抗體輕鏈恆定區的 弟二早價單鏈多肽。 在另〜態樣中, 合物之可溶性蛋白 成: 本發明提供包含至少兩個雜二聚體之複 邊’其中各雜二聚體基本上由以下組 152818.doc 201130511 (1)包含哺乳動物結合分子之區域融合於抗體CH1恆定 重鏈區的第一單價單鏈多肽;及 (i〇包含相同結合分子之區域融合於抗體CL怪定輕鏈區 的第二單價單鏈多肽。 Ο
在較佳實施例中,各單鏈多肽為單價,各雜二聚體為二 價’且各複合物為至少四價。本發明之雜二聚體及可溶性 蛋白質中母條多肽鏈之價數為1。相較於先前技術分子, 本發明之可溶性蛋白質具有增加之價數。藉由在各第一及 第二單鏈多肽中併入相同結合分子,各雜二聚體之價數為 2,亦即雜二聚體内之各鏈可結合各別結合搭配物,或在 相同結合搭配物上結合兩次。此將不同於第一及第二多肽 鏈之雜二聚體的價數為Π亦即對結合搭配物之結合需要兩 條鏈)致使兩個雜二聚體之複合物的價數為2的先前技術分 子(例如揭示於WO (H/46261中之分子)。因此,本發明之 兩個-價雜二聚體之複合物之價數為4(四價),亦即該複合 物可結合多達四個結合搭配物,或在相同結合搭配物上結 合多達四次。本發明之雜二聚體為二價且雜二聚體之複合 物之價數為η X 2,其中n為複合物中所包含之雜二聚體的 數目。在較佳實施例中,複合物包含兩個雜二聚體,且價 數為4。包含多於兩個雜二聚體之複合物之價數大於4,例 人8或.本發明之可溶性蛋白質之增加之價數導致較 问親口力,從而對半衰期及功效產生有利影響。 =物在-態樣中’本發明提供包含至少兩個雜二聚體 之複5物之具有至少四價(或為至少四價)的可溶性蛋白 1528l8.doc 201130511 質’其中各雜二聚體基本上由以下組成: (1)包含哺乳動物結合分子之區域融合於抗體恆定區重 鏈的第一單價單鏈多肽;及 ⑴)包含相同哺乳動物結合分子之區域融 區輕鏈的第二單價單鏈多肽。 體丨疋 在另一態樣中,本發明提供包含至少兩個雜二聚體之複 口物之具有至少四價的可溶性蛋白質,其中各雜二聚體基 本上由以下組成: ()匕3哺乳動物結合分子之區域融合於抗體丨恆定 重鏈區的第一單價單鏈多肽;及 (11)包含相同結合分子之區域融合於抗體cl恆定輕鏈區 的第二單價單鏈多肽。 日在一較佳態樣中,結合分子之區域相肖。因此,本發明 知已3至>、兩個雜二聚體之複合物之具有至少四價的可 洛ί生蛋白中各雜二聚體基本上由以下組成: ()0 3 f乳動物結合分子之區域融合於抗體恆定區重 鏈的第一單價單鏈多肽;及 ()13相同哺乳動物結合分子之相同區域融合於抗體 恆定區輕鏈的第二單價單鏈多肽。 入在另&樣中,本發明提供包含至少兩個雜二聚體之複 口物之具有至少四價的可溶性蛋白質其中各雜二聚體基 本上由以下組成: (1)包3哺礼動物結合分子之區域融合於抗體CH1恆定 重鏈區的第一單價單鏈多肽;及 152818.doc 201130511 ⑻包3相同哺乳動物結合分子之相同區域融合於抗體 CL恆定輕鏈區的第二單價單鏈多肽。 在較佳實施例中,哺乳動物結合分子之區域與抗體序 列之N-端部分融合(亦即與CH1& CL恆定區融合)。 在一實施例中,結合分子為細胞激素、生長因子、激 素、信號傳導蛋白、低分子量化合物(藥物)、配位體或細 胞表面受體。較佳地,結合分子為哺乳動物單體或均聚合 〇、細胞表面受體°結合分子之區域可為完整分子或其可保留 其生物活性之部分或片段。結合分子之區域可為細胞外區 或細胞外域。在-實施例中,該哺乳動物單體或均聚合細 胞表面受體包含免疫球蛋白超家族(IgSF)域’例如其包含 CD47之細胞外域。 在一較佳實施例中,可溶性蛋白質為抗體樣蛋白質(在 下文中亦稱為且定義為融合體(Fus〇b〇(Jy)),其中抗體兩個 臂之可變區均經SIRPa結合域置換,藉此提供多價可溶性 Q 蛋白質。 該種SIRPa結合融合體之一實例展示於圖!中。 在一實施例中,本發明係關於經分離可溶性SIRPa結合 蛋白或SIRPa結合融合體,其包含兩個二價雜二聚體之四 價複合物,其中各雜二聚體基本上由以下組成: (0 包含第一 SIRPa結合域融合於抗體恆定CH1重鏈區之 N-端部分的第一單鏈多肽;及, (ii)包含第二SIRPa結合域融合於抗體恆定CL輕鏈區之 N-端部分的第二單鏈多肽。 152818.doc 201130511 在一較佳實施例中,可溶性蛋白質或SIRPa結合融合體 之各雜二聚體之該第一單鏈多肽另外包含免疫球蛋白之 CH2及CH3區與該CH1區融合,藉此重構抗體之全長恆定重 鏈。該等CH1、CH2及CH3區可來源於野生型或人類IgGl、 IgG2、IgG3或IgG4相應區域之具有靜止效應功能及/或減 弱之細胞殺傷、ADCC或CDC效應功能,例如減弱之ADCC 效應功能的突變型變異體。 在一實施例中,如藉由表面電漿子共振,諸如BiaCORE 檢定所量測,該可溶性蛋白質或SIRPa結合融合體以1 0 μΜ 或10 μΜ以下,例如4 μΜ或4 μΜ以下,例如1 μΜ或1 μΜ以 下、0.1 μΜ或0·1 μΜ以下之KD與人類SIRPa結合。在一實 施例中,可溶性蛋白質或SIRPa結合融合體以0.1至10 μΜ 範圍内之KD與人類SIRPa結合。 在另一實施例中,如基於分析板之細胞黏著檢定(plate-based cellular adhesion assay)所量測 ,該可 溶性蛋 白質或 SIRPa結合融合體以20 nM或20 nM以下,例如2 nM或2 nM 以下,例如介於200 pM與20 nM之間的EC5〇促進SIRPa+白 血球,諸如SIRPa+U937細胞之黏著。 在另一實施例中,該可溶性蛋白質或SIRPa結合融合體 抑制活體外產生之單核細胞源性樹突狀細胞中金黃色葡萄 球菌awrewdCowan菌株粒子刺激之促發炎 性細胞激素釋放。 舉例而言,如樹突狀細胞細胞激素釋放檢定所量測,該 可溶性蛋白質或SIRPa結合融合體以2 nM或2 nM以下、0.2 152818.doc -10- 201130511 nM或0.2 nM以下,例如介於20 pM與2 nM之間的IC5。抑制 活體外產生之單核細胞源性樹突狀細胞中金黃色葡萄球菌 Cowan菌株粒子刺激之促發炎性細胞激素釋放。 在另一相關實施例中,各雜二聚體之該第一單鏈多肽及 該第二單鏈多肽經二硫橋鍵,例如使用相應CH1及CL區之 半胱胺酸殘基之間的天然二硫橋鍵共價結合。 在一實施例中,第一及第二SIRPa結合域可經由肽連接 子分別融合至CH1及CL區。在另一實施例中,第一及/或第 二SIRPa結合域在不存在肽連接子下直接融合於各別CH1 及CL區。 在一較佳實施例中,該可溶性蛋白質或SIRPa結合融合 體基本上由兩個雜二聚體組成,其中各雜二聚體之該第一 單鏈多肽包含免疫球蛋白恆定部分之鉸鏈區,且兩個雜二 聚體經其鉸鏈區處半胱胺酸之間的二硫橋鍵彼此穩定締 合0 在一實施例中,本發明之可溶性蛋白質包含至少一個選 自由以下組成之群之SIRPa結合域: (i) 人類CD47之細胞外域; (ii) SEQ ID NO:4之多肽或 SEQ ID NO:4之保留 SIRPa結 合性質之片段;及, (iii) SEQ ID NO:4 之與 SEQ ID NO:4 具有至少 60%、 70%、80%、90%、95%、96%、97%、98%或 99%序歹|J 一致 性且保留SIRPa結合性質的變異型多肽。 在一特定實施例中,所有SIRPa結合域皆具有相同胺基 152818.doc -11 - 201130511 酸序列。舉例而言,所有SIRPα結合域皆由SEQIDNO:4或 SEQ ID ΝΟ··3 或 SEQ ID NO:21 或 SEQ ID ΝΟ··23 或 SEQ ID NO:27組成。 在一特定實施例中,本發明之該可溶性蛋白質或SIRPa 結合融合體包含兩個雜二聚體,其中各雜二聚體基本上由 以下組成:SEQ ID NO:5之第一單鏈多肽及SEQ ID NO:6 之第二單鏈多肽。與抗體之重鏈及輕鏈類似,該第一單鏈 多肽及該第二單鏈多肽至少經由一個雙硫鍵穩定締合。在 一相關實施例中,可溶性蛋白質或SIRPa結合融合體包含 兩個雜二聚體,其中各雜二聚體之第一及第二單鏈多肽分 別與SEQ ID NO:5及SEQ ID NO:6之相應第一及第二單鏈 多肽具有至少 60%、70%、80%、90%、95%、96%、 97%、98%或99%的序列一致性,同時保留SIRPa結合融合 體之如上所述之有利功能性質。 特定言之,在一特定實施例中,此可溶性蛋白質或 SIRPa結合融合體以10 μΜ或10 μΜ以下、4 μΜ或4 μΜ以 下、或2 μΜ或2 μΜ以下,例如介於0.1 μΜ與10 μΜ之間的 KD與人類SIRPa結合。 在一特定實施例中,本發明SIRPa結合融合體之四個 SIRPa結合域之序列相同。舉例而言,該SIRPa結合融合體 由分別SEQ ID NO:5及SEQ ID NO:6之第一及第二單鏈多 肽構成。 本發明另外係關於此等可溶性蛋白質或融合體,尤其例 如在治療或診斷自體免疫及急性及慢性發炎性病症中用作 152818.doc -12- 201130511 藥物或診斷工具的SIRPa結合蛋白或融合體。特定言之, SIRPa結合蛋白或融合體用於選自由以下纽成之群的治療 中:Th2介導之氣管發炎、過敏性病症、η孝喘、發炎性腸 病及關節炎。 本發明之可溶性蛋白質或融合體亦可用於治療或診斷缺 血性病症、白血病或其他癌症病症,或用於增強有需要之 個體中的造血幹細胞移植。 Ο
定義 為使本發明可更容易理解,首先定義某些術語《其他定 義在[實施方式]中描述。 術語SIRPa係指人類信號調控蛋白α(亦稱為CD172a或 SHPS-1),其展示與CD47整合素相關蛋白質黏著。人類 SIRPa包括SEQ ID ΝΟ:1,且進一步包括(但不限於)人類 SIRPa之任何天然多形變異體(例如包含單核苷酸多形現象 (single nucleotide polymorphism,SNP))、或拼接變異體。 人類中所見之拼接變異體或SIRPa核苷酸序列中之SNP的 實例描述於表1中。 表1 : SIRPa蛋白質之變異體 變異體類型 變異體ID 描述 拼接變異體 NP 542970.1 ENSP00000382941 參考;短變異體;序列編號Γ2 長變異體,接近C-端插入四個胺基酸 單核苷酸多 形現象 rsl 7855609 DNA : A或1 ;蛋白質:丁或8㈣)542970.1之 位置50) ' rsl7855610 DNA : C或T ;蛋白質:τ或职p 542970.1之 位置52) " rsl7855611 DNA : 0或八;蛋白質:R或H(NP 542970.1之 位置54) _ 152818.doc 13 201130511 rsl7855612 rsl057114 DNA : C或T ;蛋白質:a或V(NP 542970.1 之 位置57) _ DNA : G或C ;蛋白質:(^或入㈣75297〇」之 位置75) rsl 135200 DNA : C或G ;蛋白質:D或E(NP 542970.1 之 位置95) " rsl7855613 DNA : A或G ;蛋白質:n或D(NP 542970.1 之 位置100) rsl7855614 DNA : C或A ;蛋白質:n或K(NP 542970.1 之 位置100) rsl7855615 DNA : C或A ;蛋白質·· r或S(NP 542970.1 之 位置107) rsl 135202 DNA : G或A ;蛋白質:G或S(NP 542970.1 之 位置109) rsl7855616 DNA : G或A ;蛋白質:G或S(NP 542970.1之 位置109) rs2422666 DNA : G或C ;蛋白質:v或l(NP 3022970.1 之 位置302) rsl2624995 DNA : T或G ;蛋白質:v或G(NP 542970.1 之 位置3 79) rs41278990 DNA : C或T ;蛋白質:p或s(NP 542970.1 之 位置482) 術§吾CD47係指細胞表面嗔乳動物整合素相關蛋白質。 人類CD47包括SEQ ID n〇:2以及人類CD47之任何天然多 形變異體(例如包含單核苷酸多形現象(SNP))、或拼接變異 體。人類中所見之拼接變異體或CD47核苷酸序列中之SNP 之實例描述於表2中。 表2 : CD47蛋白質之變異體 變異體類型 變異體ID 丨描述 """"" 拼接變異體 NP—001768.1 參考;最長變異體;序列編號:2 NP_942088.1 不同,較短C-端 NP_001020250.1 不同,較短C-端 ENSP00000381308 不同,較短C-端 一 單核苷酸多 rsl 1546646 DNA : C或G ;蛋白質:A或P(NP 001768.1 之 形現象 位置96) ENSSNP12389584 DNA : C或G ;蛋白質:V或L(NP 001768.1之 位置246) 152818.doc -14- 201130511 如本文所用,術語「蛋白質」係指由排列於一或多條線 性鏈中且摺疊成球狀形式之胺基酸構成的任何有機化合 物。聚合物鏈中之胺基酸由相鄰胺基酸殘基之羧基與胺基 之間的肽鍵接合在一起。術語「蛋白質」進一步包括㈠旦 不限於)肽、單鏈多肽或或主要由兩條或兩條以上胺基酸 鏈組成之任何複合分子。其進一步包括(但不限於)醣蛋白 或其他已知轉譯後修飾。其進一步包括天然蛋白質之已知 0 天然或人工化學修飾,諸如(但不限於)糖基化工程改造 (glycoengineering)、聚乙二醇化、羥基化及其類似修飾、 併入非天然胺基酸、及用於與另一分子化學結合之胺基酸 修飾。 〇 如本文所用,「複合蛋白質」係指由至少兩個單鏈多肽 構成之蛋白質,其中該至少兩個單鏈多肽在適當條件下經 由非共價結合或共價結合,例如經二硫橋鍵締合在一起。 「雜二聚蛋白質」係指由形成複合蛋白質之兩個單鏈多肽 構成的蛋白質,其中該兩個單鏈多肽具有不同胺基酸序 列,特疋言之,其胺基酸序列彼此之間共有不超過90%、 80%、70%、60%或5〇%一致性。相反,「均二聚蛋白質」 係指由形成複合蛋白質之兩個相同或實質上相同之多肽構 成的蛋白質,其中該兩個單鏈多肽共有100% —致性、或 至乂 95%或至少99%一致性,其中胺基酸差異由不影響多 、較於另均一聚體之功能性質及物理性質的胺基酸取 代添加或缺失,例如保守性胺基酸取代組成。 如本文所用’蛋白質在缺乏將多肽錨定或整合至表現此 152818.doc •15- 201130511 多肽之細胞之膜中的任何跨膜域或蛋白質域時為「可溶 的」。特定言之,本發明之可溶性蛋白質可同樣排除CD47 之跨膜域及細胞内域。如本文所用,術語「抗體」係指包 含經雙硫鍵相互連接之至少兩條重(H)鏈及兩條輕(L)鏈之 蛋白質。各重鏈包含重鏈可變區(在本文中縮寫為vH)及重 鏈恒定區。重鏈恆定區包含三個域CHi、cH2及CH3。各輕 鏈包含輕鏈可變區(在本文中縮寫為VL)及輕鏈恆定區。輕 鏈怪定區包含一個域CL。VH及VL區可進一步再分為稱為 互補決定區(CDR)之高變區’其間穿插有稱為構架區(FR) 之較保守區。各VH及VL由自胺基端至羧基端按以下順序排 列之 3 個 CDR及 4個 FR構成:FR1、CDR1、FR2、CDR2、 FH3、CDR3、FR4。重鏈及輕鏈之可變區含有與抗原相互 作用之結合域。抗體之恆定區可介導免疫球蛋白與宿主組 織或因子’包括免疫系統之各種細胞(例如效應細胞)及經 典補體系統之第一組份(Clq)的結合。 為便於理解,術語「融合體」在本文中以類似於術語 抗體」之方式使用。如本文所用,術語「融合體」係指 包含兩個雜二聚體之抗體樣可溶性蛋白質,其中各雜二聚 體由例如經由一或多個雙硫鍵穩定締合在一起的一條胺基 酸重鏈及—條胺基酸輕鏈組成。各重鏈或輕鏈包含下文分 別稱為融合體之重鏈及輕鏈恆定區的抗體恆定區。重鏈恆 疋區至V包含抗體之Ch1區且可另外包含CH2及CH3區,包 括鉸鏈區。輕鏈恆定區包含抗體之&區。在融合體中,抗 體可變區經異源可溶性結合域置換。術語「異源」意謂此 152818.doc -16 - 201130511 等域在天然情況下未發現與抗體恆定區締合。特定言之, 此等異源結合域不具有由4個構架區FR1、FR2、FR3及FR4 ;中間的3個互補決定區(CDR)組成之抗體可變域的典 n融合體之各臂因此包含苐-單鏈多肽,其包含共 價連接於^i體值^ Ch1重鏈區之n•端部分的第—結合域; 及第一單鏈多肽包含共價連接於抗體怪定(^輕鏈區之 知P刀的第一結合域。共價鍵聯可為直接的,例如經由
肽結合’或為間接的’經由連接子,例如狀連接子。盘抗 體結構類似,融合體之兩個雜二聚體例如由其鉸鏈區之至 少一個二硫橋鍵共價連接。圖1為融合體分子之一實例之 示意圖。此項技術中已描述具有融合體結構之分子之實 例,特定言之包含雜二聚受體之配位體結合區之融合體 (參見例如 WO 01/46261)。 在-較佳實施例中"寿乳動物單體或均聚合細胞表面受 體之細胞外域或此細胞外域之保留配位體結合活性之變異 體或區域與抗體之重鏈及輕鏈之恆定區融合。所得分子為 保留抗體分子用作治療分子之有利性質的多價蛋白質。 如本文所用之術語「哺乳動物結合分子」為可與目標分 子、細胞、複合物及/或組織結合之任何分子或其部 片段’且其包括蛋白質、核酸、碳水化合物、脂質、低分 子量化合物及其片段,各自能夠與選自由以下組成之群i -或多種成員結合:可溶性蛋白f、細胞表面蛋白、細胞 表面受體蛋白、細胞内蛋白f、碳水化合物、核酸、敎素 或低分子量化合物(小分子藥物)、或其片段。哺乳動物結 152818.doc •17- 201130511 合分子可為蛋白質、細胞激素、生長因子、激素、信號傳 導蛋白、發炎性介體、配位體、受體、或其片段。在較佳 實施例中,哺乳動物結合分子為屬於免疫球蛋白超家族之 天然或突變型蛋白質;能夠與其天然受體結合之天然激素 或其變異體;能夠與互補序列及/或可溶性細胞表面或細 胞内核酸/聚核苷酸結合蛋白結合之核酸或聚核苷酸序 列;能夠舆其他碳水化合物結合部分及/或可溶性細胞表 面或細胞内蛋白質結合之碳水化合物結合部分;與可溶性 或細胞表面或細胞内目標蛋白結合之低分子量化合物(藥 物)。特定言之,該定義包括以下分子: -選自由以下組成之群之細胞激素:介白素-l(IL-l)、 IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10 、 IL-11 、 IL-12 、 IL-13 、 IL-14 、 IL-15 、 IL-16 、 IL-17 、 IL-18、IL-19、IL-20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-28、IL-29、IL-30、IL-31、IL-32、 IL-33、IL-34、IL-35、顆粒球巨噬細胞群落刺激因子 (granulocyte macrophage colony stimulating factor,GM-CSF)、M-CSF、SCF、TSLP、抑瘤素M(oncostatin M)、白 血病抑制因子(LIF)、CNTF、心營養素-1(€3犷(11〇1;1"〇卩111-1)、NNT-l/BSF-3、生長激素、泌乳素(Prolactin)、紅血球 生成素(Erythropoietin)、血小板生成素(Thrombopoietin)、 痩素(Leptin)、G-CSF、或其受體或配位體; -選自由以下組成之群之細胞激素的干擾素家族之成 員:IFN-γ、IFN-α及 IFN-β ; 152818.doc -18- 201130511 -選自由以下組成之群之細胞激素的免疫球蛋白超家族 之成員:B7.1(CD80)及 B7.2(B70); -選自由以下組成之群之細胞激素的TNF家族之成員: TNF-α、TNF-β、LT-β、CD40配位體、Fas配位體、CD27 配位體、CD30配位體及4-1BBL ; 選自由以下組成之群之TGF-β/ΒΜΡ家族之成員:丁0卩-βΐ、TGF-p2、TGF-p3、BMP-2、BMP-3a、BMP-3b、 BMP-4、BMP-5、BMP-6、BMP-7、BMP-8a、BMP-8b、 o BMP-9、BMP-10、BMP-11、BMP-15、BMP-16、子宮内膜 出血相關因子(EBAF)、生長分化因子-l(GDF-l)、GDF-2、 GDF-3 ' GDF-5 ' GDF-6 ' GDF-7 ' GDF-8 > GDF-9 ' GDF-12、GDF· 14、苗勒氏管抑制物質(mullerian inhibiting substance,MIS)、活化素- l(activin-l)、活化素-2、活化 素-3、活化素-4及活化素-5 ; -選自由以下組成之群之分化(CD)分子之叢集:CDl(a-◎ c, 1A,ID, IE)、CD2、CD3(y,δ,ε)、CD4、CD5、CD6、 CD7、CD8(a)、CD9、CD10、CDll(a,b,c)、CD13、 CD14 ' CD15 > CD16(A, B)、CD18、CD19、CD20、 CD21、CD22、CD23、CD24、CD25、CD26、CD27、 CD28、CD29、CD30、CD31、CD32(A,B)、CD33、 CD34 、 CD35 、 CD36 、 CD37 、 CD38 、 CD39 、 CD40 、 CD41、CD42(a,b, c,d)、CD43、CD44、CD45、CD46、 CD47、CD48、CD49(a,b,c,d,e,f)、CD50、CD51、 CD52、CD53、CD54、CD55、CD56、CD57、CD58、 •19- 152818.doc 201130511 CD59、CD61、CD62(E, L,P)、CD63、CD64(A,B,C) CD66(a, b, c, d, e, f)、CD68、CD69、CD70、CD71 CD72、CD73、CD74、CD78、CD79(a, b)、CD80 CD81、CD82、CD83、CD84、CD85(a, d,e, h, j, k) CD86、 CD87、 CD88 、 CD89 、 CD90 、CD91、 CD92 、 CD93、 CD94、 CD95、CD96、CD97 、CD98、 > CD99 、 CD100、 CD101 、CD102、 CD103 、 CD104 、 CD105 CD106、 CD107(a,b)、CD108、CD109 、CD110、 CD111 CD112、 CD113 、CD114、 CD115、 CD116、 CD117 、 CD118、 CD119 、CD120(a, b)、CD121(a, b)、 CD122 CD123、 CD124 、CD125、 CD126 、 CD127 ' CD129 CD130 、 CD131 、CD132、 CD133 、 CD134、 CD135 CD136、 CD137 、CD138、 CD140b、 CD141、 CD142 CD143、 CD144 、CD146、 CD147 ' CD148、 CD150 > CD151、 CD152 、CD153、CD154、CD155、CD156(a, b, c)、CD157、CD158(a, d, e, i,k)、CD159(a,c)、 CD160 、 CD161、 CD162、 CD163、CD164、CD166、CD167(a, b) CD168、 CD169 、CD170、 CD171 、 CD172(a, b, g) 、 CD174、 CD177、 CD178、CD179(a,b) 、CD181、 CD182 、 CD183、 CD184 、CD185、 CD186 、 CD191 、 CD192 、 CD193、 CD194 、CD195、 CD196、CD197、CDwl98 、 CDwl99 、CD200、CD201、 CD202b、 CD204、 CD205 % CD206 、 CD207 、CD208 、CD209 、 CDw210(a, b) CD212 ' CD213a(l, 2)、CD217、CD218(a, b)、CD220 r t: 152S18.doc -20- 201130511 CD221 、CD222、CD223、CD224、CD225、CD226、 Ο CD227、CD228、CD229、CD230、CD233、CD234、 CD235(a, b)、CD236、 CD238、CD239、 CD240CE CD241 CD243 、CD244、CD246 、CD247-CD248 CD249 CD252 、 CD253 、CD254、 CD256 CD257 CD258 、 CD261 、 CD262 、CD264 、 CD265 CD266 CD267 CD268 、 CD269 、CD271 、 CD272 CD273 CD274 CD275、 CD276 、CD278 、 CD279 CD280 n CD281 X CD282 ' CD283 、CD284 、 CD286 CD288 CD289 、 CD290 、 CD292 、CDw293、 CD294 > CD295 > CD297 N CD298、 CD299 、CD300A、 CD301 、 CD302 N CD303 CD304 、 CD305 、CD306 、 CD307 、 CD309 X CD312 、 CD314 、 CD315 、CD316 、 CD317 CD318 CD320 、 CD321 、 CD322 、CD324 、 CD325 CD326 、 CD328 、 CD329、 CD331 、CD332 、 CD333 > CD334 CD335 > CD336、 CD337 、CD338 、 CD339 CD340 > CD344 、CD349、CD350 ; -選 白 由以下組成之群 之分子:ADAM10、 ADAM17 、 ADAM8、 ALCAM 、ART4 、ATP1B3 、 ABCG2 阿韋舒托 (Alvircept sudotox)、多形性淋巴瘤激酶(Anaplastic lymphoma kinase) 、 B3GAT1 、 BCAM 、 BMPR1A 、 BMPR1B、BST1、BTLA、帶 3(Band 3)、基礎免疫球蛋白 (Basigin)、6型 C-C趨化因子受體(C-C chemokine receptor type 6)、7型 C-C趨化因子受體、CCR1、CCR2、CCR4、 201130511 CCR5、CCR8(基因)、CCR9、CDl、CD109、CDllc、組 織因子、CD15、CD151、CD155、CD16、CD160、 CD163、CD177、CD19、CD1A、CD1E、CD2、CD20、 CD200、CD226、CD23、CD244、CD247、CD248、 CD25、CD276、CD278、CD28、CD300A、CD31、 CD32、CD320、CD37、CD38、CD3D、CD3G、CD4、 CD40(蛋白質)、CD43、CD44、CD46、CD48、CD5、 CD5(蛋白質)、CD53、神經細胞黏著分子(Neural cell adhesion molecule)、CD59、CD6、CD63、CD64(生物 學)、CD68、CD69、CD7、CD70、CD72、CD78、CD79、 CD79A、CD79B、CD8、CD80、CD82(基因)、CD83、 CD84、CD86、CD8A、CD90、CD93、CD96、CD98、 CD99、CDCP1、CDH1(基因)、CDH2、CEACAM1、 CEACAM3 、 CEACAM5 、 CEACAM6 、CEACAM8 、 CLEC4M、CTLA-4、CXCR3、CXCR5、CXCR6、CCR3(基 因)、CD11、CD134、CD14、CD154、CD3(免疫學)、 CD34、CD3 6、CD47、CD74、CD81、群落刺激因子 1 受體 (Colony stimulating factor 1 receptor)、補體受體 l(Complement receptor 1)、DC-SIGN、DDR1、含盤菌素 域受體2(Discoidin domain-containing receptor 2)、達菲抗 原系統(Duffy antigen system)、E-選擇素(E-selectin)、 EMR2、ENTPD1、内皮蛋白(Endoglin)、内皮蛋白質C受體 (Endothelial protein C receptor)、上皮細胞黏著分子、FI 1 受體、FCAR、FCGR2B、FCGR3A、FCGR3B、FCRL5、 152818.doc -22- 201130511 FZD10、FZD4、FZD9、Fas配位體、FCGR2A、纖維母細 胞生長因子受體 l(Fibroblast growth factor receptor 1)、纖 維母細胞生長因子受體2、纖維母細胞生長因子受體3、纖 維母細胞生長因子受體4、使用MGI基因盒之 User:Frog21/Cd36(User:Frog21/Cd36 using MGI Gene box) ' 海蒸糖基轉移酶 3(Fucosyltransferase 3)、GGT1、 GP1BA、GP1BB、GP5、GPR44、GYPA、GYPB、麩胺醯 基胺基肽酶、血型醣蛋白C(Glycophorin C)、St蛋白 IX(Glycoprotein IX)、粒細胞群落刺激因子受體、粒細胞 巨噬細胞群落刺激因子受體、第1組CD1、HER2/neu、透 明質酸介導之活動力受體(Hyaluronan-mediated motility receptor)、ICAM2、ICAM3、ICOSLG、IFITM1、IGLL1、 IGSF2、IGSF8、IL13RA2、IL17RA、IL18R1、IL18RAP、 IL3RA、ITGA2B、ITGA5、ITGAV、ITGB4、胰島素受 體、胰島素樣生長因子1受體、胰島素樣生長因子2受體、 干擾素γ受體1、I型介白素1受體、II型介白素1受體、介白 素10受體α次單元、介白素10受體β次單元、介白素12受體 βΐ次單元、介白素13受體αΐ、介白素5受體α次單元、介白 素8受體α、介白素8受體β、介白素-18受體、介白素-4受 體、介白素-6受體、介白素-7受體、介白素-9受體、 ITGA6、JAG1、JAM2、KIR2DL1、KIR2DL4、KIR2DS4、 KIR3DL1、KIR3DL2、KLRB1、KLRC2、KLRD1、 KLRK1、科爾抗原系統(Kell antigen system)、激酶插入域 受體、Ll(蛋白質)、LAG3、LAIR1、LAMP1、LAMP2、 152818.doc -23- 201130511 LAMP3 、LILRA2 、LILRA3 、LILRB1 、LILRB2 、 LILRB3、LILRB4、LRP1、LY75、LY9、瘦素受體、白血 病抑制因子受體、低親和力神經生長因子受體、MFI2、 MSR1、磁性活化之細胞揀選(Magnetic-activated cell sorting)、MUC1、脊髓增生性白血病病毒致癌基因 (Myeloproliferative leukemia virus oncogene)、NCR1、 NCR2、NCR3、NKG2、NT5E、OX40L、P-醣蛋白、P-選 擇素醣蛋白配位體-1、PD-L1、PDCD1LG2、PDGFRB、 PSG1(基因)、PTGFRN、PVRL1、PVRL2、PVRL3、 PRNP、漸進式細胞死亡 l(Programmed cell death 1)、 RANK、RANKL、RHAG、RHCE(基因)、SEMA4D、 SEMA7A、SIGLEC5、SIGLEC7、SIGLEC8、SIRPB1、 SIRPG 、 SLAMF1 、SLC44A1 、唾液酸黏附素 (Sialoadhesin)、信號調控蛋白α、SuPAR、T-細胞表面聽蛋 白 CD3 ε鏈、TLR 1、TLR 2、TLR 4、TLR10、TLR6、 TLR8 、TNFRSF10A 、TNFRSF10B 、TNFRSF10C 、 TNFRSF10D、TNFRSF12A、TNFRSF13B、TNFRSF13C、 TNFRSF17、TNFRSF1A、TNFSF13、TNFSF14、TRAIL、 TEK酪胺酸激酶、束缚蛋白(Tetherin)、TFRC、血栓調節 蛋白(Thrombomodulin)、TLR 3、TLR9、尿激酶受體 (Urokinase receptor) 、VE-妈黏素(VE-cadherin)、 VPREB1; -選自由以下組成之群之激素:生長激素(GH)、促腎上 腺皮質激素(Adrenocorticotropic hormone,ACTH)、黃體 152818.doc -24- 201130511 生成激素(Leutinizing hormone,LH)、促瀘、泡激素(Follicle stimulating hormone,FSH)、促曱狀腺激素(TSH)、泌乳素 激素、催產素(Oxytosin)、抗利尿激素(Anti-diuretic hormone,ADH)、曱狀腺素(Thyroxin)、抑約素(Calcitonin)、 副曱狀腺素(PTH)、腎上腺素(Epinephrine)、正腎上腺素 (Nor-epinephrine)、鹽皮質激素(mineralocorticoids)、糖皮 質激素(glucocorticoids)、雄激素(androgens)、睪固明 (Testosterone)、抑黑素(Melatonin)、胸腺素(Thymosin)、 促胸腺生成素(thymopoetin)、升糖素(Glucagon)、胰島 素、雌激素(Estrogen)、及孕酮(Progesterone);或其片段 或受體。 術語「IgSF域」係指含有免疫球蛋白超家族域之蛋白 質,其包含藉由介導細胞之結合、識別或黏著過程而涉及 免疫系統之細胞表面及可溶性蛋白質的巨大群組。IgSF域 分子之免疫球蛋白域與免疫球蛋白共有結構相似性。IgSF 域含有約70-110個胺基酸,且根據其大小及功能加以分 類。Ig域具有特徵性Ig摺疊,其具有由兩個反向平行β股片 形成之夾心樣結構。Ig摺疊由在半胱胺酸殘基之間形成之 高度保守的雙硫鍵以及夾心内側上疏水性胺基酸之間的相 互作用加以穩定。Ig域之一端具有對於IgSF域之特異性重 要的稱為互補決定區之區段。大多數Ig域為可變(IgV)或恆 定(IgC)。顯示一或多個IgSF域之蛋白質實例為細胞表面共 刺激分子(CD28、CD80、CD86)、抗原受體(TCR/BCR)共 受體(CD3/CD4/CD8)。其他實例為參與細胞黏著(ICAM-1、 152818.doc -25- 201130511 VCAM-1)或具有IgSF域形成細胞激素結合受體(IL1R、 IL6R)之分子,及細胞内肌蛋白。在許多實例中,由含有 此IgSF域之該細胞表面受體觸發信號傳導的效力必需在極 接近於細胞之環境中存在多個IgSF域。一項明顯實例為免 疫突觸中含IgSF域分子(CD28、ICAM-1、CD80及CD86)的 叢集,其使得能夠形成允許抗原呈現細胞呈現最佳抗原並 且可以控制天然T細胞活化的微環境(Dustin, 2009, Immunity)。需要叢集以達成適當功能之其他含IgSF分子 之其他實例為 CD2(Li 等人 1996, J_ Mol. Biol·, 263(2):209-26)及 ICAM-l(Jun等人2001,J. Biol. Chem·; 276(31):29019-21)。 因此,藉由模擬含有IgSF域之寡價結構(oligovalent structure),包含若干IgSF域之本發明融合體可有利地用於 調節其相應結合搭配物之活性。 如本文所用,術語SIRPy係指CD172g。人類SIRPy包括 SEQ ID NO:26以及人類SIRPy之任何天然多形變異體(例如 包含單核苷酸多形現象(SNP))、或拼接變異體。人類中所 見之拼接變異體或SIRPy核苷酸序列中之SNP之實例描述 於表3中。 表3 : SIRPY蛋白質之變異體 變異體類型 變異體ID 描述 拼接變異體 NP_061026.2 序列編號:26 NP_001034597.1 胺基酸250-360缺失 NP_543006 胺基酸144-360缺失 ENSP00000370992 胺基酸1-33缺失 單核苷酸多 rs6074959 DNA : G或T ;蛋白質:A或S(NP 061026.2之 形現象 位置5) 152gl8.doc •26- 201130511 rs6043409 ϋΝλ : T或C ;蛋白質:V或A(NP_061026.2之 位置263) rs6034239 DNA : C或T ;蛋白質:S或L(NP_061026.2之 位置286) rs41275436 DNA : G或C ;蛋白質:V或L(NP_061026.2之 位置316) rs41275434 DNA : C或T ;蛋白質:A或V(NP_061026.2之 位置338) rs35062363 DNA : C或T ;蛋白質:A或V(NP_061026.2之 位置368) 如本文所用之術語「Kassoc」或「Ka」欲指特定蛋白質-蛋白質相互作用之締合速率,而如本文所用之術語 「Kdis」或「Kd」欲指特定蛋白質-蛋白質相互作用之解離 速率。如本文所用之術語「KD」欲指解離常數,其由Kd與 Ka之比率(亦即Kd/Ka)獲得且表示為莫耳濃度(M)。可使用 此項技術中已充分確立之方法測定蛋白質-蛋白質相互作 用的KD值。一種測定蛋白質/蛋白質相互作用之KD之方法 為使用表面電漿子共振或使用生物感測器系統,諸如 BiaCORE®系統。以下實例中描述至少一種測定本發明蛋 白質與SIRPa相互作用之KD的檢定。 如本文所用,術語「親和力」係指多肽與其目標之單一 位點之間的相互作用的強度。在各位點内,多肽之結合區 經由弱非共價力與其目標之眾多位點相互作用;相互作用 愈多,親和力愈強。 如本文所用,用於結合多肽或蛋白質之術語「高親和 力」係指多肽或蛋白質對其目標之KD為1 μΜ或1 μΜ以 下。 如本文所用,「促進表現SIRPa之白血球之黏著」的蛋白 152818.doc -27- 201130511 質係指藉由與功能性細胞SIRPa結合而拮抗細胞SIRPcc與細 胞CD47之相互作用的蛋白質。表現SIRPa之人類白血球 (SIRPa+細胞)與重組SIRPa結合蛋白之細胞黏著增強可用 作拮抗活性之替代評估。SIRPa+白血球之代表為發炎性骨 髓白血球或惡性SIRPa+白血球細胞株,例如U937、 Monomac 6、MUTZ-3、KG-1、THP-1。可藉由基於分析板 之細胞黏著檢定量測對黏著之此種改良之促進。使用 SIRPa+U937細胞之此基於分析板之細胞黏著檢定之實例 描述於實例中。在一特定實施例中,如基於分析板之細胞 結合檢定中所量測,「促進表現SIRPa之白血球之黏著」的 蛋白質為以20 nM或20 nM以下,例如2 nM或2 nM以下, 例如20 pM及200 pM及2 nM之EC50促進SIRPa U937細胞之 黏著的蛋白質,如實例中所述。 如本文所用,「抑制免疫複合物刺激之細胞細胞激素釋 放」的蛋白質為抑制細胞激素〇jWIL-6、IL-10、IL-12p70、IL-23、IL-8及/或TNF-a)自末梢血液單核細胞、習 知樹突狀細胞(DC)及/或經金黃色葡萄球菌Cowan 1 (Pansorbin)或可溶性CD40L及IFN-γ刺激之單核細胞源性 DC釋放的蛋白質。免疫複合物刺激之樹突狀細胞細胞激 素釋放檢定之一實例為活體外產生之單核細胞源性樹突狀 細胞中金黃色葡萄球菌Cowan菌株粒子刺激之促發炎性細 胞激素釋放,其更詳細地描述於以下實例中。在一較佳實 施例中,「抑制免疫複合物刺激之細胞細胞激素釋放」的 蛋白質為如樹突狀細胞細胞激素釋放檢定中所量測,以2 152818.doc •28- 201130511 nM或2 nM以下、〇.2咖或〇2碰以下,例如介於2祕與 20 pM之間的1(:5()抑制活體外產生之單核細胞源、性樹突狀 、’田胞中金汽色葡萄球菌c〇wan菌株粒子刺激之促發炎性細 胞素釋放的蛋白質。 如本文所用’除非另外更明確定義,否則術語「抑制」 在與功旎性檢定相關時係指相較於陰性對照,對所量測功 能的任何統計學上顯著之抑制。 〇 評估本發明之可溶性蛋白質或融合體對SIRPa之功能性 質的影響之檢定進一步詳述於實例中。 如本文所用’術語「個體」包括任何人類或非人類動 物。 術語「非人類動物」包括所有脊椎動物,例如哺乳動物 及非哺乳動物,諸如非人類靈長類動物、綿羊、犬、貓、 馬、母牛、雞、兩棲動物、爬行動物等。 如本文所用,術語「最佳化」意謂核苷酸序列已經改變 〇 以使用在生產細胞或生物體(真核細胞(例如畢赤酵母 (Pzc/πα)或酵母(以細胞、木黴(乃幻 細胞、中國倉鼠卵巢細胞(CH0)或人類細胞)抑或原核細胞 (例如大腸桿菌co/〇菌株))中為較佳之密碼子 編碼胺基酸序列。 最佳化核苷酸序列經工程改造以完全保留或儘可能多地 保留最初由起始核苷酸序列編碼之胺基酸序列(其亦稱為 「親本」序列)。本文之最佳化序列已經工程改造以具有 在相應生產細胞或生物體,例如哺乳動物細胞中為較佳的 152818.doc -29- 201130511 密碼子,然而本文中亦設想此等序列在其他原核或真核細 胞中之最佳化表現。由最佳化核苷酸序列編碼之胺基酸序 列亦稱為最佳化。 本發明之各種態樣進一步詳述於以下子章節中。 本發明之較佳實施例為選自由(Fab)樣蛋白質、(Fab)d^ 蛋白質、融合體及其衍生物組成之群且包含如下文所述之 SIRPa結合域的可溶性SIRPa結合蛋白。為便於理解,包含 SIRPa結合域之(Fab)樣蛋白質、(Fab)2樣蛋白質、融合體 及其衍生物稱為本發明之SIRPa結合蛋白。 SIRPa結合域 如本文所用,「SIRPa結合域」係指為在適當條件下與 SIRPa結合所必需的任何單鏈多肽域。SIRPa結合域包含直 接參與與SIRPa之物理相互作用之所有胺基酸殘基。其可 另外包含不直接與SIRPa相互作用但為達成SIRPa結合域與 SIRPa相互作用之適當構形所需的其他胺基酸。SIRPa結合 域可與異源域融合而不顯著改變其與SIRPa的結合性質。 SIRPa結合域可選自已知與SIRPa結合之蛋白質(諸如CD47 蛋白)之結合域。SIRPa結合域可進一步由SIRPa之人工結 合劑組成。特定言之,來源於單鏈免疫球蛋白骨架之結合 劑,諸如單域抗體、單鏈抗體(scFv)或駱駝科抗體(camelid antibody)。在一實施例中,術語「SIRPa結合域」不含有 來源於與SIRPa結合之抗體之可變區(諸如VH及Vl區)的 SIRPa抗原結合區。 在一較佳實施例中,SIRPa結合域係選自由以下組成之 152818.doc -30- 201130511 群: (i) 人類CD47之細胞外域; (ii) SEQ ID NO:4之多肽或 SEQ ID NO:4之保留 SIRPcx結 合性質之片段;及, (iii) SEQ ID NO:4 之與 SEQ ID NO:4 具有至少 60%、 70%、80%、90%、95%、96%、97%、98%或 99%序列一 致性且保留SIRPa結合性質的變異型多肽。 本發明之SIRPa結合蛋白應保留與SIRPa結合之能力。 〇 CD47之結合域已經充分表徵且人類CD47之一個細胞外域 為SEQ ID NO:4之多肽。因此SEQ ID NO:4之多肽之片段 可選自包含CD47之SIRPa結合域的彼等片段。彼等片段通 常不包含CD47之跨膜域及細胞内域。在非限制性說明性 實施例中,SIRPa結合域基本上由SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:21、SEQ ID NO:23 或 SEQ ID NO:27組 成。片段包括(但不限於)已自SEQ ID NO:4、SEQ ID ❹ NO:21或SEQ ID NO:3之C-端或N-端截短1至10個胺基酸的 較短多肽,例如 SEQ ID NO:23 或 SEQ ID NO:27。SIRPa結 合域進一步包括(但不限於)SEQ ID NO:4之變異型多肽, 其中胺基酸殘基已藉由胺基酸缺失、插入或取代而突變, 但仍與 SEQ ID NO:4 具有至少 60%、70%、80%、90%、 95%、96%、97%、98%或99%—致性;只要天然序列之改 變不實質上影響SIRPa結合蛋白之生物活性,特定言之其 與SIRPa之結合性質即可。在一些實施例中,其包括突變 型胺基酸序列,其中當與SEQ ID NO:4比較時,SIRPa結合 152818.doc -31 · 201130511 域中不超過1、2、3、4或5個胺基酸已藉由胺基酸缺失或 取代而突變。突變型胺基酸序列之實例為來源於單核苷酸 多形現象之彼等序列(參見表2)。 如本文所用,兩個序列之間的一致性百分比為該等序列 共有之相同位置數之函數(亦即一致性%=相同位置數/位置 總數X 1 00) ’考慮需要引入以達成兩個序列之最佳對準的 空隙數及各空隙之長度。序列比較及兩個序列之間一致性 百分比之測定可使用如下所述之數學演算法來完成。 可使用已併入ALIGN程式中之E. Myers及W. Miller(Comput.
