TW201945541A - 具抗原專一性的t細胞及其用途 - Google Patents

具抗原專一性的t細胞及其用途 Download PDF

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TW201945541A
TW201945541A TW108129663A TW108129663A TW201945541A TW 201945541 A TW201945541 A TW 201945541A TW 108129663 A TW108129663 A TW 108129663A TW 108129663 A TW108129663 A TW 108129663A TW 201945541 A TW201945541 A TW 201945541A
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莊國祥
陳易柔
陳挺宇
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臺北醫學大學
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Abstract

本揭示內容係關於用以誘發T細胞分化及／或增生的方法及其用途。在本發明方法中，將分離自一個體的周邊血液單核球細胞（peripheral blood mononuclear cell，PBMC）與雙功抗體（bi-specific antibody，BsAb）培養在一培養液中，據以使該PBMC分化為T細胞。各T細胞表面具有一抗-腫瘤抗原部及一抗-CD3部。本揭示內容亦提供用以治療罹患癌症之個體的方法及醫藥套組。

Description

具抗原專一性的T細胞及其用途
本揭示內容係關於癌症治療。具體來說，本揭示內容係關於具抗原專一性的T細胞及其於抑制癌症生長或轉移的用途。
T細胞為一種數量稀少的細胞群，在周邊血液中僅可發現5至10％的CD4+ T細胞。藉由細胞激素（例如IL-2、IL-4及IL-5）刺激，加上抗-CD28抗體，可促進T細胞增生。然而，其數量仍不足以進行任何臨床應用，例如涉及增加活化的T細胞數量，再將其移轉回人體（例如嵌合抗原受體（chimeric antigen receptor，CAR）T細胞治療）的應用。
用以活化T細胞或誘發T細胞分化的其中一種方式係利用抗-CD3抗體來活化由CD3調節的訊息傳導路徑來達成。及至目前為止，曾有研究人員以小鼠之抗-人類IgG2a同型（OKT3）單株抗體進行由CD3抗原複合物誘導的人類T細胞活化，其係誘發一種等同於伴刀豆球蛋白A（concanavalin A，Con A）誘導的細胞分裂反應而造成。然而，使用非人類來源的單株抗體（例如鼠類OKT3抗體）主要顧慮之一在於其免疫原性對接受者造成的影響，在某些個案中，會引起致命的過敏反應。鼠類OKT3抗體活化的人類T細胞，將不可避免地在該T細胞表面攜帶鼠類蛋白片段，因而對其接受者構成潛在威脅。
有鑑於前述情形，相關領域仍需研發可取代鼠類OKT3抗體的低免疫原性抗體，以及排除使用鼠類OKT3抗體來活化人類T細胞的改良方法。
本揭示內容提供藉由本揭示內容雙功抗體（bi-specific antibody，BsAb）來分化及增生的T細胞，及其於治療癌症的用途。
因此，本揭示內容的第一態樣提供了一種用以誘發T細胞分化及／或增生的方法，其中各T細胞表面具有一抗-腫瘤抗原部（anti-tumor antigen moiety）及一抗-CD3部（anti-CD3 moiety）。該方法包括，將一周邊血液單核球細胞（peripheral blood mononuclear cell，PBMC）與一雙功抗體培養在一培養液中，據以使該PBMC分化為T細胞，其中各BsAb包含一對應至該T細胞之抗-腫瘤抗原部的腫瘤抗原結合位點，以及一對應至該T細胞之抗-CD3部的CD3結合位點，且該BsAb非鼠類OKT3抗體。
依據本揭示內容的實施方式，各BsAb具有一單鏈變異片段（single chain variable fragment，scFv）、一抗原結合片段（Fab）、一F(ab’)2 或一IgG的結構。
依據本揭示內容的實施方式，各BsAb的腫瘤抗原結合位點可結合至上皮生長因子受器（epidermal growth factor receptor，EGFR）、計畫性細胞死亡-配體1（programmed cell death-ligand 1，PD-L1）或前列腺專一性的膜抗原（prostate specific membrane antigen，PSMA）。
依據本揭示內容非必要的實施方式，該培養液更包含一細胞激素，該細胞激素係選自由IL-2、TGF-β及其組合所組成的群組。在一較佳實施方式中，該培養液包含IL-2及TGF-β，且所生成的T細胞為調控型T細胞（regulatory T cell）。
依據本揭示內容的實施方式，在各BsAb中，該腫瘤抗原結合位點包含一與序列編號：69、77、84、90、96、102、108、114或120具有至少90％序列相似度的抗-腫瘤抗原scFv；以及該CD3結合位點包含一與序列編號：67具有至少90％序列相似度的抗-CD3 VL-Ck域（domain），以及一與序列編號：68具有至少90％序列相似度的抗-CD3 VH-CH1域。
依據本揭示內容的實施方式，在各BsAb中，該腫瘤抗原結合位點包含一與序列編號：70、78、85、91、97、109或121具有至少90％序列相似度的抗-腫瘤抗原scFv；以及該CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv。
依據本揭示內容的實施方式，在各BsAb中，該腫瘤抗原結合位點包含一與序列編號：64、75、82、88、94、100、106、112或118具有至少90％序列相似度的抗-腫瘤抗原VL-Ck域；以及一與序列編號：65、76、83、89、95、101、107、113或119具有至少90％序列相似度的抗-腫瘤抗原VH-CH1域；以及該CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv。
依據本揭示內容的實施方式，在各BsAb中，該腫瘤抗原結合位點包含一與序列編號：73、80、86、92、98、104、110、116或122具有至少90％序列相似度的抗-腫瘤抗原VL-Ck域，以及一與序列編號：74、81、87、93、99、105、111、117，或123具有至少90％序列相似度的抗-腫瘤抗原VH-CH1-Fc域；以及該CD3結合位點包含一與序列編號：71具有至少90％序列相似度的抗-CD3 VL-Ck域，以及一與序列編號：72具有至少90％序列相似度的抗-CD3 VH-CH1-Fc域。
實務上，可將依據本發明方法所製備的具抗原專一性T細胞與上述人源化之BsAb混和成一混合物，接著將該混合物投予至一有需要癌症治療之個體。
因此，本揭示內容的第三態樣提供了一種用以癌症治療的醫藥套組。該醫藥套組包含依據本發明方法分化及增生的T細胞，以及本揭示內容的人源化BsAb。
本揭示內容的第四態樣提供了一種用以治療一罹患癌症之個體的方法。該方法包括，對該個體投予一有效量之藉由上述方法所製備的T細胞，或一有效量之經本揭示內容BsAb修飾的鼠類OKT3 T細胞。
依據某些實施方式，將鼠類OKT3 T細胞與本揭示內容BsAb培養在一培養液中，可將該T細胞進行修飾而使其表面攜帶（arm）本揭示內容BsAb。此外或非必要地，該培養液更包含一細胞激素，該細胞激素係選自由IL-2、IL-7及其組合所組成的群組。
較佳地，對個體投予本揭示內容T細胞的數量為該個體每公斤體重1×104 至1×107 個細胞。該數量可以單一劑量形式，或以一劑以上的較小劑量形式投予。
本發明方法可用以治療不同癌症，特別是會表現EGFR、PSMA或PD-L1的癌症。例示性之可利用本發明方法來治療之癌症包括，但不限於，膀胱癌、膽癌、骨癌、腦瘤、乳癌、子宮頸癌、結直腸癌、大腸癌、食道癌、上皮癌、胃癌、胃腸基質瘤（gastrointestinal stromal tumor，GIST）、神經膠質瘤、淋巴譜系之造血組織腫瘤、肝癌、非何杰金氏淋巴癌（non-Hodgkin’s lymphoma）、卡波西氏肉瘤、白血病、肺癌、淋巴瘤、小腸癌、黑色素瘤、骨髓性白血病、胰臟癌、前列腺癌、視網膜母細胞瘤、卵巢癌、腎細胞癌、脾臟癌、鱗狀細胞癌、甲狀腺癌及濾泡狀甲狀腺癌。
依據本揭示內容一具體實施方式，該癌症為三陰性乳癌。依據本揭示內容另一具體實施方式，該癌症為惡性胰臟癌。
本揭示內容一或多個實施方式的詳細內容及說明闡述如下。在參閱以下的詳細說明及申請專利範圍後，本揭示內容的其餘特徵及優點將顯而易見。
下文提供了詳細說明及附隨圖式係為了使本揭示內容實施例的敘述更加詳盡與完備，而非代表用以理解或運用本揭示內容實施例的唯一形式。本說明書闡述實施例的功能以及用以建構與操作此等實施例的步驟順序。然而，亦可利用其他實施例來達成相同或均等的功能與步驟順序。
I. 定義
「抗體」（antibody）一詞係以最廣泛的意義使用，具體涵蓋單株抗體、多株抗體、多重專一性抗體（例如雙功抗體），以及抗體片段（只要其展現欲求的生物學活性即可），也就是說，當處於一蛋白及／或其他分子的複合混合物中，抗體會優先辨識其標的抗原時並專一結合該抗原。
在此使用之「單株抗體」（monoclonal antibody）係指一種自一實質上同質的抗體群中所獲得的抗體，且無須藉由任何特定方法製備該抗體。與多株抗體相反的是，多株抗體通常包括對抗不同抗原決定位（epitope）的不同抗體，而不同的單株抗體各自對抗抗原上的單一決定位置（即抗原決定位）。本揭示內容單株抗體可藉由融合瘤方法（hybridoma method）或藉由重組DNA方法來製備。單株抗體在本文中具體包括「嵌合」（chimeric）或「重組」（recombinant）抗體，其中重鏈及／或輕鏈的一部分係相同於或同源對應於一衍生自一特定物種或屬於一抗體種類（class）或亞種（subclass）的抗體序列，而該鏈的其餘部分則相同於或同源對應於一衍生自另一物種或屬於另一抗體種類或亞種，以及此類抗體片段的抗體序列，只要其展現欲求的生物學活性即可。
非人類（例如鼠類）抗體的「人源化」（humanized）形式為嵌合抗體（chimeric antibodies），其含有最少的衍生自非人類免疫球蛋白（non-human immunoglobulin）序列。人源化抗體為人類免疫球蛋白，其高度變異區殘基（hypervariable region residues）由非人類物種（例如小鼠、大鼠、兔子或非人類靈長類）中具有欲求的專一性或親和性的高度變異區殘基所取代。在某些情形下，人類免疫球蛋白的Fv框架區（framework region，FR）殘基由對應的非人類殘基所取代。一般來說，人源化抗體會包含實質上所有的至少一個（通常為兩個）的變異域，其中所有的或實質上所有的FR區為人類免疫球蛋白序列。人源化抗體非必要性地包含至少一部分的免疫球蛋白恆定區（constant region，Fc），其通常為一人類免疫球蛋白之Fc。
「雙功抗體（bi-specific antibody，BsAb）」一詞係指一抗體具有至少兩種不同的抗原專一性。在較佳實施方式中，本揭示內容BsAb具有二個抗原結合位點，其中一個對抗一腫瘤抗原（例如EGFR、PD-L1、HER2、PSMA及其他），而另一個對抗一T細胞受體（例如CD3）。
「鏈接物」（linker）或「胜肽鏈接物」（peptide linker）一詞在本揭示內容中可交替使用，係指一種具有天然或合成胺基酸殘基，用於連接二種多肽的胜肽。舉例來說，胜肽鏈接物可用於連接VH及VL，以形成單鏈變異片段（例如scFv）；或將scFv連接全長抗體以形成本揭示內容BsAb。較佳地，鏈接物為一具有至少5個胺基酸殘基長度的胜肽，例如5至100個胺基酸殘基長度，更佳地，10至30胺基酸殘基長度。scFv中的鏈接物為一具有至少5個胺基酸殘基長度的胜肽，較佳地為15至20個胺基酸殘基長度。較佳地，鏈接物包含一序列的（Gn S）m ，其中G = 甘胺酸（glycine），S = 絲胺酸（serine），且n及m為一介於1至4之間各自獨立的數字。在一實施例中，鏈接物包含一（G2 S）4 的序列。在另一實施例中，鏈接物包含一（G4 S）3 的序列。
「癌症」（cancer）或「腫瘤」（tumor）一詞在本揭示內容中可交替使用，較佳地，係指在哺乳動物（特別是人類）中的生理條件下通常具有未受控制的細胞生長特性。在此方面的癌症包括轉移癌（metastases cancer），及／或抗藥性癌症（drug-resistant cancer）。就癌症來說，較佳的為該些會展現下列分子：αvβ3、α5β1、癌胚胎抗原（carcinoembryonic antigen，CEA）、細胞毒性T-淋巴球相關抗原4（cytotoxic T-lymphocyte–associated antigen 4，CTLA4）、CD3、CD19、CD20、CD30、CD50、CIAX、cMuc1、ED-B、表皮生長因子受體（epidermal growth factor receptor，EGFR）、表皮細胞黏附分子（epithelia cell adhesion molecules，EpCAM）、生成促紅血球形成素之肝細胞A3（erythropoietin-producing hepatocellular A3，EPHA3）、家族性腺瘤息肉症（familial adenomatous polyposis，FAP）、gpA33、Globo-H、人類表皮生長因子受體2（human epidermal growth factor receptor 2，HER2）、HER3、類胰島素生長因子1受體（insulin like growth factor 1 receptor，IGF1R）、OC183B2、血小板-衍生生長因子受體（platelet-derived growth factor receptor，PDGFR）、計畫性細胞死亡-配體1（programmed cell death-ligand 1，PD-L1）、前列腺專一性的膜抗原（prostate specific membrane antigen，PSMA）、Ley 、MET、腫瘤-相關醣蛋白72（tumor-associated glycoprotein 72，TAG72）、生腱蛋白（tenascin）、血管內皮生長因子受體（vascular endothelial growth factor receptor，VEGFR）、VEGFR-2及／或VEGFR-3表現量增加的癌症。因此，可利用本揭示內容治療的癌症或腫瘤為乳癌、肺癌、大腸癌、結直腸癌、脾臟癌、腎癌、肝癌、膀胱癌、頭頸部癌、卵巢癌、前列腺癌、腦癌、胰臟癌、皮膚癌、骨癌、血癌、胸腺癌、子宮癌、睾丸癌、子宮頸癌和神經元癌。更具體來說，該癌症係選自由膀胱癌、膽癌、骨癌、腦瘤、乳癌、子宮頸癌、結直腸癌、大腸癌、食道癌、上皮癌、胃癌、胃腸基質瘤（GIST）、神經膠質瘤、淋巴譜系之造血組織腫瘤、肝癌、非何杰金氏淋巴癌、卡波西氏肉瘤、白血病、肺癌、淋巴瘤、小腸癌、黑色素瘤、骨髓性白血病、胰臟癌、前列腺癌、視網膜母細胞瘤、卵巢癌、腎細胞癌、脾臟癌、鱗狀細胞癌、甲狀腺癌及濾泡狀甲狀腺癌所組成的群組。在一實施例中，該癌症為惡性胰臟癌。在另一實施例中，該癌症為三陰性乳癌（TNBC）。
在此使用之「一有效量」（an effective amount）一詞係指一有效的量，在劑量及必要的時間內，對癌症治療可達到欲求的治療結果。
「投予」（administered、administering或administration）一詞在本文中可交替使用，係指直接投予本揭示內容BsAb或其組合來分化及增生T細胞。
「個體」（subject）或「病患」（patient）一詞係指一種可用本揭示內容組合物及／或方法治療的動物，包括人類。除非有具體指出其中一種性別，「個體」或「病患」一詞意指男性及女性二者。因此，「個體」或「病患」一詞包含任一種可自癌症治療獲益的哺乳動物。例示性之「個體」或「病患」包括，但不限於，人、大鼠、小鼠、豚鼠、猴子、豬、山羊、牛、馬、狗、貓、鳥及雞。在一例示性實施方式中，該病患為人類。
在此使用之「相同」（identical）或「相似度百分比」（percent identity）一詞係指當比較及排列序列（即序列比對）求最大序列對應值時，兩個或兩個以上序列或次序列相同或特定百分比的胺基酸殘基相同。為確認相似度百分比，序列以求取最佳排列結果為目的來進行排列（例如可在一第一胺基酸序列中引入間隙來達到與一第二胺基酸序列的最佳排列）。接著比較在對應的胺基酸位置上的胺基酸殘基。當該第一序列的一個位置由該第二序列對應位置的相同胺基酸殘基佔據時，則該分子在該位置是相同的。二序列之間的相似度百分比為該二序列共有的相同位置數目的函數（即％相似度 = 相同位置／位置的總數（例如，重疊位置）×100）。在某些實施例中，兩個序列長度相同。
除非上下文另有明確說明，單數形式「一」（a或an）及「該」（the）在本文中包括複數對象。
II. 發明敍述
因此，本揭示內容的第一態樣係提供具抗原專一性T細胞，特別是指藉由本揭示內容重組的雙功抗體（BsAb）活化（或誘發分化）的T細胞，該T細胞係由周邊血液單核球細胞（PBMC）轉換成表面帶有專一性抗-腫瘤抗原及抗-CD3片段的T細胞。因此，該些具抗原專一性T細胞將會更強有力地結合腫瘤細胞（包括惡性腫瘤細胞及三陰性乳癌（TNBC）細胞），因而可抑制該腫瘤細胞的生長及轉移。
1. 本揭示內容之BsAb
抗體屬於免疫球蛋白，其包括IgG、IgA、IgE、IgM及IgD等種類。血清中發現含量最豐富的免疫球蛋白為IgG，其結構具有四條鏈，兩條輕鏈及兩條重鏈；每一輕鏈具有二個結構域（domain）且每一重鏈具有四個結構域。抗原結合位點係位於片段抗原結合（Fab）區，該Fab包含變異輕鏈（variable light，VL）及變異重鏈（variable heavy，VH）結構域，以及恆定輕鏈（constant light，CL）及恆定重鏈（constant heavy，CH1）結構域。該重鏈的CH2及CH3結構域稱為可結晶片段（fragment crystallizable，Fc）區域。因此，全長的抗體重鏈自N端至C端為一種由一VH、一CH1、一絞鏈區（hinge region，HR）、一CH2及一CH3所組成的多肽；簡稱為VH-CH1-HR-CH2-CH3。全長的抗體輕鏈自N端往C端方向為一種由一VL及一CL所組成的多肽，簡稱為VL-CL，其中該CL可為κ（kappa）或λ（lambda）。目前認為IgG係一種藉由雙硫鍵（disulfide bonds，-S-S-）將二個重鏈結合在一起的異四聯體（heterotetramer），其中該雙硫鍵係介於CL結構域與CH1結構域之間及介於兩個重鏈的鉸鏈區之間。
如在上文「定義」章節所述，BsAb係指對不同抗原具有專一性的抗體；因此，本揭示內容之BsAb為一種重組抗體，其經改造而包含能夠分別結合二種不同抗原的序列，其中該二抗原為一腫瘤抗原及一CD3抗原。因此，本揭示內容的各BsAb包含一抗-腫瘤抗原序列及一抗-CD3序列。本揭示內容研發不同的重組BsAb，並利用其來誘發單核球細胞分化及／或增生為表面帶有對應該BsAb抗原之具抗原專一性T細胞。
第1圖為闡述本揭示內容BsAb之結構示意圖。
在某些實施方式中，本揭示內容BsAb係單體（monomeric）二價（divalent）的雙功抗體，其中對抗一腫瘤抗原（即抗-腫瘤抗原Fab）的一VH-CH1域及一輕鏈VL-Ck係融合至一抗-CD3 scFv（scFv），其中該scFv由一重鏈變異域（VH）及一輕鏈變異域（VL）所組成，簡稱為VH-VL（第1圖之圖A）。在其他實施方式中，該單體二價BsAb在其結構中包含一抗-CD3 Fab，其中該抗-CD3 Fab係由對抗CD3的一VH-CH1域及一輕鏈VL-Ck所組成，且該抗-CD3 Fab係經由一胜肽鏈接物融合至一對抗一腫瘤抗原scFv（第1圖之圖B）。在其他實施方式中，本揭示內容的單體二價BsAb係由一抗-腫瘤抗原scFv及一抗-CD3 scFv所組成，其中該二個scFv係經由一胜肽鏈接物連接（第1圖之圖C）。在再其他實施方式中，本揭示內容之BsAb具有一「孔中球」（knob into hole）的結構，其中第一重鏈CH3域的球狀凸起部分係藉由將數個胺基酸側鏈取代為替代胺基酸而造成，且第二重鏈CH3域對應於該球狀凸起部分的孔狀凹陷部分係藉由將適當胺基酸側鏈取代為替代胺基酸而造成。該BsAb「孔中球」結構的示意圖繪示於第1圖之圖D。該孔中球技術為本領域習知技藝人士所熟知，且可方便地用來製備本揭示內容之BsAb。
編碼本揭示內容BsAb的DNA係衍生自已知抗體，將其基因進行選殖及融合來建立具有欲求的人源化BsAb之DNA構築載體。詳細的製備方法闡述於實施例。
因此，可建立具有雙結合位點的重組BsAb，其中該結合位點可結合至一T細胞之CD3及一腫瘤抗原，且該腫瘤抗原係選自由PSMA、EGFR、PD-L1、CEA、FAP、EpCAM、HER2及VCAM-1所組成的群組。
依據某些實施方式，可製備抗-PSMA／抗-CD3 BsAb。在一實施例中，該抗-PSMA／抗-CD3 BsAb包含一PSMA結合位點（包含一序列編號：65的VH-CH1域及一序列編號：64的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-PSMA／抗-CD3 BsAb包含一PSMA結合位點（包含一序列編號：69的抗-PSMA scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-PSMA／抗-CD3 BsAb包含一PSMA結合位點（包含一序列編號：70的抗-PSMA scFv）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在再一其他實施例中，該抗-PSMA／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該PSMA結合位點包含一序列編號：73的VL-Ck及一序列編號：74的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-EGFR／抗-CD3 BsAb。在一實施例中，該抗-EGFR／抗-CD3 BsAb包含一EGFR結合位點（包含一序列編號：76的VH-CH1域及一序列編號：75的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-EGFR／抗-CD3 BsAb包含一EGFR結合位點（包含一序列編號：77的抗-EGFR scFv；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-EGFR／抗-CD3 BsAb包含一EGFR結合位點（包含一序列編號：78的抗-EGFR scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-EGFR／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該EGFR結合位點包含一序列編號：80的VL-Ck及一序列編號：81的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-PD-L1／抗-CD3 BsAb。在一實施例中，該抗-PD-L1／抗-CD3 BsAb包含一PD-L1結合位點（包含一序列編號：83的VH-CH1域及一序列編號：82的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-PD-L1／抗-CD3 BsAb包含一PD-L1結合位點（包含一序列編號：84的抗-PD-L1 scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-PD-L1／抗-CD3 BsAb包含一PD-L1結合位點（包含一序列編號：85的抗-PD-L1 scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-PD-L1／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該PD-L1結合位點包含一序列編號：86的VL-Ck及一序列編號：87的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-HER2／抗-CD3 BsAb。在一實施例中，該抗-HER2／抗-CD3 BsAb包含一HER2結合位點（包含一序列編號：89的VH-CH1域及一序列編號：88的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-HER2／抗-CD3 BsAb包含一HER2結合位點（包含一序列編號：90的抗-HER2 scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-HER2／抗-CD3 BsAb包含一HER2結合位點（包含一序列編號：91的抗-HER2 scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-HER2／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該HER2結合位點包含一序列編號：92的VL-Ck及一序列編號：93的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-FAP／抗-CD3 BsAb。在一實施例中，該抗-FAP／抗-CD3 BsAb包含一FAP結合位點（包含一序列編號：95的VH-CH1域及一序列編號：94的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-FAP／抗-CD3 BsAb包含一FAP結合位點（包含一序列編號：96的抗-FAP scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-FAP／抗-CD3 BsAb包含一FAP結合位點（包含一序列編號：97的抗-FAP scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-FAP／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該FAP結合位點包含一序列編號：98的VL-Ck及一序列編號：99的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-EpCAM（MOC31）／抗-CD3 BsAb。在一實施例中，該抗-EpCAM（MOC31）／抗-CD3 BsAb包含一EpCAM（MOC31）結合位點（包含一序列編號：101的VH-CH1域及一序列編號：100的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-EpCAM（MOC31）／抗-CD3 BsAb包含一EpCAM（MOC31）結合位點（包含一序列編號：102的抗-EpCAM（MOC31） scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-EpCAM（MOC31）／抗-CD3 BsAb包含一EpCAM（MOC31）結合位點（包含一序列編號：103的抗-EpCAM（MOC31） scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-EpCAM（MOC31）／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該EpCAM（MOC31）結合位點包含一序列編號：104的VL-Ck及一序列編號：105的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-EpCAM（MT201）／抗-CD3 BsAb。在一實施例中，該抗-EpCAM（MT201）／抗-CD3 BsAb包含一EpCAM（MT201）結合位點（包含一序列編號：107的VH-CH1域及一序列編號：106的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-EpCAM（MT201）／抗-CD3 BsAb包含一EpCAM（MT201）結合位點（包含一序列編號：108的抗-EpCAM（MT201） scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-EpCAM（MT201）／抗-CD3 BsAb包含一EpCAM（MT201）結合位點（包含一序列編號：109的抗-EpCAM（MT201） scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-EpCAM（MT201）／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該EpCAM（MT201）結合位點包含一序列編號：110的VL-Ck及一序列編號：111的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-CEA／抗-CD3 BsAb。在一實施例中，該抗-CEA／抗-CD3 BsAb包含一CEA結合位點（包含一序列編號：113的VH-CH1域及一序列編號：112的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-CEA／抗-CD3 BsAb包含一CEA結合位點（包含一序列編號：114的抗-CEA scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-CEA／抗-CD3 BsAb包含一CEA結合位點（包含一序列編號：115的抗-CEA scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-CEA／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該CEA結合位點包含一序列編號：116的VL-Ck及一序列編號：117的VH1-CH1-Fc孔狀凹陷域。
