TW202227477A - 識別p53中r273c或y220c突變的t細胞受體 - Google Patents
識別p53中r273c或y220c突變的t細胞受體 Download PDFInfo
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Abstract
本發明揭示具有人類p53
R273C或人類p53
Y220C之抗原特異性的經分離或經純化T細胞受體(TCR)。亦提供相關之多肽及蛋白質,以及相關之核酸、重組表現載體、宿主細胞、細胞群及醫藥組合物。亦揭示偵測哺乳動物中癌症之存在的方法及治療或預防哺乳動物之癌症的方法。
Description
一些癌症之治療選項可能非常有限,在癌症變成轉移性的且不可切除時尤為如此。儘管在諸如手術、化學療法及放射療法之治療中取得進展,但諸如胰臟癌、大腸直腸癌、肺癌、子宮內膜癌、卵巢癌及前列腺癌之許多癌症的預後可能不良。因此,對癌症之額外治療存在未滿足之需求。
本發明之一實施例提供一種經分離或經純化之T細胞受體(TCR),其對人類p53
R273C或人類p53
Y220C胺基酸序列具有抗原特異性,其中該TCR包含如下胺基酸序列:(1) SEQ ID NO: 2-7全部;(2) SEQ ID NO: 21-26全部;(3) SEQ ID NO: 40-45全部;(4) SEQ ID NO: 59-64全部;或(5) SEQ ID NO: 78-83全部。
本發明之其他實施例提供與本發明之TCR相關的多肽、蛋白質、核酸、重組表現載體、宿主細胞、細胞群及醫藥組合物。
本發明之其他實施例提供偵測哺乳動物中癌症之存在的方法、誘導針對哺乳動物之癌症之免疫反應的方法及治療或預防哺乳動物之癌症的方法。
本發明之額外實施例提供產生表現TCR之宿主細胞的方法及產生TCR、多肽或蛋白質的方法。
相關申請案之交叉參考
本申請案主張2020年9月4日申請之美國臨時專利申請案第63/074,747號之優先權,其以全文引用之方式併入本文中。
關於聯邦政府獎助研究或開發之聲明
本發明係在政府支援之情況下,以國立衛生研究院(National Institutes of Health)、國立癌症研究院(National Cancer Institute)授予之項目編號BC010985進行。政府對本發明具有某些權利。
以引用之方式併入以電子方式提交之材料
與本申請案同時提交且如下標識之電腦可讀核苷酸/胺基酸序列表以全文引用之方式併入本文中:一個222,016位元組ASCII (Text)檔案,其命名為「757043_ST25.txt」,創建日期2021年8月18日。
腫瘤蛋白P53 (亦稱為「TP53」或「p53」)藉由例如調節細胞分裂而充當腫瘤抑制劑。p53蛋白位於細胞之細胞核中,p53蛋白在細胞核中直接結合DNA。當DNA受損時,p53蛋白參與確定是否將修復DNA或受損細胞是否將經歷細胞凋亡。若可修復DNA,則p53活化其他基因以修復損傷。若不能修復DNA,則p53蛋白防止細胞分裂,且對經歷細胞凋亡之細胞進行信號傳導。藉由阻止含有突變或受損DNA之細胞分裂,p53有助於防止腫瘤發展。WT (正常)全長p53包含胺基酸序列SEQ ID NO: 1。
p53蛋白中之突變可能降低或消除p53蛋白的腫瘤抑制功能。或者或另外,p53突變可藉由以顯性陰性方式干擾WT p53而成為功能獲得型突變。突變p53蛋白可表現於多種人類癌症中之任一種中,諸如膽管癌、黑色素瘤、大腸癌、直腸癌、卵巢癌、子宮內膜癌、非小細胞肺癌(NSCLC)、神經膠母細胞瘤、子宮頸癌、頭頸癌、乳癌、胰臟癌或膀胱癌。
本發明之一實施例提供一種經分離或經純化T細胞受體(TCR),其對人類p53
R273C或人類p53
Y220C胺基酸序列(在下文中,「突變p53」)具有抗原特異性。在下文中,除非另有規定,否則提及「TCR」亦指代TCR之功能部分及功能變體。本文中參考胺基酸序列全長WT p53 (SEQ ID NO: 1)來定義p53之突變。本文參考存在於特定位置處的胺基酸殘基,繼之以位置編號,繼之以在所論述特定突變中置換殘基的胺基酸來描述p53之突變。p53胺基酸序列(例如p53肽)可包含少於全長WT p53蛋白之全部胺基酸殘基。因此,在理解p53胺基酸序列之一特定實例中的對應殘基之實際位置可不同的情況下,本文參考WT全長p53蛋白(亦即SEQ ID NO: 1)來定義位置編號。由於位置如由SEQ ID NO: 1所定義,故術語「R273C」指示存在於SEQ ID NO: 1之位置273處的精胺酸經半胱胺酸置換,而「Y220C」指示存在於SEQ ID NO: 1之位置220處的酪胺酸經半胱胺酸置換。舉例而言,當p53胺基酸序列之特定實例為例如SGNLLGRNSFEV
R VCACPGRDRRTE (SEQ ID NO: 116)(對應於SEQ ID NO: 1之連續胺基酸殘基261至285之例示性WT p53肽)時,「R273C」係指SEQ ID NO: 116中加底線之精胺酸經半胱胺酸取代,即使SEQ ID NO: 116中加底線之精胺酸之實際位置為13。含有R273C突變之人類p53胺基酸序列在下文中稱為「R273C」或「p53
R273C」。含有Y220C突變之人類p53胺基酸序列在下文中稱為「Y220C」或「p53
Y220C」。如本文所用,「突變p53」係指人類p53
R273C或人類p53
Y220C。
P53具有九個已知剪接變體。本文所描述之p53突變保留於全部九個p53剪接變體上。九個p53剪接變體之比對展示於圖4中。因此,本發明TCR可對本文所描述之由九個p53剪接變體中之任一者編碼的任何突變p53胺基酸序列具有抗原特異性。由於位置如由SEQ ID NO: 1所定義,故p53之特定剪接變體的胺基酸序列之實際位置係相對於SEQ ID NO: 1之對應位置而定義,且如由SEQ ID NO: 1所定義之位置可不同於特定剪接變體中的實際位置。因此,舉例而言,在理解剪接變體中之實際位置可不同的情況下,突變係指對應於SEQ ID NO: 1之393-胺基酸序列之所指示位置的p53之特定剪接變體之胺基酸序列中的胺基酸殘基的置換。
在本發明之一實施例中,TCR對在如由SEQ ID NO: 1所定義之位置273處含有突變之人類p53具有抗原特異性。位置273處的p53突變可為任何誤義突變。因此,在位置273處之突變可為存在於位置273處之原生(WT)精胺酸殘基經除精胺酸外之任何胺基酸殘基取代。在本發明之一實施例中,TCR對人類p53
R273C胺基酸序列具有抗原特異性。舉例而言,TCR可對人類p53
R273C胺基酸序列SGNLLGRNSFEV
C VCACPGRDRRTE (SEQ ID NO: 117)具有抗原特異性。在本發明之一實施例中,TCR對野生型人類p53胺基酸序列SGNLLGRNSFEV
R VCACPGRDRRTE (SEQ ID NO: 116)不具有抗原特異性。
在本發明之一實施例中,TCR對在如由SEQ ID NO: 1所定義之位置220處含有突變的人類p53具有抗原特異性。位置220處的p53突變可為任何誤義突變。因此,在位置220處之突變可為存在於位置220處之原生(WT)酪胺酸殘基經除酪胺酸外之任何胺基酸殘基取代。在本發明之一實施例中,TCR對人類p53
Y220C胺基酸序列具有抗原特異性。舉例而言,TCR可對人類p53
Y220C胺基酸序列DRNTFRHSVVVP
C EPPEVGSDCTTI (SEQ ID NO: 115)具有抗原特異性。在本發明之一實施例中,TCR對野生型人類p53胺基酸序列DRNTFRHSVVVP
Y EPPEVGSDCTTI (SEQ ID NO: 114)不具有抗原特異性。
在本發明之一實施例中,本發明TCR可能夠以HLA (人類白血球抗原)分子依賴性方式識別突變p53。如本文所用之「HLA分子依賴性方式」意謂TCR在於HLA分子之環境內與突變p53結合後引發免疫反應,該HLA分子由分離TCR之患者表現。本發明TCR可能夠識別由適用HLA分子呈現之突變p53,且除突變p53外,可與HLA分子結合。
在本發明之一實施例中,本發明TCR能夠識別由II類HLA分子呈現之R273C。就此而言,TCR可在於II類HLA分子之環境內與R273C結合後引發免疫反應。本發明TCR可能夠識別由II類HLA分子呈現之R273C,且除R273C外,可與II類HLA分子結合。
在本發明之一實施例中,II類HLA分子為HLA-DP分子。HLA-DP分子為α鏈(DPA)及β鏈(DPB)之異二聚體。HLA-DPA鏈可為任何HLA-DPA鏈。HLA-DPB鏈可為任何HLA-DPB鏈。在本發明之一實施例中,II類HLA分子為HLA-DPA1鏈及HLA-DPB1鏈之異二聚體。HLA-DPA1分子之實例可包括但不限於由以下編碼之彼等分子:HLA-DPA1*01:03、HLA-DPA1*01:04、HLA-DPA1*01:05、HLA-DPA1*01:06、HLA-DPA1*01:07、HLA-DPA1*01:08、HLA-DPA1*01:09、HLA-DPA1*01:10、HLA-DPA1*02:01、HLA-DPA1*02:02、HLA-DPA1*02:03、HLA-DPA1*02:04、HLA-DPA1*03:01、HLA-DPA1*03:02、HLA-DPA1*03:03及HLA-DPA1*04:01等位基因。HLA-DPB1分子之實例可包括但不限於由以下編碼之彼等分子:HLA-DPB1*01:01、HLA-DPB1*02:01、HLA-DPB1*02:02、HLA-DPB1*03:01、HLA-DPB1*04:01、HLA-DPB1*04:02、HLA-DPB1*05:01、HLA-DPB1*06:01、HLA-DPB1*07:01、HLA-DPB1*08:01、HLA-DPB1*09:01及HLA-DPB1*10:01等位基因。較佳地,II類HLA分子為HLA-DPA1*01:03鏈及HLA-DPB1*04:02鏈之異二聚體。