Appl. Biosci. 4:11-17,1988)之演算法測定兩個胺基酸序列之 間的一致性百分比。此外,可使用已併入GCG套裝軟體中 之 GAP程式中的 Needleman及 Wunsch(J. Mol. Biol. 48:443-453,1970)演算法測定兩個胺基酸序列之間的一致性百分 比。測定一致性百分比之另一程式為CLUSTAL(M. Larkin 等人Bioinformatics 23:2947-2948,2007;首先由 D. Higgins及 Ρ· Sharp, Gene 73:237-244, 1988描述),其可以單獨程式形 式或經由網站祠服器(參見http://www.clustal.org/)獲得。 在一特定實施例中’ SIRPa結合域包括SEQ ID NO:4或 SEQ ID NO:3 之改變,其中 SEQ ID NO:4 或 SEQ ID NO:3 之 該等改變基本上由保守性胺基酸取代組成。 保守性胺基酸取代為胺基酸殘基經具有類似側鏈之胺基 酸殘基置換之取代。此項技術中已定義具有類似側鏈之胺 基酸殘基的家族。此等家族包括具有鹼性側鏈之胺基酸 (例如離胺酸、精胺酸、組胺酸)、具有酸性側鏈之胺基酸 152818.doc -32- 201130511 (例如天冬胺酸、麩胺酸)、具有不帶電極性側鏈之胺基酸 (例如甘胺酸、天冬醯胺、麵胺醯胺、絲胺酸、蘇胺酸、 酪胺酸、半胱胺酸、色胺酸)、具有非極性側鏈之胺基酸 (例如丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯 丙胺酸、甲硫胺酸)、具有β分支側鏈之胺基酸(例如蘇胺 酸、纈胺酸、異白胺酸)及具有芳族側鏈之胺基酸(例如酪 胺酸、苯丙胺酸、色胺酸、組胺酸)。因此,SEQ ID ΝΟ:4 或SEQ ID ΝΟ··3之SIRPa結合域内之一或多個胺基酸殘基可 經來自同一側鏈家族之其他胺基酸殘基置換,且可使用本 文所述之結合或功能檢定測試新多肽變異體之所保留功 能。 在另一實施例中,SIRPa結合域選自與非人類靈長類動 物(諸如獼猴(cynomolgus monkey)或恒河猴(rhesus monkey))之SIRPa交叉反應的SIRPa結合域。 在另一實施例中,SIRPa結合域選自不與密切相關於 SIRPa之人類蛋白質(諸如SIRPy)交叉反應的SIRPa結合 域。 在一些實施例中,SIRPa結合域選自保留包含此SIRPa結 合域之SIRPa結合蛋白抑制CD47-FC融合物與SIRPa+ U937 細胞結合之能力的SIRPa結合域,其中如基於分析板之細 胞黏著檢定所量測,該抑制程度至少與包含SEQ ID NO:4 之人類SIRPa之細胞外域的SIRPa結合蛋白相同。 在其他實施例中,SIRPa結合域選自保留包含此SIRPa結 合域之SIRPa結合蛋白抑制活體外分化之骨髓樹突狀細胞 152818.doc -33- 201130511 中金黃色葡萄球菌Cowan菌株粒子刺激之促發炎性細胞激 素釋放之能力的SIRPa結合域,其中如樹突狀細胞細胞激 素釋放檢定中所量測,該抑制程度至少與包含SEQID NO:4之人類SIRPa之細胞外域的SIRPa結合蛋白相同。 本發明之(Fab)樣或(Fab’)2樣SIRPa結合蛋白 在一實施例中,本發明之SIRPa結合蛋白為與SIRPa結合 之(Fab)樣或(Fab')2樣蛋白質。 抗體之Fab片段已知為含有抗體之結合區的片段,由輕 鏈之CL及VL區及重鏈之CH1及VH區組成。(Fab)樣蛋白質為 與VH及VL區經異源結合域,例如SIRPa結合域置換之(Fab) 片段類似之蛋白質。在SIRPa結合域相同之實施例中,所 得本發明(Fab)樣蛋白質包含兩個相同結合域且因此關於 SIRPa結合可為二價。 (Fab')2樣蛋白質進一步包含使兩個(Fab)樣蛋白質能夠經 由鉸鍵區處之二硫橋鍵共價締合的抗體鉸鏈區。所得蛋白 質包含四個結合域。在一實施例中,此等異源結合域為來 源於I g S F域之結合域。 在一實施例中,本發明之SIRPa結合蛋白為(Fab)樣蛋白 質,其由以下組成:(i)包含第一 SIRPa結合域與抗體恆定 CH1重鏈區共價連接之第一單鏈多肽,及(ii)包含第二 SIRPa結合域與抗體恆定CL輕鏈區共價連接之第二單鏈多 肽。 SIRPa結合域可與恆定區直接同框融合或經由多肽連接 子(間隔子(spacer))融合。此等間隔子可為單一胺基酸(諸 152818.doc -34- 201130511 如甘胺馱玟基)或5-1〇〇個胺基酸,例如5_2〇個胺基酸。連 接子應允許SIRPa結合域採取適當空間定向以形成與siRpa 之結合位點。適合多肽連接子可選自採用可撓性構形之多 肽連接子itb等連接子之實例為(但不限於)包含甘胺酸及 絲胺酸殘基之彼等連接子,例如(Gly4Ser)n,其中η為介於 1-12之間,例如介於丨與4之間的整數,例如2。 本發明之(Fab)樣或(Fabg SIRp〇[結合蛋白可結合或融 0 合在一起以形成多價蛋白質。 熟習此項技術者宜進一步使用為工程改造抗體分子開發 之为景技術以增加分子價數或改良或改適經工程改造之分 子之性質以用於其特定用途。 實%例中’本發明之(Fab)樣或(Fab)2樣結 合蛋白可與另一異源蛋白質融合,此能夠增加所得融合蛋 白於血液中之半衰期。 此異源蛋白質可為例如免疫球蛋白、血清白蛋白及其片 〇段。此異源蛋白質亦可為能夠與血清白蛋白結合以便投鱼 個體時增加所得分子之半衰期的多狀。此方 # EP0486525中。 質進—步包含用於 或者或此外,(Fab)樣或(Fab)2樣蛋白 多聚化之結構域。 SIRPa結合融合體 在另-態樣中’本發明係關於包含如以上段落中 至少-個SIRPa結合域或(Fab)樣蛋白質的融合體。 融合體之兩個雜:聚體可含有具有不同結合特異性之不 152818.doc •35- 201130511 同結合域,藉此產生雙特異性融合體。舉例而言,融合體 可包含一個含有SIRPa結合域之雜二聚體及另一含有另一 異源結合域之雜二聚體。或者,融合體之兩個雜二聚體均 包含SIRPa結合域。在後者中,此等SIRPa結合域之結構或 胺基酸序列可相同或不同。在一較佳實施例中,融合體之 兩個雜二聚體均包含相同SIRPa結合域。 在一特定實施例中,與抗體結構類似,各雜二聚體之重 鏈包含抗體之CH2及CH3區,稱為融合體之Fc部分或Fc部 分。融合體之Fc部分之詳細描述在以下其他段落中描述。 本發明SIRPa結合融合體之特定實例
本發明融合體包括(但不限於)如實例中之表4中所述經 結構表徵的融合體。此等實例中所用之SIRPct結合域展示 於 SEQ ID NO:4、SEQ ID NO:21、SEQ ID NO:23 或 SEQ ID NO:27中。本發明SIRPa結合融合體之重鏈胺基酸序列之 特定實例為選自由以下組成之群之多肽序列:SEQ ID NO:5、SEQ ID NO:12、SEQ ID NO:18、SEQ ID NO:19、 SEQ ID NO:24、SEQ ID NO:29、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42、SEQ ID NO:44、 SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:50、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56及 SEQ ID NO:58。 本發明SIRPa結合融合體之輕鏈胺基酸序列之特定實例為 選自由以下組成之群之多肽序列:SEQ ID NO:6、SEQ ID NO:13、SEQ ID NO:20、SEQ ID NO:25、SEQ ID NO:37、 SEQ ID NO:39、SEQ ID NO:41、SEQ ID NO:43、SEQ ID 152818.doc -36- 201130511 NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51、 SEQ ID NO:53、SEQ ID NO:55及 SEQ ID NO:57。 本發明之其他SIRPa結合融合體包含已藉由胺基酸缺 失、插入或取代而突變,但仍與SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:21、SEQ ID NO:23 或 SEQ ID NO:27之 任一相應SIRPa結合域具有至少60%、70%、80%、90%、 95%、96%、97%、98%或99%序列一致性的SIRPa結合 域。在一些實施例中,本發明融合體包含包括突變型胺基 酸序列之SIRPa結合域,其中當與如任一序列SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:21、SEQ ID NO:23 或 SEQ ID NO:27中描述之SIRPa結合域比較時,在SIRPa結 合域中不超過1、2、3、4或5個胺基酸已藉由胺基酸缺失 或取代而改變。 在一實施例中,描述為1號實例之本發明SIRPa結合融合 體包含8丑()10>^0:5之重鏈及8£(5 10]^0:6之輕鏈。 I在一實施例中,描述為2號實例之本發明SIRPa結合融 合體包含SEQIDNO:18之重鏈及SEQIDNO:6之輕鏈。 在一實施例中,描述為3號實例之本發明SIRPa結合融合 體包含8£卩1〇1^〇:19之重鏈及8£(5 1〇]^〇:20之輕鏈。 在一實施例中,描述為4號實例之本發明SIRPa結合融合 體包含SEQIDNO:12之重鏈及SEQIDNO:13之輕鏈。 在一實施例中,描述為5號實例之本發明SIRPa結合融合 體包含SEQ ID NO:24之重鏈及SEQ ID NO:25之輕鏈。 在一實施例中,描述為6號實例之本發明SIRPa結合融合 152818.doc -37- 201130511 體包含SEQ ID NO:36之重鏈及SEQ ID NO:37之輕鏈。 在一實施例中,描述為7號實例之本發明SIRPa結合融合 體包含SEQ ID NO:38之重鏈及SEQ ID NO:39之輕鏈。 在一實施例中,描述為8號實例之本發明SIRPa結合融合 體包含SEQ ID NO:40之重鏈及SEQ ID NO:41之輕鏈。 在一實施例中,描述為9號實例之本發明SIRPa結合融合 體包含SEQ ID N〇:42之重鏈及SEQ ID NO:43之輕鏈。 在一實施例中,描述為1 〇號實例之本發明SIRPa結合融 合體包含SEQ ID NO:44之重鏈及SEQ ID NO:45之輕鏈。 在一實施例中,描述為11號實例之本發明SIRPa結合融 合體包含SEQ ID NO:46之重鏈及SEQ ID NO:47之輕鏈。 在一實施例中,描述為12號實例之本發明SIRPa結合融 合體包含SEQ ID NO:48之重鏈及SEQ ID NO:49之輕鏈。 在一實施例中,描述為1 3號實例之本發明SIRPa結合融 合體包含SEQIDNO:5 0之重鏈及SEQIDNO:51之輕鏈。 在一實施例中,描述為14號實例之本發明SIRPa結合融 合體包含SEQ ID NO:52之重鏈及SEQ ID NO:53之輕鏈。 在一實施例中,描述為1 5號實例之本發明SIRPa結合融 合體包含SEQ ID NO:54之重鏈及SEQ ID NO:55之輕鏈。 在一實施例中,描述為1 6號實例之本發明SIRPa結合融 合體包含8£卩10 1^0:5 6之重鏈及8£(5 10 1^0:5 7之輕鏈。 在一實施例中,描述為17號實例之本發明SIRPa結合融 合體包含SEQ ID NO:5 8之重鏈及SEQ ID NO:20之輕鏈。 在一實施例中,描述為18號實例之本發明SIRPa結合融 152818.doc -38- 201130511 合體包含SEQ ID NO:29之重鏈及SEQ ID NO:20之輕鏈。 在另一態樣中,本發明提供描述為1號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:10之核苷酸序列 編碼之重鏈;及由SEQ ID NO: 11之核苷酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為3號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:59之核苷酸序列 _ 編碼之重鏈;及由SEQ ID NO:60之核苷酸序列編碼之輕 〇 鏈。 在另一態樣中,本發明提供描述為4號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:61之核苷酸序列 編碼之重鏈;及由SEQ ID NO:62之核苷酸序列編碼之輕 鏈。 在另一態樣中,本發明提供描述為5號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:63之核苷酸序列 Q 編碼之重鏈;及由選自由SEQ ID NO:64組成之群之核苷酸 序列編碼的輕鍵。 在另一態樣中,本發明提供描述為6號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:65之核苷酸序列 編碼之重鍵,及由SEQ ID NO:66之核普酸序列編碼之輕 鏈。 在另一態樣中,本發明提供描述為7號實例之本發明之 經分離之融合體,其具有··由SEQ ID NO:67之核苷酸序列 編碼之重鏈;及由SEQ ID NO:68之核苦酸序列編碼之輕 152818.doc -39- 201130511 鍵。 在另一態樣中,本發明提供描述為8號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:69之核苷酸序列 編碼之重鏈;及由SEQ ID NO:70之核苷酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為9號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:71之核苷酸序列 編碼之重鏈;及由SEQ ID NO:72之核苷酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為10號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:73之核苷酸序列 編碼之重鏈;及由SEQ ID NO:74之核苷酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為11號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:75之核苷酸序列 編碼之重鏈;及由SEQ ID NO:76之核苦酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為12號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:77之核苷酸序列 編碼之重鏈;及由SEQ ID NO:78之核苷酸序列編碼之輕 鍵。 在另一態樣中,本發明提供描述為13號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:79之核苷酸序列 編碼之重鏈;及由SEQ ID NO:80之核苷酸序列編碼之輕 152818.doc -40- 201130511 鍵。 在另一態樣中,本發明提供描述為14號實例之本發明之 經分離之融合體,其具有:由SEQ ID N〇:81之核苷酸序列 編碼之重鏈;及由SEQ ID NO:82之核苷酸序列編碼之輕 鏈。 在另一態樣中,本發明提供描述為15號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO: 83之核苷酸序列 _ 編碼之重鏈;及由SEQ ID NO:84之核苷酸序列編碼之輕 〇 鏈。 在另一態樣中,本發明提供描述為16號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:85之核苷酸序列 編碼之重鏈;及由SEQ ID NO:86之核苷酸序列編碼之輕 鏈。 在另一態樣中,本發明提供描述為17號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:87之核苷酸序列 0 編碼之重鍵;及由SEQ ID NO:60之核苦酸序列編碼之輕 鏈。 在另一態樣中,本發明提供描述為1 8號實例之本發明之 經分離之融合體,其具有:由SEQ ID NO:88之核苷酸序列 編碼之重鏈;及由SEQ ID NO:60之核苷酸序列編碼之輕 鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 曰以寄存編號 152818.doc -41 - 201130511 DSM 24361寄存在DSMZ之質體p3HC_5460_ID59内所含之 相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24362寄存在DSMZ之質體 p3LC_5401_ID00内所含之相應核苷酸序歹ij編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel,Switzerland在 2010年 12 月 13 日以寄存編號 081^ 243 63寄存在081^2之質體?411(:_5444_1061内所含之 相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus,CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24364寄存在DSMZ之質體 p4LC」445_ID62内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010年 12 月 10 日以寄存編號 DSM 24330寄存在DSMZ之質體p5HC_5466_ID63内所含之 相應核苦酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel,Switzerland在 2010 年12月13日以寄存編號DSM 24365寄存在DSMZ之質體 p5LC_5467_ID64内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel,Switzerland在 2010年 12 月 13 日以寄存編號 152818.doc -42- 201130511 〇8皿243 66寄存在〇8河2之質體?611(:_5440_1〇65内所含之 相應核苷酸序列編碼的重鍵,及由如由Novartis Pharma AG, Novartis Campus,CH-4002 Basel, Switzerland在 2010 年12月13曰以寄存編號DSM 24367寄存在DSMZ之質體 p6LC_5441_ID66内所含之相應核苷酸序列編碼的輕鏈。
Ο 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel,Switzerland 在 2010 年 12 月 13 日以寄存編號 DSM 24368寄存在DSMZ之質體p7HC_5450_ID67内所含之 相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13曰以寄存編號DSM 24369寄存在DSMZ之質體 p7LC—545 1—ID68内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010年 12 月 13 日以寄存編號 DSM 24370寄存在DSMZ之質體p8HC_5442_ID69内所含之 相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24371寄存在DSMZ之質體 p8LC_5443_ID70内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel,Switzerland 在 2010 年 12 月 10 日以寄存編號 152818.doc -43- 201130511 DSM 24331寄存在DSMZ之質體p9HC_5452_ID71内所含之 相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24372寄存在DSMZ之質體 p9LC—5453—ID72内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 日以寄存編號 DSM 24373寄存在DSMZ之質體pl0HC_5454_ID73内所含 之相應核苦酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24734寄存在DSMZ之質體 pl0LC_545 5_ID74内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 日以寄存編號 DSM 243 75寄存在DSMZ之質體pi 1HC_5446_ID75内所含 之相應核苷酸序列編碼的重鍵,及由如由Novartis Pharma AG,Novartis Campus,CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24376寄存在DSMZ之質體 pllLC_5447_ID76内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12月 10 日以寄存編號 152818.doc •44- 201130511 DSM 24332寄存在DSMZ之質體pl2HC_5456_ID77内所含 之相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus, CH-4002 Basel,Switzerland在 2010 年12月13曰以寄存編號DSM 24377寄存在DSMZ之質體 pl2LC_5457_ID78内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 日以寄存編號 DSM 243 78寄存在081^12之質體?1311(:_5448」079内所含 之相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24379寄存在DSMZ之質體 pl3LC_5449_ID80内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 日以寄存編號 DSM 24380寄存在DSMZ之質體pl4HC_5468_ID81内所含 之相應核普酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24381寄存在DSMZ之質體 pl4LC_5469_ID82内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel,Switzerland 在 2010 年 12 月 10 日以寄存編號 152818.doc -45- 201130511 DSM 24333寄存在DSMZ之質體pl5HC_5458_ID83内所含 之相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13日以寄存編號DSM 24382寄存在DSMZ之質體 pl5LC_5459_ID84内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel,Switzerland 在 2010 年 12 月 10 曰以寄存編號 DSM 24334寄存在DSMZ之質體pl6HC_5464_ID85内所含 之相應核苷酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus,CH-4002 Basel, Switzerland在 2010 年12月13曰以寄存編號DSM 24383寄存在DSMZ之質體 pl6LC_5465_ID86内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland在 2010 年 12 月 13 日以寄存編號 DSM 24384寄存在DSMZ之質體p31HC_5470_ID89内所含 之相應核苦酸序列編碼的重鏈,及由如由Novartis Pharma AG, Novartis Campus, CH-4002 Basel, Switzerland在 2010 年12月13曰以寄存編號DSM 24385寄存在DSMZ之質體 p32LC_5471_ID90内所含之相應核苷酸序列編碼的輕鏈。 在另一態樣中,本發明提供本發明之經分離之融合體, 其具有:由如由 Novartis Pharma AG,Novartis Campus, CH-4002 Basel, Switzerland 在 2010 年 12 月 13 曰以寄存編號 152818.doc • 46- 201130511 DSM 24386寄存在DSMZ之質體p34HC_5472_ID91内所含 之相應核苦酸序列編碼的重鏈,及由如由Novartis Pharma AG,Novartis Campus,CH-4002 Basel, Switzerland在 2010 年12月13曰以寄存編號DSM 24387寄存在DSMZ之質體 p3 5LC_5473_ID92内所含之相應核苷酸序列編碼的輕鏈。 本發明之其他SIRPcx結合融合體包含由已藉由核苷酸缺 失、插入或取代而突變,但仍與SEQ ID NO:10或SEQ ID NO:14或 SEQ ID NO:59 或 SEQ ID NO:63 或 SEQ ID NO:67具 有至少 60%、70%、80%、90% ' 95%、96%、97%、98%或 99%序列一致性之核苷酸序列編碼的重鏈,及由已藉由核 苷酸缺失、插入或取代而突變,但仍與SEQ ID NO: 11或 SEQ ID NO:15 或 SEQ ID NO:60或 SEQ ID NO:64或 SEQ ID NO:68 具有至少 60%、70%、80%、90%、95%、96%、 97°/。、98°/。或99%序列一致性之核苷酸序列編碼的輕鍵。 在一些實施例中,本發明融合體包含由包括當與SEQ ID NO:10或 SEQ ID NO:14或 SEQ ID NO:59或 SEQ ID NO:63 或 SEQ ID NO:67比較時,不超過1、2、3、4或5個核苷酸已 藉由核苷酸缺失、插入或取代而改變之突變型核苷酸序列 之核苷酸序列編碼的重鏈,及由包括當與SEQ ID NO: 11或 SEQ ID NO:15 或 SEQ ID NO:60 或 SEQ ID NO:64或 SEQ ID NO:68比較時’不超過1、2、3、4或5個核苷酸已藉由核苷 酸缺失、插入或取代而改變之突變型核苷酸序列之核苷酸 序列編碼的輕鏈。 功能性融合體 152818.doc -47- 201130511 在另一實施例中,本發明SIRPa結合融合體具有與以上 段落中所述之特定SIRPa結合融合體,特定言之如表4中所 述之1-1 8號實例之相應胺基酸及核苷酸序列同源的重鏈及 輕鏈胺基酸序列;重鏈及輕鏈核苷酸序列或與重鏈及輕鏈 恆定區融合之SIRPa結合域,且其中該等融合體保留與以 上段落中所述之特定SIRPa結合融合體,特定言之如表4中 所述之1-1 8號實例之至少一者實質上相同的功能性質。 舉例而言,本發明提供包含重鏈胺基酸序列及輕鏈胺基 酸序列之經分離之融合體,其中:該重鏈具有與選自由 SEQ ID NO: 5 ' SEQ ID NO:12 ' SEQ ID NO:18 ' SEQ ID NO:19及 SEQ ID NO:24、SEQ ID NO:29、SEQ ID NO:36、 SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42、SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:50、 SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56或 SEQ ID NO:58組成之群之胺基酸序列至少80%、至少90%、至少 95%或至少99% —致的胺基酸序列;該輕鏈具有與選自由 SEQ ID NO:6、SEQ ID NO:13、SEQ ID NO:20、SEQ ID NO:25、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:41、 SEQ ID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:55及 SEQ ID NO:57組成之群之胺基酸序列至少80%、至少 90%、至少95%或至少99% —致的胺基酸序列;該融合體 特異性結合SIRPa,且該融合體展現至少一種以下功能性 質:其促進SIRPa+白血球之黏著,或其抑制活體外產生之 152818.doc -48- 201130511 單核細胞源性樹突狀細胞中金黃色葡萄球菌Cowan菌株粒 子刺激之促發炎性細胞激素釋放。 如本文所用,「特異性結合SIRPcx」之融合體欲指在實例 中所述之至少一種結合親和力檢定中,例如根據BiaCORE 檢定中之表面電漿子共振,以4 μΜ或4 μΜ以下、2 μΜ 或2 μΜ以下、400 ηΜ或400 ηΜ以下之KD與SEQ ID ΝΟ:1之 人類SIRPa多肽結合的融合體。「與除SIRPa以外之多肽交 叉反應」之融合體欲指以4 μΜ或4 μΜ以下、2 μΜ或2 μΜ 以下、400 ηΜ或400 ηΜ以下之KD結合另一多肽的融合 體。「不與特定多肽交叉反應」之融合體欲指在類似條件 下以比量度該融合體與人類SIRPa之結合親和力的KD高至 少10倍,較佳至少百倍之KD與彼多肽結合的融合體。在某 些實施例中,在標準結合檢定中,不與另一多肽交叉反應 之此等融合體對此等蛋白質展現基本上不可偵測之結合。 在各種實施例中,融合體可展現一或多種或所有以上論 述之功能性質。
在其他實施例中,SIRPa結合域可與以上關於「SIRPa結 合域」之段落中所述之至少一個特定SIRPa結合域序列, 包括(但不限於)SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:21、SEQ ID NO:23 或 SEQ ID NO:27 50%、60%、 70%、80%、90%、95%、96%、97%、98%或 99%—致。在 其他實施例中,SIRPa結合域可與以上關於「SIRPa結合 域」之段落中所述之至少一個特定SIRPa結合域序列,包 括(但不限於)SEQ ID NO:3、SEQ ID NO:4、SEQ ID 152818.doc •49- 201130511 NO:21、SEQ ID NO:23 或 SEQ ID NO:27—致,除該特定序 列中不超過1、2、3、4或5個胺基酸位置中存在胺基酸取 代以外。 具有與特定描述之SIRPa結合域高度(亦即至少80%、 90%、95%、99%或99%以上)一致之SIRPa結合域的融合體 可藉由分別對編碼該等特定SIRPa結合域之核酸分子進行 突變誘發(例如定點突變誘發或PCR介導之突變誘發),隨 後使用本文所述之功能檢定測試所編碼改變之融合體的保 留功能(亦即以上所述之功能)來獲得。 在其他實施例中,重鏈及輕鏈胺基酸序列可與以上所述 之1-1 8號特定融合體實例之重鏈及輕鏈50%、60%、70%、 80%、90%、95%、96%、97%、98% 或 99%—致,同時保 留上述SIRPa結合融合體之至少一種功能性質。具有分別 與 SEQ ID NO: 5、SEQ ID NO:12、SEQ ID NO:18、SEQ ID NO:19 及 SEQ ID NO:24、SEQ ID NO:29、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42、 SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:50、SEQ ID NO:52、SEQ ID N〇:54、SEQ ID NO:56或 SEQ ID NO:58中任一者之相應重鏈及SEQ ID NO:6、SEQ ID NO:13、SEQ ID NO:20、SEQ ID NO:25、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:41、SEQ ID ΝΟ··43、 SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:55及 SEQ ID NO:57 中 任一者之相應輕鏈高度(亦即至少80%、90%、95%或95% 152818.doc -50- 201130511 以上)一致之重鏈及輕鏈的SIRPa結合融合體可藉由分別對 編碼重鏈 SEQ ID NO: 5、SEQ ID NO:12、SEQ ID NO:18、
SEQ ID NO:19及 SEQ ID NO:24、SEQ ID NO:29、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42、
SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:50、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56或
SEQ ID NO:58 及輕鏈 SEQ ID ΝΟ··6、SEQ ID NO:13、SEQ
^ ID NO:20、SEQ ID NO:25、SEQ ID NO:37、SEQ ID 〇 NO:39、SEQ ID NO:41、SEQ ID NO:43、SEQ ID NO:45、 SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:55或SEQ ID NO:57之核酸分子進行突 變誘發(例如定點突變誘發或PCR介導之突變誘發),隨後 使用本文所述之功能檢定測試所編碼改變之SIRPa結合融 合體的保留功能(亦即以上所述之功能)來獲得。 在一實施例中’本發明SIRPa結合融合體為1號實例之變 q 異體,其具有與SEQ ID NO:5至少80%、90% ' 95%或99% 一致之重鏈及與SEQ ID NO:6至少80%、90%、95%或99% 一致之輕鍵,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為2號實例之變 異體,其具有與SEQ ID NO: 18至少80%、90%、95°/。或99% 152818.doc •51 · 201130511 一致之重鏈及與SEQ ID NO:6至少80%、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為3號實例之變 異體,其具有與SEQ ID NO: 19至少80%、90%、95%或99% 一致之重鏈及與8£(5 10 1^0:20至少80%、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為4號實例之變 異體,其具有與SEQ ID NO: 12至少80%、90%、95%或99% 一致之重鏈及與SEQ ID NO:13至少80%、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為5號實例之變 異體,其具有與SEQ ID NO:24至少80%、90%、95%或99% 152818.doc •52- 201130511 一致之重鏈及與SEQ ID NO:25至少80°/。、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中金黃色 葡萄球菌Cowan菌株粒子刺激之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為6號實例之變 異體,其具有與SEQ ID NCh3 6至少80%、90%、95%或99% 一致之重鏈及與SEQ ID NO:3 7至少80%、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為7號實例之變 異體,其具有與SEQ ID NO:38至少80%、90%、95%或99% 一致之重鏈及與SEQ ID NO:39至少80°/。、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為8號實例之變 異體,其具有與SEQ ID NO:40至少80%、90%、95%或99% 一致之重鏈及與SEQ ID NO:41至少80°/。、90%、95%或99% 152818.doc -53 - 201130511 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質··其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為9號實例之變 異體,其具有與SEQ ID NO:42至少80%、90%、95%或99% 一致之重鏈及與SEQ ID ΝΟ··43至少80%、90%、95%或99% 一致之輕鏈,該融合體特異性結合SIRPa,且該融合體展 現至少一種以下功能性質:其促進SIRPa+白血球之黏著, 或其抑制活體外產生之單核細胞源性樹突狀細胞中由各種 細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或其他 細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為10號實例之 變異體,其具有與SEQ ID NO:44至少80%、90%、95%或 99%—致之重鏈及與8£(^10>10:45至少80%、90°/。、95%或 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為11號實例之 變異體,其具有與SEQ ID NO:46至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:47至少80%、90%、95%或 152818.doc -54- 201130511 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為12號實例之 變異體,其具有與SEQ ID NO:48至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:49至少80%、90%、95%或 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為13號實例之 變異體,其具有與SEQ ID NO: 50至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:51至少80%、90%、95%或 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為14號實例之 變異體,其具有與SEQ ID NO:52至少80%、90°/。、95%或 99%—致之重鏈及與SEQ ID NO: 53至少80%、90%、95%或 152818.doc -55- 201130511 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細議衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為1 5號實例之 變異體,其具有與SEQ ID NO:54至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:55至少80%、90%、95%或 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為16號實例之 變異體,其具有與SEQ ID NO:56至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:57至少80%、90%、95%或 99% —致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著,或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為17號實例之 變異體,其具有與SEQ ID NO:58至少80%、90%、95%或 99%—致之重鏈及與SEQ ID NO:20至少80%、90%、95%或 152818.doc -56- 201130511 99°/。一致之輕鏈,該融合體特異性結合siRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著’或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物,諸如金黃色葡萄球菌Cowan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 在一實施例中,本發明SIRPa結合融合體為18號實例之 變異體,其具有與SEQ ID NO:29至少80%、90%、95%或 q 99% 一致之重鏈及與SEQ ID NO:20至少80%、90%、95%或 99°/。一致之輕鏈,該融合體特異性結合SIRPa,且該融合 體展現至少一種以下功能性質:其促進SIRPa+白血球之黏 著’或其抑制活體外產生之單核細胞源性樹突狀細胞中由 各種細菌衍生物’諸如金黃色葡萄球菌C〇wan菌株粒子或 其他細菌衍生物引發之促發炎性細胞激素釋放。 融合體之Fc域
Fc域至少包含cH2及CH3域。如本文所用,術語Fc域進一 Ο 步包括(但不限於)相較於抗體之天然Fc片段(例如人類!^片 段),已在1、2、3、4或5個胺基酸位置處引入胺基酸取 代、缺失或插入的Fc變異體。
Fc域用於製備在人類中之活體内半衰期增加之可溶性構 築體的用途在此項技術中為熟知的,且例如描述KCap〇n 等人(US 5,428,130)令。在一實施例中,提出在融合體構 築體中使用類似Fc部分。然*,應瞭解本發明不涉及此項 技術之有時稱為「Fc融合蛋白」或「免疫黏附素 (immunoadhesin)」之已知蛋白質。實際上,術語「Fc融合 152818.doc -57- 201130511 蛋白」或Γ免疫黏附素」在此項技術中通常指直接與ch2 及ch3域融合但不包含Cl或Ch1區中至少一者的異源結合 區。所得蛋白質包含兩個異源結合區。融合體可包含以部 融&於CH1區之N-端,藉此重構可通常經由cHi及^雙 破鍵結與輕鏈相互作用之全長恆定重鏈。 在一實施例中,修飾融合體或SiRpa結合蛋白之Ch1之鉸 鏈區以使得鉸鏈區中半胱胺酸之數目改變,例如增加或減 少。此方法進一步描述於美國專利第5,677,425號(B〇dmer 等人)中。改變CH1之鉸鏈區中半胱胺酸殘基之數目以例如 促進輕鏈及重鏈之裝配或增加或減小融合多肽之穩定性。 在另—實施例中’修飾融合體或合蛋白之Fc區 以增加其生物半衰期。可使用各種方法。舉例而言,如美 國專利第6,277,3 75號中所述,可使一或多個以下位置突 反.252、254、256,例如:M252Y、S254T、T256E。 在其他實施例中,藉由以不同胺基酸殘基置換至少一個 胺基酸殘基來改變融合體或SIRPa結合蛋白之以區以改變 Fc部分之效應功能。舉例而言’可以不同胺基酸殘基置換 一或多個胺基酸以使Fc部分對效應配位體之親和力改變。 親和力改變之效應配位體可為例如Fc受體或補體之C1組 分。此方法進一步詳述於Winter等人之美國專利第 5,624,821 號及第 5,648,260號中。 在另一實施例中,可以不同胺基酸殘基置換一或多個選 自胺基酸殘基之胺基酸以使所得Fc部分具有改變之C 1 q結 合及/或減弱或消除之補體依賴性細胞毒性(CDC)。此方法 152818.doc • 58 - 201130511 進一步詳述於美國專利第6,194,551號(Idusogie等人)中。 在另一實施例中,改變一或多個胺基酸殘基以藉此改變 Fc區固定補體之能力。此方法進一步描述於Bodmer等人之 PCT公開案 WO 94/29351 中。 在另一實施例中,藉由修飾一或多個胺基酸對融合體或 SIRPa結合蛋白之Fc區進行修飾以增強融合多肽介導抗體 依賴性細胞毒性(ADCC)之能力及/或增加或減小Fc區對Fey 受體的親和力。此方法進一步描述於PCT公開案WO 00/42072中。此外,已定位人類IgGl上對FcyRJ、FcyRII、 FcyRIII及FeRn之結合位點且具有改良之結合的變異體已 有描述(參見 Shields, R.L.等人 2001 J· Biol. Chem. 276:6591-6604) ° 在一實施例中,融合體或SIRPa結合蛋白之Fc域具有人 類來源且可來自任何免疫球蛋白類別,諸如IgG或IgA,且 可來自任何次型,諸如人類IgGl、IgG2、IgG3及IgG4或 IgGl、IgG2、IgG3及IgG4之嵌合體。在其他實施例中,Fc 域來自非人類動物,例如(但不限於)小鼠、大鼠、兔、駱 駝科動物、鯊、非人類靈長類動物或倉鼠。 在某些實施例中,在融合體或SIRPa結合蛋白中使用 IgGl同型之Fc域。在一些特定實施例中,使用IgGl Fc片 段之突變型變異體,例如減弱或消除融合多肽介導抗體依 賴性細胞毒性(ADCC)及/或與Fey受體結合之能力的靜止 IgGl Fc。IgGl同型靜止突變體之一實例為所謂LALA突變 體,其中胺基酸位置234及235處之白胺酸殘基經丙胺酸殘 152818.doc -59- 201130511 基置換,如由Hezareh 等人(J. Virol 2001 Dec;75(24):12161-8) 所述。IgGl同型靜止突變體之另一實例包含D265A突變。 在某些實施例中,Fc域為防止Fc域之位置297處之殘基糖 基化的突變體,例如Fc域位置297處之天冬醯胺殘基的胺 基酸取代。此胺基酸取代之實例為N297經甘胺酸或丙胺酸 置換。 在另一實施例中,Fc域來源於IgG2、IgG3或IgG4。 在一實施例中,融合體或SIRPcx結合蛋白之Fc域包含二 聚化域’較佳經由能夠在包含此以域之兩個融合多肽之間 產生共價二硫橋鍵的半胱胺酸。 糖基化修飾 在另一實施例中,相較於典型哺乳動物糖基化型態(諸 如CHO或人類細胞株中獲得之糖基化型態),本發明可溶 性蛋白質,特定言之包括SIRPa結合蛋白或融合體之糖基 化^忍可改變。舉例而1* ,可藉由使用原核細胞株作為宿 主細胞或使用已經工程改造以使糖基化缺乏之哺乳動物細 胞來製備非糖基化蛋白質。亦可藉由例如改變SiRpa結合 融合體内之一或多個糖基化位點來完成碳水化合物修飾。 或者或另外,可製備糖基化類型改變之糖基化蛋白質。 可藉由例如在糖基化機構改變(亦即相較於相應野生型細 胞中觀測敎糖基化型態,可溶性蛋白質之糖基化型態改 變)之伯主細胞中表現本發明可溶性蛋白質來完成此等碳 火化口物修飾。糖基化機構改變之細胞已在此項技 述且可用作表現重組可溶性蛋白質以藉此產生糖基化田 152818.doc 201130511 之此等可溶性蛋白質的宿主細胞。舉例而言,EP 1,176,195(1^1^等人)描述編碼海藻糖基轉移酶之?1;丁8基 因之功能受到破壞的細胞株,以致該種細胞株中表現之醣 蛋白展現低海藻糖基化。WO 03/035835描述變異型CHO細 胞株Lecl3細胞,其使海藻糖連接至Asn(297)連接型碳水化 合物之能力減弱,從而亦導致彼宿主細胞中表現之醣蛋白 具有低海藻糖基化(亦參見Shields, R.L.等人2002 J. Biol. Chem. 277:26733-26740)。或者,可在經工程改造成哺乳 動物樣糖基化型態之酵母(例如曱醇酵母 或絲狀真菌(例如里氏木黴(TWc/zoi/erma reesei))中產生可 溶性蛋白質(參見例如EP1297172B1)。彼等經糖基化工程 改造之宿主細胞之優點尤其為提供具有均勻糖基化型態及/ 或較高產率之多肽組合物。 聚乙二醇化可溶性蛋白質及其他結合物 本文中由本發明涵蓋之可溶性蛋白質之另一實施例為聚 乙二醇化。本發明之可溶性蛋白質,例如SIRPa結合蛋白 或融合體可經聚乙二醇化。聚乙二醇化為一種使所得生物 製劑相較於未經聚乙二醇化之相同生物製劑之生物(例如 血清)半衰期增加的熟知技術。為使多肽聚乙二醇化,通 常使多肽與聚乙二醇(PEG),諸如PEG之反應性酯或醛衍 生物在可使一或多個PEG基團連接至多肽之條件下反應。 可藉由醯化反應或烷基化反應利用反應性PEG分子(或類似 反應性水溶性聚合物)進行聚乙二醇化。如本文中所用, 術語「聚乙二醇」意欲涵蓋已用於衍生化其他蛋白質之任 152818.doc -61 - 201130511 何形式的PEG,諸如單(C1_C10)烷氧基_聚乙二醇或單(ci· CIO)芳氧基聚乙二醇或聚乙二醇·順丁烯二醯亞胺。使蛋 白質聚乙二醇化之方法在此項技術中為已知的且可應用於 本發明之可溶性蛋白質。參見例如Nishimura等人之EP 0 154 316 及 Ishikawa 等人之 EP 0 401 384。 可使用替代結合物或聚合載體,特定言之以改良所得結 合物之藥物動力學性質。聚合載體可包含至少一種天然或 合成分支、線性或樹枝狀聚合物。聚合載體較佳可溶於水 及體液中且較佳為醫藥學上可接受之聚合物。水溶性聚合 物部分包括(但不限於)例如聚伸烷二醇及其衍生物,包括 PEG、PEG均聚物、mPEG、聚丙二醇均聚物、乙二醇與丙 二醇之共聚物’其中該等均聚物及共聚物未經取代或在一 端例如經醯基取代;聚甘油或聚唾液酸;碳水化合物、多 醋、纖維素及纖維素衍生物,包括曱基纖維素及羧甲基纖 維素;殿粉(例如羥烷基澱粉(HAS),尤其羥乙基澱粉 (HES))及糊精及其衍生物;葡聚糖及葡聚糖衍生物,包括 硫酸葡聚糖、交聯糊精及羧甲基糊精;聚葡萄胺糖 (chitosan)(—種線性多醣)、肝素(heparin)及肝素片段·,聚 乙烯醇及聚乙烯基乙趟;聚乙浠吼嘻咬酮;〇1,@_聚[(2_羥 乙基)-DL-天冬醯胺;及聚氧乙基化多元醇。 SIRPa結合蛋白作為藥劑之用途 SIRPa結合蛋白且特定言之SIRPa結合融合體可用作藥 劑’以便特定言之(以統計學上或生物學上顯著之方式)減 少或抑制個體之發炎性及/或自體免疫性反應,特定言之 15281B.doc -62- 201130511 由SIRPa+細胞介導之反應。當與細胞毒性劑或由Fc部分提 供之細胞殺傷效應功能部分結合時,SIRPa結合蛋白且特 定言之SIRPa結合融合體亦可有利地用於治療、減少或抑 制癌症或腫瘤,諸如特定言之骨髓淋巴增生性疾病,諸如 急性骨髓淋巴增生性(AML)病症或膀胱癌。 編碼本發明可溶性蛋白質之核酸分子 本發明之另一態樣係關於編碼本發明可溶性蛋白質,包 括(但不限於)與例如如實例之表4中所述之融合體相關之實 施例的核酸分子。編碼SIRPa結合融合體之核苷酸序列之 非限制性實例包含分別編碼SIRPa結合融合體之重鏈及輕 鏈的 SEQ ID NO: 10及 11。 核酸可存在於完整細胞、細胞溶解產物中,或可為呈部 分純化或實質上純形式之核酸。當核酸藉由標準技術(包 括鹼/SDS處理、CsCl條帶分離(CsCl banding)、管柱層 析、瓊脂糖凝膠電泳及此項技術中熟知之其他技術)自其 他細胞組分或其他污染物(例如其他細胞核酸或蛋白質)純 化時,其係「經分離」或「變得實質上純」。參見F. Ausubel等人編 1987 Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York。本發明之 核酸可為例如DNA或RNA且可含有或可不含有内含子序 列。在一實施例中,核酸為cDNA分子。核酸可存在於諸 如噬菌體呈現載體之载體、或重組質體載體中。 一旦獲得編碼可溶性SIRPa結合蛋白,例如如上文及實 例中所述之SIRPa結合融合體的DNA片段,即可利用標準 152818.doc •63- 201130511 重組飄技術進一步操作此等祖片段,例如以納入用於 在表現系統中適當分泌的任何信號序列、用於進—步純化 步驟之任何純化標籤及可裂解㈣。在此等操作中,使 腿片段可操作地連接於另—腦分子或編碼另—蛋白質 之片段,諸如純化/分泌標籤或可撓性連接子。如此上下 文中所用之術語「可操作地連接」欲意謂兩個隱片段以 功能性方式接合,例如以使得由該兩個dna片段編碼之胺 基酸序列簡㈣,或錢得蛋白質在所錢動子控制下 表現。 產生SIRPa結合蛋白之轉染瘤之產生 本發明之可溶性蛋白質,例如融合體之SIRPa結合蛋白 可使用例如如此項技術中熟知之重組DNA技術與基因轉染 方法之組合於宿主細胞轉染瘤中產生。為了在宿主細胞轉 染瘤中表現及產生重組融合體,熟習此項技術者宜使用其 自身的與抗體分子或抗體樣分子之表現及重組產生相關的 一般知識。 舉例而言’為了表現本發明之可溶性蛋白質或其中間 物,可利用標準分子生物學技術(例如PCR擴增或使用表現 相關多肽之融合瘤進行的c D N A選殖)獲得編碼相應多肽之 DNA,且可將該等DNA插入表現載體中以使得相應基因可 操作地連接於轉錄及轉譯控制序列。對表現載體及表現控 制序列進行選擇以與所用表現宿主細胞相容。利用標準方 法(例如連接基因片段及載體上之互補限制位點,或若不 存在限制位點,則使用鈍端連接)將編碼本發明可溶性蛋 152818.doc -64- 201130511 白質’例如SIRPa結合融合體或中間物之重鏈及輕鏈的基 因插入表現载體中。或者或另外,重組表現載體可編碼促 進多肽鏈自宿主細胞分泌之信號肽。可將該基因選殖至載 體中以使得信號肽與多肽鏈之胺基末端同框連接。在以 CD47源性序列作為SIRp〇^#合區之特定實施例中,信號肽 可為CD47彳5號肽或異源信號肽(亦即信號肽不與序列 天然相關)。 〇 除多肽編碼序列外,本發明之重組表現載體亦攜帶控制 基因在宿主細胞中之表現的調控序列。術語「調控序列」 思欲包括啟動子、強化子、及控制多肽鏈基因之轉錄或轉 譯的其他表現控制元件(例如聚腺苷酸化信號)。此等調控 序列描述於例如 GoeddeKGene Expressi〇n Techn〇i〇gy
Methods in Enzymology 185, Academic Press, San Diego, CA iSSO)中。熟習此項技術者應瞭解,表現載體之設計, 包括調控序列之選擇,可視諸如欲轉型之宿主細胞之選 〇 擇、所要蛋白質之表現量等因素而定。用於哺乳動物宿主 細胞表現之調控序列包括指導蛋白質在喷乳動物細胞中高 含量表現之病毒元件,諸如來源於細胞巨大病毒、 猿猴病毒40(Simian Virus 4〇, SV4〇)、腺病毒(例如腺病毒 主要晚期啟動子(AdMLP))及多瘤病毒之啟動子及/或強化 子。或者,可使用非病毒調控序列’諸如泛素⑽㈣⑷ 啟動子或P-血球蛋白啟動子。此外,調控元件由來自不同 來源之序列構成,諸如SRa啟動子系統,其含有來自§ν4〇 早期啟動子之序列及丨型人類T細胞白血病病毒之長末端重 152S18.doc •65- 201130511 複序列(Takebe,Y.等人,1988 Mol. Cell. Biol. 8:466-472)。 此外’本發明之重組表現載體可攜帶其他序列,諸如調 控載體於宿主細胞中之複製的序列(例如複製起點)及可選 擇標記基因。可選擇標記基因便於選擇已引入了載體之宿 主細胞(參見例如美國專利第4,399,216號、第4,634,665號 及第5,179,017號,均屬於Axei等人)。舉例而言,通常可 選擇標記基因賦予已引入了載體之宿主細胞對藥物(諸如 G418、潮黴素(hygromycin)或甲胺喋呤(meth〇trexate))之抗 性。可選擇標記基因包括二氫葉酸還原酶(DHFR)基因(同 甲胺喋呤選擇/擴增用於dhfr_宿主細胞)及狀〇基因(用於 G418選擇)。 為了表現蛋白質,利用標準技術將編碼可溶性蛋白質或 中間物,諸如SIRPa結合融合體之重鏈及輕鏈序列之表現 載體轉染至宿主細财。彳轉「轉染」之各種形式意欲涵 蓋通常用於將外源DNA引入原核或真核宿主細胞中之多種 技術’例如電穿孔 '磷酸舞沈澱、DEAE葡聚糖轉染及其 類似技術。理論上有可能在原核或真核宿主細胞中表現本 發明之可溶性蛋白質。論述糖蛋白在真核細胞,特定言之 哺乳動物宿主細胞中之表現,因為此等真核細胞且特定言 之哺乳動物細胞比原核細胞更可能裝配及分泌適當摺疊且 具生物活性之醣蛋白,諸如SIRPa結合融合體。 宜使用為抗體分子開發之熟知表現系 用於表現可溶性蛋白質及中間物, 合融合體之重鏈及輕鏈之哺乳動物宿 統產生融合體 諸如本發明SIRPa結 主細胞包括中國倉鼠 152818.doc -66 - 201130511 印巢細胞(CHO細胞),包括與例如如R.J. Kaufman及卩.八· Sharp,1982 Mol. Biol. 159:601-621 中所述之 DH FR 可選擇 標記一起使用的dhfr-CHO細胞(由Urlaub及Chasin,1980, Proc. Natl. Acad. Sci. USA 77:4216-4220描述);NSO骨趙 瘤細胞;COS細胞及SP2細胞或人類細胞株(包括PER-C6細 胞株 Crucell 或 HEK293 細胞,Yves Durocher 等人 2002, Nucleic acids research 第 30卷,第 2期 e9)。當將編碼多 肽之重組表現載體引入哺乳動物宿主細胞中時,藉由培養 宿主細胞持續一段足以允許重組多肽在宿主細胞中表現或 重組多肽分泌至宿主細胞所生長之培養基中的時間來產生 可溶性蛋白質及中間物,諸如本發明SIRPa結合融合體之 重鏈及輕鏈。接著可使用標準蛋白質純化方法自培養基回 收多肽。 多價SIRPa結合蛋白 在另一態樣中,本發明提供包含至少兩個相同或不同之 本發明可溶性SIRPa結合蛋白的多價蛋白質。在一實施例 中,多價蛋白質包含至少兩個、三個或四個本發明可溶性 SIRPa結合蛋白。可溶性SIRPa結合蛋白可經由蛋白質融合 或共價或非共價鍵聯連接在一起。本發明之多價蛋白質可 藉由使用此項技術中已知之方法使構成結合特異性結合來 製備。舉例而言,可分別產生多價蛋白質之各結合特異性 且接著使其彼此結合。 多種偶合或交聯劑可用於共價結合。交聯劑之實例包括 蛋白質A、碳化二醯亞胺、N-丁二醯亞胺基-S-乙醯基-硫 152818.doc •67- 201130511 代乙酸酯(SATA)、5,5'-二硫基雙(2-硝基苯甲酸)(DTNB)、 鄰伸苯基二順丁烯二醯亞胺(oPDM)、N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)及4-(N-順丁烯二醯亞胺基 甲基)環己烷-1-甲酸磺基丁二醯亞胺酯(磺基-SMCC)(參見 例如 Karpovsky 等人 1984 J. Exp. Med. 160:1686 ; Liu, MA 等人 1985 Proc. Natl. Acad· Sci· USA 82:8648)。其他方法 包括描述於Paulus, 1985 Behring Ins. Mitt.第 78期,118-132 ; Brennan 等人 1985 Science 229:8 1-83 及 Glennie 等人 1987 J. Immunol. 139: 23 67-2375中之彼等方法。可利用兩 個半胱胺酸之間的二硫橋鍵,例如由Fc域之半胱胺酸形成 之二硫橋鍵獲得共價鍵聯。 結合之SIRPa結合蛋白 在另一態樣中,本發明特徵在於SIRPa結合蛋白,特定 言之與諸如細胞毒素、藥物(例如免疫抑制劑)或放射性毒 素之治療部分結合的SIRPcx結合融合體。此等結合物在本 文中稱為「結合之SIRPa結合蛋白」。細胞毒素或細胞毒性 劑包括對細胞有害(例如殺傷細胞)之任何藥劑。此等藥劑 已用於製備抗體結合物或免疫結合物。此等技術可有利地 應用於SIRPa結合蛋白,特定言之SIRPoi結合融合體。細胞 毒素或細胞毒性劑之實例包括紫杉醇、細胞遲緩素 B(cytochalasin B)、短桿菌肽 D(gramicidin D)、漠-化乙鍵 (ethidium bromide)、吐根素(emetine)、絲裂黴素 (mitomycin)、依託泊苦(etoposide)、特諾波赛(tenoposide)、 長春新驗(vincristine)、長春驗(vinblastine)、t.秋水仙驗(t. 152818.doc -68- 201130511