依據某些實施方式，可製備抗-VCAM1／抗-CD3 BsAb。在一實施例中，該抗-VCAM1／抗-CD3 BsAb包含一VCAM1結合位點（包含一序列編號：119的VH-CH1域及一序列編號：118的VL-Ck域）；以及一CD3結合位點（包含一序列編號：66的抗-CD3 scFv）。在另一實施例中，該抗-VCAM1／抗-CD3 BsAb包含一VCAM1結合位點（包含一序列編號：120的抗-VCAM1 scFv）；以及一CD3結合位點（包含一序列編號：68的VH-CH1域及一序列編號：67的VL-Ck域）。在一其他實施例中，該抗-VCAM1／抗-CD3 BsAb包含一VCAM1結合位點（包含一序列編號：121的抗-VCAM1 scFv）；以及一CD3結合位點（包含一序列編號：79的抗-CD3 scFv）。在再一其他實施例中，該抗-VCAM1／抗-CD3 BsAb具有一「孔中球」結構，其中該CD3結合位點包含一序列編號：71的VL-Ck及一序列編號：72的VH-CH1-Fc球狀凸起域；以及該VCAM1結合位點包含一序列編號：122的VL-Ck及一序列編號：123的VH1-CH1-Fc孔狀凹陷域。
依據本揭示內容的其他實施方式，可製備抗-CD3 VH及CL的人源化OKT3，該些序列（參照表39至42）可與本揭示內容所述相關抗-腫瘤抗原序列融合以製備欲求的BsAb。
2. 藉由本揭示內容BsAb活化具抗原專一性T細胞
可利用本揭示內容BsAb來誘發單核球細胞（例如周邊血液單核球細胞）分化及增生成本揭示內容具抗原專一性T細胞。因此，本揭示內容一態樣係關於製備具抗原專一性的T細胞，其表面分別包含一抗-腫瘤抗原部及一抗-CD3部。
因此，本揭示內容涵蓋一種用以誘發T細胞分化及／或增生的方法。該方法包含，將採集自一個體的周邊血液單核球細胞（PBMC）與本揭示內容雙功抗體（BsAb）培養在一培養液中，據以使該PBMC分化為T細胞，並將該分化的T細胞進行增殖，其中，各BsAb包含一對應至各T細胞上之抗-腫瘤抗原部的腫瘤抗原結合位點，及一對應至各T細胞上之抗-CD3部的CD3結合位點，且該BsAb非鼠類OKT3抗體。
可利用本領域習知技藝人士所知的任一方法自一個體的新鮮血液中分離PBMC，例如藉由等密度離心（density centrifugation）（Ficoll-Paque），因血液的不同成分具有不同的密度而可據以分離。
為達到T細胞的分化及增生，可將分離的PBMC與本揭示內容任一BsAb培養在一普通培養液中一段足夠的時間，舉例來說，至少7天，例如7、8、9、10、11、12、13及14天；較佳地，至少14天。在某些實施方式中，培養7天後CD3+ T細胞的數量倍增。在其他實施方式中，繼續培養14天，CD3+ T細胞的數量增加3倍。此外或非必要地，培養液可包括細胞激素，例如IL-2、IL-7及其組合。
依據本揭示內容的實施方式，所製備的T細胞表面，分別包含一對應至BsAb抗-腫瘤抗原的抗-腫瘤抗原部，及一對應至BsAb抗-CD3的抗-CD3部。在某些實施例中，所製備的T細胞表面分別包含抗-PSMA及抗-CD3部。在其他實施例中，所製備的T細胞表面分別包含抗-EGFR及抗-CD3部。在再其他實施例中，所製備的T細胞表面分別包含抗-PD-L1及抗-CD3部。
依據本揭示內容的再其他實施方式，將PBMC與該本揭示內容BsAb培養至少7天後，可製備周邊衍生調控型T細胞，該T細胞表面出現細胞標識分子FoxP3。在此情形下，該培養液除細胞激素IL-2之外，更包含抗-CD28抗體。
依據本揭示內容的實施方式，本揭示內容具抗原專一性T細胞（包括周邊衍生調控型T細胞）不僅對於腫瘤細胞展現強有力的結合親和力，亦生產較高量的細胞激素，包括，但不限於，IL-2、IFN-γ、TNF-α、顆粒酶B及穿孔素。因此，相較於藉由鼠類OKT3抗體活化的T細胞，上述該些T細胞對於腫瘤細胞（包括惡性癌細胞及TNBC細胞）具有更高的細胞毒性功效。
3. 治療癌症的方法
3.1 利用具抗原專一性的T細胞來治療癌症
因此，本揭示內容的再一態樣係提供一種用以治療癌症的方法。該方法利用第2章節所述具抗原專一性T細胞的優勢，對一罹患癌症之個體投予一有效量之T細胞，或進一步以BsAb修飾的T細胞，據以抑制（suppress或inhibit）癌細胞的生長。
第2A圖為本發明方法之示意圖，首先自一個體的新鮮血液中分離PBMC，接著以一步法擴增及分化處理該分離的PBMC，以使該分化的T細胞攜帶分別對應該BsAb抗-腫瘤抗原及抗-CD3的部分。具體來說，該一步法擴增及分化處理，包括將PBMC與本揭示內容BsAb培養在一培養液中至少7天，更佳地，至少14天，直到製備足夠數量的欲求的T細胞。此外或非必要地，可進一步以BsAb修飾製得的具抗原專一性T細胞，在此情形下，將本揭示內容具抗原專一性T細胞進一步與本揭示內容BsAb作用的步驟稱為「一步法擴增、分化及修飾」（one-step expanding, differentiation and modification）處理，如第2A圖所述。
在某些實施方式中，對個體直接投予一有效量之該具抗原專一性T細胞（即未進一步以BsAb修飾）來治療癌症。在其他實施方式中，對該個體投予一有效量之該進一步以BsAb修飾的具抗原專一性T細胞來治療癌症。投予該個體的T細胞數量可約為個體每公斤體重1×104 至1×107 個細胞。在特定實施方式中，投予該個體的T細胞數量可約為個體每公斤體重1×105 至1×106 細胞。該劑量可以單一劑量形式，或選擇性地以一劑以上的較小劑量形式投予。
3.2 利用經本揭示內容BsAb修飾的鼠類OKT3 T細胞來治療癌症
在某些實施方式中，並非利用上述在第2章節中的具抗原專一性T細胞，而是利用進一步以本揭示內容BsAb修飾的鼠類OKT3 T細胞（即經由鼠類OKT3抗體活化PBMC所衍生的T細胞）來治療癌症。參照第2B圖，其類似於第2A圖，除鼠類OKT3 T細胞係經本揭示內容BsAb修飾，並投予該個體。類似於第2A圖的是，係藉由將鼠類OKT3 T細胞與本揭示內容BsAb培養來進行該修飾，據以使鼠類OKT3 T細胞攜帶該BsAb的抗-腫瘤抗原及抗-CD3。
依據本揭示內容的實施方式，至少500奈克，例如500、600、700、800、900、1,000、1,100、1,200、1,300、1,400、1,500、1,600、1,700、1,800、1,900、2,000、2,100、2,200、2,300、2,400、2,500、2,600、2,700、2,800、2,900及3,000奈克的本揭示內容BsAb方足以修飾鼠類OKT3 T細胞（例如3×105 細胞），以致使欲求的本揭示內容BsAb的抗-腫瘤抗原表現在該T細胞表面。在某些實施例中，鼠類OKT3 T細胞進一步以本揭示內容抗-PSMA／抗-CD3 BsAb修飾。在其他實施例中，相較於未經修飾的鼠類OKT3 T細胞，經本揭示內容抗-PSMA／抗-CD3 BsAb修飾的鼠類OKT3 T細胞可生產更高量的細胞激素，包括，但不限於，IL-2、IFN-γ、TNF-α、顆粒酶B及穿孔素。因此，相較於未經修飾的鼠類OKT3 T細胞，該些經修飾的鼠類OKT3 T細胞對於腫瘤細胞（包括惡性癌細胞及TNBC細胞）具有更高的細胞毒性功效。
可藉由任一種可有效將BsAb或T細胞傳遞至特定作用位置的途徑，對一哺乳動物（較佳為人類）投予本揭示內容之BsAb、具抗原專一性的T細胞，以及經修飾的鼠類OKT3 T細胞，例如經口、經鼻、經肺、經皮膚，例如被動式或離子導入輸送（iontophoretic delivery），或非經腸，例如經直腸、經儲槽（depot）、皮下、靜脈內、肌肉內、鼻內、小腦內（intracerebellar）、眼藥水或軟膏。當可理解，本揭示內容的劑量會隨病患而有所不同，不僅由於所選擇的癌症治療藥劑、投予途徑，以及該BsAb、該T細胞及／或其組合，在該病患體內引發欲求反應之能力，並可因下列因素：欲緩解病狀的疾病病況或嚴重程度、病患年齡、性別、體重、病患的狀態及所治療病理病狀的嚴重程度、病患隨後遵循的並行藥物或特殊飲食，以及本領域習知技藝人士將辨識的其他因素，該適當劑量最終由主治醫師裁量。可調節劑量以改進治療反應。治療有效量亦為一種癌症治療藥劑的治療有益效應超過任何毒性或有害效應的量。較佳地，BsAb、T細胞或其組合，係以癌細胞生長受到抑制的劑量投予一段時間。
現將參考以下實施方式更具體地描述本揭示內容，該等實施方式係出於示範性而非限制性的目的而提供。
實施例
材料及方法
細胞及動物
本揭示內容使用人類T淋巴球細胞株Jurkat T細胞（CD3+ ）、人類前列腺腺癌細胞株LNCaP（PSMA+ ／PD-L1+ ）、人類大腸腺癌細胞株HT-29（EGFR+ ）、惡性胰臟癌細胞株MIA PaCa-2（PD-L1+ ）、三陰性乳癌（TNBC）細胞株MDA-MB-231（EGFR+ ／PD-L1+ ）及Expi293細胞。
一般來說，在37°C、5％CO2 下，將HT-29、MIA PaCa-2及MDA-MB-231細胞培養在基礎培養液（Dulbecco’s modified Eagle’s medium）（Sigma，St Louis，MO，USA）中，輔以10％的胎牛血清（FCS，HyClone，Logan，UT）、每毫升100單位之青黴素及每毫升100微克之鏈黴素。將Jurkat T及LNCaP細胞培養在包含具有相同補充物的RPMI-1640中。在37°C、5％CO2 下，將Expi293細胞培養在Expi293™表現培養液中。
SCID小鼠（6–8週齡）得自臺灣臺北市國家實驗研究院國家實驗動物中心。所有動物實驗皆依現行制度規範執行，並取得臺北醫學大學（臺灣臺北市）實驗室動物設施及病理學核心委員會核准。
製備重組BsAb
為製備本揭示內容之BsAb，將編碼抗-腫瘤抗原（例如抗-PSMA、抗-EGFR、抗-PD-L1及其他）及抗-CD3的核酸與其他DNA序列（例如訊息胜肽、IRES、鏈接物及其他）以全基因合成方式進行移植及融合，以建構欲求的構築載體。
接著在37°C、8％CO2 下，在Expi293細胞中（每25.5毫升7.5×107 細胞，加入30微克之核酸以進行轉染）將所製備的DNA構築載體進行增殖。藉由鎳-親和力層析法，自6天後收集的培養液中純化BsAb，並利用Pierce™之BCA蛋白分析套組來確認該BsAb的濃度。
製備人源化OKT3之VH及VL
為選擇用以進行互補性決定區（complementarity-determining region，CDR）移植的人類框架序列，發明人利用IgBLAST程式，將OKT3之VH及VL序列與美國國家生物技術資訊中心資料庫的人類生殖細胞系免疫球蛋白變異區及連接區的序列進行比較。發明人發現IGHV1-46^03／IGHJ4與OKT3之VH的變異區／連接區最為相似。發明人並發現IGKV1-39^01／IgKJ4與OKT3之VL的變異區及連接區最為相似。為建構人源化OKT3之VH，該CDR藉由Kabat等人（Sequences of Proteins of Immunological Interest. 5th ed. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; 1991:103–511）的法則來確認，且將OKT3 VH的2個殘基（Thr 71及Lys 73）植入IGHV1-46^03／IGHJ4。為建構人源化OKT3之VL，該CDR藉由Kabat等人的法則來確認，且OKT3 VL的1個殘基（Tyr 71）植入IGKV1-39^01／IgKJ4。該人源化OKT3之VH及VL片段係以全基因合成方式建構。
分析純化之BsAb
將BsAb以10％的SDS-PAGE凝膠、在還原或非還原條件下進行電泳，接著以考馬斯藍（Coomassie Blue）進行染色。
分化T細胞
CD8+ T細胞。將分離自健康個體血液的周邊血液單核球細胞（PBMC）或初始的CD8+ T細胞以磷酸鹽緩衝生理鹽水（phosphate buffer solution，PBS）清洗，並以每毫升2×106 個細胞的濃度懸浮在AIM-V培養液中。接著在37°C、5％CO2 下，將該些懸浮細胞與BsAb（每毫升1-1,000奈克）及人源化IL-2（每毫升3,000國際單位）培養一段指定時間。在第7天及第14天分別收集部分該T細胞，並利用流式細胞分析進行分析。
CD4+ T細胞。CD4+ T細胞分化方法類似於CD8+ T細胞，除將PBMC以每毫升1×106 個細胞的濃度懸浮，並培養在具有BsAb（每毫升1-1,000奈克）及人源化IL-2（每毫升2,000國際單位）及IL-7（每毫升20國際單位）的AIM-V培養液中。
調控型T細胞。調控型T細胞的分化方法類似於CD8+ T細胞，除將PBMC或初始的CD4+ T細胞以每毫升1×106 個細胞的濃度懸浮，並培養在具有BsAb（每毫升1-1,000奈克）、抗-CD28抗體（每毫升100奈克），人源化IL-2（每毫升2,000國際單位）及D-甘露糖（每升25毫摩爾）的AIM-V培養液中。
流式細胞儀分析
辨識及／或標定（targeting）腫瘤專一性抗原。在4°C下，將BsAb（每毫升1微克）與LNCaP（PSMA+ ／PD-L1+ ）、HT-29（EGFR+ ）、MDA-MB-231（EGFR+ ／PD-L1+ ）、MIA PaCa-2（PD-L1+ ）或Jurkat（CD3+ ）細胞（3×105 個細胞）作用60分鐘，接著在4°C下作用與小鼠抗-組胺酸抗體（每毫升1微克）及FITC標記的山羊F(ab)2抗-小鼠免疫球蛋白二級抗體（每毫升1微克）。利用FACSCalibur流式細胞儀（Becton Dickinson，Mountain View，CA，USA）測量螢光，接著以Flowjo（Tree Star Inc.，San Carlos，CA，USA）軟體進行分析。
T細胞分化。在4°C下，將分化的T細胞（3×105 個細胞）與FITC標記的抗-人類CD3抗體（每毫升1微克）、FITC標記的抗-人類CD4抗體（每毫升1微克）、FITC標記的抗-人類CD8抗體（每毫升1微克）或PE標記的抗-人類FoxP3抗體混和。以冷的PBS清洗後，利用FACSCalibur流式細胞儀（Becton Dickinson，Mountain View，CA，USA）測量活細胞數之螢光，接著以Flowjo（Tree Star Inc.，San Carlos，CA，USA）軟體進行分析。
殘留在T細胞表面之BsAb量。將T細胞或攜帶實施例1 BsAb的T細胞（3×105 個細胞）培養在一包含20％FCS的培養液中，及分別在0、24、48及72小時採集樣本。以PBS清洗後，在4°C下，將採集的T細胞與小鼠抗-組胺酸抗體（每毫升1微克）及FITC標記的山羊F(ab)2抗-小鼠免疫球蛋白二級抗體（每毫升1微克）混和。接著利用FACSCalibur流式細胞儀（Becton Dickinson，Mountain View，CA，USA）測量螢光，接著以Flowjo（Tree Star Inc.，San Carlos，CA，USA）軟體進行分析。
細胞毒性分析
將腫瘤細胞（每孔104 個細胞）種在96孔盤中並在37°C、5％CO2 下培養24小時。接著，將分化的T細胞（例如實施例2之T細胞）或OKT3 T細胞以3：1、5：1或10：1的E／T比例加入腫瘤細胞，並繼續培養16小時。之後採集該細胞及上清液，並利用CytoTox96® 非放射性細胞毒性套組分析來評估各分化的T細胞之細胞毒性功效。
酵素連結免疫吸附分析法（ELISA）
利用市售的ELISA套組，並依據使用操作說明分別測量分泌自分化的T細胞的IL-2、INF-γ、TNF-α、顆粒酶B及穿孔素量。簡單來說，收集以實施例2之T細胞的或OKT3 T細胞處理的腫瘤細胞上清液，將其注入96-孔盤（每孔100微升）中，並在36°C之培養箱中作用1.5小時。之後以清洗緩衝液清洗，加入抗體（每孔100微升），並將該混合物置回培養箱，在36°C下繼續作用1小時。在清洗後，加入辣根過氧化物酶（horse radish peroxidase，HRP）（每孔100微升）並繼續作用30分鐘。在清洗後，加入四甲基聯苯胺（tetramethylbenzidine，TMB）（每孔100微升），並將該混合物在36°C下避光作用15分鐘。接著，加入終止反應溶液（每孔100微升），並利用微孔盤光譜分析儀測量每孔吸光值（405奈米）。
活體攝影帶有EGFR+ 腫瘤的SCID小鼠
將SCID小鼠背部分別注射HT-29（EGFR+ ）細胞（每100微升2×106 個細胞）以誘發腫瘤形成。使腫瘤生長14-17天，直到其體積大小約為80-100立方毫米，接著將NIR797標記進一步以抗-EGFR／抗-CD3 BsAb修飾的OKT3 T細胞（107 個細胞）以靜脈注射方式注射該動物。在注射後4及24小時，分別將戊巴比妥（Pentobarbital）麻醉的小鼠利用IVIS光譜光學攝影系統（激發波長，745奈米；放射波長，840奈米；Perkin-Elmer，Inc.，MA，USA）進行攝影。接著犧牲小鼠，收集腫瘤及器官（包括心臟、肺臟、腎臟、肝臟、胃、肌肉、骨骼、大腸、小腸、胰臟及血液），並利用IVIS光譜光學攝影系統進行分析。
治療帶有EGFR+ 腫瘤的SCID小鼠
將SCID小鼠背部分別注射HT-29（EGFR+ ）細胞（每100微升2×106 個細胞）以誘發腫瘤形成。使腫瘤生長10-14天，直到其體積大小約為30-50立方毫米，接著將NIR797標記進一步以抗-EGFR／抗-CD3 BsAb修飾的T細胞（每小鼠107 個細胞）以靜脈注射方式注射該動物。在治療期間每週二次紀錄各小鼠之體重及測量腫瘤體積大小（長×寬×高×1／2）。接著犧牲小鼠，並將腫瘤進行解剖及進行H&E染色或以抗-CD3抗體進行免疫染色分析。
統計分析
利用JMP 9.0軟體（SAS Institute，Inc.，Cary，NC）（藉由非參數式的Mann–Whitney檢定）估計介於各平均值之間差異的統計顯著性。在細胞毒性分析及活體毒性分析中P值>0.05，以及在活體治療中P值>0.01認為具有統計顯著性。
實施例1 製備及確認人源化抗-腫瘤／抗-CD3之抗體
1.1 製備抗-腫瘤／抗-CD3 BsAb
在此實施例中，分別具有如第1圖所示的結構之重組人源化雙功抗體，經由使用如第3圖所示的DNA構築載體來製備。就抗-腫瘤Fab／抗-CD3 scFv BsAb來說，該構築載體依序包含IgG訊息胜肽（LS）、抗-腫瘤 VL-CK（例如抗-EGFR之VL-CK）、內部核糖體進入位點（internal ribosomal entry site，IRES）、LS、抗-腫瘤VH-CH1（例如抗-EGFR VH-CH1）、鏈接胜肽（L）及抗-CD3 VH-VL（第3圖之圖A）。就抗-CD3 Fab／抗-腫瘤scFv BsAb來說，該構築載體依序包含LS、抗-CD3 VL-CK、IRES、LS、抗-CD3 VH-CH1、L及抗-腫瘤VH-VL（第3圖之圖B）。就抗-腫瘤scFv／抗-CD3 scFv BsAb來說，該構築載體依序包含LS、抗-腫瘤VL-VH、L及抗-CD3 VH-VL（第3圖之圖C）。就抗-CD3球狀凸起／抗-腫瘤孔狀凹陷BsAb來說，該抗-CD3球狀凸起構築載體依序包含LS、抗-CD3 VL-CK、IRES、LS及抗-CD3 VH-CH1-球狀凸起Fc，而該抗-腫瘤孔狀凹陷依序包含LS、抗-腫瘤 VL-CK、IRES、LS及抗-腫瘤VH-CH1-孔狀凹陷Fc（第3圖之圖D）。
因此，製備包含一抗-CD3及一抗-腫瘤抗原（即抗-PSMA、抗-EGFR、抗-PD-L1、抗-HER2、抗-FAP、抗-EpCAM（MOC31）、抗-EpCAM（MO201）、抗-CEA及抗-VCAM-1）之BsAb。本揭示內容BsAb的成分及各自的核酸及胺基酸序列為總結在表1至表36中。BsAb係經由Expi-293™表現系統所製備，且每一BsAb的產率高於每升100毫克，並具有超過95％的組裝準確率。
表1 抗-PSMA Fab／抗-CD3 scFv BsAb的成分及序列
表2 抗-CD3 Fab／抗-PSMA scFv BsAb的成分及序列
表3 抗-PSMA scFv／抗-CD3 scFv BsAb的成分及序列
表4 抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb的成分及序列
表5 抗-EGFR Fab／抗-CD3 scFv BsAb的成分及序列
表6 抗-CD3 Fab／抗-EGFR scFv BsAb的成分及序列
表7 抗-EGFR scFv／抗-CD3 scFv BsAb的成分及序列
表8 抗-CD3球狀凸起／抗-EGFR孔狀凹陷BsAb的成分及序列
表9 抗-PD-L1 Fab／抗-CD3 scFv BsAb的成分及序列
表10 抗-CD3 Fab／抗-PD-L1 scFv BsAb的成分及序列
表11 抗-PD-L1 scFv／抗-CD3 scFv BsAb的成分及序列
表12 抗-CD3球狀凸起／抗-PD-L1孔狀凹陷BsAb的成分及序列
表13 抗-HER2 Fab／抗-CD3 scFv BsAb的成分及序列
表14 抗-CD3 Fab／抗-HER2 scFv BsAb的成分及序列
表15 抗-HER2 scFv／抗-CD3 scFv BsAb的成分及序列
表16 抗-CD3球狀凸起／抗-HER2孔狀凹陷BsAb的成分及序列
表17 抗-FAP之Fab／抗-CD3 scFv BsAb的成分及序列
表18 抗-CD3 Fab／抗-FAP scFv BsAb的成分及序列
表19 抗-FAP scFv／抗-CD3 scFv BsAb的成分及序列
表20 抗-CD3球狀凸起／抗-FAP孔狀凹陷BsAb的成分及序列
表21 抗-EpCAM（MOC31） Fab／抗-CD3 scFv BsAb的成分及序列
表22 抗-CD3 Fab／抗-EpCAM（MOC31） scFv BsAb的成分及序列
表23 抗-EpCAM（MOC31） scFv／抗-CD3 scFv BsAb的成分及序列
表24 抗-CD3球狀凸起／抗-EpCAM（MOC31）孔狀凹陷BsAb的成分及序列
表25 抗-EpCAM（MT201） Fab／抗-CD3 scFv BsAb的成分及序列
表26 抗-CD3 Fab／抗-EpCAM（MT201） scFv BsAb的成分及序列
表27 抗-EpCAM（MT201） scFv／抗-CD3 scFv BsAb的成分及序列
表28 抗-CD3球狀凸起／抗-EpCAM（MT201）孔狀凹陷BsAb的成分及序列
表29 抗-CEA Fab／抗-CD3 scFv BsAb的成分及序列
表30 抗-CD3 Fab／抗-CEA scFv BsAb的成分及序列
表31 抗-CEA scFv／抗-CD3 scFv BsAb的成分及序列
表32 抗-CD3球狀凸起／抗-CEA孔狀凹陷BsAb的成分及序列
表33 抗-VCAM1之Fab／抗-CD3 scFv BsAb的成分及序列
表34 抗-CD3 Fab／抗-VCAM1 scFv BsAb的成分及序列
表35 抗-VCAM1 scFv／抗-CD3 scFv BsAb的成分及序列
表36 抗-CD3球狀凸起／抗-VCAM1孔狀凹陷BsAb的成分及序列
1.2 確認抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv及抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb
第4圖闡述SDS-PAGE分析抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-EGFR Fab／抗-CD3 scFv及抗-CD3 Fab／抗-PD-L1 scFv BsAb，在還原條件下其分別由一約95千道爾頓的Fab片段所組成；另一方面，在非還原條件下分別觀察到一170千道爾頓的抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb及一50千道爾頓的抗-PSMAscFv／抗-CD3 scFv。SDS-PAGE尚包括抗-EGFR之抗體爾必得舒（Erbitux）作為正控制組。
在此實施例中藉由利用流式細胞分析來檢驗BsAb的雙功能活性。實驗結果繪示於第3圖。
抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv及抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb能夠各別結合CD3-陽性的T細胞（即Jurkat T細胞）及PSMA-陽性的前列腺癌細胞（即LNCaP細胞），而抗-EGFR Fab／抗-CD3 scFv可專一辨識EGFR-陽性的癌細胞（即HT29細胞）；以及抗-CD3 Fab／抗-PD-L1 scFv可專一辨識CD3-陽性的T細胞（即Jurkat T細胞）及PD-L1-陽性的前列腺癌細胞（即LNCaP細胞）。第5圖的實驗數據確認實施例1的抗體確實具備對二種不同抗原的專一性。
1.3 製備人源化OKT3之抗-腫瘤／抗-CD3 BsAb