在本發明之一實施例中,本發明TCR中之一者能夠識別由II類HLA分子呈現之Y220C。就此而言,TCR可在於II類HLA分子之環境內與Y220C結合後引發免疫反應。本發明TCR可能夠識別由II類HLA分子呈現之Y220C,且除Y220C外,可與II類HLA分子結合。
在本發明之一實施例中,II類HLA分子為HLA-DR異二聚體。HLA-DR異二聚體為包括α鏈及β鏈之細胞表面受體。HLA-DR α鏈由HLA-DRA基因編碼。在一實施例中,II類HLA分子之α鏈由HLA-DRA1*01:01:01等位基因表現。HLA-DR β鏈由HLA-DRB1基因、HLA-DRB3基因、HLA-DRB4基因或HLA-DRB5基因編碼。由HLA-DRB1基因編碼之分子的實例可包括但不限於HLA-DR1、HLA-DR2、HLA-DR3、HLA-DR4、HLA-DR5、HLA-DR6、HLA-DR7、HLA-DR8、HLA-DR9、HLA-DR10、HLA-DR11、HLA-DR12、HLA-DR13、HLA-DR14、HLA-DR15、HLA-DR16及HLA-DR17。HLA-DRB3基因編碼HLA-DR52。HLA-DRB4基因編碼HLA-DR53。HLA-DRB5基因編碼HLA-DR51。在本發明之一實施例中,II類HLA分子為HLA-DRB3:HLA-DRA異二聚體。II類HLA分子之β鏈可由HLA-DRB3*01:01、HLA-DRB3*02:02或HLA-DRB3*03:01等位基因表現。較佳地,II類HLA分子之β鏈由HLA-DRB3*02:02:01等位基因表現。在一較佳實施例中,II類HLA分子為HLA-DRA1*01:01:01鏈及HLA-DRB3*02:02:01鏈之異二聚體。
本發明之TCR可提供多種優勢中之任一或多者,包括在由細胞表現時用於過繼細胞轉移。突變p53由癌細胞表現且不由正常非癌細胞表現。不受特定理論或機制之束縛,咸信本發明之TCR有利地靶向癌細胞之破壞,同時最小化或消除正常非癌細胞之破壞,從而例如藉由最小化或消除來降低毒性。此外,本發明TCR可有利地成功治療或預防對諸如化學療法、手術或放射之其他類型之治療無反應的突變p53陽性癌症。另外,本發明TCR可提供對突變p53之高度親合識別,其可提供識別未經操縱之腫瘤細胞(例如,尚未用干擾素(IFN)-γ處理、用編碼突變p53及適用HLA分子中之一或兩者的載體轉染、用含有p53突變之p53肽脈衝或其組合之腫瘤細胞)之能力。全部腫瘤中之大約一半攜帶p53中之突變,其中約一半將為誤義突變。R273C突變由所有癌症中之約2.8%表現,且HLA-DPB1*04:02等位基因由約24%之美國高加索人群體及約60%至約80%之美國西班牙裔群體表現。Y220C突變出現於所有癌症中之約1.5%中,且HLA-DRB3*02:02等位基因由約33%之美國高加索人群體表現。R273C及Y220C突變產生於許多癌症組織結構中,從而表明多種患者群體可得益於本發明TCR。因此,本發明TCR可增加可符合免疫療法治療條件之患者的數目。
如本文所用之片語「抗原特異性」意謂TCR可以高親合力特異性結合於突變p53且免疫識別突變p53。舉例而言,若在與以下共培養之後,約1×10
4至約1×10
5個表現TCR之T細胞分泌至少約200 pg/mL或更多(例如200 pg/mL或更多、300 pg/mL或更多、400 pg/mL或更多、500 pg/mL或更多、600 pg/mL或更多、700 pg/mL或更多、1,000 pg/mL或更多、5,000 pg/mL或更多、7,000 pg/mL或更多、10,000 pg/mL或更多、20,000 pg/mL或更多或任何兩個前述值限定之範圍)之IFN-γ,則可將TCR視為對突變p53具有「抗原特異性」:(a)用低濃度之突變p53肽(例如約0.05 ng/mL至約5 ng/mL、0.05 ng/mL、0.1 ng/mL、0.5 ng/mL、1 ng/mL、5 ng/mL或任何兩個前述值限定之範圍)脈衝的抗原陰性之適用HLA分子陽性目標細胞;或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53的抗原陰性之適用HLA分子陽性目標細胞。表現本發明TCR之細胞亦可在與用較高濃度之突變p53肽脈衝的抗原陰性之適用HLA分子陽性目標細胞共培養之後分泌IFN-γ。
或者或另外,若在與(a)用低濃度之突變p53肽脈衝的抗原陰性之適用HLA分子陽性目標細胞或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53的抗原陰性之適用HLA分子陽性目標細胞共培養之後,與由陰性對照表現之IFN-γ的量相比,表現TCR之T細胞分泌至少兩倍的IFN-γ,則可將TCR視為對突變p53具有「抗原特異性」。陰性對照可為例如(i)與以下共培養的表現TCR之T細胞:(a)用相同濃度之不相關肽(例如具有不同於突變p53肽之序列的某種其他的肽)脈衝的抗原陰性之適用HLA分子陽性目標細胞,或(b)已引入編碼不相關肽之核苷酸序列以使得目標細胞表現不相關肽的抗原陰性之適用HLA分子陽性目標細胞;或(ii)與以下共培養的未經轉導之T細胞(例如來源於PBMC,不表現TCR):(a)用相同濃度之突變p53肽脈衝的抗原陰性之適用HLA分子陽性目標細胞,或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53的抗原陰性之適用HLA分子陽性目標細胞。IFN-γ分泌可藉由此項技術中已知之諸如酶聯免疫吸附分析(ELISA)的方法量測。
或者或另外,若在與(a)用低濃度之突變p53肽脈衝之抗原陰性之適用HLA分子陽性目標細胞或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53之抗原陰性之適用HLA分子陽性目標細胞共培養之後,與分泌IFN-γ之陰性對照T細胞的數目相比,表現TCR之T細胞分泌至少兩倍數目之IFN-γ,則可將TCR視為對突變p53具有「抗原特異性」。肽及陰性對照之濃度可如本文關於本發明之其他態樣所描述。分泌IFN-γ之細胞的數目可藉由此項技術中已知之諸如酶聯免疫斑點(ELISpot)分析的方法來量測。
可替代地或另外,若在與(a)用低濃度之突變p53肽脈衝的抗原陰性之適用HLA分子陽性目標細胞或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53的抗原陰性之適用HLA分子陽性目標細胞共培養之後,與藉由ELISpot針對與相同目標細胞共培養之陰性對照T細胞偵測之斑點數目相比,藉由ELISpot針對表現TCR之T細胞偵測到至少兩倍的斑點,則可將TCR視為對突變p53具有「抗原特異性」。肽及陰性對照之濃度可如本文關於本發明之其他態樣所描述。
或者或另外,若在與(a)用低濃度之突變p53肽脈衝的抗原陰性之適用HLA分子陽性目標細胞或(b)已引入編碼突變p53之核苷酸序列以使得目標細胞表現突變p53的抗原陰性之適用HLA分子陽性目標細胞共培養之後,藉由ELISpot針對表現TCR之T細胞偵測到大於約50個斑點,則可將TCR視為對突變p53具有「抗原特異性」。肽之濃度可如本文關於本發明之其他態樣所描述。
或者或另外,若在用表現突變p53之目標細胞刺激之後,如藉由例如流動式細胞測量術所量測,表現TCR之T細胞上調4-1BB及OX40中之一或兩者之表現,則可將TCR視為對突變p53具有「抗原特異性」。
本發明之一實施例提供一種TCR,其包含兩種多肽(亦即多肽鏈),諸如TCR之α鏈、TCR的β鏈、TCR之γ鏈、TCR的δ鏈或其組合。本發明TCR之多肽可包含任何胺基酸序列,其限制條件為TCR對突變p53具有抗原特異性。
在本發明之一實施例中,TCR包含兩個多肽鏈,其中之每一者包含可變區,該可變區包含TCR之互補決定區(CDR) 1、CDR2及CDR3。在本發明之一實施例中,TCR包含:第一多肽鏈,其包含α鏈CDR1 (CDR1α)、α鏈CDR2 (CDR2α)及α鏈CDR3 (CDR3α);及第二多肽鏈,其包含β鏈CDR1 (CDR1β)、β鏈CDR2 (CDR2β)及β鏈CDR3 (CDR3β)。在本發明之一實施例中,TCR包含以下胺基酸序列:(1) SEQ ID NO: 2-7全部;(2) SEQ ID NO: 21-26全部;(3) SEQ ID NO: 40-45全部;(4) SEQ ID NO: 59-64全部;或(5) SEQ ID NO: 78-83全部。在此段落中之胺基酸序列的前述五個集合中之每一者闡述對突變人類p53具有抗原特異性的五種不同TCR中之每一者的六個CDR區。各集合中之六個胺基酸序列分別對應於TCR的CDR1α、CDR2α、CDR3α、CDR1β、CDR2β及CDR3β。