colchicin)、阿黴素(doxorubicin)、道諾比星(daunorubicin)、 二經基炭症菌素二酮(dihydroxy anthracin dione)、米托蒽 鲲(mitoxantrone)、光神黴素(mithramycin)、放線菌素 D(actinomycin D)、1-去氫睾固 _ (Ι-dehydrotestosterone)、 糠皮質激素(glucocorticoid)、普魯卡因(procaine)、四卡因 (tetracaine)、利多卡因(lidocaine)、普萘洛爾(propranolol) 及嘌吟黴素(puromycin)及其類似物或同系物。治療劑亦包 括例如抗代謝物(例如甲胺喋呤、6-疏基嘌呤(6-mercaptopurine)、6-硫鳥 σ票吟(6-thioguanine)、阿糖胞苦 (cytarabine)、5-氣尿,咬達卡巴嗪(5-fluorouracil dacarbazine)) ' 消融劑(ablating agent)(例如氣芬 (mechlorethamine)、。塞替派苯丁 酸氮芥(thioepa chloraxnbucil)、美法侖(meiphalan)、卡莫司汀 (carmustine)(BSNU)及洛莫司汀(lomustine)(CCNU)、環填 醯胺(cyclothosphamide)、白消安(busulfan)、二溴甘露糖 醇(dibromomannitol)、鏈佐黴素(streptozotocin)、絲裂黴 素 C(mitomycin C)及順二氯二胺始(II)(cis-dichlorodiamine platinum(II))(DDP)川貝始(cisplatin))、蒽環黴素 (anthracycline)(例如道諾比星(daunorubicin)(之前稱為道話 黴素(daunomycin))及阿黴素(doxorubicin))、抗生素(例如 更生菌素(dactinomycin)(之前稱為放線菌素(actinomycin))、 博萊黴素(bleomycin)、光神黴素(mithramycin)及胺茴黴素 (anthramycin)(AMC))及抗有絲分裂劑(例如長春新驗及長 春驗)。 152818.doc -69- 201130511 可與本發明SIRPa結合蛋白或融合體結合之治療性細胞 毒素之其他實例包括多卡米辛(duocarmycin)、卡奇黴素 (calicheamicin)、美登素(maytansine)及阿瑞他汀 (auristatin)及其衍生物。 細胞毒素可使用此項技術中可用之連接子技術與本發明 之SIRPcx結合蛋白或融合體結合。已用於使細胞毒素與本 發明之SIRPa結合蛋白或融合體結合之連接子類型之實例 包括(但不限於)腙、硫醚、酯、二硫化物及含肽連接子。 可選擇例如易於在溶酶體代謝區中因低pH值裂解或易於經 諸如優先表現於腫瘤組織中之蛋白酶(諸如組織蛋白酶 (cathepsin)(例如組織蛋白酶B、C、D))之蛋白酶裂解的連 接子。 關於細胞毒素、連接子之類型及使治療劑與抗體結合之 方法的進一步論述,亦參見Saito, G.等人2003 Adv. Drug Deliv. Rev. 55:199-215 ; Trail,P.A·等人 2003 Cancer Immunol. Immunother. 52:328-337 ; Payne, G., 2003 Cancer Cell 3:207-212 ; Allen, T.M., 2002 Nat. Rev. Cancer 2:750-763 ; Pastan,I.及 Kreitman, R. J·,2002 Curr· Opin. Investig. Drugs 3:1089-1091 ; Senter, P.D·及 Springer, C.J., 2001 Adv. Drug Deliv. Rev. 53:247-264 ° 本發明之SIRPa結合蛋白或融合體亦可與放射性同位素 結合以產生細胞毒性放射性醫藥劑。可與本發明之SIRPa 結合蛋白或融合體結合以供診斷或治療使用之放射性同位 素的實例包括(但不限於)碘131、銦111、釔90及餾177。此 152818.doc -70- 201130511 項技術中已建立製備放射性免疫結合物之方法。放射性免 疫結合物之實例可購得,包括ZevalinTM(DEC Pharmaceuticals)及 BexxarTM(Corixa Pharmaceuticals),且 可使用類似方法來使用本發明之SIRPa結合蛋白或融合體 製備放射性醫藥劑。此外,使毒素或放射性同位素與抗體 結合之技術為熟知的,參見例如Thorpe,「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」,Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera等 人(編),第 475-506 頁(1985) ;「Analysis,Results,And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy」,Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin等人(編),第 303-16 頁(Academic Press 1985);及 Thorpe 等人「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」,Inmunol· Rev., 62:119-58 (1982)。 醫藥組合物 在另一態樣中,本發明提供組合物,例如醫藥組合物, 其含有一種本發明之可溶性SIRPa結合蛋白或融合體或本 發明可溶性SIRPa結合蛋白或融合體之組合與醫藥學上可 接受之載劑調配在一起。 可藉由混合具有所要純度之蛋白質與視情況選用之生理 上可接受之載劑、賦形劑或穩定劑(Remington: The Science and Practice of Pharmacy 第 20版(2000))來製備包含 本發明之可溶性SIRPa結合蛋白或融合體之醫藥調配物成 152818.doc •71 - 201130511 或:他乾燥調配物形式以供儲存。本發明進 社入夕包含本發明可溶性蛋白質(例如本發明SiRPa 、··《 口融合體)及適當醫藥學上可 私妥找 牧之载劑的凍乾袓人 二本發明亦係關於預先填充有至少包含本發明可容性: 以例如_«結合融合…及適當醫 & 劑之液體調配物的注射器。 了接又之載 本發明之醫藥組合物亦可以組合療法 ^ 組合投盥。舉例而一. 、’、(7,、其他藥劑 ❹ QT 例而5,組合療法可包括本發明之可、容性 瓣《結合蛋白或融合體與至少一種 / 學治療劑組合。可用於組合療法中 X 5另化 關於本發明可溶性瓣《結合蛋白中之之^療劑之實例在下文 描述。 蛋白之用相章節中更詳細 如本文所用,「醫藥學上可接受之 七卞^ 、 戰W J包括任何及所 有洛劑、为散介質、包衣、抗細菌 闽久机異囷劑、等張及吸 收延遲劑、及其生理學上相容 ^ 類似栽劑。載劑應適於靜 脈内、肌肉内、皮下、非經腸、脊 i 背椎或表皮投與(例如藉 =射或輸注)。視投藥途徑而定,活性成分可包覆於物 ^以使其免㈣和可使該活性成分失活之其他自然 的作用。 本發明醫藥組合物可包括-或多種醫藥學上可接受之 鹽。「醫藥學上可接受之鹽」係指保留母體化合物之所要 生物活性且不造成任何不當毒理學作用的鹽(參見例如 Berge,S.M.等人 1977 J. Phann· Sci. 66:1,。此等鹽之實 例包括酸加成鹽及鹼加成鹽。酸加成鹽包括自諸如鹽酸、 152818.doc •72- 201130511 硝酸、磷酸、硫酸、氫溴酸、氫蛾酸、亞磷酸及其類似酸 之無毒無機酸以及自諸如脂族單羧酸及脂族二羧酸、苯基 取代烷酸、羥基烷酸、芳族酸、脂族項酸及芳族磺酸及其 類似酸之無毒有機酸衍生的酸加成鹽。鹼加成鹽包括自諸 如納、奸、鱗、^弓及其類似物之驗土金屬以及自諸如 N,N'-二节基乙二胺、N-甲基葡糖胺、氯普魯卡因 (chloroprocaine)、膽驗、二乙醇胺、乙二胺、普魯卡因及 0 其類似物之無毒有機胺衍生的鹼加成鹽。 本發明醫藥組合物亦可包括醫藥學上可接受之抗氧化 劑。醫藥學上可接受之抗氧化劑之實例包括:水溶性抗氧 化劑,諸如抗壞血酸(ascorbic acid)、半胱胺酸鹽酸鹽、硫 酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及其類似物;油溶性抗 氧化劑,諸如抗壞血酸棕櫚酸酯(asc〇rbyl palmitate)、丁 基化羥基大茴香醚(BHA)、丁基化羥基曱苯(BHT)、印磷 月曰(lecithin)、沒食子酸丙酯(pr〇pyl gaiiate)、生育酚 〇 (alPha-to⑶Pherol)及其類似物;及金屬螯合劑,諸如檸檬 文乙胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其 類似物。 可用於本發明醫藥組合物中之適合水性及非水性載劑的 實例包括水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二 f U物)及其適合混合物、植物油(諸如撤禮油)及可 注射有機S旨(諸如油酸7 、 如卵磷脂)、在分气曰:列如藉由使用包衣物質(諸 使用界面、、m 情11由維持所需粒度、及藉由 使用界面活性劑來維持適當流動性。 152818.doc •73- 201130511 此等組合物亦可含有佐劑,諸如防腐劑、濕潤劑、乳化 劑及刀散綃。可用前述滅菌程序及藉由納入各種抗細菌及 ^真菌劑(例如對經基苯甲酸s旨、氯丁醇、苯齡山梨酸及 其類似物)來確保防止微生物存在。亦可能需要在組合物 中納入等張劑’諸如糖、氯化鈉及其類似&。此外,可藉 由納入延遲吸收之藥劑(諸如單硬脂酸鋁及明膠)使可注射 醫藥形式之吸收延長。 醫樂學上可接受之載劑包括無菌水溶液或分散液,及用 於臨時製備無菌可注射溶液或分散液之無菌粉末。用於醫 藥活性物質之此等介質及藥劑的使用在此項技術中為已知 的°除非任何習知介質或藥劑與活性化合物不相容,否則 涵蓋其在本發明醫藥組合物中之使用。亦可在組合物中併 入補充活性化合物。 治療組合物通常必須無g且在製造及儲存條件下穩定。 組合物可調配成溶液、微乳液、脂f體或其他適於高藥物 濃度之有序結構。制可為含有例如纟、乙醇、多元_ (例如甘油、丙二醇及液體聚乙二醇及其類似物)及其適人 混合物之溶劑或分散介質。可例如藉由使用包衣(諸如: 磷脂)、在分散液情況下藉由維持所需粒度、及藉由使用 界面活性劑來料適當流動性。在許多情況下,可在組合 物中納入等張劑’例如糖、多元醇(諸如甘露糖醇、山: 糖醇)或氣化鈉。可藉由在組合物中納入延遲吸收之率, (例如單硬脂酸鹽及明膠)使可注射組合物之吸收延長/、片 無菌可注射溶液可藉由於適當溶劑中併入所需量之可溶 1528l8.doc -74- 201130511 性蛋白質(例如SIRPa結合蛋白或融合體)及一種上文列舉 之成分或上文列舉之成分之組合,必要時隨後進行滅菌微 過濾來製傷。通常,藉由將活性成分併入含有基本分散介 質及來自以上所列舉成分之所需其他成分的無菌媒劑中來 製備分散液。在用於製備無菌可注射溶液之無菌粉末的情 況下,製備方法為真空乾燥及冷凍乾燥(凍乾),其產生活 性成分加上來自其經預先無菌過濾之溶液之任何其他所要 0 成分的粉末。 可與载劑物質組合以產生單一劑型之活性成分的量將視 所治療之個體及特定投藥模式而變化。可與載劑物質組合 以產生單一劑型之活性成分的量通常為產生治療作用之組 合物的量。一般而言,以100%計,此量將在約〇〇1%至約 99〇/。活性成分、約〇·1%至約7〇%或約1%至約规活性成分 與省藥學上可接受之載劑組合的範圍内。 «給藥方案以提供最佳所要反應(例如治療反應)。舉 〇 例而言’可投與單—大丸劑,可隨時間投與若干分次劑 里’或可根據治療情形之緊急性所指示按比例降低或增加 劑量。出於投藥簡便性及劑量均一性考慮,將非經腸組合 物調配成單位劑型尤其有利。如本文所用之單位劑型係指 適合以單一劑量用於欲治療個體之物理個別單元;各單元 3有、差3十异以產生所要治療作用之預定量之活性化合物與 所需醫藥載劑聯合。本發明之單位劑型之規格由以下因素 決定且直接取決於以下因素:活性化合物之獨特特徵及欲 達成之特定治療作用’及混配該種活性化合物用於治療個 152818.doc -75· 201130511 體敏感性之技術中固有之限制。 對於投與本發明之可溶性SIRPa結合蛋白或融合體而 S,劑罝在每公斤宿主體重約〇〇〇〇1至1〇〇毫克,且更通 常每公斤宿主體重0.01至5毫克之範圍内。舉例而言,劑 量可為每公斤體重0.3毫克、每公斤體重i毫克、每公斤體 重3宅克、每公斤體重5毫克或每公斤體重1〇毫克或在每公 斤體重1-30毫克範圍内。例示性治療方案要求每週投與— 次、每2週投與一次、每3週投與一次、每4週投與一次、工 個月投與-次、每3個月投與—次或每3至6個月投與— 次。本發明之可溶性SIRPag合蛋白或融合體之給藥方案 包括每公斤體重靜脈内投與1毫克或每公斤體重靜脈内投 與3毫克’其中所給予之蛋白質使用以下給藥時程之_ : 每4週一次給予6次劑量,接著每3個月一次;每3週一次; 每公斤體重3毫克給予一次’隨後每3週每公斤體重給予i 毫克。 可溶性SIRPa結合蛋白或融合體通常在多個時刻投盘。 單-劑量間之時間間隔可為例如i週、i個月、每3個月或 :。時間間隔亦可如藉由量測患者中可溶性多肽之血液4 量所指示為不定期的。在一些方法中,調整劑量以達成么 (M-刪―之血襞多肽濃度,且在一些方法中為約5 300 pg/ml。 或者,可溶性瓣《結合蛋白或融合體可以持續釋放畜 配物形式投與,在此情況下需要較低頻率之投藥。劑量2 頻率視可溶性蛋白質在患者中之半衰期而變化。投藥^ 152818.doc •76· 201130511 及頻率可視治療為預防性抑或治療性而變化。在預防性用 樂中1歷經長時期以相對不頻繁之時間間隔投與相對較低 之^里:一些患者在其餘生中持續接受治療。在治療性應 用,日寺需要以相對較短之時間間隔投與相對較高之劑 量直至疾病進展得以減缓或終止,或直至患者展示疾病症 狀部分或完全改善。此後,可對患者投與預防性方案。 可改變本發明之醫藥組合物中活性成分之實際劑量濃度 O u獲得對於特定患者、組合物及投藥模式可有效達成所要 治療反應,而不對患者造成毒性之活性成分的量。所選劑 量濃度將視多種藥物動力學因素而定,該等藥物動力學因 素包括所用本發明特定組合物或其酉旨、鹽或酿胺的活性; 投藥途徑;投藥時間;所用特定化合物之排出速率;治療 持續時間;與所用特定組合物組合使用之其他藥物、化二 物及/或物質;所治療患者之年齡、性別、體重、病狀: -般健康狀況及先前病史;及醫學技術中熟知之類似 ϋ 素。 「治療有效劑量」之可溶j±SIRPa結合蛋白或融合體可 使疾病症狀嚴重性降低’無疾病症狀時期之頻率及持續時 間增加,或防止由疾病痛苦所致之損傷或殘疾。 本發明組合物可使用此項技術中已知之多種方法之一或 多者經一或多種投藥途徑投與。如熟習此項技術者所: 解,投藥之途徑及/或模式將視所要結果而變化。本發明 可溶性蛋白質之投藥途徑包括靜脈内、肌肉内、皮内、腹 膜内、皮下、脊椎或其他非經腸投藥途徑,例如藉由注射 152818.doc •77- 201130511 或輸注。如本文所用之片語「非經腸投藥」意謂除經腸及 局部投藥以外,通常藉由注射之投藥模式,且包括(但不 限於)靜脈内、肌肉内、動脈内、鞘内、囊内、眶内、心 内、皮内、腹膜内、眼内、經氣管、皮下、表皮下、關節 内、囊下、蛛網膜下、脊椎内、硬膜外及腦幹内注射及輸 注。 或者,可溶性SIRPa結合蛋白或融合體可經諸如局部、 表皮或黏膜投藥途徑之非非經腸途徑,例如鼻内、經口、 陰道、直腸、舌下或局部投與。 活性成分可與將保護蛋白質防止快速釋放之載劑一起製 備’諸如控制釋放調配物,包括植入物、經皮貼片及微囊 化傳遞系統。可使用生物可降解生物相容性聚合物,諸如 乙稀乙酸乙烯S旨、聚酸肝、聚乙醇酸、膠原蛋白 (collagen)、聚原酸酯及聚乳酸。製備此等調配物之許多方 法已公開或通常為熟習此項技術者所已知。參見例如 Sustained and Controlled Release Drug Delivery Systems J.R. Robinson編,Marcel Dekker,Inc.,New York, 1978。 治療組合物可利用此項技術中已知之醫學裝置投與。舉 例而言,在一實施例中,本發明之治療組合物可利用無針 皮下注射裝置’諸如美國專利第5,399,163號;第5,383,85 1 號;第 5,312,335 號;第 5,064,413 號;第4,941,880號;第 4,790,824號或第4,596,556號中所示之裝置投與。適用於本 發明中之熟知植入物及模組之實例包括:美國專利第 4,487,603號’其展示一種用於以控制速率分配藥物之可植 152818.doc •78- 201130511 Ο
入式微輸注泵;美國專利第4,486,194號,其展示一種用於 經由皮膚投與藥物之治療裝置;美國專利第4,447,233號, 其展示一種用於以精確輸注速率傳遞藥物之藥物輸注泵; 美國專利第4,447,224號’其展示—種用於持續藥物傳遞之 可變流速可植入式輸注設備;美國專利第4,439,196號,其 展示一種具有多腔隔室之滲透藥物傳遞系統;及美國專利 第4,475,196號,其展示一種滲透藥物傳遞系統。許多其他 此類植入物、傳遞系統及模組為熟習此項技術者所已知。 在某些實施例中,可溶性SIRP(^4合蛋白或融合體可經 調配以確保活體内適當分佈。舉例雨言,血腦障壁(bbb) 排除許多高度親水性化合物。為了確保本發明之治療化合 物穿過BBB(若需要)’可將其調配於例如脂質體中。關於 製造知質體之方法,參見例如美國專利4,522,8U ; 5,374,548 ;及5,399,331。脂質體可包含一或多個選擇性轉 運至特定細胞或器官中之部分,由此增強靶向藥物傳遞 (參見例如 V.V. Ranade,1989 J. Cline Pharmac〇l· 29:685)。 本發明之用途及方法 可溶性SIRPa結合蛋白或融合體具有活體外及活體内診 斷及治療效用。舉例而言,可向培養物中(例如活體外或 活體内)或個體中(例如活體内)之細胞投與此等分子,以治 療、預防或診斷多種病症。在一實施例中,可溶性SIRpa 結合融合體可用於在原本會干擾擴增之其他細胞類型之存 在下’於活體外擴增幹細胞或其他細胞類型(如胰臟β細 胞)。此外,特定言之,可溶性SIRPa結合蛋白或融合體可 152818.doc -79- 201130511 用於活體外定性及定量功能性SIRPa在來自生物體(諸如人 類)生物樣品之細胞之細胞表面的表現。此應用適用於市 售SIRPa抗體,其會與SIRPp之各種同功異型物交叉反應, 從而難以明確定量細胞表面上之SIRPa蛋白質表現。因此 可溶性SIRPa結合蛋白或融合體之定量可用於診斷目的, 例如評估SIRPa蛋白質表現量與免疫或癌症病症之關係, 且因此允許選擇患者(患者分級(patient stratification)),以 便接受例如結合之SIRPa結合蛋白或靶向SIRPa之基於抗體 的療法之治療。 該等方法尤其適於治療、預防或診斷由SIRPa+細胞介導 之自體免疫及發炎性病症,例如過敏性哮喘或潰瘍性結腸 炎。其包括急性及慢性發炎性病狀、過敏症及過敏性病 狀、自體免疫性疾病、缺血性病症、嚴重感染、及細胞或 組織或器官移植排斥反應,包括非人類組織之移植(異種 移植(xenotransplant))。該等方法尤其適於治療、預防或診 斷由表現異常或突變型變異之活化SIRPP受體(其會與 CD47反應)的細胞及藉由與CD47或其他SIRPa配位體結合 導致功能異常所介導的自體免疫及發炎性或惡性病症。 自體免疫性疾病之實例包括(但不限於)關節炎(例如類風 濕性關節炎、慢性漸進性關節炎(arthritis chronica progrediente)及畸形性關節炎(arthritis deformans))及風濕 性疾病(包括涉及骨質流失之發炎性病狀及風濕性疾病)、 發炎性疼痛、脊椎關節病(spondyloarhropathy)(包括僵直 性脊椎炎(ankolsing spondylitis))、萊特症候群(Reiter 152818.doc -80- 201130511 syndrome)、反應性關節炎、牛皮癣性關節炎(Ps〇riatic arthritis)、及腸病性關節炎(enterophathis arthritis)、過敏 (包括氣管過敏及皮膚過敏)及過敏症。自體免疫性疾病包 括自體免疫性血液病症(包括例如溶血性貧企(hem〇1ytic anaemia)、再生不能性貧血(aplastic anaemia)、純紅細胞 貧 jk (pure red cell anaemia)及特發性血小板減少(idiopathic thrombocytopenia))、全身性紅斑狼瘡症(systemic lupus ^ erythematosus)、發炎性肌肉病症、多軟骨炎 (polychondritis)、硬皮病(sclerodoma)、韋格納肉芽腫病 (Wegener granulomatosis)、皮肌炎(dermatomyositis)、慢 性活動性肝炎(chronic active hepatitis)、重症肌無力 (myasthenia gravis)、牛皮癬、史蒂芬-強森症候群(Steven-Johnson syndrome)、特發性口炎性腹瀉(idiopathic sprue)、 内分泌眼病變(endocrine ophthalmopathy)、格雷夫斯病 (Graves disease)、類肉瘤病(sarcoidosis)、多發性硬化症 Q (multiple sclerosis)、原發性膽汁性肝硬化(priniary biliary cirrhosis)、青少年糖尿病(juvenile diabetes)(I型糖尿病)、 葡萄膜炎(uveitis)(前葡萄膜炎及後葡萄膜炎)、乾燥性角 膜結膜炎(keratoconjunctivitis sicca)及春季角膜結膜炎 (vernal keratoconjunctivitis)、間質性肺纖維化(interstitiai lung fibrosis)、牛皮癬性關節炎及絲球體腎炎 (glomemlonephritis)(有及無腎病症候群,例如包括痛風、 蘭氏細胞組織細胞增多病(langerhans cell histiocytosis)、 特發性腎病症候群或最小變化腎病變)、腫瘤、多發性硬 152818.doc •81 - 201130511 化症、皮膚及角膜之發炎性疾病、肌炎(myositis)、骨植入 物鬆動、代謝障礙,諸如動脈粥樣硬化'糖尿病及血脂異 常(dislipidemia) 〇 可溶性SIRPa結合蛋白或融合體亦適用於治療、預防或 改善哮喘、支氣管炎、肺塵埃沈著症(pneum〇c〇ni〇sis)、 肺氣腫(pulmonary emphysema)、及氣管之其他阻塞性或發 炎性疾病。 可谷性SIRPa結合蛋白或融合體亦適用於治療、預防或 改善免疫系統介導之肌病或發炎性肌病,包括冠脈肌病 (coronar myopathy) ° 可溶性SIRPoc結合蛋白或融合體亦適用於治療、預防或 改善涉及表現SIRPa之内皮或平滑肌系統的疾病。 可溶性SIRPa結合蛋白或融合體亦適用於治療IgE介導之 病症。IgE介導之病症包括異位性病症,其特徵在於具有 對許多常見天然存在之吸入及攝入抗原起免疫反應的遺傳 傾向及持續產生IgE抗體。特定異位性病症包括過敏性哮 喘、過敏性鼻炎、異位性皮炎(at0pic dermatitis)及過敏性 胃腸病變。 然而’與IgE含量升高相關之病症不限於具有遺傳(異位 性)病源學之病症。似乎由IgE介導且可用本發明調配物治 療之與IgE含里升冋相關之其他病症包括過敏(例如過敏性 過敏)、濕疹(eczema)、蓴麻疹(urticaria)、過敏性支氣管 與肺麴菌病(allergic bronchopulmonary aspergillosis)、寄 生蟲病、高IgE症候群(hyper-IgE syndrome)、共濟失調毛 152818.doc -82 · 201130511 細血管擴張症(ataxia-telangiectasia)、偉-爾二氏症候群 (Wiskott-Aldrich syndrome)、胸腺淋巴發育不全(thymic alymphoplasia)、IgE骨髓瘤及移植物抗宿主反應(graft-versus-host reaction) ° 可溶性SIRPa結合蛋白或融合體適用作涉及主要神經系 統之急性疾病的第一線治療,在該等疾病中,發炎性路徑 由SIRPa+細胞(諸如活化之微神經膠質細胞)介導。特定應 用例如可為在脊髓損傷後使活化之微神經膠質細胞靜止以 加速癒合並防止形成與神經系統之部分自體反應的淋巴樣 結構及抗體。 可溶性SIRPa結合蛋白或融合體可以單一活性成分形式 或聯合例如用於治療或預防以上提及之疾病之其他藥物 (例如免疫抑制劑或免疫調節劑或其他消炎劑)(例如作為其 他藥物之佐劑或與其他藥物組合)投與。舉例而言,可溶 性SIRPa結合蛋白或融合體可與以下組合使用:DMARD, 例如金鹽、柳氮續°比咬(sulphasalazine)、抗癌疾藥 (antimalarias)、甲胺嗓吟、D-青黴胺、硫嗤嘌呤 (azathioprine)、黴紛酸(mycophenolic acid) v 環抱素 A(cyclosporine A)、他克莫司(tacrolimus)、西羅莫司 (sirolimus)、二曱胺四環素(minocycline)、來氣米特 (leflunomide)、糖皮質激素(glococorticoids);約調神經填 酸酶(calcineurin)抑制劑,例如環抱素A或FK 506;淋巴細 胞再循環調節劑,例如FTY720及FTY720類似物;mTOR抑 制劑,例如雷帕黴素(rapamycin)、40-0-(2-經乙基)-雷帕 152818.doc -83- 201130511 黴素、CCI779、ABT578、AP23573 或 TAFA-93 ;具有免疫 抑制性質之子囊黴素(ascomycin),例如ABT-281、 ASM981等,皮質類固醇(cortic〇steroids);環磷·醯胺 (cyclo-phos-phamide);硫唑嘌呤;曱胺喋呤;來氟米特; 咪唑立賓(mizoribine);黴酚酸;黴酚酸嗎啉乙酯(myco-pheno-late mofetil); 15-去氧斯匹胍素(15-deoxyspergualine)或 其免疫抑制同系物、類似物或衍生物;免疫抑制單株抗 體,例如針對白血球受體,例如MHC、CD2、CD3、 CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、 CD80、CD86或其配位體之單株抗體;其他免疫調節化合 物,例如LEA29Y ;黏著分子抑制劑,例如LFA-1拮抗劑、 ICAM-1或ICAM-3拮抗劑、VCAM-4拮抗劑或VLA-4拮抗 劑;或化學治療劑,例如太平洋紫杉醇(paclitaxel)、吉西 他濱(gemcitabine)、順鉑(cisplatinum)、阿黴素或5-氟尿嘧 啶;抗TNF劑,例如針對TNF之單株抗體,例如英利昔單 抗(infliximab)、阿達木單抗(adalimumab)、CDP870、或針 對TNF-RI或TNF-RII之受體構築體,例如依那西普 (Etanercept)、PEG-TNF-RI ;促發炎性細胞激素阻斷劑, IL-1阻斷劑(例如阿那白滯素(Anakinra)或IL-1捕獲劑)、 AAL160、ACZ 8 85、IL-6P且斷劑;趨化因子阻斷劑,例如 蛋白酶(例如金屬蛋白酶)之抑制劑或活化劑、抗IL-1 5抗 體、抗IL-6抗體、抗CD20抗體、抗CD22抗體、抗IL17抗 體、抗IL12抗體、抗IL12R抗體、抗IL23抗體、抗IL23R抗 體、抗IL2 1抗體、NS AID,諸如阿司匹靈(aspirin)、布洛 152818.doc -84· 201130511 芬(ibuprophen)、撲熱息痛(paracetam〇1)、萘普生 (naproxen)、選擇性Cox2抑制劑、組合型c〇xl及€(^2抑制 劑(如雙氣芬酸(diclofenac))或抗感染劑(清單不限於所提及 之藥劑)。 可溶性SIRPa結合蛋白或融合體亦適用作特定言之在阻 塞性或發炎性氣管疾病(諸如上文提及之氣管疾病)之治療 中聯合消炎或支氣管擴張藥物使用的共治療劑,例如作為 〇 此等藥物之治療活性的增效劑或作為降低此等藥物之所需 劑量或潛在副作用的手段。本發明藥劑可與消炎或支氣管 擴張藥物混合於固定醫藥組合物中或其可在消炎或支氣管 擴張藥物之前、與之同時或之後單獨投與。此等消炎藥包 括類固醇,特定言之糖皮質類固醇,諸如布地奈德 (budesonide)、倍氯米松(beclamethas〇ne)、氟替卡松 (fluticasone)或莫米松(mometas〇ne);及多巴胺受體促效 劑,諸如卡麥角林(cabergoline)、溴麥角環肽(br〇m〇criptine) 〇 或羅匹尼洛(ropinirole)。此等支氣管擴張藥物包括抗膽鹼 劑或抗蕈毒驗劑(antimuscarinic agent),特定言之異丙托 溴銨(ipratropium bromide)、氧托溴銨(oxitr〇pium br〇mide) 及嗟托演敍(tiotropium bromide)。 本發明藥劑與類固酵之組合可用於例如治療c〇pD或特 定言之哮喘。本發明藥劑與抗膽鹼劑或抗蕈毒鹼劑或多巴 胺受體促效劑之組合可用於例如治療哮喘或特定言之 COPD。 根據以上所述,本發明亦提供治療阻塞性或發炎性氣管 152818.doc -85· 201130511 疾病之方法,其包含向有需要之個體,特定言之人類個體 才又舁如上文所述之可溶性SIRPa結合蛋白或融合體。在另 &樣中,本發明提供如上文所述之可溶性SIRPa結合蛋 白或融合體,其係用於製備用於治療阻塞性或發炎性氣管 疾病之藥劑。 可冷I·生SIRPa結合蛋白或融合體亦尤其適用於治療、預 防或改善杈性胃腸發炎,諸如發炎性腸病,包括克羅恩氏 病(Crohn’s disease)及潰瘍性結腸炎。 k性胃腸發炎」係指胃腸道之黏膜發炎,其特徵在於 發作期相對較長、持續較久(例如數天、數週、數月、或 數年及直至個體之一生),且與單核細胞之浸潤或流入相 關且了進一步與自發緩解(spontaneous remission)及自發 發生(spontaneous occurrence)之時期相關。因此,可預期 患有慢性胃腸發炎之個體需要長期監視、觀測或護理。具 有此慢性發炎之「慢性胃腸發炎性病狀」(亦稱為「慢性 胃細發炎性疾病」)包括(但不必限於)發炎性腸病(ΙΒ〇)、 由環境損傷誘發之結腸炎(例如由治療方案(諸如投與化學 療法、放射療法及其類似療法)引起或與其相關(例如作為 副作用)之胃腸發炎(例如結腸炎))、諸如慢性肉芽腫病情 況下之結腸炎(Schappi等人Arch Dis Child. 2001年2月; 1984(2). 147-1 5 1)、乳糜;寫(celiac disease)、口炎性腹濱(― 種回應於攝入稱為麩質(gluten)之蛋白質,腸内層 (intestinal lining)發炎的可遺傳疾病)、食物過敏症、胃 炎、感染性月炎或小腸結腸炎(enterocolitis)(例如感染幽 152818.doc -86 - 201130511 門螺旋桿菌(Helicobacter pylori)之慢性活動性胃幻及由 感染物⑽之其他形式之胃腸發炎、及其他類似病狀。 如本文所用,「發炎性腸病」或「_」係指多種特徵在 於所有或部分腸道發炎之疾病的任—者。發炎性腸病之實 例包括(但不限於)克羅恩氏病及潰瘍性結腸炎。在整篇說 明書中提及IBD在本說明書中通常指例示性胃腸發炎性病 狀,且不欲具有限制性。 〇 根據以上所述,本發明亦提供治療慢性胃腸發炎或發炎 性腸病(諸如潰瘍性結腸炎)之方法,其包含向有需要之個 體’特定言之人類個體投與如上文所述之可溶性SIRPa結 合蛋白或融合體。在另一態樣中,本發明提供如上文所述 之可溶性SIRPa結合蛋白或融合體,其係用於製備用於治 療慢性胃腸發炎或發炎性腸病之藥劑。 本發明亦適用於治療、預防或改善白血病或其他癌症病 症。舉例而言,可溶性SIRPa結合蛋白或融合體可用於治 〇 療、預防或改善選自以下之癌症病症:急性骨趙白血病、 急性淋巴母細胞白血病、慢性骨髓白血病、慢性淋巴細胞 白血病、脊髓增生性病症、骨髓發育不良症候群、多發性 骨髓瘤、非霍奇金淋巴瘤(non_Hodgkin lymph〇ma)、霍奇 金病(hodgkin disease)、膀胱癌、蘭氏細胞組織細胞增多 病之惡性形式。 調節SIRPCX-CD47相互作用可用於增強造血幹細胞移植 (參見例如與使用CD47-Fc融合蛋白相關之w〇 2009/046541)。 本發明且例如可溶性SIRPa結合蛋白或融合體因此適用於 I52818.doc •87- 201130511 增強人類造血幹細胞移植。造血幹細胞移植可用於治療咬 減輕罹患造企作用受損或遣傳免疫缺乏疾病、自體免疫性 病症或造血性病症或已接受任何骨髓消融治療之患者的症 狀。舉例而言,此造血性病症係選自急性骨髓白血病、急 性淋巴母細胞白血病、慢性骨髓白血病、慢性淋巴細胞白 血病、脊髓增生性病症、骨腾發育不良症候群、多發性骨 髓瘤、非霍奇金淋巴瘤、霍奇金病、再生不能性貧血、純 紅細胞發育不全(pure red cell aplasia)、陣發性夜間血紅素 尿(paroxysmal nocturnal hemoglobinuria)、範可尼貧血 (fanconi anemi)、地中海重貧血症(thalassemia maj〇r)、鐮 形細胞性貧血(Sickle cell anemia)、重度複合免疫缺乏症 (severe combined immunodeHciency)、偉-爾二氏症候群、 嗔血細胞性淋巴組織細胞增生症(hem〇phag〇cytic lymphohistiocytosis)及先天性代謝異常(inb〇m err〇rs 〇f metabolism)。因此,在一實施例中,本發明係關於可溶性 SIRPoi結合蛋白或融合體,其係用於特定言之在用含有造 血幹細胞之經擴增細胞群體治療後,治療選自以下之造血 性病症以改良造血幹細胞移植:急性骨髓白血病、急性淋 巴母細胞白血病、慢性骨髓白血病、慢性淋巴細胞白血 病、脊髓增生性病症、骨髓發育不良症候群、多發性骨髓 瘤、非隹奇金淋巴瘤、霍奇金病、再生不能性貧血、純紅 細胞發育不全、陣發性夜間血紅素尿、範可尼貧血、地中 海重貧血症、鐮形細胞性貧血、重度複合免疫缺乏症、 偉-爾二氏症候群、噬血細胞性淋巴組織細胞增生症及先 152818.doc -88 - 201130511 天性代謝異常。 本發明之範嘴内亦涵蓋如上定義之方法,其包含共投與 (例如伴隨或依序)治療有效量之可溶性SIRpa結合蛋白或 融合體及至少一種第二藥物’該第二藥物為例如如上所指 示之免疫抑制性/免疫調節性、消炎性化學治療性或 染性藥物。 〜 或者,治療組合(例如套組)包含治療有效量之a)可溶性 O SIRPa結合蛋白或融合體及b)至少一種選自例如如上所指 示之免疫抑制性/免疫調節性、肖炎性化學治療性或抗感 染性藥物的第二物質。套組可包含關於其投與之說明書: 當可溶性SIRPcx結合蛋白或融合體聯合其他免疫抑制性/ 免疫調節性、消炎性化學治療性或抗感染性療法投與時, 所共投與組合化合物之劑量當然將視所用纟投與藥物之類 型、所治療病狀等而變化。 —本發明已經充分描述,其進一步由以下實例及申請專利 〇 範㈣3月,料實例及申請專利範圍為說明性的且不欲另 外具有限制性。 【實施方式】 實例 1·本發明SIRPa結合融合體之實例 下表4提供可使用編碼所揭示重鏈及輕鏈胺基 DNA ’藉由重、组方法產生之本發明SIRp_合融合體的實 例0 編碼重鏈及/或輕鏈之DNA可進一步包含(:1)47信號序列 1528l8.doc 89· 201130511 之編碼序列(參見例如SEQ ID NO:10)。CD47信號序列例如 表現於重鏈及輕鏈之N-端部分以引導融合體分泌至生產細 胞外部。 表4 : 實例 Fc部分 CHI區或C3L區 連接子 SIRPa結合區 SEQ ID 1號重鏈 SEQ ID NO:9 SEQ ID NO:7 無連接子 SEQ ID NO:4 SEQ ID NO:5 1號輕鏈 不適用 SEQ ID NO:8 無連接子 SEQ ID NO:4 SEQ ID NO:6 2號重鏈 SEQ ID NO:22 SEQ ID NO:7 無連接子 SEQ ID NO:4 SEQ ID NO: 18 2號輕鏈 不適用 SEQ ID NO:8 無連接子 SEQ ID NO:4 SEQ IDNO:6 3號重鏈 SEQIDNO:9 SEQ ID NO:7 (Gly4Ser)2 SEQ ID NO:4 SEQ ID NO: 19 3號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)2 SEQ ID NO:4 SEQ IDNO:20 4號重鏈 SEQ IDNO:9 SEQ ID NO:7 (Gly4Ser)2 SEQ ID NO: 21 SEQ ID NO: 12 4號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)2 SEQ ID NO: 21 SEQ ID NO: 13 5號重鏈 SEQ ID NO:9 SEQ ID NO:7 無連接子 SEQ ID NO:23 SEQ ID NO:24 5號輕鏈 不適用 SEQ IDNO:8 無連接子 SEQ ID NO:23 SEQ ID NO:25 6號重鏈 SEQ ID NO:9 SEQ ID NO:7 無連接子 SEQ ID NO: 21 SEQ ID NO:36 6號輕鏈 不適用 SEQ ID NO:8 無連接子 SEQ ID NO: 21 SEQ ID NO:37 7號重鏈 SEQ ID NO:9 SEQ ID NO:7 無連接子 SEQ ID NO: 27 SEQ ID NO:38 7號輕鏈 不適用 SEQ ID NO: 8 無連接子 SEQ ID NO: 27 SEQ ID NO:39 8號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)l SEQ ID NO: 21 SEQ ID NO:40 8號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)l SEQ ID NO: 21 SEQ ID NO:41 9號重鏈 SEQ ID NO:9 SEQ IDNO:7 (Gly4Ser)l SEQ ID NO: 27 SEQ IDNO:42 9號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)l SEQ ID NO: 27 SEQ ID NO:43 10號重鏈 SEQ ID NO:9 SEQ IDNO:7 (Gly4Ser)2 SEQ ID NO: 27 SEQ IDNO:44 10號輕鏈 不適用 SEQ ID NO:8 (G3y4Ser)2 SEQ ID NO: 27 SEQ ID NO:45 11號重鏈 SEQ ID NO:9 SEQ IDNO:7 (G】y4Ser)3 SEQ ID NO: 21 SEQ IDNO:46 11號輕鏈 不適用 SEQ ID NO:8 (G3y4Ser)3 SEQ ID NO: 21 SEQ ID NO:47 12號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)3 SEQ ID NO: 27 SEQ ID NO:48 12號輕鏈 不適用 SEQ ID NO: 8 (Gly4Ser)3 SEQ ID NO: 27 SEQ ID NO:49 13號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)5 SEQ ID NO: 21 SEQ ID NO:50 13號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)5 SEQ ID NO: 21 SEQ ID NO:51 14號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)l SEQ IDNO:23 SEQ IDNO:52 14號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)l SEQ ID NO:23 SEQ ID NO:53 15號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)l SEQ ID NO:4 SEQ ID NO:54 15號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)l SEQ ID NO:4 SEQ IDNO:55 16號重鏈 SEQ ID NO:9 SEQ ID NO:7 (Gly4Ser)5 SEQ ID NO:4 SEQ ID NO:56 16號輕鍵 不適用 SEQ ID NO:8 (Gly4Ser)5 SEQ ID NO:4 SEQ ID NO:57 17號重鏈 SEQ ID NO:22 SEQ ID NO:7 (Gly4Ser)2 SEQ ID NO:4 SEQ ID NO:58 17號輕鏈 不適用 SEQ ID NO:8 (Gly4Ser)2 SEQ ID NO:4 SEQ ID NO:20 18號重鏈 SEQ ID NO:28 SEQ IDNO:7 (Gly4Ser)2 SEQ ID NO:4 SEQ ID NO:29 18號輕鏈 不適用 SEQ ID NO:8 (G]y4Ser)2 SEQ ID NO:4 SEQ ID NO:20 2. 親和力測定 2丄單價SIRPa之結合檢定(BiaCORE檢定) -90-
152818.doc 201130511 人類單體SIRPa-APP CD47之單價親和力可使用例如 BiaCORE T100儀器藉由BiaCORE評估。應用標率胺偶合 程序,利用蛋白質A固定CM5晶片。流槽(Flow cell)1進# 空白固定以用作參考。經由蛋白質A之Fc結合性質固疋 SIRPa結合蛋白。單價-例如經APP標記之SIRPa V威黃白 質在HEK293細胞中表現。APP-SIRPa以1:2之倍數連續稀 釋12次。起始濃度為25 μΜ-0.5 μΜ。藉由隨後在參考及重 測流槽上注射APP-SIRPa濃度系列獲得親和力資料。在注 〇 射各分析物之後用50 mM擰檬酸鹽溶液再生晶片表面。 與SIRPa-APP之單價相互作用經量測kd為3 μΜ,此展示 與所報導(1-2 μΜ’ Heatherley等人2008 Mol Cell.)或使用 二價SIRPtx結合蛋白(CD47- Fc)所測得(3 μΜ)之CD47 V域 與SIRPa之單價相互作用類似的親和力。
或者’ SIRPa結合蛋白與二價重組siRpa之結合可藉由 BiaCORE表徵。為此’在分別藉由如EDC/NHS或乙醇胺之 Q 標準程序進行表面活化/去活之後,可於乙酸鹽緩衝液(pH 4.5)中將人類 SIRPa-Fc(10 Kg/mL,R&D systems, UK)固定 於如CM5 (羧甲基化葡聚糖基質)之BiaC〇RE晶片上。評估 可以120秒之接觸時間、240秒之解離時間及5〇微升/分鐘 之流動速率進行。在每次注射分析物之後,晶片可用溫和 洛離缓衝液(Gentle elution buffer,ThermoScientific)再 生。 2.2,與重組<ΖΣ>4Ί融合蛋白競爭結合slRPa之競爭檢定 實驗於384孔微量滴定板(Nunc)中進行。固定之人類 152818.doc -91 · 201130511 SIRPa-Fc 融合蛋白(0.5 pg/mL,R&D systems,UK)與由 CD47-ECD IgGl Fc融合蛋白(CD47-Fc,5 nM)或生物素化 CD47融合體(4號實例,1 nM)組成之生物素化SIRPa結合 蛋白與不同濃度(30 ηΜ-0·003 nM)未標記SIRPa結合蛋白或 未標記SIRPa結合融合體的混合物一起培育。在室溫下複 合物形成18小時後,藉由澈底洗滌來移除未結合蛋白質。 經由抗生蛋白鏈菌素銪(Streptavidin-Europium, PerkinElmer試劑)偵測結合之生物素化CD47融合蛋白。使 用解離增強型時差式螢光術(TRF),利用VICTOR2讀取器 〇 (PerkinElmer)量測標記 Eu3+。 2.3.使用細胞之基於分析板之細胞黏著檢定 在標準細胞培養條件下,使U937細胞(表現SIRPa之組織 細胞株(ATCC))於補充有10%胎牛血清及抗生素(皆來自 Invitrogen)之RPMI1 640中生長。在實驗前1天以1:1劃分細 胞。收集細胞並將其再懸浮於含有牛血清白蛋白(BSA, SIGMA)之磷酸鹽缓衝鹽水(PBS,SIGMA)(PBS/BSA)中。 可在 37°c下用 5 pg/mL BCECF-AM(Invitrogen)或如鈣黃綠 素AM(Calcein AM,Invitrogen)之等效染料標記細胞20分 鐘。藉由洗滌步驟移除未結合之BCECF-AM。計數細胞並 調整數目至每毫升補充有0.5°/〇 BSA之RPMI 1640中lxlO6 個細胞。96孔板用每孔60 μΐ含3 pg/ml抗人類Fc山羊 IgG(Jackson ImmunoResearch Laboratories)之0.1 M NaHC〇3/Na2C〇3 缓衝液塗佈隔夜。板用PBS洗滌兩次,用含1.5% BSA之 PBS阻斷30分鐘(250微升/孔)且接著與不同濃度之SIRPa結 152818.doc -92· 201130511 合蛋白’如可溶性SIRPtx結合融合體或CD47-ECD IgGl Fc 融合蛋白(CD47-Fc,CD47 ECD 之 Seql)(CD47-Fc)(0.01 及 30 nM)—起培育。在室溫下2小時後,板用PBS/BSA洗滌2 次,隨後添加經BCECF標記之U937細胞(每孔100000個細 胞)。在37°C下培育30分鐘後,使用補充有0.5% BSA之 RPMI 1640藉由重複手動或自動洗滌步驟使U937細胞經受 流體剪切應力。一般而言,需要4-5個洗滌步驟來移除鬆 散黏著或未結合之細胞。藉由使用VICTOR2板讀取器 (PerkinElmer)定量所保留U937黏著細胞之螢光。 2. 4.全血人類細胞結合檢定 應用倫理準則,自健康自願者收集人類血液至經肝素鈉 塗佈之採血·管(BectonDickinison,BD)中。血液等分至96孔 深孔聚丙稀板(Co star)中並在冰上在最終0.1% w/v疊氮化 鈉存在下與各種濃度之SIRPa結合蛋白,如可溶性SIRPa結 合融合體或CD47-ECD IgGl Fc融合蛋白(CD47-Fc,CD47 ECD之Seql)(CD47-Fc) —起培育。可使用標記套組 (Invitrogen)使螢光染料 Alexa Fluor 647(AX647)結合於 SIRPa結合蛋白。在冰上,可將AX647結合之SIRPa結合蛋 白(如4號實例中所列之融合體)以1-10 nM之濃度添加至全 血樣品中,持續30分鐘。在最後15分鐘期間,添加濃度最 佳化之針對表型細胞表面標記之抗體:CD14-PE(純系 MEM18,Immunotools, Germany)、CD3 Percp-Cy5.5(純系 SK7,BD)、CD16 FITC(純系 3G8,BD)。藉由添加 10倍體 積之FACSLYSING溶液(BD)並在室溫下培育10分鐘使全血 152818.doc •93· 201130511 溶解。樣品用含有〇·5%牛血清白蛋白(SIGMA-ALDRICH) 之磷酸鹽緩衝溶液洗滌2次。在溶解之後24小時内於Facs Canto II(BD)上獲得樣品。根據單核細胞光散射概況及 CD14+及CD3-表現對細胞子集進行閘控。在此等細胞子集 中,可繪製螢光直方圖並採用中值螢光強度作為讀數進行 統計學評估。 3. 量測對金黃色葡萄球菌Cowan 1菌株粒子刺激之促發炎 性細胞激素釋放之抑制的樹突狀細胞細胞激素釋放檢定 如所描述(Latour 等人 J of Immunol, 2001: 167:2547)製備 〇 末梢血液單核細胞(CD14+)以及單核細胞源性樹突狀細胞 (DC)。習知(DC)藉由使用別藻藍蛋白(allophycocyanin, APC)標記之抗CDllc(B-ly6)、FITC標記之針對譜系標記 CD3、CD14、CD15、CD16、CD19 及 CD56 之 mAb 的混合 物、及 APC-Cy7 標記之 CD4(RPA-T4)用 FACS Aria(BD Biosciences)分離成CDllc+,譜系-,以達到>99%純度。 在各種濃度之人類SIRPa結合融合體(1至10000 pM)存在 〇 下,於HB101或X-VIV015無血清培養基中用1M0.000金黃 色葡萄球菌Cowan 1粒子(Pansorbin)刺激APC。藉由ELISA 評估24小時或48小時培養上清液中細胞激素(!L-1、IL-6、 IL-10、IL-12p70、IL-23、IL-8 及 TNF-α)之釋放。 4. 關於使用SIRPa結合蛋白來預防肺發炎之發炎性肺病 (OVA-哮喘)的小鼠模型 雌性BALB/c(6至8週齡)購自Charles River,供養在無特 定病原條件下。在第0天及第5天,藉由在不存在(PBS對 152818.doc -94- 201130511 照)或存在100 gg含有有(mCD47 C15G融合體)或無C15G突 變(mCD47融合體)融合於人類IgGl主鏈之鼠類CD47細胞外 IgSF域的鼠類SIRPa結合融合體(mCD47融合體:重鏈SEQ ID: 34,輕鏈 SEQ ID: 35,或 mCD47 C15G 融合體:重鏈 SEQ ID: 31,輕鏈SEQ ID: 32)或對照人類IgGl下腹膜内 (IP)注射 10 pg 吸附於 lmg Imject 明礬(Pierce)之 OVA 使 BALB/c小鼠敏感。在第12天、第16天及第20天,小鼠用 0.5% OVA氣霧劑(Sigma, V級)攻毒30分鐘。在末次攻毒後 24小時處死小鼠。用〇·5 mL生理鹽水收集支氣管肺泡灌洗 流體(Bronchoalveolar lavage fluid,BALF)4次。模型之示 意圖描繪於圖6中。 BALF中之總細胞用抗CCR3、抗B220(R&D systems)及 抗CD3(純系145-2C11)染色並用流動式細胞測量術分析。 所有資料皆在FACSAria II(BD Biosciences)上獲得。使用 非配對史都登氏T檢定(unpaired student's T test)及非參數 曼-惠特尼 U檢驗(non-parametric Mann-Whitney U test)進行 統計分析。_Ρ<〇·〇〇1,**Ρ<〇.〇1,*P<0.05。 5.關於使用SIRPa結合蛋白之結腸炎的鼠類動物模型 三硝基苯磺酸(TNBS)(2或3 mg)溶於50%乙醇中並經由 3.5F導管滴注至雄性Balb/c小鼠(野生型(WT)及CD47 KO) 之結腸中。對照小鼠僅給予乙醇。在第7天,藉由滴注1.5 mg TNBS小鼠於若干動物中再誘發TNBS結腸炎(如圖7中 指示)。每24小時稱重小鼠。在第14天處死小鼠。收集血 清、腸系膜淋巴結及結腸用於進一步分析。可使用考慮存 152818.doc -95· 201130511 在腹瀉、黏著、腸壁變厚及潰瘍之華萊士準則(Wallace criteria)對結腸進行宏觀計分。亦可使用阿默霍準則 (Ameho criteria)(—種基於黏膜下層(submucosa)變厚、黏 膜下層及固有層(lamina propria)被單核細胞浸潤、黏液耗 盡、隱窩架構喪失及水腫之計分系統),評估結腸發炎之 顯微標記(資料未展示)。僅在TNBS結腸炎誘發之前及此後 24小時、及48小時及在一些動物中72小時腹膜内投與重組 小鼠SIRPa結合蛋白(mCD47 C15G融合體)。對照小鼠僅接 受磷酸鹽緩衝鹽水(PBS)或對照IgGl。 結果 如表4中所述之SIRPa結合融合體(4號實例)之結合及其 他功能性質呈示於下表5中,且與二價CD47-FC融合物之性 質進行比較。 表5 :
檢定 4號實例 CD47-Fc 單價SIRPa之結合檢定[μΜ] (方法2.1) 3 μΜ 3 μΜ 與二價CD47-FC競爭結合SIRPa之競爭檢定 (方法2.2)IC50 [nM] 0.4-0.6 nM 3-6 nM 使用U937細胞之基於分析板之細胞黏著檢定 (方法2.3)EC5〇 [nM] 0.3-0.6 nM 3-5 nM 全血人類細胞結合檢定(方法2.4)IC50 [nM] 1-2 nM >90nM 細胞激素自SAC觸發之單核細胞源性樹突狀細胞 釋放之減弱TNFa/IL6/IL12 [nM] (方法3) <0.25 nM <0.25 nM 本發明實例之重鏈之功能性質詳述於表6中。 152818.doc -96- 201130511 實例 舆二價CD47-FC競爭結 合SIRPa之競爭檢定 (方法2.2) ICS0 _] 全血人類細胞結合 檢定(方法2·4) ICs〇 [nM] 對 SIRPa-Fc KD 之親和力[nM】 (BiaCORE) 3號重鏈 0.06 4.8 18-20 4號重鏈 0.03-0.07* 30-52 5號重鏈 0.03-0.04 1.7 22 6號重鏈 0.03-0.05* 7號重鏈 0.03 8號重鏈 0.12 9號重鏈 0.08 10號重鏈 0.04-0.05* 11號重鏈 0.04-0.05* 12號重鏈 0.08* 13號重鏈 0.09 14號重鏈 0.05-0.06 1.5 28 15號重鏈 0.04-0.05 5.3 30 16號重鏈 0.06 11.8 35 17號重鏈 33 18號重鏈 7.3 33
^與huCD47 -融合體競爭 發炎性肺病(OVA-哮喘)之模型中SIRPa結合融合體之活體 内功效 因為未產生人類與齧齒動物CD47/SIRPa蛋白質之間的 物種間交叉反應性(未展示),所以類似於人類SIRPa結合 蛋白產生鼠類SIRPa結合融合體。於哺乳動物短暫表現系 統中產生含有野生型(SEQ ID: 33)或C15G突變型(SEQ ID: 30)CD47部分的SIRPa結合融合體(mCD47融合體:重鏈 SEQ ID: 34,輕鏈 SEQ ID: 35,或 mCD47 C15G 融合體:重 鏈SEQ ID: 31,輕鏈SEQ ID: 32)為人類IgG融合蛋白,並 藉由標準程序純化以產生無聚集體及無内毒素之物質。 用鼠類SIRPa結合融合體(mCD47 C15G融合體或mCD47 152818.doc •97- 201130511 融合體)處理小鼠有效防止小鼠發生過敏性哮喘。如圖6中 所示,相較於對照,以每隻動物2χ 1 00 pg任一 SIRPa結合 融合體腹膜内處理小鼠有效使氣霧劑抗原攻毒後支氣管肺 泡灌洗流體(BALF)中之總細胞計數以及嗜伊紅血球、嗜中 性白血球及淋巴細胞的數目減少。相反,在經具有無關特 異性之人類IgGl或PBS處理之對照組中,觀測到白血球爆 發性浸潤至B ALF中。此等各種白血球子集流入B ALF中通 常視為與發炎性肺病之嚴重性強烈相關的標誌。此模型亦 視為適用於模擬人類過敏性哮喘中所見之病理學之態樣。 此等資料證明a)融合體蛋白質形式在活體内具有活性,及 b)SIRPa結合融合體介導有效活體内功效,及c)CD47之C15, 例如通常與細胞CD47之跨膜環之C235形成二硫橋鍵的胺基酸 (Rebres等人Biol Chem 2001)不為活體内有效功效所需。 發炎性結腸疾病(TNBS結腸炎)之模型中SIRPa結合融合體 之活體內功效 如藉由統計學上顯著降低之體重減輕所指示,以每隻動 物腹膜内投與100 gg鼠類SIRPa結合融合體(mCD47 C15G 融合體,重鏈SEQ ID: 31,輕鏈SEQ ID: 32)3-4次處理小 鼠降低由TNBS引發之發炎性結腸炎的嚴重性。在第7天用 TNBS再誘發疾病之後,經mCD47 C15G融合體處理之動物 的體重保持高於PBS或對照IgG對照組。注射鼠類SIRPa結 合蛋白(mCD47-C15G融合體)因此有效阻斷TNBS結腸炎中 疾病發展之嚴重性。資料為以3或4次連續投與測試化合物 進行之2個不同實驗的概述。n=每組所用動物之數目。 152818.doc -98 - 201130511 適用於實施本發明之胺基酸及核苷睃序列。 表7Α :適用於實施本發明之胺基酸及核苷酸序列之簡要描述 SEQ ID NO: 序列之描述 1 全長人類SIRPa胺基酸序列(包括信號序列胺基酸i_3〇(CAC12723V) 2 全長人類CD47胺1·酸序列(包括信號序列(008722)胺基酸1-18) 3 人類CD47胺基酸序列之細胞外域(ECDX無信號序列) 4 人類CD47胺基酸每列之其他可能ECD區(無信號岸列) 5 融合體1號實例之全長重鏈(無信號序列) 6 融合體1號實例之全長輕鏈(無信號序列) 7 融合體1號或4號實例之重鏈之CH1區 8 融合體1號或4號實例之輕鏈之CL區 9 融合體之Fc部分(I^GILALA)' -- 10 SEQ ID NO:5之重鏈之核苷酸序列(包括編碼信號序列) 11 SEQ ID NO:6之輕鏈之核苷酸序列(包括編碼信號序列) 12 融合體4號貫例之室鏈(SEQ IDNO:5之半胱胺酸突變體(C15G), 進一步包括連接子) 13 融合體4號實例之輕鏈(SEQ ID NO:5之半胱胺酸突變體(C15G), 進一步包括連接子) 14 SEQ ID NO: 12之重鏈之核苷酸序列(包括編碼信號序列) 15 SEQ ID NO: 13之輕鏈之核苷酸序列(包括編碼信號序列) ~ 16 缺乏C-端離胺酸之SEQ ID NO:5 17 缺乏C-端離胺酸之SEQ ID NO: 12 18 融合體2號實例之重鏈(野生型IgGl恆定區)(無信號序列) 19 融合體3號貫例之重鏈(包含連接子序列)(無信號序列) 20 融合體3號實例之輕鏈(包含連接子序列)(無信號序列) 21 8£(5©>10:4之具有(:150突變之€0 47細胞外域蠻異體 — 22 融合體之Fc部分(野生型IgGl) 23 CD47細胞外域截奴變異體(縮短之C-端部分) 24 融合體5號實例之重鍵(無信號序列) 25 融合體5號實例之輕鏈(無信號序列) 26 SIRPyNP 061026.2 ' 27 0047細胞> 域(C15G突變體)截短變異體(縮短之c-端部分y-- 28 融合體18號實例之Fe部分(IgGlN297A) 29 融合體18號實例之重鏈(無信號序列) — 30 小鼠CD47(C15G)胺基酸序列之可能ECD區(無信號庠歹Π 31 mCD47C15G融合體重鏈 —-- 32 mCD47 C15G融合體輕鏈 ~~-- 33 小鼠CD47野生型胺基酸序列之可能ECD區(無信號庠列1 '-- 34 mCD47野生型融合體重鏈 ~~- 35 mCD47野生型融合體輕鏈 -- 36 融合體6號實例之重鏈(無信號序列) __ 37 融合體6號實例之韃鏈(無信號序列) 152818.doc -99- 201130511 38 融合體7號實例之重鏈(無信號序列) 39 融合體7號實例之輕鏈(無信號序列) 40 融合體8_號實例之重鏈(無信號序列) 41 融合體8號實例之輕鏈(無信號序列) 42 融合體9號實例之重鏈(無信號序列) 43 融合體9號實例之輕鏈(無信號序列) 44 融合體10號實例之重鏈(無信號序列) 45 融合體10號實例之輕鏈(無信號序列) 46 融合體11號實例之重鏈(無信號序列) 47 融合體11號實例之輕鍵(無信號序列) 48 融合體12號實例之重鏈(無信號序列) 49 融合體Γ2號實例之輕鏈(無信號序列) 50 融合體13號實例之重鏈(無信號序列) 51 融合體13號實例之輕鍵(無信號序列) 52 融合體14號實例之重鏈(無信號序列) 53 融合體14號實例之輕鏈(無信號序列) 54 融合體15號實例之重鏈(無信號序列) 55 融合體15號實例之輕鏈(▲信號序列) 56 融合體16號實例之重鏈(無信號序列) 57 融合體16號實例之輕鏈(無信號序列) 58 融合體17號實例之重鏈(無信號序列) 59 融合體3號實例之SEQ ID 19重鏈之核苷酸序列(無信號序列) 60 融合體3號、17號及18號實例之SEQ ID 20輕鏈之核苷酸序列 (無信號序列) 61 融合體4號實例之SEQ ID 12重鏈之核苷酸序列(無信號序列) 62 融合體4號實例之SEQ ID 13輕鏈之核苷酸序列(無信號序列) 63 融合體5號實例之SEQ ID 24重鏈之核苷酸序列(無信號序列) 64 融合體5號實例之SEQ ID 25輕鏈之核苷酸序列(無信號序列) 65 融合體6號實例之SEQ ID 36重鏈之核苷酸序列(無信號序列) 66 融合體6旎實例之SEQ ID 37輕鏈之核苷酸序列(無信號序列) 67 融合體7號實例之SEQ ID 38重鏈之核苷酸序列(無信號序列) 68 融合體7號實例之SEQ ID 39輕鏈之核苷酸序列(無信號序列) 69 融合體8號實例之SEQ ID 40重鏈之核苷酸序列(無信號序列) 70 融合體8號實例之SEQ ID 41輕鏈之核苷酸序列(無信號序列) 71 融合體9號實例之SEQ ID 42重鏈之核苷酸序列(無信號序列) 72 融合體9號實例之SEQ ID 43輕鏈之核苷酸序列(無信號序列) 73 融合體10號實例之SEQ ID 44重鏈之核苷酸序列(無信號序列) 74 融合體10號實例之SEQ ID 45輕鏈之核苷酸序列(無信號序列) 75 融合體11號實例之SEQ ID 46重鏈之核苷酸序列(無信號序列) 76 融合體11鐃實例之SEQ ID 47輕鏈之核苷酸序列(無信號岸列) 77 融合體12號實例之SEQ ID 48重鏈之核苷酸序列(無信號庠列) 78 融合體12號實例之SEQ ID 49輕鏈之核苷酸序列(無信號庠列) 79 融合體13號實例之SEQ ID 50重鏈之核苷酸序列(無信號庠列) 80 融合體13號實例之SEQ ID 51輕鏈之核苷酸序列(無信號序列) 152818.doc -100- 201130511 81 融合體14號實例之SEQ ID 52重鏈之核苷酸序列(無信號序列) 82 融合體14號實例之SEQ ID 53輕鏈之核苷酸序列(無信號序列) 83 融合體15號實例之SEQ ID 54重鏈之核苷酸序列(無信號序列) 84 融合體15號實例之SEQ ID 55輕鏈之核苷酸序列(無信號序列) 85 融合體16號實例之SEQ ID 56重鏈之核苷酸序列(無信號序列) 86 融合體16號實例之SEQ ID 57輕鏈之核苷酸序列(無信號序列) 87 融合體17號實例之SEQ ID 58重鏈之核苷酸序列(無信號序列) 88 融合體18號實例之SEQ ID 29重鏈之核苷酸序列(無信號序列) 89 SEQ ID 31之核苷酸序列 90 SEQ ID 32之核苷酸序列 91 SEQ ID 34之核苷酸序列 92 SEQ ID 35之核苷酸序列