在此實施例中，依據「材料及方法」章節所述的步驟來製備重組人源化OKT3之VH及VL序列。表37及表38提供該人源化OKT3之VH及VL胺基酸序列及各別的CDR。
表37 人源化OKT3之VH及其CDR的胺基酸序列
表38 人源化OKT3之VL及其CDR的胺基酸序列
可將人源化OKT3之VH及VL序列與上述在表1至表36中的抗-腫瘤序列融合，從而建構欲求的人源化OKT3之抗-腫瘤／抗-CD3 BsAb。表39提供用以建構抗-腫瘤Fab／抗-CD3 scFv之人源化OKT3之抗-CD3 scFv序列；表40提供用以建構抗-CD3 Fab／抗-腫瘤scFv之人源化OKT3之抗-CD3 VL-CK及VH-CH1序列；表41提供用以建構抗-腫瘤scFv／抗-CD3 scFv之人源化OKT3之抗-CD3 scFv序列；以及表42提供用以建構抗-CD3球狀凸起／抗-腫瘤孔狀凹陷之人源化OKT3之抗-CD3 VL球狀凸起及VH球狀凸起序列。
表39 用以建構抗-腫瘤Fab／抗-CD3 scFv之人源化OKT3之抗-CD3 scFv序列
表40 用以建構抗-CD3 Fab／抗-腫瘤scFv之人源化OKT3之抗-CD3 VL-CK及VH-CH1序列
表41 用以建構抗-腫瘤scFv／抗-CD3 scFv之人源化OKT3之抗-CD3 scFv序列
表42 用以建構抗-CD3球狀凸起／抗-腫瘤孔狀凹陷之人源化OKT3之抗-CD3 VL球狀凸起及VH球狀凸起序列
實施例2 增生及確認藉由實施例1 BsAb所分化的CD3+ ／CD8+ 細胞
為製備攜帶實施例1 BsAb的T細胞，可將周邊血液單核球細胞（PBMC）自健康個體血液中分離，並培養在一包含細胞激素IL-2加上鼠類單株抗體OKT3或細胞激素IL-2加上實施例1.2 BsAb（即抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv及抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb）的培養液中進行分化。培養的細胞分別在第7天及第14天採集，並利用FITC接合的抗-CD3、抗-CD4及抗-CD8抗體進行流式細胞儀分析。定量結果總結在表43及第6圖中。
表43的實驗數據指出實施例1.2人類BsAb與鼠類OKT3在誘發PBMC分化為CD3+ ／CD8+ 細胞上同樣有效。進一步地，除該些藉由抗-PSMA scFv／抗-CD3 scFv BsAb誘發的細胞之外，藉由實施例1.2 BsAb誘發的CD3+ 細胞群在培養7天後超過80％，在培養14天後超過90％，且在培養18天後CD3+ ／CD8+ 細胞的總數增加約4-5倍（第6圖）。
表43 藉由實施例1.2 OKT3或BsAb誘發PBMC分化為CD3+ ／CD8+ 細胞
為確認分化的T細胞是否確實已攜帶實施例1.2 BsAb，可利用FITC接合的山羊抗-人類Fab抗體藉由流式細胞儀分析該些增生的T細胞表面的抗-抗原片段（例如抗-PSMA及抗-CD3）。實驗結果繪示於第7圖。
第7圖的實驗數據確認，藉由表面攜帶實施例1.2 BsAb的抗-PSMA之片段的作用，與實施例1.2 BsAb培養14天後的PBMC成功地分化為PSMA專一性的T細胞。
實施例3 實施例2之T細胞對癌細胞的功效
3.1 實施例2之T細胞的細胞毒性功效
利用CytoTox 96® 非放射性細胞毒性分析套組（Promega，G1780），並依據該廠商的使用操作說明來評估分別藉由鼠類OKT3及實施例1.2 BsAb分化的CD3+ ／CD8+ T細胞在LNCaP（PSMA+ ）細胞中的癌細胞殺害功效。實驗結果總結在表44及第8圖中。
發明人發現在不同的效應細胞：標的細胞比例（E／T比例）：3:1、5:1及10:1下，藉由鼠類OKT3誘發的CD3+ ／CD8+ T細胞分別殺害約8.4％、11.6％及19.3％的LNCaP細胞；而在相同的E／T比例下，攜帶抗-PSMA Fab／抗-CD3 scFv BsAb的T細胞殺害約65％、87％及97％的LNCaP細胞。類似的改進細胞毒性效應亦發現在攜帶抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv及抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb的T細胞上（第8圖）。
攝影分析進一步顯示，當一接觸腫瘤細胞，大量的實施例2之T細胞（或攜帶實施例1抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv或抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb的T細胞）專一結合在LNCaP細胞表面，然而藉由鼠類OKT3分化的T細胞甚至在作用8小時後大部分仍未結合（第9圖）。
表44 分別藉由鼠類OKT3及實施例1.2 BsAb分化的T細胞之細胞毒性效應
3.2 確認實施例2之T細胞的癌細胞殺害功效
為進一步分析實施例2之T細胞（攜帶實施例1 BsAb的CD3+ ／CD8+ T細胞）所展現的癌細胞殺害功效，收集該些T細胞所分泌的細胞激素並利用ELSA進行分析，而實驗結果指出IL-2、INF-γ、TNF-α、顆粒酶B及穿孔素的量全部皆顯著高於藉由鼠類OKT3分化的T細胞所分泌的細胞激素（第10圖）。
3.3 經修飾的實施例2之T細胞（進一步經實施例1.2 BsAb修飾）可增強癌細胞殺害功效
在此實施例中，進一步將實施例1.2 BsAb以E／T為3：1、5：1及10：1的比例加入培養實施例2之T細胞的培養液中，並培養18小時，接著將該混合物加至PSMA+ 癌細胞（即LNCaP細胞）。藉由實施例3.1中所述之細胞毒性分析來評估癌細胞殺害功效，且藉由ELISA分析收集自LNCaP細胞的上清液中細胞激素量。實驗結果繪示於第11及12圖。
如第11圖所示，經修飾的實施例2之T細胞（進一步經實施例1.2 BsAb修飾）可展現更高的細胞殺害功效，在E／T比例為10：1時具有超過90％的殺害功效，而藉由鼠類OKT3分化的T細胞在相同的E／T比例下僅有約20％的量。如意料中的，各別的細胞激素（包括IL-2、INF-γ、TNF-α、顆粒酶B及穿孔素）量亦更高於控制組細胞（即藉由鼠類OKT3分化的T細胞）的細胞激素量（第12圖）。
3.4 攜帶實施例1抗-CD3／抗-PD-L1 BsAb的T細胞對惡性胰臟癌或三陰性乳癌（TNBC）的功效
惡性胰臟癌及三陰性乳癌（TNBC）二者皆以高死亡率及極低治癒率著稱。在此實施例中，利用惡性胰臟癌細胞株MIA PaCa-2及TNBC細胞株MDA-MB-231來測試攜帶實施例1.2抗-CD3／抗-PD-L1 BsAb的T細胞對該二種惡性癌症的效應。
在惡性胰臟癌細胞中，相較於控制組T細胞（即藉由鼠類OKT3誘發分化的T細胞）的細胞毒性效應，攜帶實施例1.2抗-CD3／抗-PD-L1 BsAb的T細胞的可展現更高的細胞毒性效應，且若該T細胞進一步以實施例1.2抗-CD3／抗-PD-L1 BsAb修飾後，其殺害功效增強更多。攜帶實施例1.2抗-CD3／抗-PD-L1 BsAb的T細胞對TNBC細胞的癌症殺害功效甚至更為顯著，甚至在3:1的低E／T比例時，仍具有近乎100％的殺害功效；而控制組T細胞在相同比例時僅展現10％的 殺害功效（第13圖）。
攝影分析顯示，藉由鼠類OKT3分化的T細胞大部分未結合MIA PaCa-2及MDA-MB-231細胞二者，而大量的MIA PaCa-2及MDA-MB-231細胞在與進一步以實施例1.2抗-CD3／抗-PD-L1 BsAb修飾的T細胞作用後呈現出細胞凋亡徵象（第14A及14B圖）。
3.5 殘留在T細胞表面的BsAb量的時間效應
將實施例1.2抗-PSMA／抗-CD3 BsAb與血清作用不同時間（即0、24、48及72小時），並利用流式細胞分析來評估殘留在T細胞表面的BsAb的殘留量。實驗結果繪示於第15圖。
T細胞表面的BsAb量隨著時間遞減，在四種類型或結構的BsAb中，抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb受降解影響程度最低，在72小時後約47％的BsAb仍殘留在T細胞表面，而殘留在T細胞表面的抗-PSMA scFv／抗-CD3 scFv量驟降至15％的低量。
實施例4 經實施例1.2 BsAb修飾的鼠類OKT3 T細胞的效應
如在實施例1至4中所提供的發現結果，鼠類OKT3分化的T細胞在癌症殺害功效方面並非如實施例2之T細胞（即攜帶實施例1 BsAb的T細胞）一樣有效，係導因於其對癌細胞的低結合親和力及低細胞激素分泌量。因此，在此實施例中，將鼠類OKT3 T細胞藉由與實施例1.2 BsAb共同作用來進行修飾，接著評估其對癌細胞的細胞毒性效應。
4.1 經實施例1.2 BsAb修飾的鼠類OKT3 T細胞
為將鼠類OKT3 T細胞進行修飾，將約3×105 個鼠類OKT3 T細胞與不同數量（8、24、120、600及3,000奈克）的實施例1.2抗-PSMA／抗-CD3 BsAb混和並利用流式細胞分析進行分析。實驗結果指出，約600奈克的實施例1.2 BsAb足以將實施例1.2 BsAb覆蓋於鼠類OKT3 T細胞表面（實驗數據未顯示）。
4.2 經實施例1.2 BsAb修飾的鼠類OKT3 T細胞對PSMA+ 細胞的效應
如意料中的，相較於修飾前，經實施例1 BsAb（包括抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv及抗-CD3球狀凸起／抗-PSMA孔狀凹陷）修飾的鼠類OKT3分化的T細胞對於LNCaP細胞（PSMA+ ）的癌細胞殺害能力顯著增加。其中，在E／T比例為10:1時，經抗-PSMA Fab／抗-CD3 scFv修飾的鼠類OKT3 T細胞可展現近乎100％的細胞殺害功效（第16圖）。相較於未經修飾的控制組T細胞，分泌自經實施例1.2 BsAb修飾的鼠類OKT3 T細胞的各細胞激素（包括IL-2、INF-γ、TNF-α、顆粒酶B及穿孔素）量亦顯著增加（第17圖）。
攝影分析顯示，相較於未經修飾的OKT3 T細胞，經抗-PSMA Fab／抗-CD3 scFv、抗-CD3 Fab／抗-PSMA scFv、抗-PSMA scFv／抗-CD3 scFv或抗-CD3球狀凸起／抗-PSMA孔狀凹陷BsAb修飾的鼠類OKT3 T細胞更專一結合LNCaP細胞表面（第18圖）。
4.3 經實施例1.2 BsAb修飾的鼠類OKT3 T細胞對EGFR+ 細胞的效應
在此實施例中，將鼠類OKT3 T細胞以實施例1.2抗-EGFR Fab／抗-CD3 scFv BsAb進行修飾，並進行分析來評估其殺害EGFR+ 癌細胞（即HT29 細胞）的能力。
類似於實施例5.1的發現結果，經實施例1.2抗-EGFR Fab／抗-CD3 scFv BsAb修飾後，鼠類OKT3 T細胞可展現增強的細胞毒性功效，在E／T比例為10：1時具有約50％的細胞殺害功效（第19A圖），以及具有增加的細胞激素（INF-γ、TNF-α、顆粒酶B及穿孔素）量（第19B圖）。
攝影分析顯示，相較於未經修飾的OKT3 T細胞，經抗-EGFR Fab／抗-CD3 scFv BsAb修飾的鼠類OKT3 T細胞更專一結合HT29細胞表面（第20圖）。
4.4 經實施例1.2 BsAb修飾的鼠類OKT3 T細胞對PD-L1+ 細胞的效應
在此實施例中，將鼠類OKT3 T細胞以實施例1.2抗-CD3 Fab／抗-PD-L1 scFv BsAb進行修飾，並進行分析來評估其殺害PD-L1+ 癌細胞（即LNCaP細胞）的能力。
類似於實施例5.1及5.2的發現結果，經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾後，鼠類OKT3 T細胞可展現增強的細胞毒性功效，在E／T比例為10：1時具有約92％的細胞殺害功效（第21A圖），以及具有增加的細胞激素（INF-γ、TNF-α、顆粒酶B及穿孔素）量（第21B圖）。
攝影分析顯示，相較於未經修飾的OKT3 T細胞，經抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾的鼠類OKT3 T細胞更專一結合LNCaP細胞表面（第22圖）。
4.5 經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾的鼠類OKT3 T細胞對惡性胰臟癌細胞及TNBC細胞的效應
在此實施例中，依據實施例3.4所述之類似步驟來測試經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾的鼠類OKT3 T細胞對惡性胰臟癌細胞株MIA PaCa-2（PD-L1+ 細胞）及TNBC細胞（MDA-MB-231細胞）的癌症殺害功效。
在惡性胰臟癌細胞中，相較於控制組T細胞（即未經修飾的鼠類OKT3 T細胞），經實施例1抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾的鼠類OKT3 T細胞可展現更高的細胞毒性功效（殺害約40％的癌細胞）。在TNBC細胞中癌症殺害功效更為顯著，甚至在3：1的低E／T比例時，仍可殺害近乎80％的癌細胞；而該控制組T細胞在相同比例時僅展現20-30％的殺害功效（第23圖）。
攝影分析顯示，相較於未經修飾的OKT3 T細胞，經抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾的鼠類OKT3 T細胞專一結合MIA PaCa-2細胞（第24A圖）及MDA-MB-231細胞（第24B圖）表面，並增強癌細胞的細胞凋亡。
實施例5 經實施例1 BsAb修飾的鼠類OKT3 T細胞的活體內效應
為探討實施例1 BsAb是否可改進鼠類OKT3 T細胞的標定功效（targeting effect），將鼠類OKT3 T細胞以實施例1.2抗-EGFR／抗-CD3 BsAb進行修飾同時，一併進行螢光指示劑-NIR797標記。接著，將該修飾及標記的鼠類OKT3 T細胞以IV注射方式注射至帶有異質的EGFR+ 腫瘤（HT29細胞）之SCID小鼠體內，並分別在第4及24小時利用IVIS攝影系統進行活體攝影。24小時後犧牲該動物，並採集腫瘤本身及包括心臟、肺臟、腎臟、脾臟、肝臟、胃、肌肉、骨骼、大腸、小腸、胰臟、及血液等器官，分別利用IVIS攝影系統進行分析。實驗結果繪示於第25及26圖。
第25圖的影像顯示，相較於以未經修飾的鼠類OKT3 T細胞處理的動物，以經修飾的OKT3 T細胞處理的動物體內發現螢光強度主要集中在腫瘤位點。該實驗結果確認以實施例1 BsAb修飾的鼠類OKT3 T細胞確實標定至該腫瘤，因而增強在腫瘤位點的螢光強度。
此外，發現經修飾的T細胞除集中在EGFR+ 腫瘤本身之外，其餘在活體內分布情形類似於該些經修飾的T細胞在普通健康動物體內的分布情形（第26圖）。
此外，當以經修飾的鼠類OKT3 T細胞處理後，腫瘤體積大小及其重量受到顯著抑制（第27圖之圖A及C），而該動物的體重在25天的治療時程內僅有輕微減少（第27圖之圖B）。
將採集自動物的腫瘤進一步利用免疫組織化學（IHC）染色及H&E染色進行分析，其實驗結果如第28圖所示。發現經修飾的鼠類OKT3 T細胞主要集中在腫瘤的附近區域。
實施例6 實施例2之T細胞及實施例4經修飾的鼠類OKT3細胞的比較性研究
在此實施例中，比較藉由實施例1.2 BsAb（即抗-PSMA Fab／抗-CD3 scFv及抗-PSMA scFv／抗-CD3 scFv）及鼠類OKT3所誘發的T細胞分化及增生。實驗結果繪示於第29至32圖。
如第29A圖所示，實施例1.2 BsAb的（即抗-PSMA Fab／抗-CD3 scFv及抗-PSMA scFv／抗-CD3 scFv）及鼠類OKT3二者皆能夠誘發PBMC分化為CD3+ 細胞，且超過95％的細胞成為CD3+ 細胞。至於CD4+ 細胞部分，實施例1.2 BsAb（即抗-PSMA Fab／抗-CD3 scFv及抗-PSMA scFv／抗-CD3 scFv）較鼠類OKT3更可有效誘發PBMC分化為CD4+ T細胞，以實施例1.2 BsAb處理後，有超過90％的PBMC分化為CD4+ 細胞，而鼠類OKT3處理後，僅有約75％的PBMC轉變成CD4+ 細胞。進一步地，藉由實施例1.2 BsAb誘發的T細胞增生比例，亦高於藉由鼠類OKT3 T細胞誘發的T細胞增生比例（第29B圖）。利用流式細胞分析進一步確認類似於藉由鼠類OKT3抗體誘發的T細胞，該抗體出現在OKT3 T細胞表面；二種實施例1.2 BsAb各自所攜帶的抗體片段亦出現在其所誘發的T細胞表面（第30圖）。
鼠類OKT3 T細胞及實施例2之T細胞對細胞毒性的比較性研究提供於第31圖。如圖所示，OKT3 T細胞能夠殺害PSMA+ 細胞（LNCaP細胞），而實施例2之T細胞（或藉由實施例1 BsAb誘發的T細胞）展現至少50％的細胞毒性，且若其進一步以實施例1.2 BsAb修飾，則該T細胞的細胞毒性將會進一步增加。舉例來說，藉由抗-CD3 Fab／抗-PSMA scFv分化的T細胞，在E／T比例為5：1及10：1時，其細胞毒性分別約51.32％及60.97％；若進一步以抗-CD3 Fab／抗-PSMA scFv修飾後，在E／T比例為5：1及10：1時，其細胞毒性增加至約78.15％及81.75％。類似的觀察亦發現在藉由抗-PSMA scFv／抗-CD3 scFv誘發的T細胞中。
實施例7 藉由實施例1.2 BsAb進行一步法分化及增生調控型T細胞
在此實施例中，藉由實施例1.2 BsAb誘發及生成調控型T細胞。簡單來說，自健康人類個體分離PBMC並將其與實施例1.2抗-CD3 Fab／抗-PSMA scFv或抗-PSMA scFv／的抗-CD3 scFv培養7天，在任一情形下，該培養液亦包含IL-2、TGF-β及抗-CD28抗體。接著，採集分化的T細胞並利用流式細胞分析進行分析。實驗結果繪示於第32圖。
實驗數據指出，抗-CD3 Fab／抗-PSMA scFv BsAb及抗-PSMA scFv／抗-CD3 scFv可分別誘發約19.3％（第32圖之圖A）及7.2％的（第32圖之圖B）的CD4+ FoxP3+ 調控型T細胞的形成。
雖然上文實施方式中揭露本揭示內容的具體實施例，本發明所屬技術領域中具有通常知識者當可對其進行各種更動與修飾。上文的說明書、實施例及實驗數據對本揭示內容作為例示性實施方式中的結構及使用方式做出完整的描述。儘管上文已描述本揭示內容中各種實施方式有一定程度的特性，或參照一或多個各別實施方式，本發明所屬領域技術具有通常知識者仍能在不悖離本揭示內容精神及範圍情形下，對已揭示的實施方式進行眾多修改。
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在參閱以下的詳細說明、申請專利範圍及附隨圖式後，本揭示內容及其他特徵、態樣及優點將更明顯易懂，其中：
第1圖為本揭示內容BsAb的結構示意圖：（A）抗-抗原Fab／抗-CD3 scFv、（B）抗-CD3 Fab／抗-抗原scFv、（C）抗-CD3 scFv／抗-抗原scFv及（D）抗-CD3球狀凸起（knob）／抗-抗原孔狀凹陷（hole）；
第2A圖為以具抗原專一性T細胞來治療一個體的示意圖，其中係藉由本揭示內容BsAb以一步法擴增、分化及／或修飾來製備該T細胞；
第2B圖為以鼠類OKT3 T細胞來治療一個體的示意圖，其中係藉由本揭示內容BsAb以一步法修飾來製備該T細胞；
第3圖為用以表現本揭示內容BsAb之DNA構築載體的示意圖；
第4圖闡述實施例1.2 BsAb在非還原條件（左欄）及還原條件下（右欄）以SDS-PAGE分析的結果；
第5圖闡述實施例1.2 BsAb以流式細胞分析的結果；
第6圖闡述藉由本揭示內容實施例2之鼠類OKT3抗體及BsAb來誘發T細胞分化及增生的結果；
第7圖為依據本揭示內容一實施方式所繪示之流式細胞分析結果，其係關於增生T細胞的表面抗-抗原片段；
第8圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及實施例2之T細胞於前列腺癌細胞株LNCaP的細胞毒性作用；
第9圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及實施例2之T細胞分別結合腫瘤細胞的結果；
第10圖為依據本揭示內容一實施方式所繪示之細胞激素量的長條圖，其係關於在不同效應細胞：標的細胞比例（E／T比例）下，鼠類OKT3 T細胞及實施例2之T細胞分別分泌細胞激素量的結果；
第11圖為依據本揭示內容一實施方式所繪示之細胞毒性分析折線圖，其係關於在不同E／T比例下，鼠類OKT3 T細胞及經修飾的實施例2之T細胞（進一步經實施例1.2 BsAb修飾）於LNCaP細胞的細胞毒性分析結果；
第12圖為依據本揭示內容一實施方式所繪示之細胞激素量的長條圖，其係關於在不同E／T比例下，鼠類OKT3 T細胞及經修飾的實施例2之T細胞（進一步經實施例1.2 BsAb修飾）分別分泌細胞激素量的結果；
第13圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞、實施例2之T細胞或經修飾的實施例2之T細胞（進一步經抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾）於惡性胰臟癌細胞株MIA PaCa-2及三陰性乳癌（TNBC）細胞株MDA-MB-231的細胞毒性作用；
第14A圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及實施例2之T細胞分別結合MIA PaCa-2細胞的結果；
第14B圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及實施例2之T細胞分別結合MDA-MB-231細胞的結果；
第15圖為依據本揭示內容一實施方式所繪示之結果，其係關於實施例1.2 BsAb在T細胞表面的殘留量之時程變化；
第16圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2 BsAb修飾）於前列腺癌細胞株LNCaP的細胞毒性作用；
第17圖為依據本揭示內容一實施方式所繪示之細胞激素量的長條圖，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1 BsAb修飾）分別分泌細胞激素量的結果；
第18圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2 BsAb修飾）分別結合前列腺腫瘤細胞（LNCaP細胞）的結果；
第19A圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）於HT29細胞的細胞毒性作用；
第19B圖為依據本揭示內容一實施方式所繪示之細胞激素量的長條圖，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1抗-EGFR Fab／抗-CD3 scFv修飾）分別分泌細胞激素量的結果；
第20圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）分別結合HT29細胞的結果；
第21A圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾）於LNCaP細胞的細胞毒性作用；
第21B圖為依據本揭示內容一實施方式所繪示之細胞激素量的長條圖，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾）分別分泌細胞激素量的結果；
第22圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾）分別結合LNCaP細胞的結果；
第23圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經抗-CD3 Fab／抗-PD-L1 scFv BsAb修飾）於惡性胰臟癌細胞株MIA PaCa-2及三陰性乳癌（TNBC）細胞株MDA-MB-231的細胞毒性作用；
第24A圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾）分別結合MIA PaCa-2細胞的結果；
第24B圖為依據本揭示內容一實施方式所得之影像，其係關於鼠類OKT3 T細胞及經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-CD3 Fab／抗-PD-L1 scFv修飾）分別結合MDA-MB-231細胞的結果；
第25圖為依據本揭示內容一實施方式所得之活體內結果，其係關於將鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）投予動物體內並定量螢光強度的結果；
第26圖為依據本揭示內容一實施方式所繪示之活體內結果，其係關於鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（進一步經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）於受試動物體內不同器官的分布情形；
第27A圖為依據本揭示內容一實施方式所繪示之腫瘤體積大小變化的折線圖，其係關於以實施例1.2 BsAb、鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）治療腫瘤並記錄腫瘤體積大小變化的結果；
第27B圖為依據本揭示內容一實施方式所繪示之體重變化的折線圖，其係關於將實施例1.2 BsAb、鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）投予受試動物並記錄體重變化的結果；
第27C圖為依據本揭示內容一實施方式所得之腫瘤重量的結果，其係關於以實施例1.2 BsAb、鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）治療腫瘤並記錄腫瘤重量的變化；
第28圖為依據本揭示內容一實施方式所得之影像，其係關於以實施例1.2 BsAb、鼠類OKT3 T細胞或經修飾的鼠類OKT3 T細胞（經實施例1.2抗-EGFR Fab／抗-CD3 scFv修飾）治療腫瘤後的免疫組織化學（immunohistochemical，IHC） 染色及H&E染色結果；
第29A圖為依據本揭示內容一實施方式所繪示之流式細胞分析結果，其係關於利用流式細胞分析分析藉由鼠類OKT3、及抗-PSMA Fab／抗-CD3 scFv或抗-PSMA scFv／抗-CD3 scFv分化的T細胞；
第29B圖為依據本揭示內容一實施方式所繪示之式細胞分析結果，其係關於藉由鼠類OKT3、及抗-CD3 Fab／抗-PSMA scFv或抗-PSMA scFv／抗-CD3 scFv分別分化的T細胞增生結果；
第30圖為依據本揭示內容一實施方式所繪示之流式細胞分析結果，其係關於利用流式細胞分析分析OKT3 T細胞，或攜帶抗-CD3 Fab／抗-PSMA scFv或抗-PSMA scFv／抗-CD3 scFv的T細胞所攜帶的二種類型抗體片段結果；
第31圖為依據本揭示內容一實施方式所繪示之細胞毒性分析結果，其係關於鼠類OKT3 T細胞及實施例2之T細胞分別於LNCaP細胞的細胞毒性作用；以及
第32圖為依據本揭示內容一實施方式所繪示之流式細胞分析結果，其係關於藉由抗-CD3 Fab／抗-PSMA scFv及抗-PSMA scFv／抗-CD3 scFv BsAb來誘發CD4+ FoxP3+ 調控型T細胞結果。
序列表