在本發明之一實施例中,TCR包含一同包含上文所闡述之CDR集合中之一者的α鏈可變區胺基酸序列及β鏈可變區胺基酸序列。就此而言,TCR可例如包含以下任一胺基酸序列:SEQ ID NO: 8、9、10、11、12、13、27、28、29、30、31、32、46、47、48、49、50、51、65、66、67、68、69、70、84、85、86、87、88、89、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137及138。舉例而言,TCR可包含以下胺基酸序列:(1) SEQ ID NO: 8及9兩者;(2) SEQ ID NO: 10及11兩者;(3) SEQ ID NO: 12及13兩者;(4) SEQ ID NO: 12及11兩者;(5) SEQ ID NO: 121及13兩者;(6) SEQ ID NO: 121及122兩者;(7) SEQ ID NO: 8及120兩者;(8) SEQ ID NO: 119及9兩者;(9) SEQ ID NO: 119及120兩者;(10) SEQ ID NO: 27及28兩者;(11) SEQ ID NO: 29及30兩者;(12) SEQ ID NO: 31及32兩者;(13) SEQ ID NO: 31及30兩者;(14) SEQ ID NO: 125及32兩者;(15) SEQ ID NO: 125及126兩者;(16) SEQ ID NO: 27及124兩者;(17) SEQ ID NO: 123及28兩者;(18) SEQ ID NO: 123及124兩者;(19) SEQ ID NO: 46及47兩者;(20) SEQ ID NO: 48及49兩者;(21) SEQ ID NO: 50及51兩者;(22) SEQ ID NO: 50及49兩者;(23) SEQ ID NO: 129及51兩者;(24) SEQ ID NO: 129及130兩者;(25) SEQ ID NO: 46及128兩者;(26) SEQ ID NO: 127及47兩者;(27) SEQ ID NO: 127及128兩者;(28) SEQ ID NO: 65及66兩者;(29) SEQ ID NO: 67及68兩者;(30) SEQ ID NO: 69及70兩者;(31) SEQ ID NO: 69及68兩者;(32) SEQ ID NO: 133及70兩者;(33) SEQ ID NO: 133及134兩者;(34) SEQ ID NO: 65及132兩者;(35) SEQ ID NO: 131及66兩者;(36) SEQ ID NO: 131及132兩者;(37) SEQ ID NO: 84及85兩者;(38) SEQ ID NO: 86及87兩者;(39) SEQ ID NO: 88及89兩者;(40) SEQ ID NO: 88及87兩者;(41) SEQ ID NO: 137及89兩者;(42) SEQ ID NO: 137及138兩者;(43) SEQ ID NO: 84及136兩者;(44) SEQ ID NO: 135及85兩者;或(45) SEQ ID NO: 135及136兩者。在此段落中之胺基酸序列的前述集合中之每一者闡述對突變人類p53具有抗原特異性的不同TCR中之每一者的兩個可變區。各集合中之兩個胺基酸序列分別對應於TCR的α鏈之可變區及β鏈之可變區。
本發明TCR可進一步包含恆定區。恆定區可來源於諸如人類或小鼠之任何適合物種。在本發明之一實施例中,TCR進一步包含鼠類恆定區。如本文所用,當提及本文所描述之TCR或TCR之任何組分(例如互補決定區(CDR)、可變區、恆定區、α鏈及/或β鏈)時,術語「鼠類」或「人類」分別意謂來源於小鼠或人類的TCR (或其組分),亦即分別來源於小鼠T細胞或人類T細胞或曾經由小鼠T細胞或人類T細胞表現之TCR (或其組分)。在本發明之一實施例中,TCR可包含鼠類α鏈恆定區及鼠類β鏈恆定區。鼠類α鏈恆定區可經修飾或未經修飾。經修飾鼠類α鏈恆定區可為例如經半胱胺酸取代、經LVL修飾或經半胱胺酸取代且經LVL修飾兩者,如例如在美國專利第10,174,098號中所描述。鼠類β鏈恆定區可經修飾或未經修飾。經修飾鼠類β鏈恆定區可例如經半胱胺酸取代,如例如在美國專利第10,174,098號中所描述。在本發明之一些實施例中,TCR包含經半胱胺酸取代、經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 97。在本發明之一些實施例中TCR包含經半胱胺酸取代、經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 98。在本發明之一些實施例中,TCR包含經半胱胺酸取代、經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 143。在本發明之一些實施例中,TCR包含經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 144。在本發明之一些實施例中,TCR包含經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 145。在本發明之一些實施例中,TCR包含經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 146。在本發明之一些實施例中,TCR包含經LVL修飾之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 147。在本發明之一些實施例中,TCR包含經半胱胺酸取代之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 148。在本發明之一些實施例中,TCR包含經半胱胺酸取代之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 149。在本發明之一實施例中,TCR包含D1鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 139。在本發明之一些實施例中,TCR包含簡併胺基酸序列中所描述之鼠類α鏈恆定區,其包含胺基酸序列SEQ ID NO: 141。在本發明之一實施例中,TCR包含經半胱胺酸取代之鼠類β鏈恆定區,其包含胺基酸序列SEQ ID NO: 99。在本發明之一實施例中,TCR包含野生型鼠類β鏈恆定區,其包含胺基酸序列SEQ ID NO: 140。在本發明之一些實施例中,TCR包含簡併胺基酸序列中所描述之鼠類β鏈恆定區,其包含胺基酸序列SEQ ID NO: 142。
例示性Cα區序列及Cβ區序列展示於表1及表2中。
表1
TCR Cα 區之胺基酸序列。
表2
TCR C β 區之胺基酸序列。
描述 | 序列 | SEQ ID NO: |
Cα (D1變體) | DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSS | 139 |
Cα (簡併) | XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKXVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLXVXXLRILLLKVAGFNLLMTLRLWSS 位置1處的X為Asn、Asp、His或Tyr; 位置48處的X為Thr或Cys; 位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp; 位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp | 141 |
Cα (經半胱胺酸及LVL修飾,經取代,胺基酸1處為X) | XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS 位置1處的X為Asn、Asp、His或Tyr | 143 |
Cα (經半胱胺酸及LVL修飾,經取代,胺基酸1處為N) | NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS | 97 |
Cα (經半胱胺酸及LVL修飾,經取代,胺基酸1處為D) | DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS | 98 |
Cα (經LVL修飾,胺基酸1處為X) | XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS 位置1處的X為Asn、Asp、His或Tyr | 144 |
Cα (經LVL修飾,胺基酸1處為N) | NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS | 145 |
Cα (經LVL修飾,胺基酸1處為D) | DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS | 146 |
Cα (經半胱胺酸取代,胺基酸1處為X) | XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSS 位置1處的X為Asn、Asp、His或Tyr | 147 |
Cα (經半胱胺酸取代,胺基酸1處為N) | NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSS | 148 |
Cα (經半胱胺酸取代,胺基酸1處為D) | DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSS | 149 |
描述 | 序列 | SEQ ID NO: |
Cβ (經半胱胺酸取代) | EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS | 99 |
Cβ (野生型) | EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVSTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS | 140 |
Cβ (簡併) | EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVXTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS 位置57處的X為Ser或Cys | 142 |
在本發明之一實施例中,本發明TCR可包含TCR之α鏈及TCR之β鏈。TCR之α鏈可包含α鏈之可變區及α鏈之恆定區。此類型之α鏈可與TCR的任何β鏈配對。該β鏈可包含β鏈之可變區及β鏈之恆定區。
在一些實施例中,本文所揭示的α鏈及/或β鏈中之任一者的胺基酸序列在C端末端處進一步包含胺基酸序列RAKR (SEQ ID NO: 118)。