表7B :序列表
SEQID NO: 胺基酸或核苷酸序列 1 MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVIQPDKSVLVAAGETAT LRCTATSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDF SIRIGNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSAPVVSGP AARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYS IHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQ PVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDGTYN WMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVSAHPKEQGSNT AAENTGSNERNIYIVVGVVCTLLVALLMAALYLVRIRQKKAQGSTSSTRLHE PEKNAREITQDTNDITYADLNLPKGKKPAPQAAEPNNHTEYASIQTSPQPASE DTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK 2 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNT TEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMD KSDAYSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFPIFAILLF WGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPGEYSLKNATG LGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYILAVVGLSLCIAACIPM HGPLLISGLSILALAQLLGLVYMKFVASNQKTIQPPRKAVEEPLNAFKESKG MMNDE 3 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNE 4 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGE^LKYRWSWFSPNEN 5 QLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 152818.doc -101 - 201130511
6 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KV YACEVTHQGLS SPVTKSFNRGEC 7 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKYDKRV 8 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC 9 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK 10 ATGTGGCCCCTGGTAGCGGCGCTGTTGCTGGGCTCGGCGTGCTGCGGATC AGCTCAGCTACTATTTAATAAAACAAAATCTGTAGAATTCACGTTTTGTAA TGACACTGTCGTCATTCCATGCTTTGTTACTAATATGGAGGCACAAAACA CTACTGAAGTATACGTAAAGTGGAAATTTAAAGGAAGAGATATTTACACC TTTGATGGAGCTCTAAACAAGTCCACTGTCCCCACTGACTTTAGTAGTGC AAAAATTGAAGTCTCACAATTACTAAAAGGAGATGCCTCTTTGAAGATGG ATAAGAGTGATGCTGTCTCACACACAGGAAACTACACTTGTGAAGTAAC AGAATTAACCAGAGAAGGTGAAACGATCATCGAGCTAAAATATCGTGTTG TTTCATGGTTTTCTCCAAATGAAAATTCAGCTAGCACCAAGGGCCCCAGC GTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCC GCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCTCCGGCGTGCACACCTTCCCCGCCGT GCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCC AGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACA AGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGGCAGCGGGCGGAC CCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGC AGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGAC CCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAAC GCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAAT ACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGAC CATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCT GCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGT CTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCA ACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA GCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAG GTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTG CACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGGCAAG 11 ATGTGGCCCCTGGTAGCGGCGCTGTTGCTGGGCTCGGCGTGCTGCGGATC AGCTCAGCTACTATTTAATAAAACAAAATCTGTAGAATTCACGTTTTGTAA TGACACTGTCGTCATTCCATGCTTTGTTACTAATATGGAGGCACAAAACA CTACTGAAGTATACGTAAAGTGGAAATTTAAAGGAAGAGATATTTACACC TTTGATGGAGCTCTAAACAAGTCCACTGTCCCCACTGACTTTAGTAGTGC AAAAATTGAAGTCTCACAATTACTAAAAGGAGATGCCTCTTTGAAGATGG ATAAGAGTGATGCTGTCTCACACACAGGAAACTACACTTGTGAAGTAAC AGAATTAACCAGAGAAGGTGAAACGATCATCGAGCTAAAATATCGTGTTG TTTCATGGTTTTCTCCAAATGAAAATCGTACGGTGGCCGCTCCCAGCGTG 152818.doc -102- 201130511
TTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCG TGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTG GAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCAC CGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGAC CCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTG ACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGC GAGTGC 12 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTYP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 13 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC 14 ATGTGGCCCCTGGTAGCGGCGCTGTTGCTGGGCTCGGCGTGCTGCGGATC AGCTCAGCTACTATTTAATAAAACAAAATCTGTAGAATTCACGTTTGGTAA TGACACTGTCGTCATTCCATGCTTTGTTACTAATATGGAGGCACAAAACA CTACTGAAGTATACGTAAAGTGGAAATTTAAAGGAAGAGATATTTACACC TTTGATGGAGCTCTAAACAAGTCCACTGTCCCCACTGACTTTAGTAGTGC AAAAATTGAAGTCTCACAATTACTAAAAGGAGATGCCTCTTTGAAGATGG ATAAGAGTGATGCTGTCTCACACACAGGAAACTACACTTGTGAAGTAAC AGAATTAACCAGAGAAGGTGAAACGATCATCGAGCTAAAATATCGTGTTG TTTCATGGTTTTCTCCAAATGAAAATGGAGGTGGTGGATCTGGAGGTGGA GGTAGCTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCA GCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGA AGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCT GACCTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTG TACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCC AGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCC CCTGCCCAGCCCCAGAGGCAGCGGGCGGACCCTCCGTGTTCCTGTTCCC CCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACC TGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGA GAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGC TGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCA ACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGG GCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGA GATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTAC CCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAAC AACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCC TGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACG TGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCA GAAGAGCCTGAGCCTGTCCCCCGGCAAG 152818.doc •103· 201130511
15 ATGTGGCCCCTGGTAGCGGCGCTGTTGCTGGGCTCGGCGTGCTGCGGATC AGCTCAGCTACTATTTAATAAAACAAAATCTGTAGAATTCACGTTTGGTAA TGACACTGTCGTCATTCCATGCTTTGTTACTAATATGGAGGCACAAAACA CTACTGAAGTATACGTAAAGTGGAAATTTAAAGGAAGAGATATTTACACC TTTGATGGAGCTCTAAACAAGTCCACTGTCCCCACTGACTTTAGTAGTGC AAAAATTGAAGTCTCACAATTACTAAAAGGAGATGCCTCTTTGAAGATGG ATAAGAGTGATGCTGTCTCACACACAGGAAACTACACTTGTGAAGTAAC AGAATTAACCAGAGAAGGTGAAACGATCATCGAGCTAAAATATCGTGTTG TTTCATGGTTTTCTCCAAATGAAAATGGAGGTGGTGGATCTGGAGGTGGA GGTAGCCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGA CGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAA CTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTG CAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGA CTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCA GCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 16 QLLFNKTKSVEFTFCNDTWIPCFVTOMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 17 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQN 丁 TEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 18 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSWLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 19 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTR EGETIIELKYRVVSWFSPNENGGGGSGGGGSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCWYDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDLAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK •104- 152818.doc 201130511
20 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 21 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNEN 22 EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK 23 QLLFNKTKSVEFTFCNDTWIPCFVTOMEAQNTTEVYVKWKFKGRDIYTFD GALTNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVS 24 QLLFNKTKSVEFTFCNDTVVIPCFVTOMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCS VMHE ALHNHYTQKSLSLSPGK 25 QLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC 26 MPVPASWPHPPGPFLLLTLLLGLTEVAGEEELQMIQPEKLLLVTVGKTATLH CTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSI RISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPSAPVVLGPAA RTTPEHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPTGQSVAYSIRS TARVVLDPWDVRSQVICEVAHVTLQGDPLRGTANLSEAIRVPPTLEVTQQP MRVGNQVNVTCQVRKFYPQSLQLTWSENGNVCQRETASTLTENKDGTYN WTSWFLVNISDQRDDVVLTCQVKHDGQLAVSKRLALEVTVHQKDQSSDAT PGPASSLTALLLIAVLLGPIYVPWKQKT 27 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVS 28 EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVKFN'WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK 29 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSWTVP 152818.doc •105- 201130511
SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 30 QLLFSNVNSIEFTSGNETWIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKI 31 QLLFSNVNSIEFTSGNETWIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKIGGGGSGGGGSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 32 QLLFSNVNSIEFTSGNETWIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKIGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 33 QLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKI 34 QLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKIGGGGSGGGGSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGYHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVYSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 35 QLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGN KNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGK TVIELKNRTVSWFSPNEKIGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 36 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 37 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 152818.doc •106- 201130511
FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC 38 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 39 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC 40 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK PKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 41 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 42 QLLFNKTKSVEFTFGNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS RTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQOWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 43 qllfnktksveftfgndtwipcfvtnmeaqnttevyvkwkfkgrdiytfd GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGEraELKYRVVSGGGGSRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC 44 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVYSGGGGSGGGGSSASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT ΥΙ€ΝνΝΗΚΡ8ΝΤΚΛΊ)ΚΚνΕΡΚ5€ΟΚΤΗΤαΡΡ〇ΡΑΡΕΑΑ(3αΡ8νΡΙ^ΡΡΚΡΚϋ TLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHODWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPQVYT •107· 152818.doc 201130511
LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 45 QLLFNKTKSVEFTFGNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC 46 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSGGGGSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK 47 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSGGGGSRTVAAPSYFIFPPSDE QLKSGTASVVCLLNNFYPREAKYQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 48 QLLFNKTKSVEFTFGNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSGGGGSGGGGSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 49 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEYYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSGGGGSGGGGSRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 50 QLLFNKTKSVEFTFGNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSGGGGSGGGGSGGGGSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 51 QLLFNKTKSVEFTFGNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFDG ALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREG ETnELKYRWSWFSPNENGGGGSGGGGSGGGGSGGGGSGGGGSRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEYTHQGLSSPVTKSFNRGEC 152818.doc -108- 201130511
52 QLLFNKTKSVEFTFCNDTWIPCFVTOMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 53 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSGGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC 54 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 55 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLS SPVTKSFNRGEC 56 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSGGGGSGGGGSGGGGSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 57 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSGGGGSGGGGSGGGGSRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 58 QLLFNKTKSVEFTFCNDTWIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFD GALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT REGETIIELKYRVVSWFSPNENGGGGSGGGGSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNYNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 152818.doc -109- 201130511 59 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagctcagctag caccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctg cctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacctt ccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacc cagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcg acaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaag cccaaggacaccctgatgatcagcaggacecccgaggtgacctgcgtggtggtggacgtgagccacgaggacccag aggtgaagttcaactggtaegtggacggcgtggaggtgcacaacgccaagaccaagcceagagaggagcagtacaa cagcacctacagggtggtgtccgtgctgaecgtgctgcaccaggactggctgaaeggcaaggaatacaagtgcaagg tctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagceacgggagccccagg tgtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccc cagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctgga cagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctg cagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 60 Cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagccgtacg gtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcct gctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagcca ggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccga ctacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaaca ggggcgagtgc 61 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagctcagcta gcaccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggct gcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacct tccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacc cagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcg acaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaag cccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccag aggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaa cagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaagg tctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccagg tgtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccc cagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctgga cagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctg cagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 62 Cagctacta伽 al^aacaaaatct 典 gaattcac 碑 ggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagccgtacg gtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcct gctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagcca ggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccga •110· 152818.doc 201130511
ctacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaaca ggggcgagtgc 63 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcaagcgctagcaccaagggccccagcgtgttccccctggcccccagcagcaagagca ccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagc ggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggt gacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtg gacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgcccagccccagaggcagcggg cggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgt ggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgcc aagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggact ggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagcccccatcgaaaagaccatcagcaa ggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggaggagatgaccaagaaccaggt gtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtgggagagcaacggccagcccgaga acaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagt ccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacccagaagag cctgagcctgtcccccggcaag 64 Cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactectgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcacgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaa gagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggac aacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagc agcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgt ccagccccgtgaccaagagcttcaacaggggcgagtgc 65 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatagcgctagcaccaagggccccagcgtgttccccctg gcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagccc gtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcct gtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccaca agcccagcaacaccaaggtggacaagagagtggageccaagagctgcgacaagacccacacctgccccccctgcc cagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcagg acccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacg gcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgct gacegtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagecccc atcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggag gagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtgggag ageaacggccagcccgagaacaactacaagaccacccccecagtgctggacagcgacggcagcttcttcctgtacag caagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcac aaccactacacccagaagagcctgagcctgtcccccggcaag 66 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatcgtacggtggccgctcccagcgtgttcatcttcccccc cagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaag 152818.doc -111 - 201130511 gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaagga ctccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgagg tgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 67 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaagcgctagcaccaagggccccagcgtgttccccctggcccccagcagcaagagc accagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacag cggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtgg tgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggt ggacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgcccagccccagaggcagcgg gcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcaggacccccgaggtgacctgcg tggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgc caagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggac tggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagcccccatcgaaaagaccatcagcaa ggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggaggagatgaccaagaaccaggt gtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtgggagagcaacggccagcccgaga acaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagt ccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacccagaagag cctgagcctgtcccccggcaag 68 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcacgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaa gagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggac aacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagc agcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgt ccagccccgtgaccaagagcttcaacaggggcgagtgc 69 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggcggcggcggatccagcgctagcaccaagggccc cagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaagga ctacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgct gcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatct gcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccaca cctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacacc ctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaa ctggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacag ggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaagg ccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgc ccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcg ccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggca gcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgc acgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 70 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctetaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggcggcggcggatcccgtacggtggccgctcccagc gtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacc 152818.doc -112- 201130511
cccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgag caggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataagg tgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 71 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggcggcggcggatccagcgctagcaccaagggccccagcgtgttccccctggcc cccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagcccgtga ccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcctgtac agcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcc cagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgcccagc cccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcaggaccc ccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacggcgt ggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgacc gtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagcccccatcga aaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggaggagat gaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtgggagagca acggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaag ctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaacca ctacacccagaagagcctgagcctgtcccccggcaag 72 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggcggcggcggatcccgtacggtggccgctcccagcgtgttcatcttcccccccag cgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtg cagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactc cacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtga cccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 73 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggcggcggcggcagcggcggcggcggatccagcgctagcaccaagggcccca gcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggacta cttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgca gagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgca acgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacct gccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctg atgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactg gtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggt ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccc tgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccc cctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgccg tggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggcagct tcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacg aggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 74 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacageiattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggcggcggcggcagcggcggcggcggatcccgtacggtggccgctcccagcgt gttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggt 邮 cctgctgaacaacttctaccc 152818.doc -113· 201130511 ccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagc aggacagcaaggactccacctacagcctgagcagcacectgacectgagcaaggcegactacgagaagcataaggt gtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 75 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagtggcg gaggaggatccagcgctagcaccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcg gcacagccgccctgggctgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctg acctccggcgtgeacaccttccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgccc agcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagaga gtggagcccaagagctgcgacaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctcc gtgttcctgttcccccccaagcccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggac gtgagccacgaggacccagaggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagc ccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacgg caaggaatacaagtgcaaggtctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggc cagccacgggagccccaggtgtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacct gtctggtgaagggcttctaccccagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaa gaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggc agcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctg tcccccggcaag 76 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagtggcg gaggaggatcccgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcacc gccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgca gagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac cctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtg accaagagcttcaacaggggcgagtgc 77 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggaggcggaggatctggcggcggaggaagtggcggaggaggatccagcgctag caccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctg cctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacctt ccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacc cagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcg acaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaag cccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccag aggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaa cagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaagg tctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccagg tgtacaccctgcccccctcecgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccc cagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctgga cagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctg cagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 78 Cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagl对 acgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc 152818.doc -114- 201130511