<110> 臺北醫學大學

<120> 具抗原專一性的T細胞及其用途

<150> US62/478,280
<151> 2017-03-29

<160> 143

<170> BiSSAP 1.3.6

<210> 1
<211> 63
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 1
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60

gac 63


<210> 2
<211> 645
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 2
gacatcgtga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagagtgacc 60

atcacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactgg gccagcacca gacacaccgg cgtgcccgac 180

agattcaccg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccgactactt ctgccagcag tacaacagct accccctgac cttcggcggc 300

ggcaccaagc tggagatcaa gagaactgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa ctctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gctga 645


<210> 3
<211> 585
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 3
gcccctctcc ctcccccccc cctaacgtta ctggccgaag ccgcttggaa taaggccggt 60

gtgcgtttgt ctatatgtta ttttccacca tattgccgtc ttttggcaat gtgagggccc 120

ggaaacctgg ccctgtcttc ttgacgagca ttcctagggg tctttcccct ctcgccaaag 180

gaatgcaagg tctgttgaat gtcgtgaagg aagcagttcc tctggaagct tcttgaagac 240

aaacaacgtc tgtagcgacc ctttgcaggc agcggaaccc cccacctggc gacaggtgcc 300

tctgcggcca aaagccacgt gtataagata cacctgcaaa ggcggcacaa ccccagtgcc 360

acgttgtgag ttggatagtt gtggaaagag tcaaatggct ctcctcaagc gtattcaaca 420

aggggctgaa ggatgcccag aaggtacccc attgtatggg atctgatctg gggcctcggt 480

gcacatgctt tacatgtgtt tagtcgaggt taaaaaaacg tctaggcccc ccgaaccacg 540

gggacgtggt tttcctttga aaaacacgat gataatatgg ccaca 585


<210> 4
<211> 660
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 4
gaggtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcgccag cgtgaagatc 60

agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120

agcggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180

aaccagaagt tcgaggacag agccaccctg accgtggaca agagcaccag caccgcctac 240

atggagctga gcagcctgag aagcgaggac accgccgtgt actactgcgc cgccggctgg 300

aacttcgact actggggcca gggcaccacc gtgaccgtga gcagcgcctc caccaagggc 360

ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480

ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540

agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600

aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660


<210> 5
<211> 774
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 5
ggtggcggct caggtggagg cgacatcaag ctgcagcaga gcggcgccga gctggccaga 60

cccggcgcca gcgtgaagat gagctgcaag accagcggct acaccttcac cagatacacc 120

atgcactggg tgaagcagag acccggccag ggcctggagt ggatcggcta catcaacccc 180

agcagaggct acaccaacta caaccagaag ttcaaggaca aggccaccct gaccaccgac 240

aagagcagca gcaccgccta catgcagctg agcagcctga ccagcgagga cagcgccgtg 300

tactactgcg ccagatacta cgacgaccac tactgcctgg actactgggg ccagggcacc 360

accctgaccg tgagcagcgt ggagggcggc agcggcggca gcggcggcag cggcggcagc 420

ggcggcgtgg acgacatcca gctgacccag agccccgcca tcatgagcgc cagccccggc 480

gagaaggtga ccatgacctg cagagccagc agcagcgtga gctacatgaa ctggtaccag 540

cagaagagcg gcaccagccc caagagatgg atctacgaca ccagcaaggt ggccagcggc 600

gtgccctaca gattcagcgg cagcggcagc ggcaccagct acagcctgac catcagcagc 660

atggaggccg aggacgccgc cacctactac tgccagcagt ggagcagcaa ccccctgacc 720

ttcggcgctg gcaccaagct ggagctgaag agacaccacc accaccacca ctga 774


<210> 6
<211> 642
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 6
gacatccagc tgacccagag ccccgccatc atgagcgcca gccccggcga gaaggtgacc 60

atgacctgca gagccagcag cagcgtgagc tacatgaact ggtaccagca gaagagcggc 120

accagcccca agagatggat ctacgacacc agcaaggtgg ccagcggcgt gccctacaga 180

ttcagcggca gcggcagcgg caccagctac agcctgacca tcagcagcat ggaggccgag 240

gacgccgcca cctactactg ccagcagtgg agcagcaacc ccctgacctt cggcgctggc 300

accaagctgg agctgaagag aactgtggct gcaccatctg tcttcatctt cccgccatct 360

gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420

agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480

agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540

agcaaagcag actacgagaa acacaaactc tacgcctgcg aagtcaccca tcagggcctg 600

agctcgcccg tcacaaagag cttcaacagg ggagagtgct ga 642


<210> 7
<211> 651
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 7
gacatcaagc tgcagcagag cggcgccgag ctggccagac ccggcgccag cgtgaagatg 60

agctgcaaga ccagcggcta caccttcacc agatacacca tgcactgggt gaagcagaga 120

cccggccagg gcctggagtg gatcggctac atcaacccca gcagaggcta caccaactac 180

aaccagaagt tcaaggacaa ggccaccctg accaccgaca agagcagcag caccgcctac 240

atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc cagatactac 300

gacgaccact actgcctgga ctactggggc cagggcacca ccctgaccgt gagcagcgcc 360

tccaccaaag gtccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480

aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 600

acctgcaacg tagatcacaa gcccagtaac accaaggtgg acaagacagt t 651


<210> 8
<211> 759
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 8
ggcggcggca gcggcggcgg cgaggtgcag ctggtgcaga gcggcgccga ggtgaagaag 60

cccggcgcca gcgtgaagat cagctgcaag accagcggct acaccttcac cgagtacacc 120

atccactggg tgaagcaggc cagcggcaag ggcctggagt ggatcggcaa catcaacccc 180

aacaacggcg gcaccaccta caaccagaag ttcgaggaca gagccaccct gaccgtggac 240

aagagcacca gcaccgccta catggagctg agcagcctga gaagcgagga caccgccgtg 300

tactactgcg ccgccggctg gaacttcgac tactggggcc agggcaccac cgtgaccgtg 360

agcagcgccg gtggaggcgg ttcaggcgga ggtggctctg gcggtggcgg atcggacatc 420

gtgatgaccc agagccccag cagcctgagc gccagcgtgg gcgacagagt gaccatcacc 480

tgcaaggcca gccaggacgt gggcaccgcc gtggactggt accagcagaa gcccggcaag 540

gcccccaagc tgctgatcta ctgggccagc accagacaca ccggcgtgcc cgacagattc 600

accggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgca gcccgaggac 660

ttcgccgact acttctgcca gcagtacaac agctaccccc tgaccttcgg cggcggcacc 720

aagctggaga tcaagagaca ccaccaccac caccactga 759


<210> 9
<211> 717
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 9
gacatcgtga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagagtgacc 60

atcacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactgg gccagcacca gacacaccgg cgtgcccgac 180

agattcaccg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccgactactt ctgccagcag tacaacagct accccctgac cttcggcggc 300

ggcaccaagc tggagatcaa gagaggtgga ggcggttcag gcggaggtgg ctctggcggt 360

ggcggatcgg aggtgcagct ggtgcagagc ggcgccgagg tgaagaagcc cggcgccagc 420

gtgaagatca gctgcaagac cagcggctac accttcaccg agtacaccat ccactgggtg 480

aagcaggcca gcggcaaggg cctggagtgg attggcaaca tcaaccccaa caacggcggc 540

accacctaca accagaagtt cgaggacaga gccaccctga ccgtggacaa gagcaccagc 600

accgcctaca tggagctgag cagcctgaga agcgaggaca ccgccgtgta ctactgcgcc 660

gctggctgga acttcgacta ctggggccag ggcaccaccg tgaccgtgag cagcgcc 717


<210> 10
<211> 672
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 10
gacatccagc tgacccagag cccagcaatc atgtctgcca gcccaggaga gaaggtgacc 60

atgacatgcc gggccagcag cagcgtgagc tacatgaact ggtatcagcg gaagagcggc 120

acctccccta agagatggat ctacgacaca tctaaggtgg ccagcggcgt gccatatagg 180

ttctccggct ctggcagcgg cacctcctac tctctgacaa tcagctccat ggaggccgag 240

gatgccgcca cctactattg ccagcagtgg tctagcaatc ccctgacctt tggcgccggc 300

acaaagctgg agctgaagag gaccgtggca gcacctagcg tgttcatctt tcccccttcc 360

gacgagcagc tgaagtccgg cacagcctct gtggtgtgcc tgctgaacaa tttctatcca 420

cgcgaggcca aggtgcagtg gaaggtggat aacgccctgc agtctggcaa tagccaggag 480

tccgtgaccg agcaggactc taaggatagc acatactccc tgtcctctac cctgacactg 540

agcaaggccg attacgagaa gcacaagctg tatgcatgcg aggtgaccca ccagggcctg 600

agctccccag tgacaaagtc ttttaaccgg ggcgagtgtg gcggcggctc ccaccaccac 660

caccaccact ga 672


<210> 11
<211> 1350
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 11
gacatcaagc tgcagcagag cggagcagag ctggccaggc ccggagcctc tgtgaagatg 60

agctgcaaga cctccggcta caccttcaca cggtatacaa tgcactgggt gaagtacaga 120

cctggccagg gcctggagtg gatcggctat atcaacccat cccgcggcta caccaactat 180

aatcagaagt ttaaggacaa ggccaccctg accacagata agagctcctc tacagcctac 240

atgcagctga gctccctgac ctctgaggac agcgccgtgt actattgcgc ccggtactat 300

gacgatcact actgtctgga ttattggggc cagggcacca cactgaccgt gtctagcgcc 360

tctacaaagg gacctagcgt gttcccactg gcaccctcct ctaagtccac ctctggagga 420

acagccgccc tgggatgcct ggtgaaggat tacttcccag agcccgtgac cgtgtcctgg 480

aactctggcg ccctgaccag cggagtgcac acatttcctg ccgtgctgca gagctccggc 540

ctgtactccc tgtctagcgt ggtgacagtg ccatcctcta gcctgggcac ccagacatat 600

atctgcaacg tgaatcacaa gccaagcaat accaaggtcg acaagaaggt ggagcccaag 660

tcctgtgata agacccacac atgcccccct tgtcctgcac cagagctgct gggaggacca 720

agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctctcg gaccccagag 780

gtgacatgcg tggtggtgga cgtgagccac gaggatcccg aggtgaagtt taactggtac 840

gtggatggcg tggaggtgca caatgccaag accaagccca gggaggagca gtacaattcc 900

acctatcgcg tggtgtctgt gctgacagtg ctgcaccagg actggctgaa cggcaaggag 960

tataagtgca aggtgtccaa taaggccctg cccgccccta tcgagaagac aatctctaag 1020

gcaaagggac agcctcggga gccacaggtg tacaccctgc ctccatccag agatgagctg 1080

accaagaacc aggtgtctct gacatgtctg gtgaagggct tctatccctc tgacatcgcc 1140

gtggagtggg agagcaatgg ccagcctgag aacaattacg ataccacacc ccctgtgctg 1200

gacagcgatg gctccttctt tctgtatagc gacctgacag tggataagtc cagatggcag 1260

cagggcaacg tgtttagctg ttccgtgatg cacgaggccc tgcacaatca ctacacccag 1320

aagtctctga gcctgtcccc cggcaagtaa 1350


<210> 12
<211> 684
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 12
aggatcgtga tgacccagtc tcctagctcc ctgagcgcct ccgtgggcga ccgcgtgacc 60

atcacatgca aggccagcca ggatgtggga accgcagtgg actggtacca ggataagcca 120

ggcaaggccc ccaagctgct gatctattgg gcctccacca ggcacacagg agtgccagac 180

agattcaccg gctctggcag cggcacagac ttcaccctga caatctctag cctgcagccc 240

gaggacttcg ccgattactt ttgccagcag tacaacagct atcctctgac cttcggcggc 300

ggcacaaagc tggagatcaa gaggaccgtg gcagcaccat ccgtgttcat ctttccccct 360

tctgacgagc agctgaagtc tggcacagcc agcgtggtgt gctacctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gataacgccc tgcagtccgg caattctcag 480

gagagcgtga ccgagcagga ctccaaggat tctacataca gcctgtggtc caccctgaca 540

ctgtccaagg ccgactacga gaagcacaag ctgtatgcat gcgaggtgac ccaccagggc 600

ctgtcctctc ccgtgacaaa gagcttcaat aggggagagt gtggaggagg atcctaccct 660

tatgacgtgc cagattatgc ctaa 684


<210> 13
<211> 1338
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 13
gaggtgcagc tggtgcagtc cggagcagag gtgaagaagc ctggagcctc tgtgaagatc 60

agctgcaaga cctccggcta caccttcaca gagtatacaa tccactgggt gaagaaggcc 120

agcggcaagg gcctggagtg gatcggcaac atcaatccaa acaatggcgg caccacatac 180

aaccaggagt ttgaggaccg ggccaccctg acagtggata agtccacctc tacagcctat 240

atggagctga gctccctgag atccgaggac accgccgtgt actattgcgc cgccggctgg 300

aatttcgatt actggggcca gggcaccaca gtgaccgtgt ctagcgcctc tacaaaggga 360

ccaagcgtgt ttccactggc accctcctct aagagcacct ccggaggaac agccgccctg 420

ggctgtctgg tgaaggacta tttcccagag cccgtgaccg tgtcctggaa ctctggcgcc 480

ctgacctccg gagtggcaac aggaccagcc gtgctgcaga gctccggcct gtacagcctg 540

tctagcgtgg tgaccgtgcc ctcctctagc ctgggcaccc agacatatat ctgcaacgtg 600

aatcacaagc caagcaatac aaaggtcgac aagaaggtgg agcccaagtc ctgtgataag 660

acccacacat gccccccttg tcctgcacca gagctgctgg gaggaccaag cgtgttcctg 720

tttccaccca agcctaagga caccctgatg atctctagga cccccgaggt gacatgcgtg 780

gtggtggacg tgagccacga ggatcctgag gtgaagttta actggtacgt ggatggcgtg 840

gaggtgcaca atgccaagac caagccccgg gaggagcagt acaactccac ctatagagtg 900

gtgtctgtgc tgacagtgct gcaccaggac tggctgaacg gcaaggagta taagtgcaag 960

gtgtccaata aggccctgcc cgcccctatc gagaagacca tctctaaggc caagggccag 1020

cctagggagc cacaggtgta cacactgcct ccatcccgca aggagctgac caagaaccag 1080

gtgtctctga catgtctggt gaagggcttc tatccttctg atatcgccgt ggagtgggag 1140

agcaatggcc agccagagaa caattacaag accacacccc ctgtgctgaa gagcgacggc 1200

tccttctttc tgtatagcaa gctgaccgtg gataagtcca gatggcagca gggcaacgtg 1260

ttttcttgta gcgtgatgca cgaggccctg cacaatcact acacacagaa gtccctgtct 1320

ctgagccctg gcaagtaa 1338


<210> 14
<211> 645
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 14
gatattctgc tgacccagag cccggttatt ctgagcgtta gcccgggtga acgtgttagc 60

tttagctgtc gtgcaagcca gagcattggt accaatattc attggtatca gcagcgtacc 120

aatggtagcc cgcgtctgct gattaaatat gcaagcgaaa gcattagcgg tattccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga gcattaatag cgttgaaagc 240

gaagatattg cagattatta ttgtcagcag aataataatt ggccgaccac ctttggtgca 300

ggtaccaaac tggaactgaa acgtactgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa ctctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gctga 645