在本發明之一實施例中,TCR包含以下任一胺基酸序列:SEQ ID NO: 14、15、16、17、18、19、33、34、35、36、37、38、52、53、54、55、56、57、71、72、73、74、75、76、90、91、92、93、94及95。舉例而言,TCR可包含以下胺基酸序列:(1) SEQ ID NO: 14及15兩者;(2) SEQ ID NO: 16及17兩者;(3) SEQ ID NO: 18及19兩者;(4) SEQ ID NO: 33及34兩者;(5) SEQ ID NO: 35及36兩者;(6) SEQ ID NO: 37及38兩者;(7) SEQ ID NO: 52及53兩者;(8) SEQ ID NO: 54及55兩者;(9) SEQ ID NO: 56及57兩者;(10) SEQ ID NO: 71及72兩者;(11) SEQ ID NO: 73及74兩者;(12) SEQ ID NO: 75及76兩者;(13) SEQ ID NO: 90及91兩者;(14) SEQ ID NO: 92及93兩者;或(15) SEQ ID NO: 94及95兩者。在此段落中之胺基酸序列的前述集合中之每一者闡述對突變人類p53具有抗原特異性的不同TCR中之每一者的α鏈及β鏈。各集合中之兩個胺基酸序列分別對應於TCR的α鏈及β鏈。
本文所描述之本發明TCR之功能變體包括於本發明之範疇中。如本文所用,術語「功能變體」係指與親本TCR、多肽或蛋白質具有實質或顯著序列一致性或類似性之TCR、多肽或蛋白質,該功能變體保留其作為變體之TCR、多肽或蛋白質的生物活性。功能變體涵蓋例如本文所描述之TCR、多肽或蛋白質(親本TCR、多肽或蛋白質)之彼等變體,其保留以與親本TCR、多肽或蛋白質類似之程度、相同之程度或更高之程度特異性結合於突變p53的能力,親本TCR對該突變p53具有抗原特異性或者親本多肽或蛋白質特異性結合於該突變p53。參考親本TCR、多肽或蛋白質,功能變體可在胺基酸序列方面分別與親本TCR、多肽或蛋白質例如至少約30%、至少約50%、至少約75%、至少約80%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%一致或具更高一致性。
功能變體可例如包含含有至少一個保守胺基酸取代之親本TCR、多肽或蛋白質之胺基酸序列。保守胺基酸取代為此項技術中已知的且包括其中一個具有某些物理及/或化學特性之胺基酸經另一個具有相同化學或物理特性之胺基酸交換的胺基酸取代。舉例而言,保守胺基酸取代可為酸性胺基酸經取代成另一酸性胺基酸(例如Asp或Glu)、具有非極性側鏈之胺基酸經取代成另一具有非極性側鏈之胺基酸(例如Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Val等)、鹼性胺基酸經取代成另一鹼性胺基酸(Lys、Arg等)、具有極性側鏈之胺基酸經取代成另一具有極性側鏈之胺基酸(Asn、Cys、Gln、Ser、Thr、Tyr等),等等。
或者或另外,功能變體可包含含有至少一個非保守胺基酸取代之親本TCR、多肽或蛋白質之胺基酸序列。在此情況下,非保守胺基酸取代不干擾或抑制功能變體之生物活性較佳。較佳地,非保守性胺基酸取代增強功能變體之生物活性,使得與親本TCR、多肽或蛋白質相比,功能變體之生物活性增加。
TCR、多肽或蛋白質可基本上由本文所描述之指定胺基酸序列或序列組成,使得TCR、多肽或蛋白質的其他組分(例如其他胺基酸)不實質上改變TCR、多肽或蛋白質之生物活性。
本發明亦提供一種多肽,其包含本文所描述之TCR中之任一者之功能部分。如本文所用之術語「多肽」包括寡肽,且係指由一或多個肽鍵連接之單個胺基酸鏈。
關於本發明多肽,功能部分可為包含其作為組成部分之TCR的連續胺基酸之任何部分,其限制條件為功能部分特異性結合於突變p53。術語「功能部分」當在提及TCR使用時,係指本發明之TCR之任何部分或片段,該部分或片段保留其作為組成部分之TCR (親本TCR)之生物活性。功能部分涵蓋例如保留以與親本TCR類似之程度、相同之程度或更高之程度特異性結合於突變p53 (例如以適用HLA分子依賴性方式)或偵測、治療或防止癌症之能力的TCR之彼等部分。關於親本TCR,功能部分可包含親本TCR之例如約10%、約25%、約30%、約50%、約70%、約80%、約90%、約95%或更多。
功能部分可在該部分之胺基或羧基端或在兩個端處包含額外胺基酸,該等額外胺基酸在親本TCR之胺基酸序列中未發現。理想地,該等額外胺基酸不干擾功能部分之生物功能,例如特異性結合於突變p53;及/或能夠偵測癌症、治療或預防癌症等。更理想地,與親本TCR之生物活性相比,該等額外胺基酸增強生物活性。
多肽可包含本發明之TCR之α鏈及β鏈中的任一者或兩者之功能部分,諸如包含本發明之TCR之α鏈及/或β鏈之可變區的CDR1、CDR2及CDR3中之一或多者的功能部分。在本發明之一實施例中,多肽可包含以下胺基酸序列:(1) SEQ ID NO: 2-7全部;(2) SEQ ID NO: 21-26全部;(3) SEQ ID NO: 40-45全部;(4) SEQ ID NO: 59-64全部;或(5) SEQ ID NO: 78-83全部。
在本發明之一實施例中,本發明多肽可包含例如本發明TCR的可變區,其包含上文闡述之CDR區的組合。就此而言,多肽可包含例如以下胺基酸序列:(1) SEQ ID NO: 8及9兩者;(2) SEQ ID NO: 10及11兩者;(3) SEQ ID NO: 12及13兩者;(4) SEQ ID NO: 12及11兩者;(5) SEQ ID NO: 121及13兩者;(6) SEQ ID NO: 121及122兩者;(7) SEQ ID NO: 8及120兩者;(8) SEQ ID NO: 119及9兩者;(9) SEQ ID NO: 119及120兩者;(10) SEQ ID NO: 27及28兩者;(11) SEQ ID NO: 29及30兩者;(12) SEQ ID NO: 31及32兩者;(13) SEQ ID NO: 31及30兩者;(14) SEQ ID NO: 125及32兩者;(15) SEQ ID NO: 125及126兩者;(16) SEQ ID NO: 27及124兩者;(17) SEQ ID NO: 123及28兩者;(18) SEQ ID NO: 123及124兩者;(19) SEQ ID NO: 46及47兩者;(20) SEQ ID NO: 48及49兩者;(21) SEQ ID NO: 50及51兩者;(22) SEQ ID NO: 50及49兩者;(23) SEQ ID NO: 129及51兩者;(24) SEQ ID NO: 129及130兩者;(25) SEQ ID NO: 46及128兩者;(26) SEQ ID NO: 127及47兩者;(27) SEQ ID NO: 127及128兩者;(28) SEQ ID NO: 65及66兩者;(29) SEQ ID NO: 67及68兩者;(30) SEQ ID NO: 69及70兩者;(31) SEQ ID NO: 69及68兩者;(32) SEQ ID NO: 133及70兩者;(33) SEQ ID NO: 133及134兩者;(34) SEQ ID NO: 65及132兩者;(35) SEQ ID NO: 131及66兩者;(36) SEQ ID NO: 131及132兩者;(37) SEQ ID NO: 84及85兩者;(38) SEQ ID NO: 86及87兩者;(39) SEQ ID NO: 88及89兩者;(40) SEQ ID NO: 88及87兩者;(41) SEQ ID NO: 137及89兩者;(42) SEQ ID NO: 137及138兩者;(43) SEQ ID NO: 84及136兩者;(44) SEQ ID NO: 135及85兩者;或(45) SEQ ID NO: 135及136兩者。
在本發明之一實施例中,本發明多肽可進一步包含上文闡述之本發明TCR之恆定區。就此而言,多肽可包含例如以下胺基酸序列:(i) SEQ ID NO 97-99及139-149中之一者;或(ii) SEQ ID NO: 99、140及142中之一者及SEQ ID NO: 97、98、139、141及143-149中之一者。
在本發明之一實施例中,本發明多肽可包含本發明TCR的α鏈及β鏈。就此而言,多肽可包含例如以下胺基酸序列:(1) SEQ ID NO: 14及15兩者;(2) SEQ ID NO: 16及17兩者;(3) SEQ ID NO: 18及19兩者;(4) SEQ ID NO: 33及34兩者;(5) SEQ ID NO: 35及36兩者;(6) SEQ ID NO: 37及38兩者;(7) SEQ ID NO: 52及53兩者;(8) SEQ ID NO: 54及55兩者;(9) SEQ ID NO: 56及57兩者;(10) SEQ ID NO: 71及72兩者;(11) SEQ ID NO: 73及74兩者;(12) SEQ ID NO: 75及76兩者;(13) SEQ ID NO: 90及91兩者;(14) SEQ ID NO: 92及93兩者;或(15) SEQ ID NO: 94及95兩者。
本發明之一實施例進一步提供一種蛋白質,其包含本文所描述之多肽中之至少一者。「蛋白質」意謂包含一或多個多肽鏈之分子。在一實施例中,本發明之蛋白質可包含:(1)包含胺基酸序列SEQ ID NO: 2-4中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 5-7中全部的第二多肽鏈;(2)包含胺基酸序列SEQ ID NO: 21-23中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 24-26中全部的第二多肽鏈;(3)包含胺基酸序列SEQ ID NO: 40-42中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 43-45中全部的第二多肽鏈;(4)包含胺基酸序列SEQ ID NO: 59-61中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 62-64中全部的第二多肽鏈;或(5)包含胺基酸序列SEQ ID NO: 78-80中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 81-83中全部的第二多肽鏈。