gagctaaaatatcgtgttgtttcaggaggcggaggatctggcggcggaggaagtggcggaggaggatcccgtacggt ggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgc tgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg agagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgacta cgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacagg ggcgagtgc 79 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagcggag gcggcggaagtggagggggaggatcagggggaggaggatccagcgctagcaccaagggccccagcgtgttcccc ctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagc ccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggc ctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccac aagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgc ccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcag gacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggac ggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtg ctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagcccc catcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccggga ggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtggga gagcaacggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtaca gcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgca caaccactacacccagaagagcctgagcctgtcccccggcaag 80 cagctactatttaataaaacaaaatctgtagaattcacgtttggtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatogtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagcggag gcggcggaagtggagggggaggatcagggggaggaggatcccgtacggtggccgctcccagcgtgttcatcttccc ccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggcc aaggtgeagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaa ggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcg aggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 81 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcaggcggcggcggatccagcgctagcaccaagggccccagcgtgttccccctggccc ccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagcccgtgac cgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcctgtaca gcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagccc agcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgcccagcc ccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcaggacccc cgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacggcgtg gaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgaccg tgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagcccccatcgaa aagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggaggagatg accaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgccgtggagtgggagagcaa cggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagc tgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccac tacacccagaagagcctgagcctgtcccccggcaag 152818.doc -115- 201130511 82 Cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcaggcggcggcggatcccgtacggtggccgctcccagcgtgttcatcttcccccccag cgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggccaaggtg cagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactc cacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtga cccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 83 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggcggcggcggatccagcgctagcaccaagggcccc agcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggact acttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgc agagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgc aacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacc tgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccct gatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaact ggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacaggg tggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggcc ctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgccc ccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccccagcgacatcgcc gtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctggacagcgacggcag cttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcac gaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 84 Cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggcggcggcggatcccgtacggtggccgctcccagc gtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacc cccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgag caggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataagg tgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 85 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaziaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagcggagg cggcggaagtggagggggaggatcagggggaggaggatccagcgctagcaccaagggccccagcgtgttccccct ggcccccagcagcaagagcaccagcggcggcacagccgccctgggctgcctggtgaaggactacttccccgagcc cgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacaccttccccgccgtgctgcagagcagcggcc tgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccaca agcccagcaacaccaaggtggacaagagagtggagcccaagagctgcgacaagacccacacctgccccccctgcc cagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaagcccaaggacaccctgatgatcagcagg acccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccagaggtgaagttcaactggtacgtggacg gcgtggaggtgcacaacgeeaagaceaagcccagagaggageagtacaacagcacctacagggtggtgtcegtgct gaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggtctccaacaaggccctgccagccccc atcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggtgtacaccctgcccccctcccgggag gagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaecccagcgacatcgccgtggagtgggag agcaacggccagcccgagaacaactacaagaccacecccccagtgctggacagcgacggcagcttcttcctgtacag caagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcac aaccactacacccagaagagcctgagcctgtcccccggcaag
152818.doc -116· 201130511
86 Cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgg aggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaaca agtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatgga taagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatc gagctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggcggaggatctggcggcggaggaagcggag gcggcggaagtggagggggaggatcagggggaggaggatcccgtacggtggccgctcccagcgtgttcatcttccc ccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggaggcc aaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaa ggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcg aggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgc 87 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagctcagctag caccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggctg cctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacctt ccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcacc cagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgcg acaagacccacacctgccccccctgcccagccccagagctgctgggcggaccctccgtgttcctgttcccccccaagc ccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggacccaga ggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtacaac agcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaaggt ctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccaggt gtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctaccc cagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctgga cagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcagctg eagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 88 cagctactatttaataaaacaaaatctgtagaattcacgttttgtaatgacactgtcgtcattccatgctttgttactaatatgga ggcacaaaacactactgaagtatacgtaaagtggaaatttaaaggaagagatatttacacctttgatggagctctaaacaa gtccactgtccccactgactttagtagtgcaaaaattgaagtctcacaattactaaaaggagatgcctctttgaagatggat aagagtgatgctgtctcacacacaggaaactacacttgtgaagtaacagaattaaccagagaaggtgaaacgatcatcg agctaaaatatcgtgttgtttcatggttttctccaaatgaaaatggaggtggtggatctggaggtggaggtagctcagcctc caccaagggtccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcct ggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttccc ggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaact cacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggac accctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtacc gggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaa gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacectgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcg ccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctc cttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatg aggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa 89 caactactgtttagtaacgtcaactccatagagttcacttcaggcaatgaaactgtggtcatcccttgcatcgtccgtaatgt ggaggcgcaaagcaccgaagaaatgtttgtgaagtggaagttgaacaaatcgtatattttcatctatgatggaaataaaaa tagcactactacagatcaaaactttaccagtgcaaaaatctcagtctcagacttaatcaatggcattgcctctttgaaaatgg ataagcgcgatgccatggtgggaaactacacttgcgaagtgacagagttatccagagaaggcaaaacagttatagagc tgaaaaaccgcacggtttcgtggttttctccaaatgaaaagatcggaggtggtggatctggaggtggaggtagctcagct agcaccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggc tgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacc ttccccgcegtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcac 152818.doc -117- 201130511 ccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgc gacaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaa gcccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggaccca gaggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtaca acagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaag gtctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccag gtgtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctac cccagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctg gacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcag ctgcagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 90 caactactgtttagtaacgtcaactccatagagttcacttcaggcaatgaaactgtggtcatcccttgcatcgtccgtaatgt gg^ggcgc^^gcaccgaagaaatgtttgtgaagtggaagttgaacaaatcgtatattttcatctatgatggaaataaaaa tagcactactacagatcaaaac伽 ccagtgcaaaaatctcagtctcagacttaatcaatggcattgcctctttgaaaatgg ataagcgcgatgccatggtgggaaactacacttgcgaagtgacagagttatccagagaaggcaaaacagttatagagc tgaaaaaccgcacggtttcgtggttttctccaaatgaaaagatcggaggtggtggatctggaggtggaggtagccgtac ggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcc tgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagcca ggagagcgtcaccgagcaggacagcaaggactecacctacagcctgagcagcacectgaecctgagcaaggcega ctacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaaca ggggcgagtgc 91 caactactgtttagtaacgtcaactccatagagttcacttcatgcaatgaaactgtggtcatcccttgcatcgtccgtaatgt ggaggcgcaaagcaccgaagaaatgtttgtgaagtggaagttgaacaaatcgtatattttcatctatgatggaaataaaaa tagcactactacagatcaaaactttaccagtgcaaaaatctcagtctcagacttaatcaatggcattgcctctttgaaaatgg ataagcgcgatgccatggtgggaaactacacttgcgaagtgacagagttatccagagaaggcaaaacagttatagagc tgaaaaaccgcacggtttcgtggttttctccaaatgaaaagatcggaggtggtggatctggaggtggaggtagctcagct agcaccaagggccccagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacagccgccctgggc tgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctgacctccggcgtgcacacc ttccccgccgtgctgcagagcagcggcctgtacagcctgtccagcgtggtgacagtgcccagcagcagcctgggcac ccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaagagagtggagcccaagagctgc gacaagacccacacctgccccccctgcccagccccagaggcagcgggcggaccctccgtgttcctgttcccccccaa gcccaaggacaccctgatgatcagcaggacccccgaggtgacctgcgtggtggtggacgtgagccacgaggaccca gaggtgaagttcaactggtacgtggacggcgtggaggtgcacaacgccaagaccaagcccagagaggagcagtaca acagcacctacagggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaggaatacaagtgcaag gtctccaacaaggccctgccagcccccatcgaaaagaccatcagcaaggccaagggccagccacgggagccccag gtgtacaccctgcccccctcccgggaggagatgaccaagaaccaggtgtccctgacctgtctggtgaagggcttctac cccagcgacatcgccgtggagtgggagagcaacggccagcccgagaacaactacaagaccacccccccagtgctg gacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagtccaggtggcagcagggcaacgtgttcag ctgcagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcccccggcaag 92 caactactgtttagtaacgtcaactccatagagttcacttcatgcaatgaaactgtggtcatcccttgcatcgtccgtaatgt ggaggcgcaaagcaccgaagaaatgtttgtgaagtggaagttgaacaaatcgtatattttcatctatgatggaaataaaaa tagcactactacagatcaaaactttaccagtgcaaaaatctcagtctcagacttaatcaatggcattgcctctttgaaaatgg ataagcgcgatgccatggtgggaaactacacttgcgaagtgacagagttatccagagaaggcaaaacagttatagagc tgaaaaaccgcacggtttcgtggttttctccaaatgaaaagatcggaggtggtggatctggaggtggaggtagccgtac ggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcc tgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagcca ggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccga ctacgagaagcataaggtgtacgcctgcgaggtgaeeeaccagggcctgtccagccecgtgaceaagagcttcaaca ggggcgagtgc
【圖式簡單說明】 圖1 : SIRPa結合融合體之一實例之示意圖。 -118· 152818.doc 201130511 圖2:重組SIRPa結合融合體與先前技術二價SIRPa結合 蛋白(CD47-FC)之SIRPa結合活性的比較。 如在2.2下所述,比較SIRPa結合融合體4號實例及二價 SIRPa結合蛋白與二價生物素化SIRPa結合蛋白(CD47-FC) 競爭結合固定之SIRPa-Fc的能力。相較於二價SIRPa結合 蛋白(黑圓圈),SIRPa結合融合體4號實例(三角)與生物素 化CD47-FC(以5 nM使用)之競爭結合更有效,倍數>5倍。 八 因為兩種競爭劑之單一 CD47部分之親和力相同,所以此 Ο 等資料證明SIRPa結合融合體之親合力獲得優於先前技術 CD47_Fc融合蛋白之改良。 圖3 :重組SIRPa結合融合體與細胞SIRPa之結合活性。 比較SIRPa結合融合體4號實例支持SIRPa依賴性細胞黏 著之能力。在靜態條件下使螢光標記之U937細胞與各種濃 度之經固定SIRPa結合融合體4號實例或二價SIRPa結合蛋 白(CD47-FC)黏著30分鐘。藉由流體剪切力,例如如2.3中 Q 所述之重複洗滌步驟移除鬆散黏著或未結合之細胞。資料 顯示相較於二價SIRPa結合蛋白(CD47-Fc)(黑圓圈), SIRPa結合融合體4號實例(三角)支持SIRPa+ U937細胞之 牢固黏著更有效,倍數>5倍(表5)。因為兩種競爭劑之親 和力相同,所以此等資料證明SIRPa結合融合體與其細胞 結合目標之親合力獲得優於先前技術CD47-FC融合蛋白之 改良。 圖4 : SIRPa結合融合體(4號實例)與全血中人類SIRPa+單 核細胞之特異性結合及與未標記SIRPa結合蛋白之競爭。 152818.doc •119· 201130511 例如在CD47高表現紅血球存在下,SIRPa結合融合體4 號實例有效結合全血中之CD14 +單核細胞。使用Ax647-螢 光染料標記之SIRPa結合融合體4號實例,用流動式細胞測 量術定量人類全血中之結合(方法如2.4中)。結合由未標記 SIRPa結合融合體(三角)或先前技術SIRPa結合蛋白(CD47-Fc)(黑圓圈)以濃度依賴性方式阻斷。在添加Ax647-螢光染 料標記之SIRPa結合融合體4號實例之前,當血液樣品用20 pg/ml抗SIRPa抗體(純系148)處理時,Ax647-螢光染料標 記之SIRPa結合融合體4號實例不能與CD 14 +單核細胞相互 作用。未觀測到與淋巴細胞T或B細胞之結合(未展示)。 SIRPa結合融合體與全血中人類SIRPa.單核細胞之優良結 合由利用未標記先前技術二價SIRPa結合蛋白(CD47-FC)獲 得之明顯不太有效之競爭(所得IC50值高約20-50倍,表5) 反映。對照人類IgGl(方塊)不影響Ax647-螢光染料標記之 SIRPa結合融合體與CD14 +單核細胞的結合。 圖5: SIRPa結合融合體4號實例以pM效能使細胞激素自 活體外單核細胞源性人類樹突狀細胞之釋放靜止。 在SIRPa結合融合體4號實例或作為對照之人類IgGl存在 下,GMSCF/IL4分化之單核細胞源性樹突狀細胞用SAC粒 子(金黃色葡萄球菌Cowan菌株,0.01%)刺激隔夜。SIRPa 結合融合體4號實例以pM效能阻斷細胞激素TNFa、IL6及 IL12釋放至上清液中。 圖6 : SIRPa結合融合體之鼠類替代物保護動物免於發 生抗原觸發之肺發炎,一種模擬人類過敏性哮喘之疾病參 152818.doc -120- 201130511 數的模型。 相較於對照,以每隻動物腹膜内投與1 00 pg鼠類SIRPa 結合融合體(mCD47 C15G融合體(重鏈SEQ ID: 31,輕鏈 SEQ ID: 32,左圖)或mCD47融合體(重鏈SEQ ID: 33,輕 鏈SEQ ID: 34,右圖)2次處理小鼠使氣溶膠抗原攻毒後 BALF中之總細胞計數以及°耆伊紅血球(eos)、嗜中性白血 球(neu)及淋巴細胞(lymp)的數目減少。兩種鼠類SIRPa結 合融合體因此均有效保護小鼠免於發生過敏性哮喘。η = 每組所用動物之數目。 圖7 : SIRPa結合融合體之鼠類替代物降低TNBS結腸炎 (一種模擬人類結腸炎之病理學態樣之模型)之嚴重性。 如藉由體重減輕所指示,以每隻動物腹膜内投與100 eg 鼠類SIRPa結合融合體(mCD47 C15G融合體,重鏈SEQ ID: 31,輕鏈SEQ ID: 32)3-4次處理小鼠以統計學上顯著之方 式降低由TNBS引發之發炎性結腸炎的嚴重性。在第7天用 TNBS再誘發疾病之後,經mCD47 C15G融合體處理之動物 的體重保持高於PBS或對照IgG對照組。因此注射鼠類 SIRPa結合蛋白(mCD47-C15G融合體)有效阻斷疾病發展之 嚴重性。資料為用3或4次連續投與測試化合物進行之2個 不同實驗的概述。n=每組所用動物之數目。 152818.doc -121 - 201130511 序 列表 <11〇>瑞士商諾華公司 <120>作為治療劑之可溶性蛋白質 <130> PAT053999 <140> 099145049 <141> 2010-12-21 <150> 61/289,007 <151> 2009-12-22 <160> 92 〇 <170> Patentln version 3. 3 <210> 1 <211> 504 <212〉 PRT <213〉智人 <400〉 1
Met Glu Pro Ala Gly Pro Ala Pro Gly Arg Leu Gly Pro Leu Leu Cys 1 5 10 15
Leu Leu Leu Ala Ala Ser Cys Ala Trp Ser Gly Val Ala Gly Glu Glu 20 25 30
Q
Glu Leu Gin Val lie Gin Pro Asp Lys Ser Val Leu Val Ala Ala Gly 35 40 45
Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu He Pro Val Gly 50 55 60
Pro He Gin Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu lie Tyr 65 70 75 80
Asn Gin Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu 85 90 95 152818·序列表.doc 201130511
Thr Lys Arg Asn Asn Met Asp Phe Ser He Arg lie Gly Asn He Thr 100 105 110
Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser 115 120 125
Pro Asp Asp Val Glu Phe L}7s Ser Gly Ala Gly Thr Glu Leu Ser Val 130 135 140
Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg Ala 145 150 155 160
Thr Pro Gin His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser 165 170 175
Pro Arg Asp lie Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser 180 185 190
Asp Phe Gin Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser 195 200 205 lie His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His Ser 210 215 220
Gin Val Tie Cys Glu Val Ala His Val Thr Leu Gin Gly Asp Pro Leu 225 230 235 240
Arg Gly Thr Ala Asn Leu Ser Glu Thr lie Arg Val Pro Pro Thr Leu 245 250 255
Glu Val Thr Gin Gin Pro Val Arg Ala Glu Asn Gin Val Asn Val Thr 260 265 270
Cys Gin Val Arg Lys Phe Tyr Pro Gin Arg Leu Gin Leu Thr Trp Leu 275 280 285 -2- 152818-序列表.doc 201130511
Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr Glu 290 295 300
Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn Val 305 310 315 320
Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gin Val Glu His Asp 325 330 335
Gly Gin Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala His 340 345 350 o
Pro Lys Glu Gin Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser Asn 355 360 365
Glu Arg Asn lie Tyr lie Val Val Gly Val Val Cys Thr Leu Leu Val 370 375 380
Ala Leu Leu Met Ala Ala Leu Tyr Leu Val Arg lie Arg Gin Lys Lys 385 390 395 400
Ala Gin Gly Ser Thr Ser Ser Thr Arg Leu His Glu Pro Glu Lys Asn 405 410 415 o
Ala Arg Glu lie Thr Gin Asp Thr Asn Asp lie Thr Tyr Ala Asp Leu 420 425 430
Asn Leu Pro Lys Gly Lys Lys Pro Ala Pro Gin Ala Ala Glu Pro Asn 435 440 445
Asn His Thr Glu Tyr Ala Ser lie Gin Thr Ser Pro Gin Pro Ala Ser 450 455 460
Glu Asp Thr Leu Thr Tyr Ala Asp Leu Asp Met Val His Leu Asn Arg 465 470 475 480 152818-序列表.doc 201130511
Thr Pro Lys Gin Pro Ala Pro Lys Pro Glu Pro Ser Phe Ser Glu Tyr 485 490 495
Ala Ser Val Gin Val Pro Arg Lys 500 〈210〉 2 <211> 323 <212> PRT <213〉智人 <400> 2
Met Trp Pro Leu Val Ala Ala Leu Leu Leu Gly Ser Ala Cys Cys Gly 15 10 15
Ser Ala Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe 20 25 30
Cys Asn Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala 35 40 45
Gin Asn Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp 50 55 60 lie Tyr Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp 65 70 75 80
Phe Ser Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala 85 90 95
Ser Leu Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr 100 105 110
Thr Cys Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu 115 120 125 152818·序列表.doc 201130511
Leu Lys Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn lie Leu 130 135 140 lie Val lie Phe Pro lie Phe Ala lie Leu Leu Phe Trp Gly Gin Phe 145 150 155 160
Gly lie Lys Thr Leu Lys Tyr Arg Ser Gly Gly Met Asp Glu Lys Thr 165 170 175 lie Ala Leu Leu Val Ala Gly Leu Val He Thr Val He Val lie Val 180 185 190 〇
Gly Ala lie Leu Phe Val Pro Gly Glu Tyr Ser Leu Lys Asn Ala Thr 195 200 205
Gly Leu Gly Leu lie Val Thr Ser Thr Gly lie Leu lie Leu Leu His 210 215 220
Tyr Tyr Val Phe Ser Thr Ala lie Gly Leu Thr Ser Phe Val He Ala 225 230 235 240 lie Leu Val lie Gin Val lie Ala Tyr lie Leu Ala Val Val Gly Leu 245 250 255 o
Ser Leu Cys lie Ala Ala Cys lie Pro Met His Gly Pro Leu Leu He 260 265 270
Ser Gly Leu Ser lie Leu Ala Leu Ala Gin Leu Leu Gly Leu Val Tyr 275 280 285
Met Lys Phe Val Ala Ser Asn Gin Lys Thr lie Gin Pro Pro Arg Lys 290 295 300
Ala Val Glu Glu Pro Leu Asn Ala Phe Lys Glu Ser Lys Gly Met Met 305 310 315 320 152818-序列表.doc 201130511
Asn Asp Glu <210> 3 <211> 123 <212> PRT <213〉智人 <400> 3
Gin Leu Leu Phe Asn Lys Thr Lys Ser Va.1 Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Va.1 Val lie Pro Cys Phe Va.1 Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu 115 120 <210> 4 <211> 124
<212〉 PRT -6- 152818-序列表.doc 201130511 <213〉智人 <400〉 4
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
O
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 〇 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn 115 120 <210〉 5 〈211〉 455 <212> PRT <213〉智人 <400> 5
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15 152818-序列表.doc 201130511
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys • 8 - 152818-序列表.doc 201130511 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Ala Ala 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 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320 o
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Tltr Leu Pro Pro Ser Arg 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 -9- 152818·序列表.doc 201130511 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
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 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 Pro Gly Lys 450 455 <210> 6 <211> 231 <212〉 PRT <213〉智人 <400〉 6
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 10- 152818-序列表.doc 201130511
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Arg Thr Val Ala 115 120 125
Ala Pro Ser Val Phe lie Phe Fro Pro Ser Asp Glu Gin Leu Lys Ser 130 135 140
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 145 150 155 160
Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser 165 170 175
Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205
Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 210 215 220
Ser Phe Asn Arg Gly Glu Cys 225 230 <210〉 7 <211〉 99 <212〉 PRT <213〉智人 •11· 152818-序列表.doc 201130511 <400〉 7
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 15 10 15
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 20 25 30
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 35 40 45
Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr 50 55 60
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin 65 70 75 80
Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 85 90 95
Lys Arg Val <210> 8 <211> 107 <212> PRT <213〉智人 <400> 8
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu 1 5 10 15
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 •12· 152818·序列表doc 201130511
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 35 40 45
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95
O
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 〈210〉 9 <211> 232 <212> PRT 〈213>智人 〈400〉 9
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 15 10 15
Q
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30
Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin 65 70 75 80 •13- 152818-序列表-doc 201130511
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin 85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110
Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro 115 120 125
Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140
Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160
Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr 165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe 195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys 210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210〉 10 <211〉 1419 <212〉 DNA <213〉 智人 14- 152818-序列表-doc 60 60 o 201130511 <400〉 10 atgtggcccc tggtagcggc gctgttgctg ggctcggcgt gctgcggatc agctcagcta ctatttaata aaacaaaatc tgtagaattc acgttttgta atgacactgt cgtcattcca tgctttgtta ctaatatgga ggcacaaaac actactgaag tatacgtaaa gtggaaattt aaaggaagag atatttacac ctttgatgga gctctaaaca agtccactgt ccccactgac tttagtagtg caaaaattga agtctcacaa ttactaaaag gagatgcctc tttgaagatg gataagagtg atgctgtctc acacacagga aactacactt gtgaagtaac agaattaacc agagaaggtg aa.acgatca.t cga.gctaaaa. tatcgtgttg tttcatggtt ttctccaaat. gaaaattcag ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg accgtgtcct ggaacagcgg agccctgacc tccggcgtgc acaccttccc cgccgtgctg cagagcagcg gcctgtacag cctgtccagc gtggtgacag tgcccagcag cagcctgggc acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc cccagaggca gcgggcggac cctccgtgtt cctgttcccc cccaagccca aggacaccct gatgatcagc aggacccccg aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc agaggtgaag ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc cagagaggag cagtacaaca gcacctacag ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg aacggcaagg aatacaagtg caaggtctcc aacaaggccc tgccagcccc catcgaaaag accatcagca aggccaaggg ccagccacgg gagccccagg tgtacaccct gcccccctcc cgggaggaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaggg cttctacccc agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaacta caagaccacc cccccagtgc tggacagcga cggcagcttc ttcctgtaca gcaagctgac cgtggacaag tccaggtggc agcagggcaa cgtgttcagc tgcagcgtga tgcacgaggc cctgcacaac 152818-序列表.doc -15- 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 201130511 cactacaccc agaagagcct gagcctgtcc cccggcaag 1419 <210〉 11 <211> 747 <212> DNA <213〉智人 <400〉 11 atgtggcccc tggtagcggc gctgttgctg ggctcggcgt gctgcggatc agctcagcta 60 ctatttaata aaacaaaatc tgtagaattc acgttttgta atgacactgt cgtcattcca 120 tgctttgtta ctaatatgga ggcacaaaac actactgaag tatacgtaaa gtggaaattt 180 aaaggaagag atatttacac ctttgatgga gctctaaaca agtccactgt ccccactgac 240 tttagtagtg caaaaattga agtctcacaa ttactaaaag gagatgcctc tttgaagatg 300 gataagagtg atgctgtctc acacacagga aactacactt gtgaagtaac agaattaacc 360 agagaaggtg aaacgatcat cgagctaaaa tatcgtgttg tttcatggtt ttctccaaat 420 gaaaatcgta cggtggccgc tcccagcgtg ttcatcttcc cccccagcga cgagcagctg 480 aagagcggca ccgccagcgt ggtgtgcctg ctgaacaact tctacccccg ggaggccaag 540 gtgcagtgga aggtggacaa cgccctgcag agcggcaaca gccaggagag cgtcaccgag 600 caggacagca aggactccac ctacagcctg agcagcaccc tgaccctgag caaggccgac 660 tacgagaagc ataaggtgta cgcctgcgag gtgacccacc agggcctgtc cagccccgtg 720 accaagagct tcaacagggg cgagtgc 747 <210〉 12 <211〉 465 <212> PRT <213〉智人 <400〉 12
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15 •16- 152818·序列表.doc 201130511
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
O
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 〇 130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 •17 152818-序列表.doc 201130511
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 305 310 315 320
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 340 345 350
Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 370 375 380 -18· 152818·序列表.doc 201130511
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu 385 . 390 395 400
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460
Lys 465 <210> 13 <211> 241 <212> PRT <213〉智人
<400〉 13
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser -19- 152818-序列表.doc 201130511 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie 130 135 140
Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val 145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys 165 170 175
Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu 180 185 190
Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 210 215 220
His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 225 230 235 240 20- 152818·序列表.doc
201130511
Cys <210> 14 <211> 1449 <212> DNA 〈213〉智人 <400> 14 atgtggcccc tggtagcggc gctgttgctg ggctcggcgt gctgcggatc agctcagcta ctatttaata aaacaaaatc tgtagaattc acgtttggta atgacactgt cgtcattcca tgctttgtta ctaatatgga ggcacaaaac actactgaag tatacgtaaa gtggaaattt aaaggaagag atatttacac ctttgatgga gctctaaaca agtccactgt ccccactgac tttagtagtg caaaaattga agtctcacaa ttactaaaag gagatgcctc tttgaagatg gataagagtg atgctgtctc acacacagga aactacactt gtgaagtaac agaattaacc agagaaggtg aaacgatcat cgagcteiaaa tatcgtgttg tttcatggtt ttctccaaat gaaaatggag gtggtggatc tggaggtgga ggtagctcag ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg accgtgtcct ggaacagcgg agccctgacc 〇 tccggcgtgc acaccttccc cgccgtgctg cagagcagcg gcctgtacag cctgtccagc gtggtgacag tgcccagcag cagcctgggc acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc cccagaggca gcgggcggac cctccgtgtt cctgttcccc cccaagccca aggacaccct gatgatcagc aggacccccg aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc agaggtgaag ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc cagagaggag cagtacaaca gcacctacag ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg aacggcaagg aatacaagtg caaggtctcc 152818-序列表.doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 •21- 1080 201130511 aacaaggccc tgccagcccc catcgaaaag gagccccagg tgtacaccct gcccccctcc ctgacctgtc tggtgaaggg cttctacccc ggccagcccg agaacaacta caagaccacc ttcctgtaca gcaagctgac cgtggacaag tgcagcgtga tgcacgaggc cctgcacaac cccggcaag <210〉 15 <211〉 777 <212〉 DNA <213〉智人 <400> 15 atgtggcccc tggtagcggc gctgttgctg ctatttaata aaacaaaatc tgtagaattc tgctttgtta ctaatatgga ggcacaaaac aaaggaagag atatttacac ctttgatgga tttagtagtg caaaaattga agtctcacaa gataagagtg atgctgtctc acacacagga agagaaggtg aaacgatcat cgagctaaaa gaaaatggag gtggtggatc tggaggtgga ttcatcttcc cccccagcga cgagcagctg ctgaacaact tctacccccg ggaggccaag agcggcaaca gccaggagag cgtcaccgag agcagcaccc tgaccctgag caaggccgac accatcagca aggccaaggg ccagccacgg 1140 cgggaggaga tgaccaagaa ccaggtgtcc 1200 agcgacatcg ccgtggagtg ggagagcaac 1260 cccccagtgc tggacagcga cggcagcttc 1320 tccaggtggc agcagggcaa cgtgttcagc 1380 cactacaccc agaagagcct gagcctgtcc 1440 1449 ggctcggcgt gctgcggatc agctcagcta 60 acgtttggta atgacactgt cgtcattcca 120 actactgaag tatacgtaaa gtggaaattt 180 gctctaaaca agtccactgt ccccactgac 240 ttactaaaag gagatgcctc tttgaagatg 300 aactacactt gtgaagtaac agaattaacc 360 tatcgtgttg tttcatggtt ttctccaaat 420 ggtagccgta cggtggccgc tcccagcgtg 480 aagagcggca ccgccagcgt ggtgtgcctg 540 gtgcagtgga aggtggacaa cgccctgcag 600 caggacagca aggactccac ctacagcctg 660 tacgagaagc ataaggtgta cgcctgcgag 720 -22- 152818-序列表.doc 201130511 gtgacccacc agggcctgtc cagccccgtg accaagagct tcaacagggg cgagtgc 〈210〉 16 <211> 454 <212> PRT <213〉智人 <400> 16