<210> 15
<211> 672
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 15
caggttcagc tgaaacagag cggtccgggt ctggttcagc cgagccagag cctgagcatt 60

acctgtaccg ttagcggttt tagcctgacc aattatggtg ttcattgggt tcgtcagagc 120

ccgggtaaag gtctggaatg gctgggtgtt atttggagcg gtggtaatac cgattataat 180

accccgttta ccagccgtct gagcattaat aaagataata gcaaaagcca ggtttttttt 240

aaaatgaata gcctgcagag caatgatacc gcaatttatt attgtgcacg tgcactgacc 300

tattatgatt atgaatttgc atattggggt cagggtaccc tggttaccgt tagcgcagcc 360

tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660

tcttgtgaca aa 672


<210> 16
<211> 768
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 16
ggcggcggca gcggcggcgg ccaggttcag ctgaaacaga gcggtccggg tctggttcag 60

ccgagccaga gcctgagcat tacctgtacc gttagcggtt ttagcctgac caattatggt 120

gttcattggg ttcgtcagag cccgggtaaa ggtctggaat ggctgggtgt tatttggagc 180

ggtggtaata ccgattataa taccccgttt accagccgtc tgagcattaa taaagataat 240

agcaaaagcc aggttttttt taaaatgaat agcctgcaga gcaatgatac cgcaatttat 300

tattgtgcac gtgcactgac ctattatgat tatgaatttg catattgggg tcagggtacc 360

ctggttaccg ttagcgcagg cggcggcggc agcggcggcg gcggcagcgg cggcggcggc 420

agcgatattc tgctgaccca gagcccggtt attctgagcg ttagcccggg tgaacgtgtt 480

agctttagct gtcgtgcaag ccagagcatt ggtaccaata ttcattggta tcagcagcgt 540

accaatggta gcccgcgtct gctgattaaa tatgcaagcg aaagcattag cggtattccg 600

agccgtttta gcggtagcgg tagcggtacc gattttaccc tgagcattaa tagcgttgaa 660

agcgaagata ttgcagatta ttattgtcag cagaataata attggccgac cacctttggt 720

gcaggtacca aactggaact gaaacgtcac caccaccacc accactga 768


<210> 17
<211> 726
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 17
gatattctgc tgacccagag cccggttatt ctgagcgtta gcccgggtga acgtgttagc 60

tttagctgtc gtgcaagcca gagcattggt accaatattc attggtatca gcagcgtacc 120

aatggtagcc cgcgtctgct gattaaatat gcaagcgaaa gcattagcgg tattccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga gcattaatag cgttgaaagc 240

gaagatattg cagattatta ttgtcagcag aataataatt ggccgaccac ctttggtgca 300

ggtaccaaac tggaactgaa acgtggtgga ggcggttcag gcggaggtgg ctctggcggt 360

ggcggatcgc aggttcagct gaaacagagc ggtccgggtc tggttcagcc gagccagagc 420

ctgagcatta cctgtaccgt tagcggtttt agcctgacca attatggtgt tcattgggtt 480

cgtcagagcc cgggtaaagg tctggaatgg ctgggtgtta tttggagcgg tggtaatacc 540

gattataata ccccgtttac cagccgtctg agcattaata aagataatag caaaagccag 600

gtttttttta aaatgaatag cctgcagagc aatgataccg caatttatta ttgtgcacgt 660

gcactgacct attatgatta tgaatttgca tattggggtc agggtaccct ggttaccgtt 720

agcgca 726


<210> 18
<211> 765
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 18
ggcggtggat cagacatcaa gctgcagcag agcggcgccg agctggccag acccggcgcc 60

agcgtgaaga tgagctgcaa gaccagcggc tacaccttca ccagatacac catgcactgg 120

gtgaagcaga gacccggcca gggcctggag tggatcggct acatcaaccc cagcagaggc 180

tacaccaact acaaccagaa gttcaaggac aaggccaccc tgaccaccga caagagcagc 240

agcaccgcct acatgcagct gagcagcctg accagcgagg acagcgccgt gtactactgc 300

gccagatact acgacgacca ctactgcctg gactactggg gccagggcac caccctgacc 360

gtgagcagcg tggagggcgg cagcggcggc agcggcggca gcggcggcag cggcggcgtg 420

gacgacatcc agctgaccca gagccccgcc atcatgagcg ccagccccgg cgagaaggtg 480

accatgacct gcagagccag cagcagcgtg agctacatga actggtacca gcagaagagc 540

ggcaccagcc ccaagagatg gatctacgac accagcaagg tggccagcgg cgtgccctac 600

agattcagcg gcagcggcag cggcaccagc tacagcctga ccatcagcag catggaggcc 660

gaggacgccg ccacctacta ctgccagcag tggagcagca accccctgac cttcggcgct 720

ggcaccaagc tggagctgaa gagacaccac caccaccacc actga 765


<210> 19
<211> 684
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 19
aggattctgc tgacccagag cccggttatt ctgagcgtta gcccgggtga acgtgttagc 60

tttagctgtc gtgcaagcca gagcattggt accaatattc attggtatca ggatcgtacc 120

aatggtagcc cgcgtctgct gattaaatat gcaagcgaaa gcattagcgg tattccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga gcattaatag cgttgaaagc 240

gaagatattg cagattatta ttgtcagcag aataataatt ggccgaccac ctttggtgca 300

ggtaccaaac tggaactgaa acgtaccgtg gcagcaccat ccgtgttcat ctttccccct 360

tctgacgagc agctgaagtc tggcacagcc agcgtggtgt gctacctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gataacgccc tgcagtccgg caattctcag 480

gagagcgtga ccgagcagga ctccaaggat tctacataca gcctgtggtc caccctgaca 540

ctgtccaagg ccgactacga gaagcacaag ctgtatgcat gcgaggtgac ccaccagggc 600

ctgtcctctc ccgtgacaaa gagcttcaat aggggagagt gtggaggagg atcctaccct 660

tatgacgtgc cagattatgc ctaa 684


<210> 20
<211> 1350
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 20
caggttcagc tgaaacagag cggtccgggt ctggttcagc cgagccagag cctgagcatt 60

acctgtaccg ttagcggttt tagcctgacc aattatggtg ttcattgggt tcgtaagagc 120

ccgggtaaag gtctggaatg gctgggtgtt atttggagcg gtggtaatac cgattataat 180

accgagttta ccagccgtct gagcattaat aaagataata gcaaaagcca ggtttttttt 240

aaaatgaata gcctgcagag caatgatacc gcaatttatt attgtgcacg tgcactgacc 300

tattatgatt atgaatttgc atattggggt cagggtaccc tggttaccgt tagcgcagcc 360

tctacaaagg gaccaagcgt gtttccactg gcaccctcct ctaagagcac ctccggagga 420

acagccgccc tgggctgtct ggtgaaggac tatttcccag agcccgtgac cgtgtcctgg 480

aactctggcg ccctgacctc cggagtggca acaggaccag ccgtgctgca gagctccggc 540

ctgtacagcc tgtctagcgt ggtgaccgtg ccctcctcta gcctgggcac ccagacatat 600

atctgcaacg tgaatcacaa gccaagcaat acaaaggtcg acaagaaggt ggagcccaag 660

tcctgtgata agacccacac atgcccccct tgtcctgcac cagagctgct gggaggacca 720

agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctctag gacccccgag 780

gtgacatgcg tggtggtgga cgtgagccac gaggatcctg aggtgaagtt taactggtac 840

gtggatggcg tggaggtgca caatgccaag accaagcccc gggaggagca gtacaactcc 900

acctatagag tggtgtctgt gctgacagtg ctgcaccagg actggctgaa cggcaaggag 960

tataagtgca aggtgtccaa taaggccctg cccgccccta tcgagaagac catctctaag 1020

gccaagggcc agcctaggga gccacaggtg tacacactgc ctccatcccg caaggagctg 1080

accaagaacc aggtgtctct gacatgtctg gtgaagggct tctatccttc tgatatcgcc 1140

gtggagtggg agagcaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200

aagagcgacg gctccttctt tctgtatagc aagctgaccg tggataagtc cagatggcag 1260

cagggcaacg tgttttcttg tagcgtgatg cacgaggccc tgcacaatca ctacacacag 1320

aagtccctgt ctctgagccc tggcaagtaa 1350


<210> 21
<211> 645
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 21
gatatccaga tgacccagag ccctagctcc ctgagcgcct ccgtgggcga cagggtgacc 60

atcacatgta gggcatccca ggacgtgagc accgcagtgg cctggtatca gcagaagccc 120

ggcaaggccc ctaagctgct gatctactct gccagcttcc tgtatagcgg cgtgccttcc 180

agattttccg gatctggaag cggaaccgac ttcaccctga caatctctag cctgcagcca 240

gaggattttg ccacatacta ttgccagcag tacctgtatc acccagcaac cttcggacag 300

ggcacaaaag tggaaatcaa gcggactgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa ctctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gctga 645


<210> 22
<211> 669
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 22
gaggtgcagc tggtggaaag cgggggagga ctggtgcagc ctggggggtc actgagactg 60

agttgcgccg cctccggctt caccttttcc gactcttgga tccactgggt gaggcaggca 120

ccaggcaagg gcctggagtg ggtggcctgg atctctccct acggcggcag cacctactat 180

gccgactccg tgaagggccg gtttacaatc tctgccgata ccagcaagaa cacagcctat 240

ctgcagatga attctctgag agccgaggac accgccgtgt actattgcgc acggagacac 300

tggccaggag gattcgatta ctggggacag ggcaccctgg tgacagtgtc cgccgcctcc 360

accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420

gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480

tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540

tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600

tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660

tgtgacaaa 669


<210> 23
<211> 774
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 23
gggggcggga gcgggggcgg cgaggtgcag ctggtggaaa gcgggggagg actggtgcag 60

cctggggggt cactgagact gagttgcgcc gcctccggct tcaccttttc cgactcttgg 120

atccactggg tgaggcaggc accaggcaag ggcctggagt gggtggcctg gatctctccc 180

tacggcggca gcacctacta tgccgactcc gtgaagggcc ggtttacaat ctctgccgat 240

accagcaaga acacagccta tctgcagatg aattctctga gagccgagga caccgccgtg 300

tactattgcg cacggagaca ctggccagga ggattcgatt actggggaca gggcaccctg 360

gtgacagtgt ccgccgtgga gggaggatcc ggaggatctg gaggaagcgg cggctccggc 420

ggcgtggacg atatccagat gacccagagc cctagctccc tgagcgcctc cgtgggcgac 480

agggtgacca tcacatgtag ggcatcccag gacgtgagca ccgcagtggc ctggtatcag 540

cagaagcccg gcaaggcccc taagctgctg atctactctg ccagcttcct gtatagcggc 600

gtgccttcca gattttccgg atctggaagc ggaaccgact tcaccctgac aatctctagc 660

ctgcagccag aggattttgc cacatactat tgccagcagt acctgtatca cccagcaacc 720

ttcggacagg gcacaaaagt ggaaatcaag cggcatcatc atcatcacca ttaa 774


<210> 24
<211> 723
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 24
gatatccaga tgacccagag ccctagctcc ctgagcgcct ccgtgggcga cagggtgacc 60

atcacatgta gggcatccca ggacgtgagc accgcagtgg cctggtatca gcagaagccc 120

ggcaaggccc ctaagctgct gatctactct gccagcttcc tgtatagcgg cgtgccttcc 180

agattttccg gatctggaag cggaaccgac ttcaccctga caatctctag cctgcagcca 240

gaggattttg ccacatacta ttgccagcag tacctgtatc acccagcaac cttcggacag 300

ggcacaaaag tggaaatcaa gcggggtgga ggcggttcag gcggaggtgg ctctggcggt 360

ggcggatcgg aggtgcagct ggtggaaagc gggggaggac tggtgcagcc tggggggtca 420

ctgagactga gttgcgccgc ctccggcttc accttttccg actcttggat ccactgggtg 480

aggcaggcac caggcaaggg cctggagtgg gtggcctgga tctctcccta cggcggcagc 540

acctactatg ccgactccgt gaagggccgg tttacaatct ctgccgatac cagcaagaac 600

acagcctatc tgcagatgaa ttctctgaga gccgaggaca ccgccgtgta ctattgcgca 660

cggagacact ggccaggagg attcgattac tggggacagg gcaccctggt gacagtgtcc 720

gcc 723


<210> 25
<211> 684
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 25
aggatccaga tgacccagag ccctagctcc ctgagcgcct ccgtgggcga cagggtgacc 60

atcacatgta gggcatccca ggacgtgagc accgcagtgg cctggtatca ggataagccc 120

ggcaaggccc ctaagctgct gatctactct gccagcttcc tgtatagcgg cgtgccttcc 180

agattttccg gatctggaag cggaaccgac ttcaccctga caatctctag cctgcagcca 240

gaggattttg ccacatacta ttgccagcag tacctgtatc acccagcaac cttcggacag 300

ggcacaaaag tggaaatcaa gcggaccgtg gcagcaccat ccgtgttcat ctttccccct 360

tctgacgagc agctgaagtc tggcacagcc agcgtggtgt gctacctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gataacgccc tgcagtccgg caattctcag 480

gagagcgtga ccgagcagga ctccaaggat tctacataca gcctgtggtc caccctgaca 540

ctgtccaagg ccgactacga gaagcacaag ctgtatgcat gcgaggtgac ccaccagggc 600

ctgtcctctc ccgtgacaaa gagcttcaat aggggagagt gtggaggagg atcctaccct 660

tatgacgtgc cagattatgc ctaa 684


<210> 26
<211> 1347
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 26
gaggtgcagc tggtggaaag cgggggagga ctggtgcagc ctggggggtc actgagactg 60

agttgcgccg cctccggctt caccttttcc gactcttgga tccactgggt gaggaaggca 120

ccaggcaagg gcctggagtg ggtggcctgg atctctccct acggcggcag cacctactat 180

gccgactccg tgaagggcga gtttacaatc tctgccgata ccagcaagaa cacagcctat 240

ctgcagatga attctctgag agccgaggac accgccgtgt actattgcgc acggagacac 300

tggccaggag gattcgatta ctggggacag ggcaccctgg tgacagtgtc cgccgcctct 360

acaaagggac caagcgtgtt tccactggca ccctcctcta agagcacctc cggaggaaca 420

gccgccctgg gctgtctggt gaaggactat ttcccagagc ccgtgaccgt gtcctggaac 480

tctggcgccc tgacctccgg agtggcaaca ggaccagccg tgctgcagag ctccggcctg 540

tacagcctgt ctagcgtggt gaccgtgccc tcctctagcc tgggcaccca gacatatatc 600

tgcaacgtga atcacaagcc aagcaataca aaggtcgaca agaaggtgga gcccaagtcc 660

tgtgataaga cccacacatg ccccccttgt cctgcaccag agctgctggg aggaccaagc 720

gtgttcctgt ttccacccaa gcctaaggac accctgatga tctctaggac ccccgaggtg 780

acatgcgtgg tggtggacgt gagccacgag gatcctgagg tgaagtttaa ctggtacgtg 840

gatggcgtgg aggtgcacaa tgccaagacc aagccccggg aggagcagta caactccacc 900

tatagagtgg tgtctgtgct gacagtgctg caccaggact ggctgaacgg caaggagtat 960

aagtgcaagg tgtccaataa ggccctgccc gcccctatcg agaagaccat ctctaaggcc 1020

aagggccagc ctagggagcc acaggtgtac acactgcctc catcccgcaa ggagctgacc 1080

aagaaccagg tgtctctgac atgtctggtg aagggcttct atccttctga tatcgccgtg 1140

gagtgggaga gcaatggcca gccagagaac aattacaaga ccacaccccc tgtgctgaag 1200

agcgacggct ccttctttct gtatagcaag ctgaccgtgg ataagtccag atggcagcag 1260

ggcaacgtgt tttcttgtag cgtgatgcac gaggccctgc acaatcacta cacacagaag 1320

tccctgtctc tgagccctgg caagtaa 1347


<210> 27
<211> 645
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 27
gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagagtgacc 60

atcacctgca gagccagcca ggacgtgaac accgccgtgg cctggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180

agattcagcg gcagcagaag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac cttcggccag 300

ggcaccaagg tggagatcaa gagaactgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa ctctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gctga 645


<210> 28
<211> 675
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 28
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgagactg 60

agctgcgccg ccagcggctt caacatcaag gacacctaca tccactgggt gagacaggcc 120

cccggcaagg gcctggagtg ggtggccaga atctacccca ccaacggcta caccagatac 180

gccgacagcg tgaagggcag attcaccatc agcgccgaca ccagcaagaa caccgcctac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgcag cagatggggc 300

ggcgacggct tctacgccat ggactactgg ggccagggca ccctggtgac cgtgagcagc 360

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660

aaatcttgtg acaaa 675


<210> 29
<211> 759
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 29
ggcggcggca gcggcggcgg cgaggtgcag ctggtgcaga gcggcgccga ggtgaagaag 60

cccggcgcca gcgtgaagat cagctgcaag accagcggct acaccttcac cgagtacacc 120

atccactggg tgaagcaggc cagcggcaag ggcctggagt ggatcggcaa catcaacccc 180

aacaacggcg gcaccaccta caaccagaag ttcgaggaca gagccaccct gaccgtggac 240

aagagcacca gcaccgccta catggagctg agcagcctga gaagcgagga caccgccgtg 300

tactactgcg ccgccggctg gaacttcgac tactggggcc agggcaccac cgtgaccgtg 360

agcagcgccg gtggaggcgg ttcaggcgga ggtggctctg gcggtggcgg atcggacatc 420

gtgatgaccc agagccccag cagcctgagc gccagcgtgg gcgacagagt gaccatcacc 480

tgcaaggcca gccaggacgt gggcaccgcc gtggactggt accagcagaa gcccggcaag 540

gcccccaagc tgctgatcta ctgggccagc accagacaca ccggcgtgcc cgacagattc 600

accggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgca gcccgaggac 660

ttcgccgact acttctgcca gcagtacaac agctaccccc tgaccttcgg cggcggcacc 720

aagctggaga tcaagagaca ccaccaccac caccactga 759


<210> 30
<211> 729
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 30
gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagagtgacc 60

atcacctgca gagccagcca ggacgtgaac accgccgtgg cctggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180

agattcagcg gcagcagaag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac cttcggccag 300

ggcaccaagg tggagatcaa gagaggtgga ggcggttcag gcggaggtgg ctctggcggt 360

ggcggatcgg aggtgcagct ggtggagagc ggcggcggcc tggtgcagcc cggcggcagc 420

ctgagactga gctgcgccgc cagcggcttc aacatcaagg acacctacat ccactgggtg 480

agacaggccc ccggcaaggg cctggagtgg gtggccagaa tctaccccac caacggctac 540

accagatacg ccgacagcgt gaagggcaga ttcaccatca gcgccgacac cagcaagaac 600

accgcctacc tgcagatgaa cagcctgaga gccgaggaca ccgccgtgta ctactgcagc 660

agatggggcg gcgacggctt ctacgccatg gactactggg gccagggcac cctggtgacc 720

gtgagcagc 729


<210> 31
<211> 684
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 31
aggatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagagtgacc 60

atcacctgca gagccagcca ggacgtgaac accgccgtgg cctggtacca ggataagccc 120

ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180

agattcagcg gcagcagaag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac cttcggccag 300

ggcaccaagg tggagatcaa gagaaccgtg gcagcaccat ccgtgttcat ctttccccct 360

tctgacgagc agctgaagtc tggcacagcc agcgtggtgt gctacctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gataacgccc tgcagtccgg caattctcag 480

gagagcgtga ccgagcagga ctccaaggat tctacataca gcctgtggtc caccctgaca 540

ctgtccaagg ccgactacga gaagcacaag ctgtatgcat gcgaggtgac ccaccagggc 600

ctgtcctctc ccgtgacaaa gagcttcaat aggggagagt gtggaggagg atcctaccct 660

tatgacgtgc cagattatgc ctaa 684


<210> 32
<211> 1353
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 32
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgagactg 60

agctgcgccg ccagcggctt caacatcaag gacacctaca tccactgggt gagaaaggcc 120

cccggcaagg gcctggagtg ggtggccaga atctacccca ccaacggcta caccagatac 180

gccgacagcg tgaagggcag gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240

ctgcagatga acagcctgag agccgaggac accgccgtgt actactgcag cagatggggc 300

ggcgacggct tctacgccat ggactactgg ggccagggca ccctggtgac cgtgagcagc 360

gcctctacaa agggaccaag cgtgtttcca ctggcaccct cctctaagag cacctccgga 420

ggaacagccg ccctgggctg tctggtgaag gactatttcc cagagcccgt gaccgtgtcc 480

tggaactctg gcgccctgac ctccggagtg gcaacaggac cagccgtgct gcagagctcc 540

ggcctgtaca gcctgtctag cgtggtgacc gtgccctcct ctagcctggg cacccagaca 600

tatatctgca acgtgaatca caagccaagc aatacaaagg tcgacaagaa ggtggagccc 660

aagtcctgtg ataagaccca cacatgcccc ccttgtcctg caccagagct gctgggagga 720

ccaagcgtgt tcctgtttcc acccaagcct aaggacaccc tgatgatctc taggaccccc 780

gaggtgacat gcgtggtggt ggacgtgagc cacgaggatc ctgaggtgaa gtttaactgg 840

tacgtggatg gcgtggaggt gcacaatgcc aagaccaagc cccgggagga gcagtacaac 900

tccacctata gagtggtgtc tgtgctgaca gtgctgcacc aggactggct gaacggcaag 960

gagtataagt gcaaggtgtc caataaggcc ctgcccgccc ctatcgagaa gaccatctct 1020

aaggccaagg gccagcctag ggagccacag gtgtacacac tgcctccatc ccgcaaggag 1080

ctgaccaaga accaggtgtc tctgacatgt ctggtgaagg gcttctatcc ttctgatatc 1140

gccgtggagt gggagagcaa tggccagcca gagaacaatt acaagaccac accccctgtg 1200

ctgaagagcg acggctcctt ctttctgtat agcaagctga ccgtggataa gtccagatgg 1260

cagcagggca acgtgttttc ttgtagcgtg atgcacgagg ccctgcacaa tcactacaca 1320

cagaagtccc tgtctctgag ccctggcaag taa 1353


<210> 33
<211> 660
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 33
gacattgtga tgacccagtc ccctgacagc ctggctgtga gcctgggaga gagggccacc 60

atcaactgca agagcagcca gagcctgctg tacagcagaa accagaaaaa ctacctggcc 120

tggtaccagc agaaacccgg ccagcctccc aagctgctga tcttctgggc cagcaccaga 180

gagagcggcg tgcctgacag attcagcggc tccggcttcg gcaccgactt caccctgacc 240

atcagcagcc tccaggccga ggatgtcgcc gtgtattact gccagcagta cttctcctat 300

cccctcacct tcggccaagg caccaaggtg gagatcaaga ctgtggctgc accatctgtc 360

ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420

ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480

tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540

agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaactcta cgcctgcgaa 600

gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgctga 660


<210> 34
<211> 687
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 34
caagtgcagc tggtgcagtc cggcgctgag gtgaagaagc ccggagcctc cgtgaaggtg 60

tcctgcaaga cctccaggta caccttcaca gagtacacca tccactgggt gagacaggct 120

cccggccaga ggctggagtg gattggcggc attaacccca acaacggcat ccccaactac 180

aaccagaagt tcaagggcag ggtgaccatc acagttgata catccgccag cacagcctat 240

atggaactga gctccctgag gagcgaggac acagccgtgt actactgcgc caggaggagg 300

attgcctacg gctatgatga gggccatgcc atggactact ggggacaggg caccctggtg 360

acagtctcca gcgcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420

agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480

gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540

ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 600

ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660

agagttgagc ccaaatcttg tgacaaa 687


<210> 35
<211> 807
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 35
ggcggcggca gcggcggcgg ccaagtgcag ctggtgcagt ccggcgctga ggtgaagaag 60

cccggagcct ccgtgaaggt gtcctgcaag acctccaggt acaccttcac agagtacacc 120

atccactggg tgagacaggc tcccggccag aggctggagt ggattggcgg cattaacccc 180

aacaacggca tccccaacta caaccagaag ttcaagggca gggtgaccat cacagttgat 240

acatccgcca gcacagccta tatggaactg agctccctga ggagcgagga cacagccgtg 300

tactactgcg ccaggaggag gattgcctac ggctatgatg agggccatgc catggactac 360

tggggacagg gcaccctggt gacagtctcc agcggcagca ccagcggatc cggaaagcct 420

ggcagcggag agggaagcac caagggcgac attgtgatga cccagtcccc tgacagcctg 480

gctgtgagcc tgggagagag ggccaccatc aactgcaaga gcagccagag cctgctgtac 540

agcagaaacc agaaaaacta cctggcctgg taccagcaga aacccggcca gcctcccaag 600

ctgctgatct tctgggccag caccagagag agcggcgtgc ctgacagatt cagcggctcc 660

ggcttcggca ccgacttcac cctgaccatc agcagcctcc aggccgagga tgtcgccgtg 720

tattactgcc agcagtactt ctcctatccc ctcaccttcg gccaaggcac caaggtggag 780

atcaagcacc accaccacca ccactga 807


<210> 36
<211> 756
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 36
gacattgtga tgacccagtc ccctgacagc ctggctgtga gcctgggaga gagggccacc 60

atcaactgca agagcagcca gagcctgctg tacagcagaa accagaaaaa ctacctggcc 120

tggtaccagc agaaacccgg ccagcctccc aagctgctga tcttctgggc cagcaccaga 180

gagagcggcg tgcctgacag attcagcggc tccggcttcg gcaccgactt caccctgacc 240

atcagcagcc tccaggccga ggatgtcgcc gtgtattact gccagcagta cttctcctat 300

cccctcacct tcggccaagg caccaaggtg gagatcaagg gtggaggcgg ttcaggcgga 360

ggtggctctg gcggtggcgg atcgcaagtg cagctggtgc agtccggcgc tgaggtgaag 420

aagcccggag cctccgtgaa ggtgtcctgc aagacctcca ggtacacctt cacagagtac 480

accatccact gggtgagaca ggctcccggc cagaggctgg agtggattgg cggcattaac 540

cccaacaacg gcatccccaa ctacaaccag aagttcaagg gcagggtgac catcacagtt 600

gatacatccg ccagcacagc ctatatggaa ctgagctccc tgaggagcga ggacacagcc 660

gtgtactact gcgccaggag gaggattgcc tacggctatg atgagggcca tgccatggac 720

tactggggac agggcaccct ggtgacagtc tccagc 756


<210> 37
<211> 699
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 37
aggattgtga tgacccagtc ccctgacagc ctggctgtga gcctgggaga gagggccacc 60