在本發明之一實施例中,蛋白質包含:(1)包含胺基酸序列SEQ ID NO: 8之第一多肽鏈及包含胺基酸序列SEQ ID NO: 9之第二多肽鏈;(2)包含胺基酸序列SEQ ID NO: 10之第一多肽鏈及包含胺基酸序列SEQ ID NO: 11之第二多肽鏈;(3)包含胺基酸序列SEQ ID NO: 12之第一多肽鏈及包含胺基酸序列SEQ ID NO: 13之第二多肽鏈;(4)包含胺基酸序列SEQ ID NO: 12之第一多肽鏈及包含胺基酸序列SEQ ID NO: 11之第二多肽鏈;(5)包含胺基酸序列SEQ ID NO: 121之第一多肽鏈及包含胺基酸序列SEQ ID NO: 13之第二多肽鏈;(6)包含胺基酸序列SEQ ID NO: 121之第一多肽鏈及包含胺基酸序列SEQ ID NO: 122之第二多肽鏈;(7)包含胺基酸序列SEQ ID NO: 8之第一多肽鏈及包含胺基酸序列SEQ ID NO: 120之第二多肽鏈;(8)包含胺基酸序列SEQ ID NO: 119之第一多肽鏈及包含胺基酸序列SEQ ID NO: 9之第二多肽鏈;(9)包含胺基酸序列SEQ ID NO: 119之第一多肽鏈及包含胺基酸序列SEQ ID NO: 120之第二多肽鏈;(10)包含胺基酸序列SEQ ID NO: 27之第一多肽鏈及包含胺基酸序列SEQ ID NO: 28之第二多肽鏈;(11)包含胺基酸序列SEQ ID NO: 29之第一多肽鏈及包含胺基酸序列SEQ ID NO: 30之第二多肽鏈;(12)包含胺基酸序列SEQ ID NO: 31之第一多肽鏈及包含胺基酸序列SEQ ID NO: 32之第二多肽鏈;(13)包含胺基酸序列SEQ ID NO: 31之第一多肽鏈及包含胺基酸序列SEQ ID NO: 30之第二多肽鏈;(14)包含胺基酸序列SEQ ID NO: 125之第一多肽鏈及包含胺基酸序列SEQ ID NO: 32之第二多肽鏈;(15)包含胺基酸序列SEQ ID NO: 125之第一多肽鏈及包含胺基酸序列SEQ ID NO: 126之第二多肽鏈;(16)包含胺基酸序列SEQ ID NO: 27之第一多肽鏈及包含胺基酸序列SEQ ID NO: 124之第二多肽鏈;(17)包含胺基酸序列SEQ ID NO: 123之第一多肽鏈及包含胺基酸序列SEQ ID NO: 28之第二多肽鏈;(18)包含胺基酸序列SEQ ID NO: 123之第一多肽鏈及包含胺基酸序列SEQ ID NO: 124之第二多肽鏈;(19)包含胺基酸序列SEQ ID NO: 46之第一多肽鏈及包含胺基酸序列SEQ ID NO: 47之第二多肽鏈;(20)包含胺基酸序列SEQ ID NO: 48之第一多肽鏈及包含胺基酸序列SEQ ID NO: 49之第二多肽鏈;(21)包含胺基酸序列SEQ ID NO: 50之第一多肽鏈及包含胺基酸序列SEQ ID NO: 51之第二多肽鏈;(22)包含胺基酸序列SEQ ID NO: 50之第一多肽鏈及包含胺基酸序列SEQ ID NO: 49之第二多肽鏈;(23)包含胺基酸序列SEQ ID NO: 129之第一多肽鏈及包含胺基酸序列SEQ ID NO: 51之第二多肽鏈;(24)包含胺基酸序列SEQ ID NO: 129之第一多肽鏈及包含胺基酸序列SEQ ID NO: 130之第二多肽鏈;(25)包含胺基酸序列SEQ ID NO: 46之第一多肽鏈及包含胺基酸序列SEQ ID NO: 128之第二多肽鏈;(26)包含胺基酸序列SEQ ID NO: 127之第一多肽鏈及包含胺基酸序列SEQ ID NO: 47之第二多肽鏈;(27)包含胺基酸序列SEQ ID NO: 127之第一多肽鏈及包含胺基酸序列SEQ ID NO: 128之第二多肽鏈;(28)包含胺基酸序列SEQ ID NO: 65之第一多肽鏈及包含胺基酸序列SEQ ID NO: 66之第二多肽鏈;(29)包含胺基酸序列SEQ ID NO: 67之第一多肽鏈及包含胺基酸序列SEQ ID NO: 68之第二多肽鏈;(30)包含胺基酸序列SEQ ID NO: 69之第一多肽鏈及包含胺基酸序列SEQ ID NO: 70之第二多肽鏈;(31)包含胺基酸序列SEQ ID NO: 69之第一多肽鏈及包含胺基酸序列SEQ ID NO: 68之第二多肽鏈;(32)包含胺基酸序列SEQ ID NO: 133之第一多肽鏈及包含胺基酸序列SEQ ID NO: 70之第二多肽鏈;(33)包含胺基酸序列SEQ ID NO: 133之第一多肽鏈及包含胺基酸序列SEQ ID NO: 134之第二多肽鏈;(34)包含胺基酸序列SEQ ID NO: 65之第一多肽鏈及包含胺基酸序列SEQ ID NO: 132之第二多肽鏈;(35)包含胺基酸序列SEQ ID NO: 131之第一多肽鏈及包含胺基酸序列SEQ ID NO: 66之第二多肽鏈;(36)包含胺基酸序列SEQ ID NO: 131之第一多肽鏈及包含胺基酸序列SEQ ID NO: 132之第二多肽鏈;(37)包含胺基酸序列SEQ ID NO: 84之第一多肽鏈及包含胺基酸序列SEQ ID NO: 85之第二多肽鏈;(38)包含胺基酸序列SEQ ID NO: 86之第一多肽鏈及包含胺基酸序列SEQ ID NO: 87之第二多肽鏈;(39)包含胺基酸序列SEQ ID NO: 88之第一多肽鏈及包含胺基酸序列SEQ ID NO: 89之第二多肽鏈;(40)包含胺基酸序列SEQ ID NO: 88之第一多肽鏈及包含胺基酸序列SEQ ID NO: 87之第二多肽鏈;(41)包含胺基酸序列SEQ ID NO: 137之第一多肽鏈及包含胺基酸序列SEQ ID NO: 89之第二多肽鏈;(42)包含胺基酸序列SEQ ID NO: 137之第一多肽鏈及包含胺基酸序列SEQ ID NO: 138之第二多肽鏈;(43)包含胺基酸序列SEQ ID NO: 84之第一多肽鏈及包含胺基酸序列SEQ ID NO: 136之第二多肽鏈;(44)包含胺基酸序列SEQ ID NO: 135之第一多肽鏈及包含胺基酸序列SEQ ID NO: 85之第二多肽鏈;或(45)包含胺基酸序列SEQ ID NO: 135之第一多肽鏈及包含胺基酸序列SEQ ID NO: 136之第二多肽鏈。
在本發明之一實施例中,蛋白質可進一步包含上文闡述之本發明TCR之恆定區。就此而言,第一多肽鏈可包含SEQ ID NO: 99、140及142中之一者,且第二多肽鏈可包含SEQ ID NO: 97、98、139、141及143-149中之一者。
在本發明之一實施例中,蛋白質包含:(1)包含胺基酸序列SEQ ID NO: 14之第一多肽鏈及包含胺基酸序列SEQ ID NO: 15之第二多肽鏈;(2)包含胺基酸序列SEQ ID NO: 16之第一多肽鏈及包含胺基酸序列SEQ ID NO: 17之第二多肽鏈;(3)包含胺基酸序列SEQ ID NO: 18之第一多肽鏈及包含胺基酸序列SEQ ID NO: 19之第二多肽鏈;(4)包含胺基酸序列SEQ ID NO: 33之第一多肽鏈及包含胺基酸序列SEQ ID NO: 34之第二多肽鏈;(5)包含胺基酸序列SEQ ID NO: 35之第一多肽鏈及包含胺基酸序列SEQ ID NO: 36之第二多肽鏈;(6)包含胺基酸序列SEQ ID NO: 37之第一多肽鏈及包含胺基酸序列SEQ ID NO: 38之第二多肽鏈;(7)包含胺基酸序列SEQ ID NO: 52之第一多肽鏈及包含胺基酸序列SEQ ID NO: 53之第二多肽鏈;(8)包含胺基酸序列SEQ ID NO: 54之第一多肽鏈及包含胺基酸序列SEQ ID NO: 55之第二多肽鏈;(9)包含胺基酸序列SEQ ID NO: 56之第一多肽鏈及包含胺基酸序列SEQ ID NO: 57之第二多肽鏈;(10)包含胺基酸序列SEQ ID NO: 71之第一多肽鏈及包含胺基酸序列SEQ ID NO: 72之第二多肽鏈;(11)包含胺基酸序列SEQ ID NO: 73之第一多肽鏈及包含胺基酸序列SEQ ID NO: 74之第二多肽鏈;(12)包含胺基酸序列SEQ ID NO: 75之第一多肽鏈及包含胺基酸序列SEQ ID NO: 76之第二多肽鏈;(13)包含胺基酸序列SEQ ID NO: 90之第一多肽鏈及包含胺基酸序列SEQ ID NO: 91之第二多肽鏈;(14)包含胺基酸序列SEQ ID NO: 92之第一多肽鏈及包含胺基酸序列SEQ ID NO: 93之第二多肽鏈;或(15)包含胺基酸序列SEQ ID NO: 94之第一多肽鏈及包含胺基酸序列SEQ ID NO: 95之第二多肽鏈。
本發明之蛋白質可為TCR。或者,若蛋白質之第一及/或第二多肽鏈進一步包含其他胺基酸序列,例如編碼免疫球蛋白或其部分的胺基酸序列,則本發明蛋白質可為融合蛋白。就此而言,本發明之一實施例亦提供一種融合蛋白,其包含本文所描述之本發明多肽中之至少一者以及至少一種其他多肽。另一種多肽可以融合蛋白之獨立多肽之形式存在,或可以多肽之形式存在,其與本文所描述之本發明多肽中之一者同框(以串聯方式)表現。另一種多肽可編碼任何肽或蛋白質分子或其部分,包括但不限於免疫球蛋白、CD3、CD4、CD8、MHC分子、CD1分子,例如CD1a、CD1b、CD1c、CD1d等。
融合蛋白可包含本發明多肽之一或多個複本及/或另一種多肽之一或多個複本。舉例而言,融合蛋白可包含本發明多肽及/或另一種多肽之1、2、3、4、5或更多個複本。製備融合蛋白之適合方法為此項技術中已知的,且包括例如重組方法。
在本發明之一些實施例中,本發明之TCR、多肽及蛋白質可表現為包含連接α鏈及β鏈之連接子肽的單一蛋白質。就此而言,本發明之TCR、多肽及蛋白質可進一步包含連接子肽。連接子肽可有利地促進重組TCR、多肽及/或蛋白質在宿主細胞中之表現。連接子肽可包含任何適合之胺基酸序列。舉例而言,連接子肽可包含胺基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 100)。當藉由宿主細胞表現包括連接子肽之構築體時,連接子肽可經裂解,從而產生分離之α鏈及β鏈。在本發明之一實施例中,TCR、多肽或蛋白質可包含含有全長α鏈、全長β鏈及位於α鏈與β鏈之間的連接子肽的胺基酸序列。