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 ❹
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 -23- 152818-序列表.doc 201130511
Gly Gly Tlir Ala Ala Leu Gly C-ys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 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 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 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 Ala Leu 325 330 335 -24- 152818·序列表.doc 201130511
Pro Ala Pro 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 Arg 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
O
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 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 Pro Gly O 450 〈210〉 17 <211〉 464 <212〉 PRT <213〉智人 <400> 17
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn •25- 152818-序列表.doc 201130511 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 -26- 152818-序列表-doc 201130511
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 305 310 315 320
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys 340 345 350
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu -27- 152818·序列表.doc 201130511 385 390 395 400 Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460 <210〉 18 <211〉 455 <212〉 PRT <213〉智人 <400〉 18
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 28- 152818-序列表_(3(^ 201130511
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
O
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205 ❹
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270 -29 152818·序列表,doc 201130511
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 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 Ala Leu 325 330 335
Pro Ala Pro 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 Arg 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
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 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 -30- 152818-序列表.doc 201130511
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 19 <211〉 465 <212> PRT 〈213>智人 〈400〉 19
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
O
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 -31 · 152818-序列表.doc 201130511
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 305 310 315 320
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 32· 152818-序列表.doc 201130511 325 330 335 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 340 345 350
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 385 390 395 400
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 〇
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460
Lys 465 <210> 20 <211〉 241 <212> PRT <213〉智人 <400〉 20 •33- 152818·序列表.doc 201130511
Gin Leu Leu Phe Asn Lys Thr Lys Ser Yal Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie 130 135 140
Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val 145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys 165 170 175
Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu 180 185 190 -34- 152818-序列表.doc 201130511
Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 210 215 220
His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 225 230 235 240
Cys o <210> 21 <211> 124 <212> PRT <213〉智人 <400> 21
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
O
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys •35· 1528〗8-序列表.doc 201130511 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn 115 120 <210> 22 <211> 232 <212> PRT <213〉智人 <400〉 22
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 15 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30
Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin 65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin 85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 -36 152818-序列表.doc 201130511
Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro 115 120 125
Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140
Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160
Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr 165 170 175
O
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe 195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys 210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
〈210〉 23 <211〉 117 〈212〉 PRT <213〉智人 <400〉 23
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30 -37- 152818-序列表.doc 201130511
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser 115 <210> 24 <211〉 448 <212〉 PRT <213〉智人 <400> 24
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60 -38- 152818·序列表.doc 201130511
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190
Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser 195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 225 230 235 240 39- 152818-序列表.doc 201130511
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255
Thr Fro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys Thr 325 330 335 lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val T}rr Thr Leu 340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser 370 375 380
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 -40· 152818-序列表 _doc 201130511
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 25 <211〉 224 <212> PRT <213〉智人 <400〉 25
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15 o
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe 115 120 125
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys -41 · 152818-序列表.doc 201130511 130 135 140
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 145 150 155 160
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 165 170 175
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 180 185 190
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 195 200 205
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 26 <211〉 387 <212> PRT <213〉智人 <400> 26
Met Pro Val Pro Ala Ser Trp Pro His Pro Pro Gly Pro Phe Leu Leu 15 10 15
Leu Thr Leu Leu Leu Gly Leu Thr Glu Val Ala Gly Glu Glu Glu Leu 20 25 30
Gin Met He Gin Pro Glu Lys Leu Leu Leu Val Thr Val Gly Lys Thr 35 40 45
Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro Val 50 55 60 -42- 1528丨8-序列表.doc 201130511
Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu He Tyr Asn Gin 65 70 75 80
Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr Lys 85 90 95
Arg Asn Asn Met Asp Phe Ser lie Arg lie Ser Ser lie Thr Pro Ala 100 105 110
Asp Val Gly Thr Tyr T)rr Cys Val Lys Phe Arg Lys Gly Ser Pro Glu 115 120 125
Asn Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly Ala 130 135 140
Lys Pro Ser Ala Pro Val Val Leu Gly Pro Ala Ala Arg Thr Thr Pro 145 150 155 160
Glu His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser Pro Arg 165 170 175
Asp lie Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser Asp Phe 180 185 190 o
Gin Thr Asn Val Asp Pro Thr Gly Gin Ser Val Ala Tyr Ser lie Arg 195 200 205
Ser Thr Ala Arg Val Val Leu Asp Pro Trp Asp Val Arg Ser Gin Val 210 215 220
He Cys Glu Val Ala His Val Thr Leu Gin Gly Asp Pro Leu Arg Gly 225 230 235 240
Thr Ala Asn Leu Ser Glu Ala lie Arg Val Pro Pro Thr Leu Glu Val 245 250 255 -43 152818-序列表.doc 201130511
Thr Gin Gin Pro Met Arg Val Gly Asn Gin Val Asn Val Thr Cys Gin 260 265 270
Val Arg Lys Phe Tyr Pro Gin Ser Leu Gin Leu Thr Trp Ser Glu Asn 275 280 285
Gly Asn Val Cys Gin Arg Glu Thr Ala Ser Thr Leu Thr Glu Asn Lys 290 295 300
Asp Gly Thr Tyr Asn Trp Thr Ser Trp Phe Leu Val Asn lie Ser Asp 305 310 315 320
Gin Arg Asp Asp Val Val Leu Thr Cys Gin Val Lys His Asp Gly Gin 325 330 335
Leu Ala Val Ser Lys Arg Leu Ala Leu Glu Val Thr Val His Gin Lys 340 345 350
Asp Gin Ser Ser Asp Ala Thr Pro Gly Pro Ala Ser Ser Leu Thr Ala 355 360 365
Leu Leu Leu lie Ala Val Leu Leu Gly Pro He Tyr Val Pro Trp Lys 370 375 380
Gin Lys Thr 385 <210〉 27 〈211〉 117 〈212〉 PRT <213〉智人 <400〉 27
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn • 44- 152818·序列表.doc 201130511 1 5 10 15 Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
O
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser 115 ❹ <210> 28 <211〉 232 <212〉 PRT <213〉智人 <400> 28
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 15 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30 •45 152818-序列表.doc 201130511
Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin 65 70 75 80
Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin 85 90 95
Asp Trp Leu Asn Gly L3rs Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110
Leu Fro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro 115 120 125
Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 130 135 140
Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160
Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr 165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe 195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys 210 215 220 -46- 152818·序列表.doc 201130511
Ser Leu Ser Leu Ser Pro Gly Lys 225 230 〈210〉 29 〈211〉 465 <212〉 PRT 〈213> 智人 <400〉 29
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe -47- 152818·序列表.doc 201130511 130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Ala Ser Thr Tyr Arg Val 305 310 315 320 -48- 152818-序列表.doc 201130511
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 340 345 350
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 370 375 380
O
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 385 390 395 400
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460
Lys 465 <210〉 30 〈211〉 123 <212> PRT <213〉小家鼠 -49- 152818-序列表.doc 201130511 <400> 30
Gin Leu Leu Phe Ser Asn Val Asn Ser lie Glu Phe Thr Ser Gly Asn 15 10 15
Glu Thr Val Val He Pro Cys He Val Arg Asn Val Glu Ala Gin Ser 20 25 30
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr He Phe 35 40 45
He Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60 '
Ser Ala Lys He Ser Val Ser Asp Leu He Asn Gly lie Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val lie Glu Leu Lys Asn Arg 100 105 110
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys He 115 120 <210> 31 <211> 464 <212〉 PRT <213〉 小家鼠 <400 31
Gin Leu Leu Phe Ser Asn Val Asn Ser He Glu Phe Thr Ser Gly Asn 15 10 15
Glu Thr Val Val lie Pro Cys He Val Arg Asn Val Glu Ala Gin Ser -50· 152818·序列表.doc 201130511 20 25 30
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr lie Phe 35 40 45 lie Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60
Ser Ala Lys lie Ser Val Ser Asp Leu lie Asn Gly lie Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val lie Glu Leu Lys Asn Arg 100 105 110
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys lie Gly Gly Gly Gly Ser 115 120 125
Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 180 185 190
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 • 51 · 152818-序列表.doc 201130511
Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser 210 215 220
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 275 280 285
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 290 295 300
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 305 310 315 320
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 325 330 335
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr 340 345 350 lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 355 360 365
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser -52· 152818-序列表.doc 201130511 385 390 395 400
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435 440 445
O
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 32 <211〉 240 〈212〉 PRT <213〉小家鼠 <400> 32
Gin Leu Leu Phe Ser Asn Val Asn Ser lie Glu Phe Thr Ser Gly Asn 15 10 15
O
Glu Thr Val Val lie Pro Cys lie Val Arg Asn Val Glu Ala Gin Ser 20 25 30
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr lie Phe 35 40 45 lie Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60
Ser Ala Lys lie Ser Val Ser Asp Leu lie Asn Gly lie Ala Ser Leu 65 70 75 80 -53- 152818-序列表.doc 201130511
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val lie Glu Leu Lys Asn Arg 100 105 110
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys lie Gly Gly Gly Gly Ser 115 120 125
Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe He Phe 130 135 140
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 165 170 175
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 210 215 220
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240 <210〉 33 <211〉 123 <212〉 PRT <213〉小家鼠 <400> 33 54- 152818-序列表.doc 201130511
Gin Leu Leu Phe Ser Asn Val Asn Ser lie Glu Phe Thr Ser Cys Asn 15 10 15
Glu Thr Val Val lie Pro Cys lie Val Arg Asn Val Glu Ala Gin Ser 20 25 30
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr lie Phe 35 40 45 lie Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60 o
Ser Ala Lys lie Ser Val Ser Asp Leu lie Asn Gly lie Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val lie Glu Leu Lys Asn Arg 100 105 110
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys lie
<210〉 34 <211〉 464 <212〉 PRT <213〉小家鼠 〈400〉 34
Gin Leu Leu Phe Ser Asn Val Asn Ser lie Glu Phe Thr Ser Cys Asn 15 10 15
Glu Thr Val Val lie Pro Cys lie Val Arg Asn Val Glu Ala Gin Ser 20 25 30 •55 152818·序列表.doc 201130511
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr lie Phe 35 40 45
He Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60
Ser Ala Lys lie Ser Val Ser Asp Leu He Asn Gly lie Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val He Glu Leu Lys Asn Arg 100 105 110
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys He Gly Gly Gly Gly Ser 115 120 125
Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 180 185 190
Ser vSer Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205
Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn His Lys Pro Ser 210 215 220 -56- 152818-序列表.doc 201130511
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 225 230 235 240
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 275 280 285 〇
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 290 295 300
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 305 310 315 320
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 325 330 335
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr 340 345 350 ❹ lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 355 360 365
Pro Pro Ser Arg Glu Glu Met Tlir Lys Asn Gin Val Ser Leu Thr Cys 370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 385 390 395 400
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415 -57 152818-序列表.doc 201130511
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435 440 445
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210〉 35 <211〉 240 <212> PRT <213〉 小家鼠 <400> 35
Gin Leu Leu Phe Ser Asn Val Asn Ser He Glu Phe Thr Ser Cys Asn 15 10 15
Glu Thr Val Val lie Pro Cys lie Val Arg Asn Val Glu Ala Gin Ser 20 25 30
Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr He Phe 35 40 45 lie Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gin Asn Phe Thr 50 55 60
Ser Ala Lys lie Ser Val Ser Asp Leu lie Asn Gly lie Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys Glu Val 85 90 95
Thr Glu Leu Ser Arg Glu Gly Lys Thr Val lie Glu Leu Lys Asn Arg 100 105 110 -58 - 152818-序列表.doc 201130511
Thr Val Ser Trp Phe Ser Pro Asn Glu Lys lie Gly Gly Gly Gly Ser 115 120 125
Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe 130 135 140
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 165 170 175 o
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 210 215 220
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 0 225 230 235 240 〈210〉 36 <211〉 455 <212> PRT 〈213>智人 〈400〉 36
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30 59· 152818-序列表.doc 201130511
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 •60- 152818·序列表.doc 201130511
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Ala Ala 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 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285 o
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 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 Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 〇 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 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 •61 - 152818-序列表.doc 201130511
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 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 Pro Gly Lys 450 455 <210〉 37 <211〉 231 <212〉 PRT <213〉 智人 <400〉 37
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Tip Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys He Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95 -62- 152818·序列表.doc 201130511
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Arg Thr Val Ala 115 120 125
Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser 130 135 140
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 145 150 155 160
O
Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser 165 170 175
Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205
Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 210 215 220
Ser Phe Asn Arg Gly Glu Cys 225 230 <210> 38 <211> 448 <212〉 PRT <213〉智人 <400> 38
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15 63· 152818-序列表.doc 201130511
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 152818·序列表.doc -64- 201130511
Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser 195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 o
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys Thr 325 330 335 lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 370 375 380 -65- 152818·序列表.doc 201130511
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 39 <211〉 224 <212〉 PRT <213〉 智人 〈400〉 39
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys He Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys -66- 152818-序列表_(1〇〇 201130511 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe 115 120 125
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys 130 135 140
O
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 145 150 155 160
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 165 170 175
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 180 185 190
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 195 200 205
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 〈210〉 40 <211〉 460 〈212〉 PRT <213〉智人 <400> 40
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15 -67 152818-序列表.doc 201130511
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys He Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Tlir Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 130 135 140
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu 180 185 190
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 68- 】528】8·序列表.doc 201130511
Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 210 215 220
Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 225 230 235 240
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe 245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295 300
Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 305 310 315 320
Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Q 325 330 335
Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala 340 345 350
Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365
Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 -69- 152818·序列表.doc 201130511
Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 405 410 415
Phe Phe Leu Tyr Ser Lys Leu Tlir Val Asp Lys Ser Arg Trp Gin Gin 420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 435 440 445
Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 41 <211> 236 〈212〉 PRT 〈213〉 智人 〈400〉 41
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 •70- 152818·序列表.doc 201130511
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 130 135 140
O
Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 165 170 175
Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 180 185 i9〇
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 〇 195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 42 <211> 453 <212> PRT <213〉智人 152818-序列表.doc -71 - 201130511 <400> 42
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 72- 152818-序列表.doc 201130511
Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val 195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 225 230 235 240 o
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255
Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser 290 295 300
O
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu 305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335
Fro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro 340 345 350
Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365 -73· 1528]8-序列表.doc 201130511
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala 370 375 380
Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415
Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser 435 440 445
Leu Ser Pro Gly Lys 450 <210> 43 <211> 229 <212〉 PRT <213〉智人 <400〉 43
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser -74- 152818-序列表.doc 201130511 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro 115 120 125
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 130 135 140
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 145 150 155 160
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 165 170 175
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 180 185 190
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 195 200 205
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 210 215 220
Asn Arg Gly Glu Cys 225 •75· 152818-序列表.doc 201130511 <210〉 44 <211> 458 <212> PRT 〈213> 智人 <400> 44
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys He Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser 115 120 125
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 130 135 140
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 145 150 155 160 -76- 152818·序列表 doc 201130511
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 165 170 175
Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 180 185 190
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 195 200 205
Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 210 215 220
O
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 225 230 235 240
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 245 250 255
Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 260 265 270
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 275 280 285
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 290 295 300
Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 305 310 315 320
His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 325 330 335 -77 152818-序列表,doc 201130511
Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 340 345 350 Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 355 360 365 Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 370 375 380
Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 385 390 395 400
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 405 410 415
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 420 425 430
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 435 440 445
Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 45 <211> 234 <212〉 PRT <213〉智人 <400> 45
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30 -78· 152818·序列表-doc 201130511
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
O
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg 115 120 125
Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin 130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr ❹ 145 150 155 160
Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 165 170 175
Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro •79- 152818·序列表.doc 201130511 210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210〉 46 <211> 470 <212〉 PRT <213〉智人 <400> 46
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125 -80- 152818-序列表-doc 201130511
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys 130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190
O
Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn 210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 245 250 255
G
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270
Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn 305 310 315 320 -81 - 152818·序列表.doc 201130511
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp 325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 340 345 350
Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu 355 360 365
Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 370 375 380
Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 450 455 460
Ser Leu Ser Pro Gly Lys 465 470 <210> 47 <211> 246 <212> PRT <213〉智人 152818·序列表doc -82- 201130511 <400> 47
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asa Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110 ◎
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Thr Val Ala Ala 130 135 140
Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 145 150 155 160
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 165 170 175 •83 152818-序列表.doc 201130511
Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 180 185 190
Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 195 200 205
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 210 215 220
Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 225 230 235 240
Phe Asn Arg Gly Glu Cys 245 〈210〉 48 <211〉 463 <212〉 PRT 〈213〉智人 〈400〉 48
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 -84 - 152818_序列表.doc 201130511
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125
Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 130 135 140
O
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 145 150 155 160
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 165 170 175
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser 180 185 190
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 195 200 205
Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn 210 215 220
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 225 230 235 240
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 245 250 255 -85· 152818-序列表.doc 201130511
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300
Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 305 310 315 320
Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 340 345 350
Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 385 390 395 400
Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430
Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 -86- 152818-序列表.doc 201130511