atcaactgca agagcagcca gagcctgctg tacagcagaa accagaaaaa ctacctggcc 120

tggtaccagg ataaacccgg ccagcctccc aagctgctga tcttctgggc cagcaccaga 180

gagagcggcg tgcctgacag attcagcggc tccggcttcg gcaccgactt caccctgacc 240

atcagcagcc tccaggccga ggatgtcgcc gtgtattact gccagcagta cttctcctat 300

cccctcacct tcggccaagg caccaaggtg gagatcaaga ccgtggcagc accatccgtg 360

ttcatctttc ccccttctga cgagcagctg aagtctggca cagccagcgt ggtgtgctac 420

ctgaacaact tctaccccag ggaggccaag gtgcagtgga aggtggataa cgccctgcag 480

tccggcaatt ctcaggagag cgtgaccgag caggactcca aggattctac atacagcctg 540

tggtccaccc tgacactgtc caaggccgac tacgagaagc acaagctgta tgcatgcgag 600

gtgacccacc agggcctgtc ctctcccgtg acaaagagct tcaatagggg agagtgtgga 660

ggaggatcct acccttatga cgtgccagat tatgcctaa 699


<210> 38
<211> 1365
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 38
caagtgcagc tggtgcagtc cggcgctgag gtgaagaagc ccggagcctc cgtgaaggtg 60

tcctgcaaga cctccaggta caccttcaca gagtacacca tccactgggt gagaaaggct 120

cccggccaga ggctggagtg gattggcggc attaacccca acaacggcat ccccaactac 180

aaccagaggt tcaagggcag ggtgaccatc acagttgata catccgccag cacagcctat 240

atggaactga gctccctgag gagcgaggac acagccgtgt actactgcgc caggaggagg 300

attgcctacg gctatgatga gggccatgcc atggactact ggggacaggg caccctggtg 360

acagtctcca gcgcctctac aaagggacca agcgtgtttc cactggcacc ctcctctaag 420

agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480

gtgaccgtgt cctggaactc tggcgccctg acctccggag tggcaacagg accagccgtg 540

ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccctc ctctagcctg 600

ggcacccaga catatatctg caacgtgaat cacaagccaa gcaatacaaa ggtcgacaag 660

aaggtggagc ccaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720

ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ctaaggacac cctgatgatc 780

tctaggaccc ccgaggtgac atgcgtggtg gtggacgtga gccacgagga tcctgaggtg 840

aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccccgggag 900

gagcagtaca actccaccta tagagtggtg tctgtgctga cagtgctgca ccaggactgg 960

ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020

aagaccatct ctaaggccaa gggccagcct agggagccac aggtgtacac actgcctcca 1080

tcccgcaagg agctgaccaa gaaccaggtg tctctgacat gtctggtgaa gggcttctat 1140

ccttctgata tcgccgtgga gtgggagagc aatggccagc cagagaacaa ttacaagacc 1200

acaccccctg tgctgaagag cgacggctcc ttctttctgt atagcaagct gaccgtggat 1260

aagtccagat ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320

aatcactaca cacagaagtc cctgtctctg agccctggca agtaa 1365


<210> 39
<211> 657
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 39
gatattcaga tgacccagag cccttcaagc ctgtccgcca gcgtcgggga tagagtgacc 60

attacttgcc ggagcaccaa gtccctgctg cactccaacg gcatcacata cctgtattgg 120

taccagcaga agcccggcaa ggcccctaag ctgctgatct atcagatgtc caatctggcc 180

tctggcgtgc caagcagatt cagctcctct ggcagcggca ccgactttac cctgacaatc 240

agctccctgc agcccgagga tttcgccaca tactattgcg cccagaacct ggagatccct 300

aggacctttg gccagggcac aaaggtggag ctgaagactg tggctgcacc atctgtcttc 360

atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420

aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480

ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540

agcaccctga cgctgagcaa agcagactac gagaaacaca aactctacgc ctgcgaagtc 600

acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgctga 657


<210> 40
<211> 663
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 40
gaggtgcagc tggtgcagtc cggacctggc ctggtgcagc caggaggctc cgtgaggatc 60

tcttgtgccg ccagcggcta taccttcaca aactacggca tgaattgggt gaagcaggca 120

cctggcaagg gcctggagtg gatgggctgg atcaacacct atacaggcga gtccacctac 180

gccgactctt ttaagggcag attcaccttt tctctggata catccgcctc tgccgcctac 240

ctgcagatca atagcctgcg ggccgaggac acagccgtgt actattgtgc cagattcgcc 300

atcaaagggg actactgggg acagggcaca ctgctgaccg tctcaagcgc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagagag ttgagcccaa atcttgtgac 660

aaa 663


<210> 41
<211> 771
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 41
ggcggcggca gcggcggcgg cgaggtgcag ctggtgcagt ccggacctgg cctggtgcag 60

ccaggaggct ccgtgaggat ctcttgtgcc gccagcggct ataccttcac aaactacggc 120

atgaattggg tgaagcaggc acctggcaag ggcctggagt ggatgggctg gatcaacacc 180

tatacaggcg agtccaccta cgccgactct tttaagggca gattcacctt ttctctggat 240

acatccgcct ctgccgccta cctgcagatc aatagcctgc gggccgagga cacagccgtg 300

tactattgtg ccagattcgc catcaaaggg gactactggg gacagggcac actgctgacc 360

gtctcaagcg gtggaggcgg ttcaggcgga ggtggctctg gcggtggcgg atcggatatt 420

cagatgaccc agagcccttc aagcctgtcc gccagcgtcg gggatagagt gaccattact 480

tgccggagca ccaagtccct gctgcactcc aacggcatca catacctgta ttggtaccag 540

cagaagcccg gcaaggcccc taagctgctg atctatcaga tgtccaatct ggcctctggc 600

gtgccaagca gattcagctc ctctggcagc ggcaccgact ttaccctgac aatcagctcc 660

ctgcagcccg aggatttcgc cacatactat tgcgcccaga acctggagat ccctaggacc 720

tttggccagg gcacaaaggt ggagctgaag caccaccacc accaccactg a 771


<210> 42
<211> 762
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 42
gatattcaga tgacccagag cccttcaagc ctgtccgcca gcgtcgggga tagagtgacc 60

attacttgcc ggagcaccaa gtccctgctg cactccaacg gcatcacata cctgtattgg 120

taccagcaga agcccggcaa ggcccctaag ctgctgatct atcagatgtc caatctggcc 180

tctggcgtgc caagcagatt cagctcctct ggcagcggca ccgactttac cctgacaatc 240

agctccctgc agcccgagga tttcgccaca tactattgcg cccagaacct ggagatccct 300

aggacctttg gccagggcac aaaggtggag ctgaagcgcg ccaccccctc tcacaacagc 360

caccaggtgc caagcgccgg aggaccaacc gccaattccg gcacatctgg aagcgaggtg 420

cagctggtgc agtccggacc tggcctggtg cagccaggag gctccgtgag gatctcttgt 480

gccgccagcg gctatacctt cacaaactac ggcatgaatt gggtgaagca ggcacctggc 540

aagggcctgg agtggatggg ctggatcaac acctatacag gcgagtccac ctacgccgac 600

tcttttaagg gcagattcac cttttctctg gatacatccg cctctgccgc ctacctgcag 660

atcaatagcc tgcgggccga ggacacagcc gtgtactatt gtgccagatt cgccatcaaa 720

ggggactact ggggacaggg cacactgctg accgtctcaa gc 762


<210> 43
<211> 696
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 43
aggattcaga tgacccagag cccttcaagc ctgtccgcca gcgtcgggga tagagtgacc 60

attacttgcc ggagcaccaa gtccctgctg cactccaacg gcatcacata cctgtattgg 120

taccaggata agcccggcaa ggcccctaag ctgctgatct atcagatgtc caatctggcc 180

tctggcgtgc caagcagatt cagctcctct ggcagcggca ccgactttac cctgacaatc 240

agctccctgc agcccgagga tttcgccaca tactattgcg cccagaacct ggagatccct 300

aggacctttg gccagggcac aaaggtggag ctgaagaccg tggcagcacc atccgtgttc 360

atctttcccc cttctgacga gcagctgaag tctggcacag ccagcgtggt gtgctacctg 420

aacaacttct accccaggga ggccaaggtg cagtggaagg tggataacgc cctgcagtcc 480

ggcaattctc aggagagcgt gaccgagcag gactccaagg attctacata cagcctgtgg 540

tccaccctga cactgtccaa ggccgactac gagaagcaca agctgtatgc atgcgaggtg 600

acccaccagg gcctgtcctc tcccgtgaca aagagcttca ataggggaga gtgtggagga 660

ggatcctacc cttatgacgt gccagattat gcctaa 696


<210> 44
<211> 1341
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 44
gaggtgcagc tggtgcagtc cggacctggc ctggtgcagc caggaggctc cgtgaggatc 60

tcttgtgccg ccagcggcta taccttcaca aactacggca tgaattgggt gaagaaggca 120

cctggcaagg gcctggagtg gatgggctgg atcaacacct atacaggcga gtccacctac 180

gccgactctt ttaagggcga gttcaccttt tctctggata catccgcctc tgccgcctac 240

ctgcagatca atagcctgcg ggccgaggac acagccgtgt actattgtgc cagattcgcc 300

atcaaagggg actactgggg acagggcaca ctgctgaccg tctcaagcgc ctctacaaag 360

ggaccaagcg tgtttccact ggcaccctcc tctaagagca cctccggagg aacagccgcc 420

ctgggctgtc tggtgaagga ctatttccca gagcccgtga ccgtgtcctg gaactctggc 480

gccctgacct ccggagtggc aacaggacca gccgtgctgc agagctccgg cctgtacagc 540

ctgtctagcg tggtgaccgt gccctcctct agcctgggca cccagacata tatctgcaac 600

gtgaatcaca agccaagcaa tacaaaggtc gacaagaagg tggagcccaa gtcctgtgat 660

aagacccaca catgcccccc ttgtcctgca ccagagctgc tgggaggacc aagcgtgttc 720

ctgtttccac ccaagcctaa ggacaccctg atgatctcta ggacccccga ggtgacatgc 780

gtggtggtgg acgtgagcca cgaggatcct gaggtgaagt ttaactggta cgtggatggc 840

gtggaggtgc acaatgccaa gaccaagccc cgggaggagc agtacaactc cacctataga 900

gtggtgtctg tgctgacagt gctgcaccag gactggctga acggcaagga gtataagtgc 960

aaggtgtcca ataaggccct gcccgcccct atcgagaaga ccatctctaa ggccaagggc 1020

cagcctaggg agccacaggt gtacacactg cctccatccc gcaaggagct gaccaagaac 1080

caggtgtctc tgacatgtct ggtgaagggc ttctatcctt ctgatatcgc cgtggagtgg 1140

gagagcaatg gccagccaga gaacaattac aagaccacac cccctgtgct gaagagcgac 1200

ggctccttct ttctgtatag caagctgacc gtggataagt ccagatggca gcagggcaac 1260

gtgttttctt gtagcgtgat gcacgaggcc ctgcacaatc actacacaca gaagtccctg 1320

tctctgagcc ctggcaagta a 1341


<210> 45
<211> 642
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 45
gagctgcaga tgacccagtc ccctagctct ttaagcgctt ccgtgggcga cagagtgacc 60

atcacatgtc gtacctccca gagcatcagc tcctatttaa actggtacca gcagaagccc 120

ggacagcccc ccaagctgct gatctactgg gcttccactc gtgaaagcgg cgtgcccgat 180

cgtttttccg gcagcggcag cggcaccgac tttactttaa ccatctcctc tttacagccc 240

gaggatagcg ccacctacta ctgccagcag agctacgaca tcccctacac attcggccaa 300

ggtaccaagc tggaaatcaa aactgtggct gcaccatctg tcttcatctt cccgccatct 360

gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420

agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480

agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540

agcaaagcag actacgagaa acacaaactc tacgcctgcg aagtcaccca tcagggcctg 600

agctcgcccg tcacaaagag cttcaacagg ggagagtgct ga 642


<210> 46
<211> 696
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 46
gaagtgcagc tgctggagag cggaggcgga gtggtgcaac ccggtcgttc tttaaggctg 60

agctgcgctg ccagcggctt caccttcagc agctatggca tgcactgggt gagacaagct 120

cccggaaaag gtttagagtg ggtggccgtg atctcctacg acggcagcaa caagtactac 180

gccgacagcg tgaagggtcg tttcaccatc tctcgtgaca actccaagaa cactttatac 240

ctccagatga actctttaag ggccgaggac accgccgtgt actactgtgc caaggacatg 300

ggctggggca gcggatggag gccctactac tactacggca tggacgtgtg gggccaaggt 360

acaaccgtga ccgtgtccag cgcctccacc aagggcccat cggtcttccc cctggcaccc 420

tcctccaaga gcacctctgg gggcacagcg gccctgggct gcctggtcaa ggactacttc 480

cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 540

ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac cgtgccctcc 600

agcagcttgg gcacccagac ctacatctgc aacgtgaatc acaagcccag caacaccaag 660

gtggacaaga gagttgagcc caaatcttgt gacaaa 696


<210> 47
<211> 789
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 47
ggcggcggca gcggcggcgg cgaagtgcag ctgctggaga gcggaggcgg agtggtgcaa 60

cccggtcgtt ctttaaggct gagctgcgct gccagcggct tcaccttcag cagctatggc 120

atgcactggg tgagacaagc tcccggaaaa ggtttagagt gggtggccgt gatctcctac 180

gacggcagca acaagtacta cgccgacagc gtgaagggtc gtttcaccat ctctcgtgac 240

aactccaaga acactttata cctccagatg aactctttaa gggccgagga caccgccgtg 300

tactactgtg ccaaggacat gggctggggc agcggatgga ggccctacta ctactacggc 360

atggacgtgt ggggccaagg tacaaccgtg accgtgtcca gcggtggagg cggttcaggc 420

ggaggtggct ctggcggtgg cggatcggag ctgcagatga cccagtcccc tagctcttta 480

agcgcttccg tgggcgacag agtgaccatc acatgtcgta cctcccagag catcagctcc 540

tatttaaact ggtaccagca gaagcccgga cagcccccca agctgctgat ctactgggct 600

tccactcgtg aaagcggcgt gcccgatcgt ttttccggca gcggcagcgg caccgacttt 660

actttaacca tctcctcttt acagcccgag gatagcgcca cctactactg ccagcagagc 720

tacgacatcc cctacacatt cggccaaggt accaagctgg aaatcaaaca ccaccaccac 780

caccactga 789


<210> 48
<211> 747
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 48
gagctgcaga tgacccagtc ccctagctct ttaagcgctt ccgtgggcga cagagtgacc 60

atcacatgtc gtacctccca gagcatcagc tcctatttaa actggtacca gcagaagccc 120

ggacagcccc ccaagctgct gatctactgg gcttccactc gtgaaagcgg cgtgcccgat 180

cgtttttccg gcagcggcag cggcaccgac tttactttaa ccatctcctc tttacagccc 240

gaggatagcg ccacctacta ctgccagcag agctacgaca tcccctacac attcggccaa 300

ggtaccaagc tggaaatcaa aggcggcggc ggcagcggcg gcggcggctc cggcggagga 360

ggctccgaag tgcagctgct ggagagcgga ggcggagtgg tgcaacccgg tcgttcttta 420

aggctgagct gcgctgccag cggcttcacc ttcagcagct atggcatgca ctgggtgaga 480

caagctcccg gaaaaggttt agagtgggtg gccgtgatct cctacgacgg cagcaacaag 540

tactacgccg acagcgtgaa gggtcgtttc accatctctc gtgacaactc caagaacact 600

ttatacctcc agatgaactc tttaagggcc gaggacaccg ccgtgtacta ctgtgccaag 660

gacatgggct ggggcagcgg atggaggccc tactactact acggcatgga cgtgtggggc 720

caaggtacaa ccgtgaccgt gtccagc 747


<210> 49
<211> 681
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 49
aggctgcaga tgacccagtc ccctagctct ttaagcgctt ccgtgggcga cagagtgacc 60

atcacatgtc gtacctccca gagcatcagc tcctatttaa actggtacca ggataagccc 120

ggacagcccc ccaagctgct gatctactgg gcttccactc gtgaaagcgg cgtgcccgat 180

cgtttttccg gcagcggcag cggcaccgac tttactttaa ccatctcctc tttacagccc 240

gaggatagcg ccacctacta ctgccagcag agctacgaca tcccctacac attcggccaa 300

ggtaccaagc tggaaatcaa aaccgtggca gcaccatccg tgttcatctt tcccccttct 360

gacgagcagc tgaagtctgg cacagccagc gtggtgtgct acctgaacaa cttctacccc 420

agggaggcca aggtgcagtg gaaggtggat aacgccctgc agtccggcaa ttctcaggag 480

agcgtgaccg agcaggactc caaggattct acatacagcc tgtggtccac cctgacactg 540

tccaaggccg actacgagaa gcacaagctg tatgcatgcg aggtgaccca ccagggcctg 600

tcctctcccg tgacaaagag cttcaatagg ggagagtgtg gaggaggatc ctacccttat 660

gacgtgccag attatgccta a 681


<210> 50
<211> 1374
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 50
gaagtgcagc tgctggagag cggaggcgga gtggtgcaac ccggtcgttc tttaaggctg 60

agctgcgctg ccagcggctt caccttcagc agctatggca tgcactgggt gagaaaggct 120

cccggaaaag gtttagagtg ggtggccgtg atctcctacg acggcagcaa caagtactac 180

gccgacagcg tgaagggtga gttcaccatc tctcgtgaca actccaagaa cactttatac 240

ctccagatga actctttaag ggccgaggac accgccgtgt actactgtgc caaggacatg 300

ggctggggca gcggatggag gccctactac tactacggca tggacgtgtg gggccaaggt 360

acaaccgtga ccgtgtccag cgcctctaca aagggaccaa gcgtgtttcc actggcaccc 420

tcctctaaga gcacctccgg aggaacagcc gccctgggct gtctggtgaa ggactatttc 480

ccagagcccg tgaccgtgtc ctggaactct ggcgccctga cctccggagt ggcaacagga 540

ccagccgtgc tgcagagctc cggcctgtac agcctgtcta gcgtggtgac cgtgccctcc 600

tctagcctgg gcacccagac atatatctgc aacgtgaatc acaagccaag caatacaaag 660

gtcgacaaga aggtggagcc caagtcctgt gataagaccc acacatgccc cccttgtcct 720

gcaccagagc tgctgggagg accaagcgtg ttcctgtttc cacccaagcc taaggacacc 780

ctgatgatct ctaggacccc cgaggtgaca tgcgtggtgg tggacgtgag ccacgaggat 840

cctgaggtga agtttaactg gtacgtggat ggcgtggagg tgcacaatgc caagaccaag 900

ccccgggagg agcagtacaa ctccacctat agagtggtgt ctgtgctgac agtgctgcac 960

caggactggc tgaacggcaa ggagtataag tgcaaggtgt ccaataaggc cctgcccgcc 1020

cctatcgaga agaccatctc taaggccaag ggccagccta gggagccaca ggtgtacaca 1080

ctgcctccat cccgcaagga gctgaccaag aaccaggtgt ctctgacatg tctggtgaag 1140

ggcttctatc cttctgatat cgccgtggag tgggagagca atggccagcc agagaacaat 1200

tacaagacca caccccctgt gctgaagagc gacggctcct tctttctgta tagcaagctg 1260

accgtggata agtccagatg gcagcagggc aacgtgtttt cttgtagcgt gatgcacgag 1320

gccctgcaca atcactacac acagaagtcc ctgtctctga gccctggcaa gtaa 1374


<210> 51
<211> 648
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 51
gatattcaga tgacccagag cccgagcagc ctgagcgcaa gcgttggtga tcgtgttacc 60

attacctgta aagcaagcca gaccgttagc gcaaatgttg catggtatca gcagaaaccg 120

ggtaaagcac cgaaactgct gatttatctg gcaagctatc gttatcgtgg tgttccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga ccattagcag cctgcagccg 240

gaagattttg caacctatta ttgtcatcag tattatacct atccgctgtt tacctttggt 300

cagggtacca aactggaaat taaacgtact gtggctgcac catctgtctt catcttcccg 360

ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420

tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480

caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540

acgctgagca aagcagacta cgagaaacac aaactctacg cctgcgaagt cacccatcag 600

ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgctga 648


<210> 52
<211> 678
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 52
caggttcagc tggttcagag cggtagcgaa ctgaaaaaac cgggtgcaag cgttaaagtt 60

agctgtaaag caagcggtta tacctttacc gaatatggta tgaatgtttg gcgtcaggca 120

ccgggtcagg gtctggaatg gatgggttgg attaatacca aaagcggtga agcaacctat 180

gttgaagaat ttaaaggtcg ttttgttttt agcctggata ccagcgttag caccgcatat 240

ctgcagatta gcagcctgaa agcagaagat accgcagttt attattgtgc acgttgggat 300

ttttatgatt atgttgatga agcaatgtat tggggtcagg gtaccaccgt taccgttagc 360

agcgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420

gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480

tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540

tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600

acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 660

cccaaatctt gtgacaaa 678


<210> 53
<211> 777
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 53
ggcggcggca gcggcggcgg ccaggttcag ctggttcaga gcggtagcga actgaaaaaa 60

ccgggtgcaa gcgttaaagt tagctgtaaa gcaagcggtt atacctttac cgaatatggt 120

atgaatgttt ggcgtcaggc accgggtcag ggtctggaat ggatgggttg gattaatacc 180

aaaagcggtg aagcaaccta tgttgaagaa tttaaaggtc gttttgtttt tagcctggat 240

accagcgtta gcaccgcata tctgcagatt agcagcctga aagcagaaga taccgcagtt 300

tattattgtg cacgttggga tttttatgat tatgttgatg aagcaatgta ttggggtcag 360

ggtaccaccg ttaccgttag cagcggtgga ggcggttcag gcggaggtgg ctctggcggt 420

ggcggatcgg atattcagat gacccagagc ccgagcagcc tgagcgcaag cgttggtgat 480

cgtgttacca ttacctgtaa agcaagccag accgttagcg caaatgttgc atggtatcag 540

cagaaaccgg gtaaagcacc gaaactgctg atttatctgg caagctatcg ttatcgtggt 600

gttccgagcc gttttagcgg tagcggtagc ggtaccgatt ttaccctgac cattagcagc 660

ctgcagccgg aagattttgc aacctattat tgtcatcagt attataccta tccgctgttt 720

acctttggtc agggtaccaa actggaaatt aaacgtcacc accaccacca ccactga 777


<210> 54
<211> 735
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 54
gatattcaga tgacccagag cccgagcagc ctgagcgcaa gcgttggtga tcgtgttacc 60

attacctgta aagcaagcca gaccgttagc gcaaatgttg catggtatca gcagaaaccg 120

ggtaaagcac cgaaactgct gatttatctg gcaagctatc gttatcgtgg tgttccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga ccattagcag cctgcagccg 240

gaagattttg caacctatta ttgtcatcag tattatacct atccgctgtt tacctttggt 300

cagggtacca aactggaaat taaacgtggt ggaggcggtt caggcggagg tggctctggc 360

ggtggcggat cgcaggttca gctggttcag agcggtagcg aactgaaaaa accgggtgca 420

agcgttaaag ttagctgtaa agcaagcggt tataccttta ccgaatatgg tatgaatgtt 480

tggcgtcagg caccgggtca gggtctggaa tggatgggtt ggattaatac caaaagcggt 540

gaagcaacct atgttgaaga atttaaaggt cgttttgttt ttagcctgga taccagcgtt 600

agcaccgcat atctgcagat tagcagcctg aaagcagaag ataccgcagt ttattattgt 660

gcacgttggg atttttatga ttatgttgat gaagcaatgt attggggtca gggtaccacc 720

gttaccgtta gcagc 735


<210> 55
<211> 687
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 55
aggattcaga tgacccagag cccgagcagc ctgagcgcaa gcgttggtga tcgtgttacc 60