在一些實施例中,本文所揭示之TCR、多肽或蛋白質包含如本文所揭示的包含信號肽之α鏈及/或β鏈。在一些實施例中,本文所揭示之α鏈及/或β鏈中的任一者之信號肽的序列包含在位置2處取代野生型殘基之丙胺酸或組胺酸殘基。
在一些實施例中,本文所揭示之TCR、多肽或蛋白質包含如本文所揭示之α鏈及/或β鏈的缺乏信號肽之成熟型式。
本發明之蛋白質可為重組抗體或其抗原結合部分,其包含本文所描述之本發明多肽中之至少一者。如本文所用,「重組抗體」係指包含本發明之多肽中之至少一者及抗體或其抗原結合部分之多肽鏈的重組(例如經基因工程改造)蛋白。抗體或其抗原結合部分之多肽可為抗體之重鏈、輕鏈、重鏈或輕鏈之可變區或恆定區、單鏈可變片段(scFv)或Fc、Fab或F(ab)
2'片段等。抗體或其抗原結合部分之多肽鏈可以重組抗體之獨立多肽形式存在。或者,抗體或其抗原結合部分之多肽鏈可以多肽之形式存在,其與本發明之多肽同框(以串聯方式)表現。抗體或其抗原結合部分之多肽可為任何抗體或任何抗體片段(包括本文所描述之任何抗體及抗體片段)之多肽。
本發明之TCR、多肽及蛋白質可具有任何長度,亦即可包含任何數目之胺基酸,其限制條件為TCR、多肽或蛋白質保留其生物活性,例如能夠特異性結合於突變p53;偵測哺乳動物之癌症;或治療或預防哺乳動物之癌症等。舉例而言,多肽之長度可在約50至約5,000個胺基酸之範圍內,諸如長度為50、70、75、100、125、150、175、200、300、400、500、600、700、800、900、1000或更多個胺基酸。就此而言,本發明之多肽亦包括寡肽。
本發明之TCR、多肽及蛋白質可包含代替一或多種天然存在之胺基酸的合成胺基酸。此類合成胺基酸為此項技術中已知的,且包括例如胺基環己烷甲酸、正白胺酸、α-胺基正癸酸、高絲胺酸、S-乙醯胺基甲基-半胱胺酸、反式-3-羥脯胺酸及反式-4-羥脯胺酸、4-胺基苯丙胺酸、4-硝基苯丙胺酸、4-氯苯丙胺酸、4-羧基苯丙胺酸、β-苯基絲胺酸β-羥基苯基丙胺酸、苯基甘胺酸、α-萘基丙胺酸、丙胺酸環己酯、環己基甘胺酸、吲哚啉-2-甲酸、1,2,3,4-四氫異喹啉-3-甲酸、胺基丙二酸、胺基丙二酸單醯胺、N'-苯甲基-N'-甲基-離胺酸、N',N'-二苯甲基-離胺酸、6-羥基離胺酸、鳥胺酸、α-胺基環戊烷甲酸、α-胺基環己烷甲酸、α-胺基環庚烷甲酸、α-(2-胺基-2-降莰烷)-甲酸、α,γ-二胺基丁酸、α,β-二胺基丙酸、高苯丙胺酸及α-三級丁基甘胺酸。
本發明之TCR、多肽及蛋白質可例如經糖基化、醯胺化、羧化、磷酸化、酯化、正醯基化、經由例如二硫橋鍵環化或轉化成酸加成鹽及/或視情況二聚合或聚合,或結合。
本發明之TCR、多肽及/或蛋白質可藉由此項技術中已知之諸如重新合成的方法獲得。此外,多肽及蛋白質可使用本文所描述之核酸、使用標準重組方法以重組方式產生。參見例如Green及Sambrook,
Molecular Cloning: A Laboratory Manual,第4版,Cold Spring Harbor Press,Cold Spring Harbor,NY (2012)。或者,本文所描述之TCR、多肽及/或蛋白質可由各種商業實體中之任一者合成。就此而言,本發明TCR、多肽及蛋白質可為合成的、重組的、分離的及/或純化的。
本發明之一實施例提供一種核酸,其包含編碼本文所描述之TCR、多肽或蛋白質中之任一者的核苷酸序列。如本文所用之「核酸」包括「聚核苷酸」、「寡核苷酸」及「核酸分子」,且通常意謂可為單股或雙股之DNA或RNA之聚合物,其可含有天然、非天然或改變之核苷酸,且其可含有天然、非天然或改變之核苷酸間鍵,諸如磷醯胺酸鍵或硫代磷酸酯鍵而非未經修飾之寡核苷酸之核苷酸之間發現的磷酸二酯。在一實施例中,核酸包含互補DNA (cDNA)。通常,核酸不包含任何插入、缺失、倒位及/或取代較佳。然而,在一些情況下,如本文所論述,核酸包含一或多個插入、缺失、倒位及/或取代可為適合的。
本發明之一實施例提供一種經分離或經純化之核酸,其自5'至3'包含第一核苷酸序列及第二核苷酸序列,其中該第一及第二核苷酸序列分別編碼以下胺基酸序列:SEQ ID NO: 8及9;9及8;10及11;11及10;12及13;13及12;12及11;11及12;121及13;13及121;121及122;122及121;8及120;120及8;119及9;9及119;119及120;120及119;14及15;15及14;16及17;17及16;18及19;19及18;27及28;28及27;29及30;30及29;31及32;32及31;31及30;30及31;125及32;32及125;125及126;126及125;27及124;124及27;123及28;28及123;123及124;124及123;33及34;34及33;35及36;36及35;37及38;38及37;46及47;47及46;48及49;49及48;50及51;51及50;50及49;49及50;129及51;51及129;129及130;130及129;46及128;128及46;127及47;47及127;127及128;128及127;52及53;53及52;54及55;55及54;56及57;57及56;65及66;66及65;67及68;68及67;69及70;70及69;69及68;68及69;133及70;70及133;133及134;134及133;65及132;132及65;131及66;66及131;131及132;132及131;71及72;72及71;73及74;74及73;75及76;76及75;84及85;85及84;86及87;87及86;88及89;89及88;88及87;87及88;137及89;89及137;137及138;138及137;84及136;136及84;135及85;85及135;135及136;136及135;90及91;91及90;92及93;93及92;94及95;或95及94。
在本發明之一實施例中,核酸進一步包含插入於第一與第二核苷酸序列之間的第三核苷酸序列,其中該第三核苷酸序列編碼可裂解連接子肽。舉例而言,可裂解連接子肽可包含胺基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 100)。在本發明之一實施例中,核酸編碼選自由以下組成之群的胺基酸序列:SEQ ID NO: 20、39、58、77及96。舉例而言,核酸可包含選自由SEQ ID NO: 109-113組成之群的核苷酸序列。
較佳地,本發明之核酸為重組的。如本文所用,術語「重組」係指(i)藉由將天然或合成之核酸片段接合至可在活細胞中複製之核酸分子而在活細胞外部構築之分子,或(ii)由上文(i)中描述之彼等分子之複製產生的分子。出於本文之目的,複製可為活體外複製或活體內複製。
核酸可使用此項技術中已知之程序基於化學合成及/或酶連接反應進行構築。參見例如Green及Sambrook等人,同上。舉例而言,核酸可使用天然存在之核苷酸或不同地經修飾之核苷酸化學合成,該等經修飾之核苷酸經設計以增加分子之生物穩定性或增加雜合時形成之雙螺旋的物理穩定性(例如,經硫代磷酸酯衍生物及吖啶取代之核苷酸)。可用以產生核酸的經修飾核苷酸之實例包括但不限於5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黃嘌呤、黃嘌呤、4-乙醯胞嘧啶、5-(羧基羥甲基)尿嘧啶、5-羧甲基胺基甲基-2-硫代尿苷、5-羧甲基胺基甲基尿嘧啶、二氫尿嘧啶、β-D-半乳糖苷基Q核苷、肌苷、N
6-異戊烯基腺嘌呤、1-甲基鳥嘌呤、1-甲基肌苷、2,2-二甲基鳥嘌呤、2-甲基腺嘌呤、2-甲基鳥嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、經N
6取代之腺嘌呤、7-甲基鳥嘌呤、5-甲胺基甲基尿嘧啶、5-甲氧基胺甲基-2-硫尿嘧啶、β-D-甘露糖苷基Q核苷、5-甲氧基羧基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N
6-異戊烯基腺嘌呤、尿嘧啶-5-氧基乙酸(v)、懷丁氧苷(wybutoxosine)、假尿嘧啶、Q核苷、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、尿嘧啶-5-氧基乙酸甲酯、3-(3-胺基-3-N-2-羧丙基)尿嘧啶及2,6-二胺基嘌呤。或者,本發明之一或多種核酸可購自各種商業實體中之任一者。
在本發明之一實施例中,核酸包含編碼本文所描述之TCR、多肽或蛋白質中之任一者的密碼子最佳化核苷酸序列。不受任何特定理論或機制束縛,咸信核苷酸序列之密碼子最佳化增加mRNA轉錄物之轉譯效率。核苷酸序列之密碼子最佳化可涉及用另一密碼子取代原生密碼子,該另一密碼子編碼相同胺基酸但可由細胞內更容易獲得之tRNA轉譯,因此增加轉譯效率。核苷酸序列之最佳化亦可減少會干擾轉譯之二級mRNA結構,因此增加轉譯效率。
本發明之一實施例亦提供一種核酸,其包含與本文所描述之核酸中之任一者之核苷酸序列互補的核苷酸序列或在嚴格條件下與本文所描述之核酸中之任一者之核苷酸序列雜合的核苷酸序列。
核苷酸序列在嚴格條件下雜合,較佳地在高嚴格度條件下雜合。「高嚴格度條件」意謂以比非特異性雜合之可偵測性更強之量將核苷酸序列特異性雜合至目標序列(本文所描述之核酸中之任一者之核苷酸序列)。高嚴格度條件包括會將具有確切互補序列之聚核苷酸,或僅含有少量分散錯配之聚核苷酸與碰巧具有匹配核苷酸序列之少量小區域(例如3至10個鹼基)之隨機序列進行區分的條件。此類具有互補性之小區域比具有14至17個或更多個鹼基之全長互補序列更易於解鏈,且高嚴格度雜合使其可易於區分。相對高嚴格度條件將包括例如低鹽及/或高溫條件,諸如在約50至70℃之溫度下藉由約0.02至0.1 M NaCl或等效物提供。此類高嚴格度條件容許核苷酸序列與模板或目標股之間的少量(若存在)錯配,且尤其適合於偵測本發明TCR中之任一者的表現。通常應瞭解,藉由添加漸增量之甲醯胺,可使條件更嚴格。