His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210〉 49 〈211〉 239 <212> PRT <213〉智人 <400〉 49
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125
Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro -87- 152818-序列表.doc 201130511 130 135 140
Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp 165 170 175
Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp 180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin 210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 50 <211> 480 <212> PRT <213〉智人 〈400〉 50
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 1 5 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45 -S8 · 152818·序列表.doc 201130511
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110 o
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140
Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 145 150 155 160
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 165 170 175 ❽
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 180 185 190
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 195 200 205
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 210 215 220
Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Ljrs Pro Ser 225 230 235 240 89- 152818-序列表.doc 201130511
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 325 330 335
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr 355 360 365 lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 370 375 380
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 405 410 415 •90- 152818-序列表.doc 201130511
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480
O <210〉 51 <211> 256 〈212〉 PRT 〈213〉智人 〈400〉 51
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Gly Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
G
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95 •91 · 152818·序列表.doc 201130511
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140
Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe 145 150 155 160
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys 165 170 175
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 180 185 190
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 195 200 205
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 210 215 220
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 225 230 235 240
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255 <210〉 52 〈211〉 453 <212> PRT <213〉智人 -92- 152818-序列表.doc 201130511 <400> 52
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 -93 152818-序列表.doc 201130511
Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val 195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255
Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser 290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu 305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335
Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro 340 345 350
Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365 -94- 152818-序列表.doc 201130511
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala 370 375 380
Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415
Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 420 425 430
O
Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser 435 440 445
Leu Ser Pro Gly Lys 450 <210〉 53 〈211〉 229 <212> PRT <213〉智人 Q <400> 53
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser -95- 152818-序列表_(1〇〇 201130511 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro 115 120 125
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 130 135 140
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 145 150 155 160
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 165 170 175
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 180 185 190
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 195 200 205
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 210 215 220
Asn Arg Gly Glu Cys 225 -96- 152818'序列表.doc 201130511 <210〉 54 <211> 460 〈212> PRT <213〉智人 <400〉 54
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr He He Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 130 135 140
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 •97- 152818-序列表.doc 201130511
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu 180 185 190
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205
Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 210 215 220
Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 225 230 235 240
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe 245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295 300
Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 305 310 315 320
Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 325 330 335 -98- 1528丨8-序列表.doc 201130511
Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala 340 345 350
Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365
Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380
Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 385 390 395 400 o
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 435 440 445
Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210〉 55 <211〉 236 〈212〉 PRT <213〉智人 <400〉 55
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30 -99· 152818-序列表.doc 201130511
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 130 135 140
Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 165 170 175
Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser -100· 152818-序列表 doc 201130511 210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 〈210〉 56 <211〉 480 <212〉 PRT <213〉智人 <400〉 56
O
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
O
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125 152818·序列表.doc •101- 201130511
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140
Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 145 150 155 160
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 165 170 175
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 180 185 190
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 195 200 205
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 210 215 220
Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser 225 230 235 240
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser 260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 305 310 315 320 -102- 152818·序列表.doc 201130511
Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 325 330 335
Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys Thr 355 360 365
He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 370 375 380
O
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser 405 410 415
Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Q 435 440 445
Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460
Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 480 <210〉 57 <211> 256 <212〉 PRT 〈213〉智人 103- 152818-序列表.doc 201130511 <400> 57
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
Asp Thr Val Val lie Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp He Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140
Gly Gly Gly Gly Ser Arg Thr Val Ala Ala Pro Ser Val Phe He Phe 145 150 155 160
Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys 165 170 175 -104 152818·序列表.doc 201130511
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val 180 185 190
Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin 195 200 205
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 210 215 220
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 225 230 235 240 ❹
Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255 <210> 58 <211> 465 <212> PRT <213〉智人 <400> 58
Gin Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn 15 10 15
O
Asp Thr Val Val He Pro Cys Phe Val Thr Asn Met Glu Ala Gin Asn 20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp lie Tyr 35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser 50 55 60
Ser Ala Lys lie Glu Val Ser Gin Leu Leu Lys Gly Asp Ala Ser Leu 65 70 75 80 -105- 152818·序列表.doc 201130511
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys 85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr lie lie Glu Leu Lys 100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Gly Gly Gly Gly 115 120 125
Ser Gly Gly Gly Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 245 250 255 •106 152818-序列表.doc 201130511
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 305 310 315 320 o
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 340 345 350
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 370 375 380 〇
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu 385 390 395 400
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 420 425 430
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 435 440 445 •107· 152818·序列表.doc 201130511
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 450 455 460
Lys 465 <210> 59 <211〉 1395 <212〉 DNA <213〉智人 <400〉 59 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggaggtgg tggatctgga ggtggaggta gctcagctag caccaagggc 420 cccagcgtgt tccccctggc ccccagcagc aagagcacca gcggcggcac agccgccctg 480 ggctgcctgg tgaaggacta cttccccgag cccgtgaccg tgtcctggaa cagcggagcc 540 ctgacctccg gcgtgcacac cttccccgcc gtgctgcaga gcagcggcct gtacagcctg 600 tccagcgtgg tgacagtgcc cagcagcagc ctgggcaccc agacctacat ctgcaacgtg 660 aaccacaagc ccagcaacac caaggtggac aagagagtgg agcccaagag ctgcgacaag 720 acccacacct gccccccctg cccagcccca gaggcagcgg gcggaccctc cgtgttcctg 780 ttccccccca agcccaagga caccctgatg atcagcagga cccccgaggt gacctgcgtg 840 gtggtggacg tgagccacga ggacccagag gtgaagttca actggtacgt ggacggcgtg 900 -108- 152818-序列表.doc 960 201130511 gaggagcagt acaacagcac ctacagggtg tggctgaacg gcaaggaata caagtgcaag gaaaagacca tcagcaaggc caagggccag ccctcccggg aggagatgac caagaaccag taccccagcg acatcgccgt ggagtgggag accacccccc cagtgctgga cagcgacggc gacaagtcca ggtggcagca gggcaacgtg cacaaccact acacccagaa gagcctgagc 1020 1080 1140 1200 1260 1320 1380 1395
gaggtgcaca acgccaagac caagcccaga gtgtccgtgc tgaccgtgct gcaccaggac gtctccaaca aggccctgcc agcccccatc ccacgggagc cccaggtgta caccctgccc gtgtccctga cctgtctggt gaagggcttc agcaacggcc agcccgagaa caactacaag agcttcttcc tgtacagcaa gctgaccgtg ttcagctgca gcgtgatgca cgaggccctg ctgtcccccg gcaag
<210> 60 <211> 723 <212> DNA <213〉智人 <400> 60 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag ccaaatgaaa atggaggtgg tggatctgga agcgtgttca tcttcccccc cagcgacgag tgcctgctga acaacttcta cccccgggag ctgcagagcg gcaacagcca ggagagcgtc agcctgagca gcaccctgac cctgagcaag gaattcacgt tttgtaatga cactgtcgtc caaaacacta ctgaagtata cgtaaagtgg gatggagctc taaacaagtc cactgtcccc tcacaattac taaaaggaga tgcctctttg acaggaaact acacttgtga agtaacagaa ctaaaatatc gtgttgtttc atggttttct ggtggaggta gccgtacggt ggccgctccc cagctgaaga gcggcaccgc cagcgtggtg gccaaggtgc agtggaaggt ggacaacgcc accgagcagg acagcaagga ctccacctac gccgactacg agaagcataa ggtgtacgcc 60 120 180 240 300 360 420 480 540 600 -109- 152818·序列表.doc 660 201130511 tgcgaggtga cccaccaggg cctgtccagc cccgtgacca agagcttcaa caggggcgag 720 tgc 723 <210〉 61 <211〉 1395 <212〉 DNA <213〉智人 <400〉 61 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgt-ga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggaggtgg tggatctgga ggtggaggta gctcagctag caccaagggc 420 cccagcgtgt tccccctggc ccccagcagc aagagcacca gcggcggcac agccgccctg 480 ggctgcctgg tgaaggacta cttccccgag cccgtgaccg tgtcctggaa cagcggagcc 540 ctgacctccg gcgtgcacac cttccccgcc gtgctgcaga gcagcggcct gtacagcctg 600 tccagcgtgg tgacagtgcc cagcagcagc ctgggcaccc agacctacat ctgcaacgtg 660 aaccacaagc ccagcaacac caaggtggac aagagagtgg agcccaagag ctgcgacaag 720 acccacacct gccccccctg cccagcccca gaggcagcgg gcggaccctc cgtgttcctg 780 ttccccccca agcccaagga caccctgatg atcagcagga cccccgaggt gacctgcgtg 840 gtggtggacg tgagccacga ggacccagag gtgaagttca actggtacgt ggacggcgtg 900 gaggtgcaca acgccaagac caagcccaga gaggagcagt acaacagcac ctacagggtg 960 gtgtccgtgc tgaccgtgct gcaccaggac tggctgaacg gcaaggaata caagtgcaag 1020 110- 152818·序列表.doc 1080 1080
❹ 201130511 gtctccaaca aggccctgcc agcccccatc gaaaagacca tcagcaaggc caagggccag ccacgggagc cccaggtgta caccctgccc ccctcccggg aggagatgac caagaaccag gtgtccctga cctgtctggt gaagggcttc taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag accacccccc cagtgctgga cagcgacggc agcttcttcc tgtacagcaa gctgaccgtg gacaagtcca ggtggcagca gggcaacgtg ttcagctgca gcgtgatgca cgaggccctg cacaaccact acacccagaa gagcctgagc ctgtcccccg gcaag <210> 62 <211> 723 <212> DNA <213〉智人 <400> 62 cagctactat tta.ataa.aac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggaggtgg tggatctgga ggtggaggta gccgtacggt ggccgctccc agcgtgttca tcttcccccc cagcgacgag cagctgaaga gcggcaccgc cagcgtggtg tgcctgctga acaacttcta cccccgggag gccaaggtgc agtggaaggt ggacaacgcc ctgcagagcg gcaacagcca ggagagcgtc accgagcagg acagcaagga ctccacctac agcctgagca gcaccctgac cctgagcaag gccgactacg agaagcataa ggtgtacgcc tgcgaggtga cccaccaggg cctgtccagc cccgtgacca agagcttcaa caggggcgag t.gc 152818-序列表.doc -Ill - 1140 1200 1260 1320 1380 1395 60 120 180 240 300 360 420 480 540 600 660 720 723 201130511 <210〉 63 <211〉 1344 <212〉 DNA 〈213> 智人 <400> 63 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca &aatttaaag gaagagetet ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag accaagggcc ccagcgtgtt ccccctggcc gccgccctgg gctgcctggt gaaggactac agcggagccc tgacctccgg cgtgcacacc tacagcctgt ccagcgtggt gacagtgccc tgcaacgtga accacaagcc cagcaacacc tgcgacaaga cccacacctg ccccccctgc gtgttcctgt tcccccccaa gcccaaggac acctgcgtgg tggtggacgt gagccacgag gacggcgtgg aggtgcacaa cgccaagacc tacagggtgg tgtccgtgct gaccgtgctg aagtgcaagg tctccaacaa ggccctgcca aagggccagc cacgggagcc ccaggtgtac aagaaccagg tgtccctgac ctgtctggtg gaattcacgt tttgtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc aagcgctagc 360 cccagcagca agagcaccag cggcggcaca 420 ttccccgagc ccgtgaccgt gtcctggaac 480 ttccccgccg tgctgcagag cagcggcctg 540 agcagcagcc tgggcaccca gacctacatc 600 aaggtggaca agagagtgga gcccaagagc 660 ccagccccag aggcagcggg cggaccctcc 720 accctgatga tcagcaggac ccccgaggtg 780 gacccagagg tgaagttcaa ctggtacgtg 840 aagcccagag aggagcagta caacagcacc 900 caccaggact ggctgaacgg caaggaatac 960 gcccccatcg aaaagaccat cagcaaggcc 1020 accctgcccc cctcccggga ggagatgacc 1080 aagggcttct accccagcga catcgccgtg 1140 •112- 152818-序列表.doc 1200201130511 gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc agtgctggac agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag agcctgagcc tgtcccccgg caag 1260 1320 1344
O <210> 64 <211〉 672 <212〉 DNA <213〉智人 <400〉 64 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aa.ggtgaa.ac gatcatcgag ctaaaatatc gtgttgtttc acgtacggtg gccgctccca gcgtgttcat cttccccccc agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 60 120 180 240 300 360 420 480 540 600 660 672 <210〉 65 <211> 1365 <212> DNA <213〉智人 <400> 65 152818-序列表.doc -113- 201130511 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagt.gatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag ccaaatgaaa atagcgctag caccaagggc aagagcacca gcggcggcac agccgccctg cccgtgaccg tgtcctggaa cagcggagcc gtgctgcaga gcagcggcct gtacagcctg ctgggcaccc agacctacat ctgcaacgtg aagagagtgg agcccaagag ctgcgacaag gaggcagcgg gcggaccctc cgtgttcctg atcagcagga cccccgaggt gacctgcgtg gtgaagttca actggtacgt ggacggcgtg gaggagcagt acaacagcac ctacagggtg tggctgaacg gcaaggaata caagtgcaag gaaaagacca tcagcaaggc caagggccag ccctcccggg aggagatgac caagaaccag taccccagcg acatcgccgt ggagtgggag accacccccc cagtgctgga cagcgacggc gacaagtcca ggtggcagca gggcaacgtg cacaaccact acacccagaa gagcctgagc gaattcacgt ttggtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc atggttttct 360 cccagcgtgt tccccctggc ccccagcagc 420 ggctgcctgg tgaaggacta cttccccgag 480 ctgacctccg gcgtgcacac cttccccgcc 540 tccagcgtgg tgacagtgcc cagcagcagc 600 aaccacaagc ccagcaacac caaggtggac 660 acccacacct gccccccctg cccagcccca 720 ttccccccca agcccaagga caccctgatg 780 gtggtggacg tgagccacga ggacccagag 840 gaggtgcaca acgccaagac caagcccaga 900 gtgtccgtgc tgaccgtgct gcaccaggac 960 gtctccaaca aggccctgcc agcccccatc 1020 ccacgggagc cccaggtgta caccctgccc 1080 gtgtccctga cctgtctggt gaagggcttc 1140 agcaacggcc agcccgagaa caactacaag 1200 agcttcttcc tgtacagcaa gctgaccgtg 1260 ttcagctgca gcgtgatgca cgaggccctg 1320 ctgtcccccg gcaag 1365 -114- 152818·序列表.doc 60 201130511 <210> 66 <211〉 693 <212〉 DNA <213〉智人 <400> 66 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg
Oaagatggata agagtgatgc tgtctcacac acagggiaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atcgtacggt ggccgctccc agcgtgttca tcttcccccc cagcgacgag cagctgaaga gcggcaccgc cagcgtggtg tgcctgctga acaacttcta cccccgggag gccaaggtgc agtggaaggt ggacaacgcc ctgcagagcg gcaacagcca ggagagcgtc accgagcagg acagcaagga ctccacctac agcctgagca gcaccctgac cctgagcaag gccgactacg agaagcataa ggtgtacgcc tgcgaggtga cccaccaggg cctgtccagc cccgtgacca agagcttcaa caggggcgag tgc ❾ <210> 67 <211> 1344 <212> DNA <213〉智人 <400> 67 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaaceiagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 152818·序列表.doc -115- 120 180 240 300 360 420 480 540 600 660 693 60 120 180 240 201130511 aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag accaagggcc ccagcgtgtt ccccctggcc gccgccctgg gctgcctggt gaaggactac agcggagccc tgacctccgg cgtgcacacc tacagcctgt ccagcgtggt gacagtgccc tgcaacgtga accacaagcc cagcaacacc tgcgacaaga cccacacctg ccccccctgc gtgttcctgt tcccccccaa gcccaaggac acctgcgtgg tggtggacgt gagccacgag gacggcgtgg aggtgcacaa cgccaagacc tacagggtgg tgtccgtgct gaccgtgctg aagtgcaagg tctccaacaa ggccctgcca aagggccagc cacgggagcc ccaggtgtac aagaaccagg tgtccctgac ctgtctggtg gagtgggaga gcaacggcca gcccgagaac agcgacggca gcttcttcct gta.ca.gcaa.g ggcaacgtgt tcagctgcag cgtgatgcac agcctgagcc tgtcccccgg caag <210〉 68 <211〉 672 <212〉 DNA <213〉智人 <400> 68 cagctactat ttaataaaac aaaatctgta acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc aagcgctagc 360 cccagcagca agagcaccag cggcggcaca 420 ttccccgagc ccgtgaccgt gtcctggaac 480 ttccccgccg tgctgcagag cagcggcctg 540 agcagcagcc tgggcaccca gacctacatc 600 aaggtggaca agagagtgga gcccaagagc 660 ccagccccag aggcagcggg cggaccctcc 720 accctgatga tcagcaggac ccccgaggtg 780 gacccagagg tgaagttcaa ctggtacgtg 840 aagcccagag aggagcagta caacagcacc 900 caccaggact ggctgaacgg caaggaatac 960 gcccccatcg aaaagaccat cagcaaggcc 1020 accctgcccc cctcccggga ggagatgacc 1080 aagggcttct accccagcga catcgccgtg 1140 aactacaaga ccaccccccc agtgctggac 1200 ctgaccgtgg acaagtccag gtggcagcag 1260 gaggccctgc acaaccacta cacccagaag 1320 1344 gaattcacgt ttggtaatga cactgtcgtc 60 • 116· 152818-序列表.doc 120 120
201130511 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc t£iaacaagtc cactgtcccc actgacttta gtagtgcaaa Eiattgaagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ciaaaatatc gtgttgtttc acgtacggtg gccgctccca gcgtgttcat cttccccccc agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcaga^cgg caacagccag gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc <210〉 69 <211> 1380 〈212〉 DNA 〈213〉智人 <400> 69 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgeiagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggcggcgg cggatccagc gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc ggcacagccg ccctgggctg cctggtgaag 152818-序列表.doc -117- 180 240 300 360 420 480 540 600 660 672 60 120 180 240 300 360 420 480 201130511 gactacttcc ccgagcccgt gaccgtgtcc tggaacagcg gagccctgac ctccggcgtg 540 cacaccttcc ccgccgtgct gcagagcagc ggcctgtaca gcctgtccag cgtggtgaca 600 gtgcccagca gcagcctggg cacccagacc tacatctgca acgtgaacca caagcccagc 660 aacaccaagg tggacaagag agtggagccc aagagctgcg acaagaccca cacctgcccc 720 ccctgcccag ccccagaggc agcgggcgga ccctccgtgt tcctgttccc ccccaagccc 780 aaggacaccc tgatgatcag caggaccccc gaggtgacct gcgtggtggt ggacgtgagc 840 cacgaggacc cagaggtgaa gttcaactgg tacgtggacg gcgtggaggt gcacaacgcc 900 aagaccaagc ccagagagga gcagtacaac agcacctaca gggtggtgtc cgtgctgacc 960 gtgctgcacc aggactggct gaacggcaag gaatacaagt gcaaggtctc caacaaggcc 1020 ctgccagccc ccatcgaaaa gaccatcagc aaggccaagg gccagccacg ggagccccag 1080 gtgtacaccc tgcccccctc ccgggaggag atgaccaaga accaggtgtc cctgacctgt 1140 ctggtgaagg gcttctaccc cagcgacatc gccgtggagt gggagagcaa cggccagccc 1200 gagaacaact acaagaccac ccccccagtg ctggacagcg acggcagctt cttcctgtac 1260 agcaagctga ccgtggacaa gtccaggtgg cagcagggca acgtgttcag ctgcagcgtg 1320 atgcacgagg ccctgcacaa ccactacacc cagaagagcc tgagcctgtc ccccggcaag 1380 <210〉 70 <211〉 708 <212> DNA <213〉智人 <400〉 70 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 -118- 152818-序列表.doc 360201130511 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggcggcgg cggatcccgt acggtggccg ctcccagcgt gttcatcttc ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac ttctaccccc gggaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac agccaggaga gcgtcaccga gcaggacagc aaggactcca cctacagcct gagcagcacc ctgaccctga gcaaggccga ctacgagaag cataaggtgt acgcctgcga ggtgacccac cagggcctgt ccagccccgt gaccaagagc ttcaacaggg gcgagtgc 420 480 540 600 660 708
〈210〉 71 〈211〉 1359 <212〉 DNA <213〉智人 <400〉 71 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg
aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggcggcggc ggatccagcg ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg accgtgtcct ggaacagcgg agccctgacc tccggcgtgc acaccttccc cgccgtgctg cagagcagcg gcctgtacag cctgtccagc gtggtgacag tgcccagcag cagcctgggc acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc cccagaggca 60 120 180 240 300 360 420 480 540 600 660 720 152818-序列表.doc -119· 201130511 gcgggcggac cctccgtgtt cctgttcccc aggacccccg aggtgacctg cgtggtggtg ttcaactggt acgtggacgg cgtggaggtg cagtacaaca gcacctacag ggtggtgtcc aacggcaagg aatacaagtg caaggtctcc accatcagca aggccaaggg ccagccacgg cgggaggaga tgaccaagaa ccaggtgtcc agcgacatcg ccgtggagt.g ggagagcaac cccccagtgc tggacagcga cggcagcttc tccaggtggc agcagggcaa cgtgttcagc cactacaccc agaagagcct gagcctgtcc <210> 72 <211〉 687 <212> DNA <213〉智人 <400> 72 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag ggatcccgta cggtggccgc tcccagcgtg aagagcggca ccgccagcgt ggtgtgcctg gtgcagtgga aggtggacaa cgccctgcag cccaagccca aggacaccct gatgatcagc 780 gacgt-gagcc acgaggaccc agaggtgaag 840 cacaacgcca agaccaagcc cagagaggag 900 gtgctgaccg tgctgcacca ggactggctg 960 aacaaggccc tgccagcccc catcgaaaag 1020 gagccccagg tgtacaccct gcccccctcc 1080 ctgacctgtc tggtgaaggg cttctacccc 1140 ggccagcccg agaacaacta caagaccacc 1200 ttcctgtaca gcaagctgac cgtggacaag 1260 tgcagcgtga tgcacgaggc cctgcacaac 1320 cccggcaag 1359 gaattcacgt ttggtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc aggcggcggc 360 ttcatcttcc cccccagcga cgagcagctg 420 ctgaacaact tctacccccg ggaggccaag 480 agcggcaaca gccaggagag cgtcaccgag 540 •120· 152818-序列表.doc 600 600 o 201130511 caggacagca aggactccac ctacagcctg agcagcaccc tgaccctgag caaggccgac tacgagaagc ataaggtgta cgcctgcgag gtgacccacc agggcctgtc cagccccgtg accaagagct tcaacagggg cgagtgc <210> 73 <211> 1374 〈212〉 DNA <213〉智人 <400〉 73 cagctactat ttaataaeiac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaiagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggcggcggc ggcagcggcg gcggcggatc cagcgctagc accaagggcc ccagcgtgtt ccccctggcc cccagcagca agagcaccag cggcggcaca gccgccctgg gctgcctggt gaaggactac ttccccgagc ccgtgaccgt gtcctggaac agcggagccc tgacctccgg cgtgcacacc ttccccgccg tgctgcagag cagcggcctg tacagcctgt ccagcgtggt gacagtgccc agcagcagcc tgggcaccca gacctacatc tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagagtgga gcccaagagc tgcgacaaga cccacacctg ccccccctgc ccagccccag aggcagcggg cggaccctcc gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg acctgcgtgg tggtggacgt gagccacgag gacccagagg tgaagttcaa ctggtacgtg gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggagcagta caacagcacc tacagggtgg tgtccgtgct gaccgtgctg 152818·序列表,doc -121 - 660 687 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 201130511 caccaggact ggctgaacgg caaggaatac aagtgcaagg tctccaacaa ggccctgcca 1020 gcccccatcg aaaagaccat cagcaaggcc aagggccagc cacgggagcc ccaggtgtac 1080 accctgcccc cctcccggga ggagatgacc aagaaccagg tgtccctgac ctgtctggtg 1140 aagggcttct accccagcga catcgccgtg gagtgggaga gcaacggcca gcccgagaac 1200 aactacaaga ccaccccccc agtgctggac agcgacggca gcttcttcct gtacagcaag 1260 ctgaccgtgg acaagtccag gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac 1320 gaggccctgc acaaccacta cacccagaag agcctgagcc tgtcccccgg caag 1374 <210> 74 <211> 702 <212〉 DNA 〈213>智人 <400〉 74 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggcggcggc 360 ggcagcggcg gcggcggatc ccgtacggtg gccgctccca gcgtgttcat cttccccccc 420 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 480 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 540 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 600 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 660 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 702 -122- 152818-序列表.doc 60 60 Ο 201130511 <210〉 75 <211〉 1410 〈212〉 DNA <213〉智人 <400> 75 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga igcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggaggcgg aggatctggc ggcggaggaa gtggcggagg aggatccagc gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc ggcctgtaca gcctgtccag cgtggtgaca gtgcccagca gcagcctggg cacccagacc tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agtggagccc aagagctgcg acaagaccca cacctgcccc ccctgcccag ccccagaggc agcgggcgga ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag caggaccccc gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc cagaggtgaa gttcaactgg tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc ccagagagga gcagtacaac agcacctaca gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaag gaatacaagt gcaaggtctc caacaaggcc ctgccagccc ccatcgaaaa gaccatcagc aaggccaagg gccagccacg ggagccccag gtgtacaccc tgcccccctc ccgggaggag atgaccaaga accaggtgtc cctgacctgt ctggtgaagg gcttctaccc cagcgacatc 152818-序列表.doc -123· 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 201130511 gccgtggagt gggagagcaa cggccagccc ctggacagcg acggcagctt cttcctgtac cagcagggca acgtgttcag ctgcagcgtg cagaagagcc tgagcctgtc ccccggcaag <210> 76 <211〉 738 <212> DNA <213〉智人 <400> 76 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatxgag ccaaatgaaa atggaggcgg aggatctggc acggtggccg ctcccagcgt gttcatcttc accgccagcg tggtgtgcct gctgaacaac aaggtggaca acgccctgca gagcggcaac aaggactcca cctacagcct gagcagcacc cataaggtgt acgcctgcga ggtgacccac ttcaacaggg gcgagtgc <210> 77 <211〉 1389 <212> DNA <213〉智人 gagaacaact acaagaccac ccccccagtg 1260 agcaagctga ccgtggacaa gtccaggtgg 1320 atgcacgagg ccctgcacaa ccactacacc 1380 1410 gaattcacgt ttggtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc atggttttct 360 ggcggaggaa gtggcggagg aggatcccgt 420 ccccccagcg acgagcagct gaagagcggc 480 ttctaccccc gggaggccaa ggtgcagtgg 540 agccaggaga gcgtcaccga gcaggacagc 600 ctgaccctga gcaaggccga ctacgagaag 660 cagggcctgt ccagccccgt gaccaagagc 720 738 •124· 】528〗8-序列表.doc 60 60