attacctgta aagcaagcca gaccgttagc gcaaatgttg catggtatca ggataaaccg 120

ggtaaagcac cgaaactgct gatttatctg gcaagctatc gttatcgtgg tgttccgagc 180

cgttttagcg gtagcggtag cggtaccgat tttaccctga ccattagcag cctgcagccg 240

gaagattttg caacctatta ttgtcatcag tattatacct atccgctgtt tacctttggt 300

cagggtacca aactggaaat taaacgtacc gtggcagcac catccgtgtt catctttccc 360

ccttctgacg agcagctgaa gtctggcaca gccagcgtgg tgtgctacct gaacaacttc 420

taccccaggg aggccaaggt gcagtggaag gtggataacg ccctgcagtc cggcaattct 480

caggagagcg tgaccgagca ggactccaag gattctacat acagcctgtg gtccaccctg 540

acactgtcca aggccgacta cgagaagcac aagctgtatg catgcgaggt gacccaccag 600

ggcctgtcct ctcccgtgac aaagagcttc aataggggag agtgtggagg aggatcctac 660

ccttatgacg tgccagatta tgcctaa 687


<210> 56
<211> 1356
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 56
caggttcagc tggttcagag cggtagcgaa ctgaaaaaac cgggtgcaag cgttaaagtt 60

agctgtaaag caagcggtta tacctttacc gaatatggta tgaatgtttg gcgtaaggca 120

ccgggtcagg gtctggaatg gatgggttgg attaatacca aaagcggtga agcaacctat 180

gttgaagaat ttaaaggtcg ttttgttttt agcctggata ccagcgttag caccgcatat 240

ctgcagatta gcagcctgaa agcagaagat accgcagttt attattgtgc acgttgggat 300

ttttatgatt atgttgatga agcaatgtat tggggtcagg gtaccaccgt taccgttagc 360

agcgcctcta caaagggacc aagcgtgttt ccactggcac cctcctctaa gagcacctcc 420

ggaggaacag ccgccctggg ctgtctggtg aaggactatt tcccagagcc cgtgaccgtg 480

tcctggaact ctggcgccct gacctccgga gtggcaacag gaccagccgt gctgcagagc 540

tccggcctgt acagcctgtc tagcgtggtg accgtgccct cctctagcct gggcacccag 600

acatatatct gcaacgtgaa tcacaagcca agcaatacaa aggtcgacaa gaaggtggag 660

cccaagtcct gtgataagac ccacacatgc cccccttgtc ctgcaccaga gctgctggga 720

ggaccaagcg tgttcctgtt tccacccaag cctaaggaca ccctgatgat ctctaggacc 780

cccgaggtga catgcgtggt ggtggacgtg agccacgagg atcctgaggt gaagtttaac 840

tggtacgtgg atggcgtgga ggtgcacaat gccaagacca agccccggga ggagcagtac 900

aactccacct atagagtggt gtctgtgctg acagtgctgc accaggactg gctgaacggc 960

aaggagtata agtgcaaggt gtccaataag gccctgcccg cccctatcga gaagaccatc 1020

tctaaggcca agggccagcc tagggagcca caggtgtaca cactgcctcc atcccgcaag 1080

gagctgacca agaaccaggt gtctctgaca tgtctggtga agggcttcta tccttctgat 1140

atcgccgtgg agtgggagag caatggccag ccagagaaca attacaagac cacaccccct 1200

gtgctgaaga gcgacggctc cttctttctg tatagcaagc tgaccgtgga taagtccaga 1260

tggcagcagg gcaacgtgtt ttcttgtagc gtgatgcacg aggccctgca caatcactac 1320

acacagaagt ccctgtctct gagccctggc aagtaa 1356


<210> 57
<211> 654
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 57
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60

attacctgcc aggcgagcca gagcattagc agcagctatc tgagctggta tcagcagaaa 120

ccgggcaaag cgccgaaact gctgatttat gcggtgagct atctggcgag cggcgtgccg 180

agccgcttta gcggcagcgg cagcggcacc gatttcaccc tgaccattag cagcctgcag 240

ccggaagatt ttgcgaccta ttattgccag agcggctatt atagcgcggg cgatctgacc 300

tttggccagg gcaccaaagt ggaaattaaa cgcactgtgg ctgcaccatc tgtcttcatc 360

ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420

aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480

aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540

accctgacgc tgagcaaagc agactacgag aaacacaaac tctacgcctg cgaagtcacc 600

catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ctga 654


<210> 58
<211> 660
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 58
gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60

agctgcgcgg cgagcggctt tagcctgagc aactattata ttaactgggt gcgccaggcg 120

ccgggcaaag gcctggaatg ggtggcgatt attttttgcg cgggcaacgc gtataacgcg 180

agctgggcga aaggccgctt taccattagc cgcgatgata gcaaaaacac cctgtatctg 240

cagatgaaca gcctgcgcgc ggaagatacc gcggtgtatt attgcgcgcg cggctggcag 300

gcgctggtga actggggcca gggcaccctg gtgaccgtga gcagcgcctc caccaagggc 360

ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480

ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540

agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600

aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660


<210> 59
<211> 765
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 59
ggcggcggca gcggcggcgg cgaagtgcag ctggtggaaa gcggcggcgg cctggtgcag 60

ccgggcggca gcctgcgcct gagctgcgcg gcgagcggct ttagcctgag caactattat 120

attaactggg tgcgccaggc gccgggcaaa ggcctggaat gggtggcgat tattttttgc 180

gcgggcaacg cgtataacgc gagctgggcg aaaggccgct ttaccattag ccgcgatgat 240

agcaaaaaca ccctgtatct gcagatgaac agcctgcgcg cggaagatac cgcggtgtat 300

tattgcgcgc gcggctggca ggcgctggtg aactggggcc agggcaccct ggtgaccgtg 360

agcagcggcg gcggcggcag cggcggcggc ggcagcggcg gcggcggcag cgatattcag 420

atgacccaga gcccgagcag cctgagcgcg agcgtgggcg atcgcgtgac cattacctgc 480

caggcgagcc agagcattag cagcagctat ctgagctggt atcagcagaa accgggcaaa 540

gcgccgaaac tgctgattta tgcggtgagc tatctggcga gcggcgtgcc gagccgcttt 600

agcggcagcg gcagcggcac cgatttcacc ctgaccatta gcagcctgca gccggaagat 660

tttgcgacct attattgcca gagcggctat tatagcgcgg gcgatctgac ctttggccag 720

ggcaccaaag tggaaattaa acgccaccac caccaccacc actga 765


<210> 60
<211> 723
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 60
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60

attacctgcc aggcgagcca gagcattagc agcagctatc tgagctggta tcagcagaaa 120

ccgggcaaag cgccgaaact gctgatttat gcggtgagct atctggcgag cggcgtgccg 180

agccgcttta gcggcagcgg cagcggcacc gatttcaccc tgaccattag cagcctgcag 240

ccggaagatt ttgcgaccta ttattgccag agcggctatt atagcgcggg cgatctgacc 300

tttggccagg gcaccaaagt ggaaattaaa cgcggtggag gcggttcagg cggaggtggc 360

tctggcggtg gcggatcgga agtgcagctg gtggaaagcg gcggcggcct ggtgcagccg 420

ggcggcagcc tgcgcctgag ctgcgcggcg agcggcttta gcctgagcaa ctattatatt 480

aactgggtgc gccaggcgcc gggcaaaggc ctggaatggg tggcgattat tttttgcgcg 540

ggcaacgcgt ataacgcgag ctgggcgaaa ggccgcttta ccattagccg cgatgatagc 600

aaaaacaccc tgtatctgca gatgaacagc ctgcgcgcgg aagataccgc ggtgtattat 660

tgcgcgcgcg gctggcaggc gctggtgaac tggggccagg gcaccctggt gaccgtgagc 720

agc 723


<210> 61
<211> 693
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 61
aggattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60

attacctgcc aggcgagcca gagcattagc agcagctatc tgagctggta tcaggataaa 120

ccgggcaaag cgccgaaact gctgatttat gcggtgagct atctggcgag cggcgtgccg 180

agccgcttta gcggcagcgg cagcggcacc gatttcaccc tgaccattag cagcctgcag 240

ccggaagatt ttgcgaccta ttattgccag agcggctatt atagcgcggg cgatctgacc 300

tttggccagg gcaccaaagt ggaaattaaa cgcaccgtgg cagcaccatc cgtgttcatc 360

tttccccctt ctgacgagca gctgaagtct ggcacagcca gcgtggtgtg ctacctgaac 420

aacttctacc ccagggaggc caaggtgcag tggaaggtgg ataacgccct gcagtccggc 480

aattctcagg agagcgtgac cgagcaggac tccaaggatt ctacatacag cctgtggtcc 540

accctgacac tgtccaaggc cgactacgag aagcacaagc tgtatgcatg cgaggtgacc 600

caccagggcc tgtcctctcc cgtgacaaag agcttcaata ggggagagtg tggaggagga 660

tcctaccctt atgacgtgcc agattatgcc taa 693


<210> 62
<211> 1338
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 62
gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60

agctgcgcgg cgagcggctt tagcctgagc aactattata ttaactgggt gcgcaaggcg 120

ccgggcaaag gcctggaatg ggtggcgatt attttttgcg cgggcaacgc gtataacgcg 180

agctgggcga aaggcgagtt taccattagc cgcgatgata gcaaaaacac cctgtatctg 240

cagatgaaca gcctgcgcgc ggaagatacc gcggtgtatt attgcgcgcg cggctggcag 300

gcgctggtga actggggcca gggcaccctg gtgaccgtga gcagcgcctc tacaaaggga 360

ccaagcgtgt ttccactggc accctcctct aagagcacct ccggaggaac agccgccctg 420

ggctgtctgg tgaaggacta tttcccagag cccgtgaccg tgtcctggaa ctctggcgcc 480

ctgacctccg gagtggcaac aggaccagcc gtgctgcaga gctccggcct gtacagcctg 540

tctagcgtgg tgaccgtgcc ctcctctagc ctgggcaccc agacatatat ctgcaacgtg 600

aatcacaagc caagcaatac aaaggtcgac aagaaggtgg agcccaagtc ctgtgataag 660

acccacacat gccccccttg tcctgcacca gagctgctgg gaggaccaag cgtgttcctg 720

tttccaccca agcctaagga caccctgatg atctctagga cccccgaggt gacatgcgtg 780

gtggtggacg tgagccacga ggatcctgag gtgaagttta actggtacgt ggatggcgtg 840

gaggtgcaca atgccaagac caagccccgg gaggagcagt acaactccac ctatagagtg 900

gtgtctgtgc tgacagtgct gcaccaggac tggctgaacg gcaaggagta taagtgcaag 960

gtgtccaata aggccctgcc cgcccctatc gagaagacca tctctaaggc caagggccag 1020

cctagggagc cacaggtgta cacactgcct ccatcccgca aggagctgac caagaaccag 1080

gtgtctctga catgtctggt gaagggcttc tatccttctg atatcgccgt ggagtgggag 1140

agcaatggcc agccagagaa caattacaag accacacccc ctgtgctgaa gagcgacggc 1200

tccttctttc tgtatagcaa gctgaccgtg gataagtcca gatggcagca gggcaacgtg 1260

ttttcttgta gcgtgatgca cgaggccctg cacaatcact acacacagaa gtccctgtct 1320

ctgagccctg gcaagtaa 1338


<210> 63
<211> 21
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 63
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20

<210> 64
<211> 214
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 64
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210

<210> 65
<211> 220
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 65
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Ser Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220

<210> 66
<211> 257
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 66
Gly Gly Gly Ser Gly Gly Gly Asp Ile Lys Leu Gln Gln Ser Gly Ala
1 5 10 15
Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser
20 25 30
Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro
35 40 45
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr
50 55 60
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp
65 70 75 80
Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu
85 90 95
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Val Glu
115 120 125
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Val Asp
130 135 140
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
145 150 155 160
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
165 170 175
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
180 185 190
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
210 215 220
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
225 230 235 240
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg His His His His His
245 250 255
His


<210> 67
<211> 213
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 67
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210

<210> 68
<211> 217
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 68
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val
210 215

<210> 69
<211> 252
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 69
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Thr Ser
20 25 30
Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys Gln Ala Ser
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn Asn Gly Gly
50 55 60
Thr Thr Tyr Asn Gln Lys Phe Glu Asp Arg Ala Thr Leu Thr Val Asp
65 70 75 80
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
180 185 190
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asp Tyr
210 215 220
Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys Arg His His His His His His
245 250

<210> 70
<211> 239
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 70
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Ile Ser
130 135 140
Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val
145 150 155 160
Lys Gln Ala Ser Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro
165 170 175
Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Arg Ala Thr
180 185 190
Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn
210 215 220
Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
225 230 235

<210> 71
<211> 223
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 71
Asp Ile Gln Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Arg Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys Gly Gly Gly Ser His His His His His His
210 215 220

<210> 72
<211> 449
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 72
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Tyr Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys


<210> 73
<211> 227
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 73
Arg Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Asp Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Trp
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val Pro
210 215 220
Asp Tyr Ala
225

<210> 74
<211> 445
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 74
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Lys Ala Ser Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Glu Phe
50 55 60
Glu Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val Ala Thr Gly Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445

<210> 75
<211> 214
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 75
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210

<210> 76
<211> 224
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 76
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220



<210> 77
<211> 255
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 77
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Lys Gln Ser Gly Pro
1 5 10 15
Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser
20 25 30
Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro
35 40 45
Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr
50 55 60
Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn
65 70 75 80
Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp
85 90 95
Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu
100 105 110
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Leu
130 135 140
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val
145 150 155 160
Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp
165 170 175
Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala
180 185 190
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile
210 215 220
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly
225 230 235 240
Ala Gly Thr Lys Leu Glu Leu Lys Arg His His His His His His
245 250 255

<210> 78
<211> 242
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 78
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys
115 120 125
Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr
130 135 140
Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val
145 150 155 160
Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser
165 170 175
Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile
180 185 190
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu
195 200 205
Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr
210 215 220
Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
225 230 235 240
Ser Ala


<210> 79
<211> 254
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 79
Gly Gly Gly Ser Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala
1 5 10 15
Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr
20 25 30
Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly
35 40 45
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr
50 55 60
Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser
65 70 75 80
Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala
85 90 95
Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Val Glu Gly Gly Ser
115 120 125
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln
130 135 140
Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val
145 150 155 160
Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser
180 185 190
Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Leu Lys Arg His His His His His His
245 250

<210> 80
<211> 227
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 80
Arg Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Asp Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Trp
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val Pro
210 215 220
Asp Tyr Ala
225

<210> 81
<211> 449
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 81
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Lys Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Glu Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val Ala Thr Gly Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys


<210> 82
<211> 214
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 82
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210

<210> 83
<211> 223
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 83
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala 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 Gln
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 Gln Thr Tyr Ile 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
210 215 220

<210> 84
<211> 257
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 84
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Thr Phe Ser Asp Ser Trp Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Trp Ile Ser Pro Tyr Gly Gly Ser
50 55 60
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp
65 70 75 80
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Val Glu Gly
115 120 125
Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp
130 135 140
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
145 150 155 160
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala Thr
225 230 235 240
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg His His His His His
245 250 255
His


<210> 85
<211> 241
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 85
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser Trp Ile His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Trp Ile Ser Pro
165 170 175
Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg His Trp
210 215 220
Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ala


<210> 86
<211> 227
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 86
Arg Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Asp Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Trp
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val Pro
210 215 220
Asp Tyr Ala
225

<210> 87
<211> 448
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 87
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Lys Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Glu Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala 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 Ala Thr Gly Pro Ala Val Leu Gln
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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 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 Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Lys
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 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445



<210> 88
<211> 214
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 88
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210

<210> 89
<211> 225
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 89
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys
225

<210> 90
<211> 256
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 90
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr
50 55 60
Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp
65 70 75 80
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
180 185 190
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg His His His His His His
245 250 255



<210> 91
<211> 243
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 91
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro
165 170 175
Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly
210 215 220
Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser


<210> 92
<211> 227
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 92
Arg Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Asp Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Trp
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val Pro
210 215 220
Asp Tyr Ala
225

<210> 93
<211> 450
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Lys Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Ala Thr Gly Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450

<210> 94
<211> 219
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 94
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215

<210> 95
<211> 229
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 95
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys
225

<210> 96
<211> 268
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 96
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser
20 25 30
Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile
50 55 60
Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp
65 70 75 80
Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr
100 105 110
Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Thr Lys Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
145 150 155 160
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
165 170 175
Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
180 185 190
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr
195 200 205
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr
210 215 220
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val
225 230 235 240
Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly
245 250 255
Thr Lys Val Glu Ile Lys His His His His His His
260 265

<210> 97
<211> 252
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 97
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
130 135 140
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
145 150 155 160
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
165 170 175
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
180 185 190
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
195 200 205
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
225 230 235 240
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250

<210> 98
<211> 232
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 98
Arg Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Asp Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Trp Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr
210 215 220
Pro Tyr Asp Val Pro Asp Tyr Ala
225 230

<210> 99
<211> 454
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 99
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Lys Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Ala Thr
165 170 175
Gly Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys
450

<210> 100
<211> 218
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 100
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Ile Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215

<210> 101
<211> 221
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 101
Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe
50 55 60
Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ala Ile Lys Gly Asp Tyr Trp Gly Gln Gly Thr Leu Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220

<210> 102
<211> 256
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 102
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Pro
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Val Arg Ile Ser Cys Ala Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu
50 55 60
Ser Thr Tyr Ala Asp Ser Phe Lys Gly Arg Phe Thr Phe Ser Leu Asp
65 70 75 80
Thr Ser Ala Ser Ala Ala Tyr Leu Gln Ile Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Ala Ile Lys Gly Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Thr Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu
165 170 175
Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Gln Met Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Ser Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn Leu Glu Ile Pro Arg Thr
225 230 235 240
Phe Gly Gln Gly Thr Lys Val Glu Leu Lys His His His His His His
245 250 255



<210> 103
<211> 254
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 103
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Ile Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
100 105 110
Arg Ala Thr Pro Ser His Asn Ser His Gln Val Pro Ser Ala Gly Gly
115 120 125
Pro Thr Ala Asn Ser Gly Thr Ser Gly Ser Glu Val Gln Leu Val Gln
130 135 140
Ser Gly Pro Gly Leu Val Gln Pro Gly Gly Ser Val Arg Ile Ser Cys
145 150 155 160
Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys
165 170 175
Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Tyr
180 185 190
Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe Lys Gly Arg Phe Thr Phe
195 200 205
Ser Leu Asp Thr Ser Ala Ser Ala Ala Tyr Leu Gln Ile Asn Ser Leu
210 215 220
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Ala Ile Lys
225 230 235 240
Gly Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
245 250

<210> 104
<211> 231
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 104
Arg Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Asp Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Ile Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Trp Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro
210 215 220
Tyr Asp Val Pro Asp Tyr Ala
225 230

<210> 105
<211> 446
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 105
Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Lys Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe
50 55 60
Lys Gly Glu Phe Thr Phe Ser Leu Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ala Ile Lys Gly Asp Tyr Trp Gly Gln Gly Thr Leu Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val Ala Thr Gly Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445

<210> 106
<211> 213
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 106
Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210

<210> 107
<211> 232
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 107
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Met Gly Trp Gly Ser Gly Trp Arg Pro Tyr Tyr Tyr Tyr
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys
225 230

<210> 108
<211> 262
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 108
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly
1 5 10 15
Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn
50 55 60
Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
65 70 75 80
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Met Gly Trp Gly Ser Gly
100 105 110
Trp Arg Pro Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr
115 120 125
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu
145 150 155 160
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln
165 170 175
Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro
180 185 190
Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro
195 200 205
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
210 215 220
Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser
225 230 235 240
Tyr Asp Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
245 250 255
His His His His His His
260

<210> 109
<211> 249
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 109
Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu
115 120 125
Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys
130 135 140
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Ser Tyr Asp
165 170 175
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Met Gly Trp
210 215 220
Gly Ser Gly Trp Arg Pro Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser
245

<210> 110
<211> 226
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 110
Arg Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Asp Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Trp Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val Pro Asp
210 215 220
Tyr Ala
225

<210> 111
<211> 457
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 111
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Lys Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Glu Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Met Gly Trp Gly Ser Gly Trp Arg Pro Tyr Tyr Tyr Tyr
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val Ala Thr Gly Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455

<210> 112
<211> 215
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 112
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215

<210> 113
<211> 226
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 113
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Gly Met Asn Val Trp Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys
225

<210> 114
<211> 258
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 114
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ser
1 5 10 15
Glu Leu Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Glu Tyr Gly Met Asn Val Trp Arg Gln Ala Pro
35 40 45
Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Lys Ser Gly Glu
50 55 60
Ala Thr Tyr Val Glu Glu Phe Lys Gly Arg Phe Val Phe Ser Leu Asp
65 70 75 80
Thr Ser Val Ser Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Asp Phe Tyr Asp Tyr Val
100 105 110
Asp Glu Ala Met Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
130 135 140
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
145 150 155 160
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn Val
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu Phe
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg His His His His
245 250 255
His His


<210> 115
<211> 245
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 115
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu
115 120 125
Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala Ser Val Lys Val
130 135 140
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Gly Met Asn Val
145 150 155 160
Trp Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn
165 170 175
Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe Lys Gly Arg Phe
180 185 190
Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr Leu Gln Ile Ser
195 200 205
Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Asp
210 215 220
Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr Trp Gly Gln Gly Thr Thr
225 230 235 240
Val Thr Val Ser Ser
245

<210> 116
<211> 228
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 116
Arg Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn
20 25 30
Val Ala Trp Tyr Gln Asp Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Trp Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr Asp Val
210 215 220
Pro Asp Tyr Ala
225

<210> 117
<211> 451
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 117
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Gly Met Asn Val Trp Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Ala Thr Gly Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Lys Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450

<210> 118
<211> 217
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 118
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Ser
20 25 30
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Val Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Gly Tyr Tyr Ser Ala
85 90 95
Gly Asp Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215

<210> 119
<211> 220
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 119
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Phe Cys Ala Gly Asn Ala Tyr Asn Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Trp Gln Ala Leu Val Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220

<210> 120
<211> 254
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 120
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Ser Leu Ser Asn Tyr Tyr Ile Asn Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Ile Ile Phe Cys Ala Gly Asn Ala
50 55 60
Tyr Asn Ala Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp
65 70 75 80
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
85 90 95
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Trp Gln Ala Leu Val Asn Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Gln Ala Ser Gln Ser Ile Ser Ser Ser Tyr Leu Ser Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Val Ser Tyr Leu
180 185 190
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Ser Gly Tyr Tyr Ser Ala Gly Asp Leu Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Arg His His His His His His
245 250

<210> 121
<211> 241
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 121
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Ser
20 25 30
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Val Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Gly Tyr Tyr Ser Ala
85 90 95
Gly Asp Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Asn Tyr Tyr Ile
145 150 155 160
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ile
165 170 175
Ile Phe Cys Ala Gly Asn Ala Tyr Asn Ala Ser Trp Ala Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly
210 215 220
Trp Gln Ala Leu Val Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser


<210> 122
<211> 230
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 122
Arg Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Ser
20 25 30
Tyr Leu Ser Trp Tyr Gln Asp Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Val Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Gly Tyr Tyr Ser Ala
85 90 95
Gly Asp Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Tyr Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Trp Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Ser Tyr Pro Tyr
210 215 220
Asp Val Pro Asp Tyr Ala
225 230

<210> 123
<211> 445
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Lys Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Phe Cys Ala Gly Asn Ala Tyr Asn Ala Ser Trp Ala Lys
50 55 60
Gly Glu Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Trp Gln Ala Leu Val Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val Ala Thr Gly Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Lys Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445

<210> 124
<211> 119
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 124
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115

<210> 125
<211> 5
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 125
Arg Tyr Thr Met His
1 5

<210> 126
<211> 17
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 126
Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly


<210> 127
<211> 10
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 127
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
1 5 10

<210> 128
<211> 107
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 128
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105

<210> 129
<211> 10
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 129
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10

<210> 130
<211> 7
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 130
Asp Thr Ser Lys Val Ala Ser
1 5

<210> 131
<211> 9
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 131
Gln Gln Trp Ser Ser Asn Pro Leu Thr
1 5

<210> 132
<211> 774
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 132
ggtggcggct caggtggagg ccaggtgcag ctggtgcaga gcggcgcgga agtgaaaaaa 60

ccgggcgcga gcgtgaaagt gagctgcaaa gcgagcggct atacctttac ccgctatacc 120

atgcattggg tgcgccaggc gccgggccag ggcctggaat ggatgggcta tattaacccg 180

agccgcggct ataccagcta tgcgcagaaa tttcagggcc gcgtgaccat gaccaccgat 240

aaaagcacca gcaccgtgta tatggaactg agcagcctgc gcagcgaaga taccgcggtg 300

tattattgcg cgcgctatta tgatgatcat tattgcctgg attattgggg ccagggcacc 360

accgtgaccg tgagcagcgt ggagggcggc agcggcggca gcggcggcag cggcggcagc 420

ggcggcgtgg acgatattca gatgacccag agcccgagca gcctgagcgc gagcgtgggc 480

gatcgcgtga ccattacctg ccgcgcgagc agcagcgtga gctatatgaa ctggtatcag 540

cagaaaccgg gcaaagcgcc gaaactgctg atttatgata ccagcaaagt ggcgagcggc 600

gtgccgagcc gctttagcgg cagcggcagc ggcaccgatt ataccctgac cattagcagc 660

ctgcagccgg aagattttgc gacctattat tgccagcagt ggagcagcaa cccgctgacc 720

tttggcggcg gcaccaaagt ggaaattaaa cgccaccacc accaccacca ctga 774


<210> 133
<211> 257
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 133
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Ser Arg Gly Tyr
50 55 60
Thr Ser Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp
65 70 75 80
Lys Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Val Glu
115 120 125
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Val Asp
130 135 140
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
145 150 155 160
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
165 170 175
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
225 230 235 240
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg His His His His His
245 250 255
His


<210> 134
<211> 642
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 134
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60

attacctgcc gcgcgagcag cagcgtgagc tatatgaact ggtatcagca gaaaccgggc 120

aaagcgccga aactgctgat ttatgatacc agcaaagtgg cgagcggcgt gccgagccgc 180

tttagcggca gcggcagcgg caccgattat accctgacca ttagcagcct gcagccggaa 240

gattttgcga cctattattg ccagcagtgg agcagcaacc cgctgacctt tggcggcggc 300

accaaagtgg aaattaaacg cactgtggct gcaccatctg tcttcatctt cccgccatct 360

gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420

agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480

agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540

agcaaagcag actacgagaa acacaaactc tacgcctgcg aagtcaccca tcagggcctg 600

agctcgcccg tcacaaagag cttcaacagg ggagagtgct ga 642


<210> 135
<211> 213
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 135
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210

<210> 136
<211> 651
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 136
caggtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60

agctgcaaag cgagcggcta tacctttacc cgctatacca tgcattgggt gcgccaggcg 120

ccgggccagg gcctggaatg gatgggctat attaacccga gccgcggcta taccagctat 180

gcgcagaaat ttcagggccg cgtgaccatg accaccgata aaagcaccag caccgtgtat 240

atggaactga gcagcctgcg cagcgaagat accgcggtgt attattgcgc gcgctattat 300

gatgatcatt attgcctgga ttattggggc cagggcacca ccgtgaccgt gagcagcgcc 360

tccaccaaag gtccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480

aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 600

acctgcaacg tagatcacaa gcccagtaac accaaggtgg acaagacagt t 651


<210> 137
<211> 217
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 137
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val
210 215

<210> 138
<211> 765
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 138
ggcggtggat cacaggtgca gctggtgcag agcggcgcgg aagtgaaaaa accgggcgcg 60

agcgtgaaag tgagctgcaa agcgagcggc tataccttta cccgctatac catgcattgg 120

gtgcgccagg cgccgggcca gggcctggaa tggatgggct atattaaccc gagccgcggc 180

tataccagct atgcgcagaa atttcagggc cgcgtgacca tgaccaccga taaaagcacc 240

agcaccgtgt atatggaact gagcagcctg cgcagcgaag ataccgcggt gtattattgc 300

gcgcgctatt atgatgatca ttattgcctg gattattggg gccagggcac caccgtgacc 360

gtgagcagcg tggagggcgg cagcggcggc agcggcggca gcggcggcag cggcggcgtg 420

gacgatattc agatgaccca gagcccgagc agcctgagcg cgagcgtggg cgatcgcgtg 480

accattacct gccgcgcgag cagcagcgtg agctatatga actggtatca gcagaaaccg 540

ggcaaagcgc cgaaactgct gatttatgat accagcaaag tggcgagcgg cgtgccgagc 600

cgctttagcg gcagcggcag cggcaccgat tataccctga ccattagcag cctgcagccg 660

gaagattttg cgacctatta ttgccagcag tggagcagca acccgctgac ctttggcggc 720

ggcaccaaag tggaaattaa acgccaccac caccaccacc actga 765


<210> 139
<211> 254
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 139
Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
1 5 10 15
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
20 25 30
Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
35 40 45
Leu Glu Trp Met Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Ser Tyr
50 55 60
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Lys Ser Thr
65 70 75 80
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
85 90 95
Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Val Glu Gly Gly Ser
115 120 125
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Thr Ser
180 185 190
Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Arg His His His His His His
245 250

<210> 140
<211> 672
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 140
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60

attacctgcc gcgcgagcag cagcgtgagc tatatgaact ggtatcagcg taaaccgggc 120

aaagcgccga aactgctgat ttatgatacc agcaaagtgg cgagcggcgt gccgagccgc 180

tttagcggca gcggcagcgg caccgattat accctgacca ttagcagcct gcagccggaa 240

gattttgcga cctattattg ccagcagtgg agcagcaacc cgctgacctt tggcggcggc 300

accaaagtgg aaattaaacg caccgtggca gcacctagcg tgttcatctt tcccccttcc 360

gacgagcagc tgaagtccgg cacagcctct gtggtgtgcc tgctgaacaa tttctatcca 420

cgcgaggcca aggtgcagtg gaaggtggat aacgccctgc agtctggcaa tagccaggag 480

tccgtgaccg agcaggactc taaggatagc acatactccc tgtcctctac cctgacactg 540

agcaaggccg attacgagaa gcacaagctg tatgcatgcg aggtgaccca ccagggcctg 600

agctccccag tgacaaagtc ttttaaccgg ggcgagtgtg gcggcggctc ccaccaccac 660

caccaccact ga 672


<210> 141
<211> 223
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 141
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Arg Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys Gly Gly Gly Ser His His His His His His
210 215 220

<210> 142
<211> 1350
<212> DNA
<213> 人工序列


<220>
<223> 合成序列

<400> 142
caggtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60

agctgcaaag cgagcggcta tacctttacc cgctatacca tgcattgggt gcgctatgcg 120

ccgggccagg gcctggaatg gatgggctat attaacccga gccgcggcta taccagctat 180

gcgcagaaat ttcagggccg cgtgaccatg accaccgata aaagcaccag caccgtgtat 240

atggaactga gcagcctgcg cagcgaagat accgcggtgt attattgcgc gcgctattat 300

gatgatcatt attgcctgga ttattggggc cagggcacca ccgtgaccgt gagcagcgcc 360

tctacaaagg gacctagcgt gttcccactg gcaccctcct ctaagtccac ctctggagga 420

acagccgccc tgggatgcct ggtgaaggat tacttcccag agcccgtgac cgtgtcctgg 480

aactctggcg ccctgaccag cggagtgcac acatttcctg ccgtgctgca gagctccggc 540

ctgtactccc tgtctagcgt ggtgacagtg ccatcctcta gcctgggcac ccagacatat 600

atctgcaacg tgaatcacaa gccaagcaat accaaggtcg acaagaaggt ggagcccaag 660

tcctgtgata agacccacac atgcccccct tgtcctgcac cagagctgct gggaggacca 720

agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctctcg gaccccagag 780

gtgacatgcg tggtggtgga cgtgagccac gaggatcccg aggtgaagtt taactggtac 840

gtggatggcg tggaggtgca caatgccaag accaagccca gggaggagca gtacaattcc 900

acctatcgcg tggtgtctgt gctgacagtg ctgcaccagg actggctgaa cggcaaggag 960

tataagtgca aggtgtccaa taaggccctg cccgccccta tcgagaagac aatctctaag 1020

gcaaagggac agcctcggga gccacaggtg tacaccctgc ctccatccag agatgagctg 1080

accaagaacc aggtgtctct gacatgtctg gtgaagggct tctatccctc tgacatcgcc 1140

gtggagtggg agagcaatgg ccagcctgag aacaattacg ataccacacc ccctgtgctg 1200

gacagcgatg gctccttctt tctgtatagc gacctgacag tggataagtc cagatggcag 1260

cagggcaacg tgtttagctg ttccgtgatg cacgaggccc tgcacaatca ctacacccag 1320

aagtctctga gcctgtcccc cggcaagtaa 1350


<210> 143
<211> 449
<212> PRT
<213> 人工序列


<220>
<223> 合成序列

<400> 143
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Tyr Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys


Figure TW201945541A_D0045
Figure TW201945541A_D0046
Figure TW201945541A_D0047
Figure TW201945541A_D0048
Figure TW201945541A_D0049
Figure TW201945541A_D0050
Figure TW201945541A_D0051
Figure TW201945541A_D0052
Figure TW201945541A_D0053
Figure TW201945541A_D0054
Figure TW201945541A_D0055
Figure TW201945541A_D0056
Figure TW201945541A_D0057
Figure TW201945541A_D0058
Figure TW201945541A_D0059
Figure TW201945541A_D0060
Figure TW201945541A_D0061
Figure TW201945541A_D0062
Figure TW201945541A_D0063
Figure TW201945541A_D0064
Figure TW201945541A_D0065
Figure TW201945541A_D0066
Figure TW201945541A_D0067
Figure TW201945541A_D0068
Figure TW201945541A_D0069
Figure TW201945541A_D0070
Figure TW201945541A_D0071
Figure TW201945541A_D0072
Figure TW201945541A_D0073
Figure TW201945541A_D0074
Figure TW201945541A_D0075
Figure TW201945541A_D0076
Figure TW201945541A_D0077
Figure TW201945541A_D0078
Figure TW201945541A_D0079
Figure TW201945541A_D0080
Figure TW201945541A_D0081
Figure TW201945541A_D0082
Figure TW201945541A_D0083
Figure TW201945541A_D0084
Figure TW201945541A_D0085
Figure TW201945541A_D0086
Figure TW201945541A_D0087
Figure TW201945541A_D0088
Figure TW201945541A_D0089
Figure TW201945541A_D0090
Figure TW201945541A_D0091
Figure TW201945541A_D0092
Figure TW201945541A_D0093
Figure TW201945541A_D0094
Figure TW201945541A_D0095
Figure TW201945541A_D0096
Figure TW201945541A_D0097
Figure TW201945541A_D0098
Figure TW201945541A_D0099
Figure TW201945541A_D0100
Figure TW201945541A_D0101
Figure TW201945541A_D0102
Figure TW201945541A_D0103
Figure TW201945541A_D0104
Figure TW201945541A_D0105
Figure TW201945541A_D0106
Figure TW201945541A_D0107
Figure TW201945541A_D0108
Figure TW201945541A_D0109
Figure TW201945541A_D0110
Figure TW201945541A_D0111
Figure TW201945541A_D0112
Figure TW201945541A_D0113
Figure TW201945541A_D0114
Figure TW201945541A_D0115
Figure TW201945541A_D0116
Figure TW201945541A_D0117
Figure TW201945541A_D0118
Figure TW201945541A_D0119
Figure TW201945541A_D0120
Figure TW201945541A_D0121
Figure TW201945541A_D0122
Figure TW201945541A_D0123
Figure TW201945541A_D0124
Figure TW201945541A_D0125
Figure TW201945541A_D0126
Figure TW201945541A_D0127
Figure TW201945541A_D0128
Figure TW201945541A_D0129
Figure TW201945541A_D0130
Figure TW201945541A_D0131
Figure TW201945541A_D0132
Figure TW201945541A_D0133
Figure TW201945541A_D0134
Figure TW201945541A_D0135
Figure TW201945541A_D0136
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Claims (16)

  1. 一種用以誘發一T細胞分化及／或增生的方法，其中該T細胞表面具有一抗-腫瘤抗原部（anti-tumor antigen moiety）及一抗-CD3部（anti-CD3 moiety），該方法包含： 將一周邊血液單核球細胞（peripheral blood mononuclear cell，PBMC）與一雙功抗體（bi- specific antibody，BsAb）培養在一培養液中，據以使該PBMC分化為T細胞， 其中， 該BsAb包含一對應至該T細胞之該抗-腫瘤抗原部的腫瘤抗原結合位點，以及一對應至該T細胞之該抗-CD3部的CD3結合位點，以及 該BsAb非鼠類OKT3抗體；以及 在該BsAb中， 該腫瘤抗原結合位點包含一與序列編號：70、78、85、91、97、103、109、115或121具有至少90％序列相似度的抗-腫瘤抗原scFv；以及 該CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv；或是 該腫瘤抗原結合位點包含一與序列編號：64、75、82、88、94、100、106、112或118具有至少90％序列相似度的抗-腫瘤抗原VL-Ck域；以及一與序列編號：65、76、83、89、95、101、107、113或119具有至少90％序列相似度的抗-腫瘤抗原VH-CH1域；以及 該CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv。
  2. 一種用以誘發一T細胞分化及／或增生的方法，包含： 將一PBMC與一多肽培養在一培養液中，據以使該PBMC分化為T細胞， 其中，該多肽包含一與序列編號：124具有至少90％序列相似度的抗-CD3 VH序列，以及一與序列編號：128具有至少90％序列相似度的抗-CD3 VL序列。
  3. 如請求項1或2所述之方法，其中該培養液更包含一細胞激素，且該細胞激素係選自由IL-2、IL-7、TGF-β及其組合所組成的群組。
  4. 如請求項3所述之方法，其中該培養液包含IL-2、IL-7及TGF-β的組合；且利用該方法所製備的T細胞為一調控型T細胞。
  5. 一種利用請求項1至4之任一方法所製備的T細胞。
  6. 一種雙功抗體，包含： 一腫瘤抗原結合位點包含一與序列編號：70、78、85、91、97、103、109、115或121具有至少90％序列相似度的抗-腫瘤抗原scFv；以及 一CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv；或是 一腫瘤抗原結合位點包含一與序列編號：64、75、82、88、94、100、106、112或118具有至少90％序列相似度的抗-腫瘤抗原VL-Ck域；以及一與序列編號：65、76、83、89、95、101、107、113或119具有至少90％序列相似度的抗-腫瘤抗原VH-CH1域；以及 一CD3結合位點包含一與序列編號：66或79具有至少90％序列相似度的抗-CD3 scFv。
  7. 一種多肽，包含： 一與序列編號：124具有至少90％序列相似度的抗-CD3 VH序列，以及 一與序列編號：128具有至少90％序列相似度的抗-CD3 VL序列。
  8. 一種如請求項5所述之T細胞，或經如請求項6所述之BsAb或經如請求項7所述之多肽修飾的鼠類OKT3 T細胞於製備一藥物之用途，其中該藥物可用以治療一罹患一癌症之個體。
  9. 如請求項8所述之用途，其中係藉由將一周邊血液單核球細胞（PBMC）與一鼠類OKT3單株抗體培養在一培養液以製備該鼠類OKT3 T細胞。
  10. 如請求項9所述之用途，其中可進一步以如請求項6所述之BsAb或以如請求項7所述之多肽來修飾該如請求項5所述之T細胞或該經修飾的鼠類OKT3 T細胞，其中係藉由將該如請求項5所述之T細胞或該經修飾的鼠類OKT3 T細胞培養在一具有如請求項6所述之BsAb或具有如請求項7所述之多肽的培養液中來進行該修飾。
  11. 如請求項10所述之用途，其中該培養液更包含一細胞激素，該細胞激素係選自由IL-2、IL-7及其組合所組成的群組。
  12. 如請求項11所述之用途，其中該培養液更包含抗-CD28抗體。
  13. 如請求項8所述之用途，其中該癌症係EGFR+ 、PSMA+ 或PD-L1+ 之癌症。
  14. 如請求項8所述之用途，其中該癌症係膀胱癌、膽癌、骨癌、腦瘤、乳癌、子宮頸癌、結直腸癌、大腸癌、食道癌、上皮癌、胃癌、胃腸基質瘤（gastrointestinal stromal tumor，GIST）、神經膠質瘤、淋巴譜系之造血組織腫瘤、肝癌、非何杰金氏淋巴癌（non-Hodgkin’s lymphoma）、卡波西氏肉瘤、白血病、肺癌、淋巴瘤、小腸癌、黑色素瘤、骨髓性白血病、胰臟癌、前列腺癌、視網膜母細胞瘤、卵巢癌、腎細胞癌、脾臟癌、鱗狀細胞癌、甲狀腺癌或濾泡狀甲狀腺癌。
  15. 如請求項14所述之用途，其中該乳癌係三陰性乳癌。
  16. 一種醫藥套組，包含該如請求項5所述之T細胞，或該經如請求項6所述之BsAb或該經如請求項7所述之多肽修飾的鼠類OKT3 T細胞；以及該如請求項6所述之BsAb或該如請求項7所述之多肽。
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Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018177371A1 (en) * 2017-03-29 2018-10-04 Taipei Medical University Antigen-specific t cells and uses thereof
IL322315A (en) 2019-05-14 2025-09-01 Provention Bio Inc Methods and preparations for preventing type 1 diabetes
JP7337373B2 (ja) * 2019-07-29 2023-09-04 サイアス株式会社 抗原特異的ｔ細胞の製造方法
EP4126954A4 (en) * 2020-03-23 2024-08-21 Cytoarm Co. Ltd. BISPECIFIC ANTIBODIES FOR USE IN THE PRODUCTION OF ARMED IMMUNE CELLS
AU2021287998B2 (en) 2020-06-11 2026-03-12 Benaroya Research Institute At Virginia Mason Methods and compositions for preventing type 1 diabetes
JP7460850B2 (ja) * 2020-06-12 2024-04-02 ジェンセルメッド インコーポレイテッド 多重標的化組換えヘルペスシンプルレックスウイルス及びその用途
US12565529B2 (en) 2021-05-24 2026-03-03 Provention Bio, Inc. Methods for treating type 1 diabetes
CN114621351B (zh) * 2022-04-27 2023-01-03 华羊生物技术股份有限公司 多特异性抗体及其治疗癌症的用途
US20250313630A1 (en) * 2022-05-27 2025-10-09 Bighat Biosciences, Inc. Ph-selective anti-cd3 antibodies and use of the same
JP2025528390A (ja) * 2022-08-24 2025-08-28 ザ・リサーチ・ファンデーション・フォー・ザ・ステート・ユニバーシティ・オブ・ニューヨーク 抗モノメチルアウリスタチン抗体および抗体フラグメント
WO2025092689A1 (zh) * 2023-10-30 2025-05-08 苏州沙砾生物科技有限公司 一种表达多特异性抗原结合蛋白的细胞及其应用
WO2025162453A1 (zh) * 2024-02-02 2025-08-07 北京昌平实验室 双特异性抗体前药及其应用
CN119859615A (zh) * 2024-12-31 2025-04-22 广州安捷生物医学技术有限公司 一种靶向成纤维细胞激活蛋白的car-msc细胞及其制备方法和应用

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004538331A (ja) * 2001-08-17 2004-12-24 ロジャー ウィリアムス ホスピタル インサイチュ免疫法
EP1694839A2 (en) * 2003-12-12 2006-08-30 Novo Nordisk A/S Laminin-5 modulators and uses thereof
JP6126782B2 (ja) * 2008-10-01 2017-05-10 アムゲン リサーチ （ミュンヘン） ゲーエムベーハー 異種間特異的ｐｓｍａ×ｃｄ３二重特異性単鎖抗体
AU2009333580B2 (en) * 2008-12-09 2016-07-07 Genentech, Inc. Anti-PD-L1 antibodies and their use to enhance T-cell function
TWI629357B (zh) * 2009-10-02 2018-07-11 安進研究（慕尼黑）有限責任公司 跨物種特異性的ＰＳＭＡｘＣＤ３雙特異性單鏈抗體
JP5818003B2 (ja) * 2009-11-18 2015-11-18 国立大学法人東北大学 ヒト型化抗ｅｇｆｒ抗体可変領域の高機能性変異体
CA2782333C (en) * 2009-12-02 2019-06-04 Imaginab, Inc. J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use
TWI653333B (zh) * 2010-04-01 2019-03-11 安進研究（慕尼黑）有限責任公司 跨物種專一性之ＰＳＭＡｘＣＤ３雙專一性單鏈抗體
CN102250245B (zh) * 2010-05-27 2014-05-14 四川大学 抗b细胞淋巴瘤的双特异性抗体及其用途
WO2012158818A2 (en) * 2011-05-16 2012-11-22 Fabion Pharmaceuticals, Inc. Multi-specific fab fusion proteins and methods of use
MY169358A (en) * 2011-08-23 2019-03-26 Roche Glycart Ag Bispecific t cell activating antigen binding molecules
WO2013163427A1 (en) * 2012-04-25 2013-10-31 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Antibodies to treat hiv-1 infection
EP2904016B1 (en) 2012-10-08 2018-11-14 Roche Glycart AG Fc-free antibodies comprising two fab-fragments and methods of use
KR101911438B1 (ko) * 2012-10-31 2018-10-24 삼성전자주식회사 이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 제조 방법
CN104271602B (zh) * 2012-11-21 2020-08-21 武汉友芝友生物制药有限公司 双特异性抗体
CN103965359B (zh) * 2013-01-24 2016-08-03 上海市肿瘤研究所 抗上皮细胞粘附分子和t细胞抗原的双特异性抗体
CN105722859B (zh) * 2013-07-25 2021-05-07 西托姆克斯治疗公司 多特异性抗体、多特异性可活化抗体及其使用方法
WO2015197582A1 (en) * 2014-06-27 2015-12-30 Innate Pharma Monomeric multispecific antigen binding proteins
BR112016030740A2 (pt) * 2014-07-01 2018-02-20 Pfizer Inc. diacorpos heterodiméricos biespecíficos e seus usos
CN104592391B (zh) * 2015-01-21 2020-08-21 武汉友芝友生物制药有限公司 一种双特异性抗体EpCAM×CD3的构建及应用
CN104558191B (zh) * 2015-01-21 2020-08-21 武汉友芝友生物制药有限公司 一种双特异性抗体cd20×cd3的构建及应用
CN104829728B (zh) * 2015-01-21 2019-03-12 武汉友芝友生物制药有限公司 一种双特异性抗体her2xcd3的构建及应用
CN104829729B (zh) * 2015-04-03 2018-08-14 复旦大学 一种携带抗Her2/CD3双特异性功能蛋白的人T细胞制备
US10844122B2 (en) * 2015-05-06 2020-11-24 Janssen Biotech, Inc. Prostate specific membrane antigen (PSMA) bispecific binding agents and uses thereof
EA201792573A1 (ru) * 2015-05-21 2018-04-30 Харпун Терапьютикс, Инк. Триспецифические связанные белки и способы их применения
EP3916018A1 (en) * 2015-06-16 2021-12-01 Genentech, Inc. Anti-cd3 antibodies and methods of use
WO2017027325A1 (en) * 2015-08-07 2017-02-16 Imaginab, Inc. Antigen binding constructs to target molecules
CN105949323A (zh) * 2016-06-24 2016-09-21 安徽未名细胞治疗有限公司 一种EpCAM特异性嵌合抗原受体及其编码基因、应用
WO2018177371A1 (en) * 2017-03-29 2018-10-04 Taipei Medical University Antigen-specific t cells and uses thereof

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