本發明之一實施例亦提供一種核酸,其包含與本文所描述之核酸中之任一者至少約70%或更高,例如約80%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%或約99%一致之核苷酸序列。就此而言,核酸可基本上由任何本文所描述之核苷酸序列組成。
本發明之核酸可併入至重組表現載體中。就此而言,本發明之一實施例提供一種重組表現載體,其包含本發明之核酸中之任一者。在本發明之一實施例中,重組表現載體包含編碼α鏈、β鏈及連接子肽之核苷酸序列。
出於本文之目的,術語「重組表現載體」意謂經基因修飾之寡核苷酸或聚核苷酸構築體,當構築體包含編碼mRNA、蛋白質、多肽或肽之核苷酸序列,且載體在足以使mRNA、蛋白質、多肽或肽在細胞內表現之條件下與細胞接觸時,允許藉由宿主細胞表現mRNA、蛋白質、多肽或肽。本發明之載體整體上不為天然存在的。然而,部分載體可為天然存在的。本發明之重組表現載體可包含任何類型的核苷酸,其包括但不限於可為單股或雙股、合成的或部分自天然來源中獲得且可含有天然、非天然或改變之核苷酸的DNA及RNA。重組表現載體可包含天然存在之、非天然存在之核苷酸間鍵或兩種類型的鍵。較佳地,非天然存在或改變之核苷酸或核苷酸間鍵不阻礙載體之轉錄或複製。
本發明之重組表現載體可為任何適合之重組表現載體,且可用以轉化或轉染任何適合之宿主細胞。適合載體包括設計成用於增殖及擴增或用於表現或用於此兩者的彼等載體,諸如質體及病毒。載體可選自由以下組成之群:轉位子/轉位酶系列pUC系列(Fermentas Life Sciences)、pBluescript系列(Stratagene, La Jolla, CA)、pET系列(Novagen, Madison, WI)、pGEX系列(Pharmacia Biotech, Uppsala, Sweden)及pEX系列(Clontech, Palo Alto, CA)。亦可使用噬菌體載體,諸如λGT10、λGT11、λZapII (Stratagene)、λEMBL4及λNM1149。植物表現載體之實例包括pBI01、pBI101.2、pBI101.3、pBI121及pBIN19 (Clontech)。動物表現載體之實例包括pEUK-Cl、pMAM及pMAMneo (Clontech)。較佳地,重組表現載體為轉位子或病毒載體,例如慢病毒載體或反轉錄病毒載體。
本發明之重組表現載體可使用描述於例如Green及Sambrook等人, 同上中之標準重組DNA技術製備。環形或線形之表現載體構築體可經製備以含有在原核或真核宿主細胞中起作用之複製系統。複製系統可來源於例如ColEl、2 μ質體、λ、SV40、牛乳突狀瘤病毒及類似者。
理想地,重組表現載體包含諸如轉錄及轉譯起始及終止密碼子之調節序列,該等調節序列按需要且考慮載體係基於DNA抑或基於RNA而對將引入載體之宿主細胞類型(例如細菌、真菌、植物或動物)具特異性。
重組表現載體可包括一或多個標記基因,其允許選擇經轉化或經轉染宿主細胞。標記基因包括殺生物劑耐性(例如,對抗生素、重金屬等具有耐性)、營養缺陷型宿主細胞中用以提供原營養的補充物及類似者。用於本發明表現載體之適合的標記基因包括例如耐新黴素/G418基因、耐潮黴素基因、耐組胺醇基因、耐四環素基因及耐安比西林(ampicillin)基因。
重組表現載體可包含可操作地連接於編碼TCR、多肽或蛋白質之核苷酸序列或連接於與編碼TCR、多肽或蛋白質之核苷酸序列互補或雜合之核苷酸序列的原生或非原生啟動子。啟動子(例如強、弱、誘導性、組織特異性及發育特異性啟動子)之選擇在技術人員之普通技能內。類似地,核苷酸序列與啟動子之組合亦在技術人員之技能內。啟動子可為例如人類延長因子-1α啟動子之非病毒啟動子,或例如巨細胞病毒(CMV)啟動子之病毒啟動子、SV40啟動子、RSV啟動子及發現於鼠類幹細胞病毒之長端重複序列中的啟動子。
本發明重組表現載體可經設計用於短暫表現、用於穩定表現或用於兩者。此外,重組表現載體可經製備用於組成性表現或用於誘導性表現。
此外,重組表現載體可經製備為包括自殺基因。如本文所用,術語「自殺基因」係指使表現自殺基因之細胞死亡之基因。自殺基因可為對表現基因之細胞賦予針對藥劑(例如藥物)之敏感性的基因,且當細胞與藥劑接觸或暴露於藥劑時,該基因使細胞死亡。自殺基因為此項技術中已知的,且包括例如單純疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脫胺酶、嘌呤核苷磷酸化酶及硝基還原酶。
本發明之另一實施例提供一種經分離或經純化TCR、多肽或蛋白質,其由本文關於本發明之其他態樣所描述之核酸或載體中之任一者編碼。
本發明之另一實施例提供一種經分離或經純化TCR、多肽或蛋白質,其由本文關於本發明之其他態樣所描述之核酸或載體中之任一者的表現產生。
本發明之另一實施例進一步提供一種宿主細胞,其包含本文所描述之核酸中之任一者或重組表現載體中之任一者。如本文所用,術語「宿主細胞」係指可含有本發明重組表現載體之任何類型的細胞。宿主細胞可為真核細胞(例如植物、動物、真菌或藻類)或可為原核細胞(例如細菌或原蟲)。宿主細胞可為經培養細胞或原代細胞,亦即直接自生物體(例如人類)分離。宿主細胞可為黏附細胞或懸浮細胞,亦即在懸浮液中生長之細胞。適合之宿主細胞為此項技術中已知的且包括例如DH5α大腸桿菌細胞、中國倉鼠卵巢細胞、猴VERO細胞、COS細胞、HEK293細胞及其類似者。出於擴增或複製重組表現載體之目的,宿主細胞較佳為原核細胞,例如DH5α細胞。出於產生重組TCR、多肽或蛋白質之目的,宿主細胞較佳為哺乳動物細胞。最佳地,宿主細胞為人類細胞。舉例而言,宿主細胞可為人類淋巴球。在本發明之一實施例中,宿主細胞係選自以下組成之群:T細胞、自然殺手T (NKT)細胞、恆定型自然殺手T (iNKT)細胞及自然殺手(NK)細胞。雖然宿主細胞可為任何細胞類型,可來源於任何類型的組織,且可為任何發育階段,但宿主細胞較佳為周邊血液淋巴球(PBL)或周邊血液單核球(PBMC)。更佳地,宿主細胞為T細胞。
出於本文之目的,T細胞可為任何T細胞,諸如經培養T細胞(例如原代T細胞),或來自經培養T細胞株之T細胞(例如Jurkat,SupT1等),或獲自哺乳動物之T細胞。若自哺乳動物獲得,則T細胞可自眾多來源獲得,包括但不限於血液、骨髓、淋巴結、胸腺或其他組織或體液。T細胞亦可經富集或純化。較佳地,T細胞為人類T細胞。T細胞可為任何類型的T細胞且可為任何發育階段,其包括但不限於CD4
+/CD8
+雙陽性T細胞、CD4
+輔助T細胞(例如Th
1及Th
2細胞)、CD4
+T細胞、CD8
+T細胞(例如細胞毒性T細胞)、腫瘤浸潤性淋巴球(TIL)、記憶T細胞(例如中樞記憶T細胞及效應記憶T細胞)、原生T細胞及類似者。
本發明之一實施例亦提供一種細胞群,其包含至少一種本文所描述之宿主細胞。細胞群可為包含宿主細胞之異質群,除了不包含重組表現載體中之任一者的至少一種其他細胞,例如宿主細胞(例如T細胞)或並非T細胞之細胞(例如B細胞、巨噬細胞、嗜中性球、紅血球、肝細胞、內皮細胞、上皮細胞、肌肉細胞、大腦細胞等)以外,該宿主細胞亦包含所描述之重組表現載體中之任一者。或者,細胞群可為實質上均質群,其中該群體包含主要包含重組表現載體(例如基本上由重組表現載體組成)之宿主細胞。該群體亦可為純系細胞群,其中群體中之所有細胞為包含重組表現載體之單一宿主細胞的純系,使得群體中之所有細胞包含重組表現載體。在本發明之一個實施例中,細胞群為包含宿主細胞之純系群體,該等宿主細胞包含如本文所描述之重組表現載體。
在本發明之一實施例中,群體中細胞之數目可快速擴增。如例如美國專利8,034,334、美國專利8,383,099、美國專利申請公開案第2012/0244133號、Dudley等人,
J. Immunother., 26:332-42 (2003)及Riddell等人,
J. Immunol. Methods, 128:189-201 (1990)中所描述,可藉由如此項技術中已知之許多方法中之任一者實現T細胞之數目的擴增。在一實施例中,藉由用OKT3抗體、IL-2及供給PBMC (例如經輻射同種異體PBMC)培養T細胞來進行T細胞之數目之擴增。
本發明之一實施例提供一種產生表現TCR之宿主細胞的方法,該TCR對肽DRNTFRHSVVVP
C EPPEVGSDCTTI (SEQ ID NO: 115)或SGNLLGRNSFEV
C VCACPGRDRRTE (SEQ ID NO:117)具有抗原特異性,該方法包含使細胞與本文所描述之載體中之任一者在允許將載體引入至細胞中的條件下接觸。
本發明TCR、多肽、蛋白質、核酸、重組表現載體及宿主細胞(包括其群體)可經分離及/或經純化。如本文所用之術語「經分離」意謂已自其天然環境移除。如本文所用之術語「經純化」意謂純度已增加,其中「純度」為相對術語,且不必解釋為絕對純度。舉例而言,純度可為至少約50%、至少約60%、至少約70%、至少約80%、至少約90%、至少約95%或可為約100%。
本發明TCR、多肽、蛋白質、核酸、重組表現載體及宿主細胞(包括其群體)在下文中皆統稱為「本發明TCR物質」,其可調配成組合物,諸如醫藥組合物。就此而言,本發明之一實施例提供一種醫藥組合物,其包含本文所描述之TCR、多肽、蛋白質、核酸、表現載體及宿主細胞(包括其群體)中之任一者及醫藥學上可接受之載劑。含有本發明TCR物質中之任一者的本發明醫藥組合物可包含超過一種本發明TCR物質,例如多肽及核酸或兩種或更多種不同TCR。或者,醫藥組合物可包含本發明TCR物質與另外醫藥活性劑或藥物之組合,醫藥活性劑或藥物諸如化學治療劑,例如天冬醯胺酶、硫酸布他卡因(busulfan)、卡鉑(carboplatin)、順鉑(cisplatin)、道諾黴素(daunorubicin)、阿黴素(doxorubicin)、氟尿嘧啶、吉西他濱(gemcitabine)、羥基脲、甲胺喋呤、太平洋紫杉醇、利妥昔單抗(rituximab)、長春鹼(vinblastine)、長春新鹼(vincristine)等。