201130511 <400〉 77 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggaggcgga ggatctggcg gcggaggaag tggcggagga ggatccagcg ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg accgtgtcct ggeiacagcgg agccctgacc tccggcgtgc acaccttccc cgccgtgctg cagagcagcg gcctgtacag cctgtccagc gtggtgacag tgcccagcag cagcctgggc acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc cccagaggca gcgggcggac cctccgtgtt cctgttcccc cccaagccca aggacaccct gatgatcagc aggacccccg aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc agaggtgaag ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc cagagaggag cagtacaaca gcacctacag ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg aacggcaagg aatacaagtg caaggtctcc aacaaggccc tgccagcccc catcgaaaag accatcagca aggccaaggg ccagccacgg gagccccagg tgtacaccct gcccccctcc cgggaggaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaggg cttctacccc agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaacta caagaccacc cccccagtgc tggacagcga cggcagcttc ttcctgtaca gcaagctgac cgtggacaag tccaggtggc agcagggcaa cgtgttcagc '152818·序列表.doc •125· 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 201130511 tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagagcct gagcctgtcc 1380 cccggcaag 1389 <210> 78 <211> 717 <212> DNA <213〉智人 <400〉 78 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggaggcgga 360 ggatctggcg gcggaggaag tggcggagga ggatcccgta cggtggccgc tcccagcgtg 420 ttcatcttcc cccccagcga cgagcagctg aagagcggca ccgccagcgt ggtgtgcctg 480 ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 540 agcggcaaca gccaggagag cgtcaccgag caggacagca aggactccac ctacagcctg 600 agcagcaccc tgaccctgag caaggccgac tacgagaagc ataaggtgta cgcctgcgag 660 gtgacccacc agggcctgtc cagccccgtg accaagagct tcaacagggg cgagtgc 717 <210> 79 <211> 1440 <212> DNA <213〉智人 <400> 79 cagctactat ttaataaaac aaaatctgta gaattcacgt ttggtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 -126-
152818·序列表.doc 180 180
201130511 aaatttaaag gaagagatat ttacacctii gatggagctc iaaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgeiagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggaggcgg aggatctggc ggcggaggaa gcggaggcgg cggaagtgga gggggaggat cagggggagg aggatccagc gctagcacca agggccccag cgtgttcccc ctggccccca gcagcaagag caccagcggc ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc ggcctgtaca gcctgtccag cgtggtgaca gtgcccagca gcagcctggg cacccagacc tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agtggagccc aagagctgcg acaagaccca cacctgcccc ccctgcccag ccccagaggc agcgggcgga ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag caggaccccc ga.ggtgacct gcgtggtggt ggacgt.gagc cacgaggacc cagaggtgaa gttcaactgg tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc ccagagagga gcagtacaac agcacctaca gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaag gaatacaagt gcaaggtctc caacaaggcc ctgccagccc ccatcgaaaa gaccatcagc aaggccaagg gccagccacg ggagccccag gtgtacaccc tgcccccctc ccgggaggag atgaccaaga accaggtgtc cctgacctgt ctggtgaagg gcttctaccc cagcgacatc gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac ccccccagtg ctggacagcg acggcagctt cttcctgtac agcaagctga ccgtggacaa gtccaggtgg cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc cagaagagcc tgagcctgtc ccccggcaag <210〉 80 152818-序列表.doc -127- 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 201130511 <211〉 768 <212〉 DNA <213〉智人 <400> 80 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc aagatggata agagtgatgc tgtctcacac ttaaccagag aaggtgaaac gatcatcgag ccaaatgaaa atggaggcgg aggatctggc gggggaggat cagggggagg aggatcccgt ccccccagcg acgagcagct gaagagcggc ttctaccccc gggaggccaa ggtgcagtgg agccaggaga gcgtcaccga gcaggacagc ctgaccctga gcaaggccga ctacgagaag cagggcctgt ccagccccgt gaccaagagc <210> 81 <211〉 1359 <212> DNA <213〉智人 <400> 81 cagctactat ttaataaaac aaaatctgta attccatgct ttgttactaa tatggaggca aaatttaaag gaagagatat ttacaccttt actgacttta gtagtgcaaa aattgaagtc gaattcacgt ttggtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 acaggaaact acacttgtga agtaacagaa 300 ctaaaatatc gtgttgtttc atggttttct 360 ggcggaggaa gcggaggcgg cggaagtgga 420 acggtggccg ctcccagcgt gttcatcttc 480 accgccagcg tggtgtgcct gctgaacaac 540 aaggtggaca acgccctgca gagcggcaac 600 aaggactcca cctacagcct gagcagcacc 660 cataaggtgt acgcctgcga ggtgacccac 720 ttcaacaggg gcgagtgc 768 gaattcacgt tttgtaatga cactgtcgtc 60 caaaacacta ctgaagtata cgtaaagtgg 120 gatggagctc taaacaagtc cactgtcccc 180 tcacaattac taaaaggaga tgcctctttg 240 -128- 152818-序列表.doc 300 300 ❹ 201130511 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa itaaccagag aaggtgaaac gatcatcgag ctaaaatatc gt-gttgttic aggcggcggc ggatccagcg ctagcaccaa gggccccagc gtgttccccc tggcccccag cagcaagagc accagcggcg gcacagccgc cctgggctgc ctggtgaagg actacttccc cgagcccgtg accgtgtcct ggaacagcgg agccctgacc tccggcgtgc acaccttccc cgccgtgctg cagagcagcg gcctgtacag cctgtccagc gtggtgacag tgcccagcag cagcctgggc acccagacct acatctgcaa cgtgaaccac aagcccagca acaccaaggt ggacaagaga gtggagccca agagctgcga caagacccac acctgccccc cctgcccagc cccagaggca gcgggcggac cctccgtgtt cctgttcccc cccaagccca aggacaccct gatgatcagc aggacccccg aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc agaggtgaag ttcaactggt acgtggacgg cgtggaggtg cacaacgcca agaccaagcc cagagaggag cagtacaaca gcacctacag ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg aacggcaagg aatacaagtg caaggtctcc aacaaggccc tgccagcccc catcgaaaag accatcagca aggccaaggg ccagccacgg gagccccagg tgtacaccct gcccccctcc cgggaggaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaggg cttctacccc agcgacatcg ccgtggagtg ggagagcaac ggccagcccg agaacaacta caagaccacc cccccagtgc tggacagcga cggcagcttc ttcctgtaca gcaagctgac cgtggacaag tccaggtggc agcagggcaa cgtgttcagc tgcagcgtga tgcacgaggc cctgcacaac cactacaccc agaagagcct gagcctgtcc cccggcaag <210〉 82 <211〉 687 <212> DNA <213〉智人 <400> 82 cagctactat ttaataaaac aaaat-ctgta gaattcacgt tttgtaatga cactgtcgtc 152818-序列表.doc -129- 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1359 201130511 attccatgct ttgttactaa tatggaggca caaaacacta ctggLagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc aggcggcggc 360 ggatcccgta cggtggccgc tcccagcgtg ttcatcttcc cccccagcga cgagcagctg 420 aagagcggca ccgccagcgt ggtgtgcctg ctgaacaact tctacccccg ggaggccaag 480 gtgcagtgga aggtggacaa cgccctgcag agcggcaaca gccaggagag cgtcaccgag 540 caggacagca aggactccac ctacagcctg agcagcaccc tgaccctgag caaggccgac 600 tacgagaagc ataaggtgta cgcctgcgag gtgacccacc agggcctgtc cagccccgtg 660 accaagagct tcaacagggg cgagtgc 687 <210〉 83 〈211〉 1380 <212> DNA 〈213> 智人 <400> 83 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggcggcgg cggatccagc gctagcacca agggccccag cgtgttcccc 420 ctggccccca gcagcaagag caccagcggc ggcacagccg ccctgggctg cctggtgaag 480 •130- 152818-序列表.doc 540201130511 gactacttcc ccgagcccgt gaccgtgtcc tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc ggcctgtaca gcctgtccag cgtggtgaca gtgcccagca gcagcctggg cacccagacc tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agtggagccc aagagctgcg acaagaccca cacctgcccc ccctgcccag ccccagaggc agcgggcgga ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag caggaccccc gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc cagaggtgaa gttcaactgg tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc ccagagagga gcagtacaac agcacctaca gggtggtgtc cgtgctgacc
gtgctgcacc aggactggct gaacggcaag gaatacaagt gcaaggtctc caacaaggcc ctgccagccc ccatcgaaaa gaccatcagc aaggccaagg gccagccacg ggagccccag gtgtacaccc tgcccccctc ccgggaggag atgaccaaga accaggtgtc cctgacctgt ctggtgaagg gcttctaccc cagcgacatc gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac ccccccagtg ctggacagcg acggcagctt cttcctgtac agcaagctga ccgtggacaa gtccaggtgg cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc cagaagagcc tgagcctgtc ccccggcaag 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380
<210> 84 <211〉 708 <212〉 DNA <213〉智人 <400> 84 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcaceiattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 60 120 180 240 300 152818-序列表.doc -131 - 201130511 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggcggcgg cggatcccgt acggtggccg ctcccagcgt gttcatcttc 420 ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac 480 ttctaccccc gggaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac 540 agccaggaga gcgtcaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 600 ctgaccctga gcaaggccga ctacgagaag cataaggtgt acgcctgcga ggtgacccac 660 cagggcctgt ccagccccgt gaccaagagc ttcaacaggg gcgagtgc 708 <210〉 85 <211> 1440 <212〉 DNA <213〉智人 <400〉 85 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggaggcgg aggatctggc ggcggaggaa gcggaggcgg cggaagtgga 420 gggggaggat cagggggagg aggatccagc gctagcacca agggccccag cgtgttcccc 480 ctggccccca gcagcaagag caccagcggc ggcacagccg ccctgggctg cctggtgaag 540 gactacttcc ccgagcccgt gaccgtgtcc tggaacagcg gagccctgac ctccggcgtg 600 cacaccttcc ccgccgtgct gcagagcagc ggcctgtaca gcctgtccag cgtggtgaca 660 gtgcccagca gcagcctggg cacccagacc tacatctgca acgtgaacca caagcccagc 720 152818-序列表.doc -132- 780 780
201130511 aacaccaagg tggacaagag agtggagccc aagagctgcg acaagaccca cacctgcccc ccctgcccag ccccagaggc agcgggcgga ccctccgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag caggaccccc gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc cagaggtgaa gttcaactgg tacgtggacg gcgtggaggt gcacaacgcc aagaccaagc ccagagagga gcagtacaac agcacctaca gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaag gaatacaagt gcaaggtctc caacaaggcc ctgccagccc ccatcgaaaa gaccatcagc aaggccaagg gccagccacg ggagccccag gtgtacaccc tgcccccctc ccgggaggag atgaccaaga accaggtgtc cctgacctgt ctggtgaagg gcttctaccc cagcgacatc gccgtggagt gggagagcaa cggccagccc gagaacaact acaagaccac ccccccagtg ctggacagcg acggcagctt cttcctgtac agcaagctga ccgtggacaa gtccaggtgg cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc cagaagagcc tgagcctgtc ccccggcaag <210〉 86 <211> 768 <212〉 DNA <213〉智人 <400> 86 cagctactat ttaataaaac aaaatctgt& gaattcacgt ttigtaatge cactgtcgtc attccatgct ttgttacteia tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttecacctit gatggagctc taaacaagte cacigtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg a^gatggata agagtgatgc t.gtctcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggaggcgg aggatctggc ggcggaggaa gcggaggcgg cggaagtgga gggggaggat cagggggagg aggatcccgt acggtggccg ctcocagcgt gttcatcttc 152818·序列表 _doc -133- 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 60 120 180 240 300 360 420 480 201130511 ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac 540 ttctaccccc gggaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac 600 agccaggaga gcgtcaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 660 ctgaccctga gcaaggccga ctacgagaag cataaggtgt acgcctgcga ggtgacccac 720 cagggcctgt ccagccccgt gaccaagagc ttcaacaggg gcgagtgc 768 <210〉 87 <211〉 1395 <212> DNA <213〉智人 〈400〉 87 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60 attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120 aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180 actgacttta gtagtgcaaa aattgeiagtc tcacaattac taaaaggaga tgcctctttg 240 aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300 ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360 ccaaatgaaa atggaggtgg tggatctgga ggtggaggta gctcagctag caccaagggc 420 cccagcgtgt tccccctggc ccccagcagc aagagcacca gcggcggcac agccgccctg 480 ggctgcctgg tgaaggacta cttccccgag cccgtgaccg tgtcctggaa cagcggagcc 540 ctgacctccg gcgtgcacac cttccccgcc gtgctgcaga gcagcggcct gtacagcctg 600 tccagcgtgg tgacagtgcc cagcagcagc ctgggcaccc agacctacat ctgcaacgtg 660 aaccacaagc ccagcaacac caaggtggac aagagagtgg agcccaagag ctgcgacaag 720 acccacacct gccccccctg cccagcccca gagctgctgg gcggaccctc cgtgttcctg 780 ttccccccca agcccaagga caccctgatg atcagcagga cccccgaggt gacctgcgtg 840 •134·
152818·序列表.doc 900 900
201130511 gtggtggacg tgagccacga ggacccagag gtgaagttca actggtacgt ggacggcgtg gaggtgcaca acgccaagac caagcccaga gaggagcagt acaacagcac ctacagggtg gtgtccgtgc tgaccgtgct gcaccaggac tggctgaacg gcaaggaata caagtgcaag gtctccaaca aggccctgcc agcccccatc gaaaagacca tcagcaaggc caagggccag ccacgggagc cccaggtgta caccctgccc ccctcccggg aggagatgac caagaaccag gtgtccctga cctgtctggt gaagggcttc taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag accacccccc cagtgctgga cagcgacggc agcttcttcc tgtacagcaa gctgaccgtg gacaagtcca ggtggcagca gggcaacgtg ttcagctgca gcgtgatgca cgaggccctg cacaaccact acacccagaa gagcctgagc ctgtcccccg gcaag <210〉 88 <211> 1395 <212〉 DNA <213〉智人 <400〉 88 cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg aaatttaaag gaagagatat ttacaccttt gatggagctc taaacsiagtc cactgtcccc actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg aagatggata agagtgatgc tgictcacac acaggaaact acacttgtga agtaacagaa ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct ccaaatgaaa atggaggtgg tggatctgga ggtggaggta gctcagcctc caccaagggt ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 152818·序列表.doc 960 1020 1080 1140 1200 1260 1320 1380 1395 60 120 180 240 300 360 420 480 540 -135- 600 201130511 agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 660 aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 720 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 780 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 840 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 900 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acgccagcac gtaccgggtg 960 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1020 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1080 ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1200 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1260 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380 ctgtctccgg gtaaa 1395 <210〉 89 〈211〉 1392 <212> DNA <213〉小家鼠 <400> 89 ceiactactgt ttagtaacgt caactccata gagttcactt caggcaatga aactgtggtc 60 atcccttgca tcgtccgtaa tgtggaggcg caeiagcaccg aagaaatgtt tgtgaagtgg 120 aagttgaaca aatcgtatat tttcatctat gatggaaata aiaaatagcac tactacagat 180 caaaacttta ccagtgcaaa aatctcagtc tcagacttaa tcaatggcat tgcctctttg 240 aaaatggata agcgcgatgc catggtggga aactacactt gcgaagtgac agagttatcc 300 -136- 152818-序列表.doc 360 360
201130511 agagaaggca aaacagttat agagctgaaa aaccgcacgg tttcgtggtt ttctccaaat gaaaagatcg gaggtggtgg atctggaggt ggaggtagct cagctagcac caagggcccc agcgtgttcc ccctggcccc cagcagcaag agcaccagcg gcggcacagc cgccctgggc tgcctggtga aggactactt ccccgagccc gtgaccgtgt cctggaacag cggagccctg acctccggcg tgcacacctt ccccgccgtg ctgcagagca gcggcctgta cagcctgtcc agcgtggtga cagtgcccag cagcagcctg ggcacccaga cctacatctg caacgtgaac cacaagccca gcaacaccaa ggtggacaag agagtggagc ccaagagctg cgacaagacc cacacctgcc ccccctgccc agccccagag gca^cgggcg gaccctccgt gttcctgttc 0 ccccccaagc ccaaggacac cctgatgatc agcaggaccc ccgaggtgac ctgcgtggtg gtggacgtga gccacgagga cccagaggtg aagttcaact ggtacgtgga cggcgtggag gtgcacaacg ccaagaccaa gcccagagag gagcagtaca acagcaccta cagggtggtg tccgtgctga ccgtgctgca ccaggactgg ctgaacggca aggaatacaa gtgcaaggtc tccaacaagg ccctgccagc ccccatcgaa aagaccatca gcaaggccaa gggccagcca cgggsgcccc aggtgtacac cctgcccccc tcccgggagg agatgaccaa gaaccaggtg tccctgacct gtctggtgaa gggcttctac cccagcgaca tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ctacaagacc acccccccag tgctggacag cgacggcagc ttcttcctgt acagcaagct gaccgtggac aagtccaggt ggcagcaggg caacgtgttc agctgcagcg tgatgcacga ggccctgcac aaccactaca cccagaagag cctgagcctg tcccccggca ag <210> 90 <211> 720 <212> DNA <213〉小家鼠 <400〉 90 caactactgt ttagtaacgt caactccata gagttcactt caggcaatga aactgtggtc 152818-序列表.doc •137· 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1392 60 201130511 atcccttgca tcgtccgtaa tgtggaggcg aagtigaaca aatcgtatat titcatctat caaaacttta ccagtgcaaa aatctcagtc aaaatggata agcgcgatgc catggtggga agagaaggca aaacagttat agagctgaaa gaaaagatcg gaggtggtgg atctggaggt gtgttcatct tcccccccag cgacgagcag ctgctgaaca acttctaccc ccgggaggcc cagagcggca acagccagga gagcgtcacc ctgagcagca ccctgaccct gagcaaggcc gaggtgaccc accagggcct gtccagcccc <210〉 91 <211〉 1392 <212> DNA <213〉小家鼠 〈400〉 91 caactactgt ttagtaacgt caactccata atcccttgca tcgtccgtaa tgtggaggcg aagttgaaca aatcgtatat tttcatctat caaaacttta ccagtgcaaa aatctcagtc aaaatggata agcgcgatgc catggtggga agagaaggca aaacagttat agagctgaaa gaaaagatcg gaggtggtgg atctggaggt agcgtgttcc ccctggcccc cagcagcaag caaagcaccg aagaaatgtt tgtgaagtgg 120 gatggaaata aaaatagcac tactacagat 180 tcagacttaa tcaatggcat tgcctctttg 240 aactacactt gcgaagtgac agagttatcc 300 aaccgcacgg tttcgtggtt ttctccaaat 360 ggaggtagcc gtacggtggc cgctcccagc 420 ctgaagagcg gcaccgccag cgtggtgtgc 480 aaggtgcagt ggaaggtgga caacgccctg 540 gagcaggaca gcaaggactc cacctacagc 600 gactacgaga agcataaggt gtacgcctgc 660 gtgaccaaga gcttcaacag gggcgagtgc 720 gagttcactt catgcaatga aactgtggtc 60 caaagcaccg aagaaatgtt tgtgaagtgg 120 gatggaaata aaaatagcac tactacagat 180 tcagacttaa tcaatggcat tgcctctttg 240 aactacactt gcgaagtgac agagttatcc 300 aaccgcacgg tttcgtggtt ttctccaaat 360 ggaggtagct cagctagcac caagggcccc 420 agcaccagcg gcggcacagc cgccctgggc 480 -138- 152818-序列表.doc 540 540
201130511 tgcctggtga aggactactt ccccgagccc gtgaccgtgt cctggaacag cggagccctg acctccggcg tgcacacctt ccccgccgtg ctgcagagca gcggcctgta cagcctgtcc agcgtggtga cagtgcccag cagcagcctg ggcacccaga cctacatctg caacgtgaac cacaagccca gcaacaccaa ggtggacaag agagtggagc ccaagagctg cgacaagacc cacacctgcc ccccctgccc agccccagag gcagcgggcg gaccctccgt gttcctgttc ccccccaagc ccaaggacac cctgatgatc agcaggaccc ccgaggtgac ctgcgtggtg gtggacgtga gccacgagga cccagaggtg aagttcaact ggtacgtgga cggcgtggag gtgcacaacg ccaagaccaa gcccagagag gagcagtaca acagcaccta cagggtggtg tccgtgctga ccgtgctgca ccaggactgg ctgaacggca aggaatacaa gtgcaaggtc tccaacaagg ccctgccagc ccccatcgaa aagaccatca gcaaggccaa gggccagcca cgggagcccc aggtgtacac cctgcccccc tcccgggagg agatgaccaa gaaccaggtg tccctgacct gtctggtgaa gggcttctac cccagcgaca tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ciacaagacc acccccccag tgctggacag cgacggcagc ttcttcctgt acagcaagct gaccgtggac aagtccaggt ggcagcaggg caacgtgttc agctgcagcg tgatgcacga ggccctgcac aaccactaca cccagaagag cctgagcctg tcccccggca ag <210> 92 <211〉 720 <212> m <213〉小家鼠 <400> 92 caactactgt ttagtaacgt caactccata gagttcactt catgcaatga aactgtggtc atcccttgca tcgtccgtaa tgtggaggcg caeiagcaccg aagaaatgtt tgtgaagtgg aagttgaaca aatcgtatat tttcatctat gatggaaata aaaatagcac tactacagat caaaacttta ccagtgcaaa aatctcagtc tcagacttaa tcaatggcat tgcctctttg 152818-序列表.doc 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1392 60 120 180 -139- 240 201130511 aaaatggata agcgcgatgc catggtggga aactacactt gcgeiagtgac agagttatcc 300 agagaaggca aaacagttat agagctgaaa aaccgcacgg tttcgtggtt ttctccaaat 360 gaaaagatcg gaggtggtgg atctggaggt ggaggtagcc gtacggtggc cgctcccagc 420 gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 480 ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 540 cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 600 ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 660 gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 720 •140- 152818-序列表.doc
Claims (1)
- 201130511 七、申請專利範圍: 1. 一種可溶性蛋白質,其包含至少兩個雜二聚體之複合 物’其中各雜二聚體基本上由以下組成: (i)第一單價單鏈多肽,其包含哺乳動物結合分子融 合於抗體之重鏈恆定區之區域;及 (11)第二單價單鏈多肽,其包含相同結合分子融合於 抗體之輕鏈丨亙定區之區域。 ^ 2. 一種可溶性蛋白質,其包含至少兩個雜二聚體之複合 物,其中各雜二聚體基本上由以下組成: (I) 第一單價單鏈多肽’其包含哺乳動物結合分子融 合於抗體之CH1恆定重鏈區之區域;及 (II) 第二單價單鏈多肽,其包含相同結合分子融合於 抗體之CL恆定輕鏈區之區域。 3.如印求項1或請求項2之可溶性蛋白質,其中該哺乳動物 結合分子之該區域相同。 〇 4· t請求項i或請求項2之可溶性蛋白質,其中該哺乳動物 、α 口刀子為蛋白質、細胞激素、生長因子、激素、信號 專導蛋白發炎性介體、低分子量化合物、配位體、細 胞表面受體、或其片段。 、 5.如請求項4之可溶性蛋白質,其中該哺乳動物結合分子 為單體或均聚合細胞表面受體之細胞外域。 4求項5之可溶性蛋白質,其中該哺乳動物 聚合細胞表面受體包含啊域。 ^ 7·如請求項5之可溶性蛋白質,其中哺乳動物單體細胞表 152818.doc 201130511 面受體之該細胞外域為CD47之細胞外域β 8. 一種可溶性蛋白質,其包含兩個雜二聚體之複合物,其 中各雜二聚體基本上由以下組成: (1)第一單價單鏈多肽’其包含第一 SIRPa結合域融合 於抗體之CH1恆定重鏈區之N-端部分,及 (ii)第二單價單鏈多肽’其包含第二SIRPa結合域融合 於抗體之CL恆定輕鏈區之N-端部分。 9. 一種可溶性蛋白質,其包含兩個雜二聚體之複合物,其 中各雜二聚體基本上由以下組成: (I) 第一單價單鏈多肽,其包含第一 SIRPa結合域融合 於抗體之重鏈恆定區;及 (II) 第二單價單鏈多肽,其包含第二SIRPa結合域融合 於抗體之輕鏈恆定區。 10. 如请求項1、2、8及9中任一項之可溶性蛋白質,其中該 等第一及第二單價單鏈多肽分別融合於該chI恆定重鏈 及CL恆定輕鏈之該N—端部分。 11. 如凊求項8及9中任一項之可溶性蛋白質,其中該等第一 及第一 SIRPa結合域彼此之間共有至少6〇%、7〇%、 80/。、90%、95%、96%、97%、98% 或 99% 的序列一致 性。 12. 如明求項7之可溶性蛋白質,如BiaC〇RE檢定中所量 測,其與人類SIRPa結合之Kd為4 μΜ或4 μΜ以下。 13. 如請求項8及9中任一項之可溶性蛋白質,如基於分析板 之細胞黏著檢定中所量測,其促進SIRpa+白血球黏著之 152818.doc 201130511 EC50為2 nM或2 nM以下。 14. 如請求項8及9中任一項之可溶性蛋白質,其抑制活體外 產生之單核細胞源性樹突狀細胞中受金黃色葡萄球菌 reWiS)c〇wan菌株粒子刺激之促發炎性 細胞激素釋放。 15. 如咕求項14之可溶性蛋白質,如樹突狀細胞細胞激素釋 放檢定中所量測,其抑制活體外產生之單核細胞源性樹 0 犬狀細胞中金黃色葡萄球菌c〇wan菌株粒子刺激之促發 k J·生細胞激素釋放之1C5。為〇 ·2 nM或〇. 2 nM以下。 I6·如明求項1、2、8及9中任一項之可溶性蛋白質,其中各 雜二聚體之該等第一及第二單鏈多肽經二硫橋鍵共價結 合0 17.如請求項8及9中任一項之可溶性蛋白質其中在不存在 肽連接子下,各雜二聚體具有其第一及第二slRpa結合 域融合於各別恆定區。 〇 18.如請求項8及9中任一項之可溶性蛋白質其中各雜二聚 體具有其第一及第二SIRPa結合域經由肽連接子融合於 各別值定區。 19. 如請求項18之可溶性蛋白f ’其中該肽連接子由5至2〇 個胺基酸構成。 20. 如請求項18之可溶性蛋自f,其中該肽連接子為甘胺酸 與絲胺酸胺基酸之聚合物,較佳_GGGs)n,其中4 介於1與4之間的任何整數,較佳為2。 21·如4求項卜2、8及9中任—項之可溶性蛋白質,其基本 1528l8.doc 201130511 上由兩個雜二聚體組成,其中各雜二聚體之該第一單鏈 多肽包含免疫球蛋白恆定部分之鉸鏈區,且該至少兩個 雜二聚體彼此經該鉸鏈區處之二硫橋鍵穩定締合。 22.如請求項9之可溶性蛋白質,其中該抗體之CH1、CH2及 CH3區來源於人類IgGl、IgG2或IgG4相應區域之減弱 ADCC效應功能的靜止突變體。 23 ·如請求項8及9中任一項之可溶性蛋白質,其中至少一個 SIRPa結合域選自由以下組成之群: (i) 人類CD47之細胞外域; (ii) SEQ ID NO:4之多肽或 SEQ ID NO:4之保留 SIRPa 結合性質之片段;及, (iii) SEQ ID NO:4之變異型多肽,其與SEQ ID ΝΟ··4具 有至少 60〇/〇、70% ' 80% ' 90% ' 95%、96%、97%、98% 或99%序列一致性且保留SIRPa結合性質。 24. 如請求項8及9中任一項之可溶性蛋白質,其中所有 SIRPa結合域皆具有相同胺基酸序列。 25. 如請求項24之可溶性蛋白質,其中SIRPa結合域之該相 同胺基酸序列選自由SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:21 及 SEQ ID NO:23 組成之群。 26. —種包含兩個雜二聚體之可溶性蛋白質,其中該等雜二 聚體包含: (i) SEQ ID NO:5之第一單鏈多肽及SEQ ID NO:6之第 二單鏈多肽; (ii) SEQ ID ΝΟ··18之第一單鏈多肽及 SEQ ID NO:6之 152818.doc 201130511 第二單鏈多肽; (iii) SEQ ID NO:19之第一單鏈多肽及 SEQ ID NO:20之 第二單鏈多肽; (iv) SEQ ID NO:12 之第一單鏈多肽及 SEQ ID NO:13 之 第二單鏈多肽; (v) SEQ ID NO:24之第一單鏈多肽及SEQ ID NO:25之 第二單鏈多肽; (vi) SEQ ID NO:36之第一單鏈多肽及 SEQ ID NO:37之 〇 第二單鏈多肽; (vii) SEQ ID NO:38之第一單鏈多肽及 SEQ ID NO:39之 第二單鏈多肽; (viii) SEQ ID ΝΟ··40之第一單鏈多肽及 SEQ ID NO:41 之第二單鏈多肽; (ix) SEQ ID NO:42之第一單鏈多肽及SEQ ID NO:43之 第二單鏈多肽; q (X) SEQ ID NO:44之第一單鏈多肽及SEQ ID NO:45之 第二單鏈多肽; (xi) SEQ ID NO:46 之第一單鏈多肽及 SEQ ID NO:47 之 第二單鏈多肽; (xii) SEQ ID NO:48 之第一單鏈多肽及 SEQ ID NO:49 之 第二單鏈多肽; (xiii) SEQ ID NO:50之第一單鏈多肽及 SEQ ID NO-.51 之 第二單鏈多肽; (xiv) SEQ ID NO:52 之第一單鏈多肽及 SEQ ID NO:53 之 152818.doc 201130511 第二單鍵多狀; (XV) SEQ ID NO:54之第一單鏈多肽及 SEQ ID NO:55之 第二單鏈多肽; (xvi) SEQ ID NO:56之第一單鏈多肽及 SEQ ID NO:57之 第二單鏈多肽; (xvii) SEQ ID NO:58之第一單鏈多肽及 SEQ ID NO:20 之第二單鏈多肽;或 (xviii) SEQ ID NO:29之第一單鏈多肽及 SEQ ID NO:20 之第二單鏈多肽。 27. 如請求項9之可溶性蛋白質,其包含與如請求項26之可 溶性蛋白質之相應第一及第二單鏈多肽具有至少60%、 70%、80%、90%、95% ' 96%、97%、98%或 99%序歹丨J 一 致性的該等第一單鏈及第二單鏈多肽序列。 28. 如請求項9之可溶性蛋白質,其包含與如請求項26之可 溶性蛋白質之相應第一及第二單鏈多肽具有至少60%、 70%、80%、90%、95% ' 96%、97%、98% 或 99%序列一 致性的SIRPa結合域序列。 29. 如請求項1、2、8、9及26中任一項之可溶性蛋白質,其 包含: (i) 由SEQ ID NO: 10之核苷酸序列編碼之重鏈;及由 SEQ ID NO: 11之核苷酸序列編碼之輕鏈, (ii) 由SEQ ID NO:59之核苷酸序列編碼之重鏈;及由 SEQ ID NO:60之核苷酸序列編碼之輕鏈, (iii) 由SEQ ID NO:61之核苷酸序列編碼之重鏈;及 152818.doc 201130511 由SEQ ID NO:62之核苷酸序列編碼之輕鏈, (iv) 由SEQ ID NO:63之核苷酸序列編碼之重鏈;及由 選自由SEQ ID NO:64組成之群之核苷酸序列編碼之輕 鏈, (v) 由SEQ ID NO:65之核苷酸序列編碼之重鏈;及由 SEQ ID NO:66之核苷酸序列編碼之輕鏈, (vi) 由SEQ ID NO:67之核苷酸序列編碼之重鏈;及由 SEQIDNO:68之核苷酸序列編碼之輕鏈, 〇 (vii) 由SEQ ID NO:69之核苷酸序列編碼之重鏈;及 由SEQ ID NO:70之核苷酸序列編碼之輕鏈, (viii) 由SEQ ID ΝΟ··71之核苷酸序列編碼之重鏈;及 由SEQ ID ΝΟ:72之核苷酸序列編碼之輕鏈, (ix) 由SEQ ID ΝΟ··73之核苷酸序列編碼之重鏈;及由 SEQIDNO:74之核苷酸序列編碼之輕鏈, (X)由SEQ ID NO:75之核苷酸序列編碼之重鏈;及由 q SEQ ID NO:76之核苷酸序列編碼之輕鏈, (xi) 由SEQ ID N〇:77之核苷酸序列編碼之重鏈;及由 SEQ ID NO:78之核苷酸序列編碼之輕鏈, (xii) 由SEQ ID NO:79之核苷酸序列編碼之重鏈;及 由SEQ ID NO:80之核苷酸序列編碼之輕鏈, (xiii) 由SEQ ID NO:81之核苷酸序列編碼之重鏈;及 由SEQ ID NO:82之核苷酸序列編碼之輕鏈, (xiv) 由SEQ ID NO:83之核苷酸序列編碼之重鏈;及 由SEQ ID NO:84之核苷酸序列編碼之輕鏈, 152818.doc 201130511 ㈣由SEQIDN〇:85之核芽酸序列編碼之 由SEQIDNO:86之核普酸序列編碼之_鏈 (xvi) 由SEQIDNO:87之核苦酸序列編碼之重鏈.及 由SEQIDNO:60之核苦酸序列編碼之輕鏈,或 ’ (xvii) 由 SEq ID NO:882 ’ 駄序列編碼之重鏈;及 由SEQ ID NO..60之核苷酸序列編碼之_鏈。 3〇_如請求項卜2、8、9及26中任—項之;_溶性蛋 係用作藥物或診斷工具。 貞 ^ 31: = 3°之可溶性蛋白質,其係用於治療或診斷自體 免疫及急性及慢性發炎性病症。 32_如請求項3丨之可溶性蛋 介導之气A 係用於治療選自由Th2 w導之乳管發炎、過敏性病症、 節炎組成之群。 孝而、發炎性腸病及關 項3〇之可溶性蛋白質’其係用於治療缺血性病 症、白血病或其他癌症病症。 34.如請求項30之可溶性蛋白装 增強造血幹細胞移植。…、侧於為有需要之個體 35·—種醫藥組合物’其包含如請求们至29中任—項之可 白質與一或多種醫藥學上可接受之媒劑組合。 =項35之醫藥組合物’其另外包含至少-種其他活 37. 38. 一種經分離之核酸, 可溶性蛋白質中一個 一種選殖或表現載體 其編碼如請求項1至29中任一項之 雜二聚體的至少一個單鏈多肽。 ,其包含至少一種選自由以下組成 152818.doc 201130511之群之核酸:SEQ ID ΝΟ··10、SEQ ID ΝΟ:11、 NO:59、 NO:62 ' NO :65 ' NO:68、 NO:71、 NO:74、 NO:77、 NO:80、 NO:83、 NO:86、 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO:60、 NO:63、 NO:66、 NO:69、 NO:72、 NO:75、 NO:78、 NO:81、 NO:84 、 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO:61 > NO:64、 NO:67 ' NO:70、 NO:73、 NO:76、 NO:79、 NO:82 > NO:85 、 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO:87及 SEQ ID NO:88。 3 9. —種適於產生如請求項1至29中任一項之可溶性蛋白質 之重組宿主細胞,其包含編碼該蛋白質中該等雜二聚體 之該等第一及第二單鏈多肽的核酸,及視情況選用之分 泌信號。SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID 40.如請求項39之重組宿主細胞,其包含穩定整合於基因組 中之 SEQ ID NO:10、SEQ ID NO:ll、SEQ ID NO:59、 SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68 SEQ ID NO:71 SEQ ID NO:74 SEQ ID NO:77 SEQ ID NO:80 NO:69、SEQ ID NO:70 NO:72 ' SEQ ID NO:73 NO:75、SEQ ID NO:76 NO:78、SEQ ID NO:79 152818.doc 201130511 NO:81、SEQ ID NO:82 > SEQ ID NO:83、SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86、SEQ ID NO:87 及SEQ ID NO:88之核酸。 41. 如請求項39或請求項40之重組宿主細胞,其中該宿主為 哺乳動物細胞株。 42. —種產生如請求項1至29中任一項之可溶性蛋白質之方 法,其包含在適合產生該可溶性蛋白質之條件下培養如 請求項39至41中任一項之宿主細胞,及分離該蛋白質。 43. —種如請求項1至29中任一項之可溶性蛋白質的用途, 其係用於製造用於治療或診斷自體免疫及急性及慢性發 炎性病症之藥劑。 44. 如請求項43之用途,其中該藥劑係用於治療選自由Th2 介導之氣管發炎、過敏性病症、哮喘、發炎性腸病及關 節炎組成之群。 45. —種如請求項1至29中任一項之可溶性蛋白質之用途, 其係用於製造用於治療缺血性病症、白血病或其他癌症 病症之藥劑。 46. —種如請求項1至29中任一項之可溶性蛋白質之用途, 其係用於製造用於為有需要之個體增強造血幹細胞移植 的藥劑。 152818.doc -10·
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- 2010-12-21 EP EP10795387A patent/EP2516458A1/en not_active Withdrawn
- 2010-12-21 AU AU2010334974A patent/AU2010334974A1/en not_active Abandoned
- 2010-12-21 CA CA2785139A patent/CA2785139A1/en not_active Abandoned
- 2010-12-21 WO PCT/EP2010/070355 patent/WO2011076781A1/en active Application Filing
- 2010-12-21 KR KR1020127019187A patent/KR20120107122A/ko not_active Application Discontinuation
- 2010-12-21 JP JP2012545290A patent/JP2013514795A/ja active Pending
- 2010-12-21 TW TW099145049A patent/TW201130511A/zh unknown
- 2010-12-21 US US13/517,989 patent/US20130011401A1/en not_active Abandoned
- 2010-12-21 BR BR112012017164A patent/BR112012017164A2/pt not_active IP Right Cessation
- 2010-12-21 MX MX2012007318A patent/MX2012007318A/es not_active Application Discontinuation
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- 2010-12-22 AR ARP100104886A patent/AR079701A1/es unknown
- 2010-12-22 UY UY33132A patent/UY33132A/xx not_active Application Discontinuation
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US11579522B2 (en) | 2015-06-11 | 2023-02-14 | Plexbio Co., Ltd. | Image differentiated multiplex assays |
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JP2013514795A (ja) | 2013-05-02 |
KR20120107122A (ko) | 2012-09-28 |
MX2012007318A (es) | 2012-07-20 |
EP2516458A1 (en) | 2012-10-31 |
BR112012017164A2 (pt) | 2019-09-24 |
CA2785139A1 (en) | 2011-06-30 |
WO2011076781A1 (en) | 2011-06-30 |
AU2010334974A1 (en) | 2012-07-12 |
CN102939303A (zh) | 2013-02-20 |
AR079701A1 (es) | 2012-02-15 |
US20130011401A1 (en) | 2013-01-10 |
UY33132A (es) | 2011-07-29 |
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