較佳地,載劑為醫藥學上可接受之載劑。關於醫藥組合物,載劑可為習知用於考慮中之特定本發明TCR物質的彼等載劑中之任一者。用於製備可投與組合物之方法對熟習此項技術者為已知的或顯而易見的且更詳細地描述於例如
Remington: The Science and Practice of Pharmacy, 第22版,Pharmaceutical Press (2012)中。較佳地,醫藥學上可接受之載劑為在使用條件下不具有有害副作用或毒性之載劑。
載劑之選擇將部分由特定本發明TCR物質以及用於投與本發明TCR物質的特定方法決定。因此,存在本發明之醫藥組合物的多種適合調配物。適合之調配物可包括用於非經腸、皮下、靜脈內、肌肉內、動脈內、鞘內、瘤內或腹膜內投與之彼等調配物中之任一者。可使用超過一種途徑來投與本發明TCR物質,且在某些情況下,特定途徑可提供比另一種途徑更直接且更有效之反應。
較佳地,本發明TCR物質係藉由注射(例如經靜脈內注射)投與。當本發明TCR物質為表現本發明TCR的宿主細胞時,用於注射之細胞的醫藥學上可接受之載劑可包括任何等張載劑,諸如標準生理鹽水(約0.90% w/v之NaCl於水中、約300 mOsm/L NaCl於水中或每公升水約9.0 g NaCl)、NORMOSOL R電解質溶液(Abbott,Chicago,IL)、PLASMA-LYTE A (Baxter,Deerfield,IL)、約5%右旋糖於水中或林格氏乳酸鹽(Ringer's lactate)。在一實施例中,醫藥學上可接受之載劑補充有人類血清蛋白。
投與的本發明TCR物質之量或劑量(例如當本發明TCR物質為一或多種細胞時,為細胞之數目)應足以在合理時段內在個體或動物中實現例如治療性或預防性反應。舉例而言,本發明TCR物質之劑量應足以在自投與之時間起約2小時或更長(例如12至24或更多個小時)之時段中結合於癌症抗原(例如突變p53),或偵測、治療或預防癌症。在某些實施例中,該時段可更長。劑量將由特定本發明TCR物質之功效及待治療的動物(例如人類)之病況以及動物(例如人類)的體重決定。
用於確定投與劑量之許多分析為此項技術中已知的。舉例而言,可使用分析來測定待向哺乳動物投與之起始劑量,該分析包含在向各自被給予不同劑量之表現本發明TCR、多肽或蛋白質之T細胞的一組哺乳動物當中之一哺乳動物投與給定劑量之T細胞後,對此等T細胞溶解目標細胞或分泌IFN-γ的程度進行比較。在投與某一劑量後溶解目標細胞或分泌IFN-γ之程度可藉由此項技術中已知之方法分析。
本發明TCR物質之劑量亦將由可能伴隨特定本發明TCR物質之投與的任何不良副作用之存在、性質及程度決定。通常,主治醫師將考慮多種諸如年齡、體重、一般健康狀況、膳食、性別、待投與之本發明TCR物質、投與途徑及所治療癌症之嚴重程度的因素來決定用以治療各個別患者之本發明TCR物質的劑量。在本發明TCR物質為細胞群之一實施例中,每次輸注投與之細胞的數目可例如自約1×10
6至約1×10
12個細胞或更多變化。在某些實施例中,可投與少於1×10
6個細胞。
一般熟習此項技術者將容易瞭解本發明之TCR物質可以多種方式進行修飾,使得經由修飾來提高本發明TCR物質之治療或預防功效。舉例而言,本發明TCR物質可直接地或間接地經由橋鍵與化學治療劑結合。將化合物與化學治療劑結合之實踐為此項技術中已知。一般熟習此項技術者認識到,本發明TCR物質上對於本發明TCR物質之功能並非必需之位點為理想地用於連接橋鍵及/或化學治療劑之位點,其限制條件為橋鍵及/或化學治療劑在連接至本發明TCR物質後不干擾本發明TCR物質之功能,亦即結合於突變p53或偵測、治療或預防癌症之能力。
考慮本發明醫藥組合物、TCR、多肽、蛋白質、核酸、重組表現載體、宿主細胞及細胞群可用於治療或預防癌症之方法中。不受特定理論之束縛,咸信本發明TCR特異性結合於突變p53,使得TCR (或相關之本發明多肽或蛋白質)在由細胞表現時,能夠介導針對表現突變p53之目標細胞的免疫反應。就此而言,本發明之一實施例提供一種治療或預防哺乳動物之癌症的方法,其包含以可有效治療或預防哺乳動物之癌症之量向哺乳動物投與本文所描述之醫藥組合物、TCR、多肽或蛋白質中之任一者,包含編碼本文所描述之TCR、多肽、蛋白質中之任一者之核苷酸序列的任何核酸或重組表現載體,或包含編碼本文所描述之TCR、多肽或蛋白質中之任一者之重組載體的任何宿主細胞或細胞群。
本發明之一實施例提供用於治療或預防哺乳動物之癌症的本文所描述之醫藥組合物、TCR、多肽或蛋白質中之任一者,包含編碼本文所描述之TCR、多肽、蛋白質中之任一者之核苷酸序列的任何核酸或重組表現載體,或包含編碼本文所描述之TCR、多肽或蛋白質中之任一者之重組載體的任何宿主細胞或細胞群。
如本文所用,術語「治療」及「預防」以及自其衍生之字語不一定暗示100%或完全治療或預防。實際上,一般熟習此項技術者識別為具有潛在益處或治療作用的治療或預防存在變化之程度。就此而言,本發明方法可提供任何量的對哺乳動物之癌症的任何程度之治療或預防。此外,藉由本發明方法提供之治療或預防可包括治療或預防所治療或預防之癌症的一或多種病況或症狀。舉例而言,治療或預防可包括促進腫瘤之消退。另外,出於本文之目的,「預防」可涵蓋延緩癌症或其症狀或病況之發作。或者或另外,「預防」可涵蓋預防或延緩癌症或其症狀或病況之復發。
亦考慮本發明醫藥組合物、TCR、多肽、蛋白質、核酸、重組表現載體、宿主細胞及細胞群可用於誘導針對哺乳動物之癌症之免疫反應的方法中。就此而言,本發明之一實施例提供一種誘導針對哺乳動物之癌症之免疫反應的方法,其包含以可有效誘導針對哺乳動物之癌症之免疫反應的量向哺乳動物投與本文所描述之醫藥組合物、TCR、多肽或蛋白質中之任一者,包含編碼本文所描述之TCR、多肽、蛋白質中之任一者之核苷酸序列的任何核酸或重組表現載體,或包含編碼本文所描述之TCR、多肽或蛋白質中之任一者之重組載體的任何宿主細胞或細胞群。
本發明之一實施例提供本文所描述之醫藥組合物、TCR、多肽或蛋白質中之任一者,包含編碼本文所描述之TCR、多肽、蛋白質中之任一者之核苷酸序列的任何核酸或重組表現載體,或包含編碼本文所描述之TCR、多肽或蛋白質中之任一者之重組載體的任何宿主細胞或細胞群,其用於誘導針對哺乳動物之癌症之免疫反應。
本發明之一實施例亦提供一種偵測哺乳動物中癌症之存在的方法。該方法包含:(i)將包含來自哺乳動物之一或多個細胞之樣本與本文所描述之本發明TCR、多肽、蛋白質、核酸、重組表現載體、宿主細胞、細胞群或醫藥組合物中之任一者進行接觸,藉此形成複合體;及(ii)偵測複合物,其中複合體之偵測指示哺乳動物中癌症之存在。
關於偵測哺乳動物之癌症的本發明方法,細胞之樣本可為包含全細胞、其溶胞產物,或全細胞溶胞產物之一部分(例如核或細胞質部分、全蛋白部分或核酸部分)之樣本。
出於本發明偵測方法之目的,關於哺乳動物,接觸可活體外或活體內進行。較佳地,接觸係在活體外。
此外,複合體之偵測可經由此項技術中已知之許多方式進行。舉例而言,可用可偵測標記來標記本文所描述之本發明TCR、多肽、蛋白質、核酸、重組表現載體、宿主細胞或細胞群,該可偵測標記諸如放射性同位素、螢光團(例如異硫氰酸螢光素(FITC)、藻紅素(PE))、酶(例如鹼性磷酸酶、辣根過氧化酶)及元素粒子(例如金粒子)。
出於本發明方法之目的,其中投與宿主細胞或細胞群,細胞可為對於哺乳動物而言同種異體或自體之細胞。較佳地,細胞為對於哺乳動物而言自體的。
關於本發明方法,癌症可為任何癌症,包括例如急性淋巴球性癌症、急性骨髓性白血病、齒槽橫紋肌肉瘤、骨癌、腦癌、乳癌、肛門癌、肛管癌或肛腸癌、眼癌、肝內膽管癌、關節癌、頸癌、膽囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、陰道癌、外陰癌、慢性淋巴球性白血病、慢性骨髓癌、大腸癌、大腸直腸癌、子宮內膜癌、食道癌、子宮頸癌、胃腸類癌瘤、神經膠質瘤、霍奇金氏淋巴瘤(Hodgkin lymphoma)、下咽癌、腎臟癌、喉癌、肝癌、肺癌、惡性間皮瘤、黑色素瘤、多發性骨髓瘤、鼻咽癌、非霍奇金氏淋巴瘤、口咽癌、卵巢癌、陰莖癌、胰臟癌、腹膜癌、網膜癌及腸系膜癌、咽癌、前列腺癌、直腸癌、腎癌、皮膚癌、小腸癌、軟組織癌、胃癌、睾丸癌、甲狀腺癌、子宮癌、尿管癌及膀胱癌中之任一者。在一較佳實施例中,癌症為表現突變p53之癌症。癌症可表現在如由SEQ ID NO: 1所定義的位置273及220中之一者或兩者處含有突變的p53。癌症可表現具有以下人類p53突變中之一者或兩者的p53:R273C及Y220C。在本發明之一實施例中,癌症為上皮癌。在本發明之一實施例中,癌症為膽管癌、黑色素瘤、大腸癌、直腸癌、卵巢癌、子宮內膜癌、非小細胞肺癌(NSCLC)、神經膠母細胞瘤、子宮頸癌、頭頸癌、乳癌、胰臟癌或膀胱癌。可已知癌症包含人類p53中之R273C或Y220C突變。
本發明方法中提及之哺乳動物可為任何哺乳動物。如本文所用,術語「哺乳動物」係指任何哺乳動物,包括但不限於嚙齒目之哺乳動物(諸如小鼠及倉鼠)及兔形目之哺乳動物(諸如兔)。較佳地,哺乳動物來自食肉目,包括貓科動物(貓)及犬科動物(狗)。更佳地,哺乳動物來自偶蹄目,包括牛科動物(奶牛)及豬科動物(豬);或奇蹄目,包括馬科動物(馬)。最佳地,哺乳動物為靈長目、猿目或猴目(猴)或類人猿目(人類及猿)。尤佳之哺乳動物為人類。
以下實施例進一步說明本發明,但當然不應解釋為以任何方式限制其範疇。
實例1
此實例展現患者4343之TIL中抗p53-Y220C T細胞反應性的鑑別。
將自患有激素陽性、HER2陽性轉移性乳癌之患者4343切除之腫瘤切成23個片段且在細胞介素IL-2存在下培養以使TIL離體生長。藉由與用DMSO (媒劑)或突變p53-Y220C肽DRNTFRHSVVVP
C EPPEVGSDCTTI (SEQ ID NO: 115)脈衝之自體樹突狀細胞共培養來測試片段(編號F1至F7及F9至F24)之腫瘤特異性新生抗原反應性,包括突變p53。藉由ELISpot分析量測IFN-γ產生。結果展示於圖1A中。鑑別出片段編號F2、F3、F11、F21及F23含有識別p53-Y220C之TIL。
實例2
此實例展現患者4386之TIL中抗p53-R273C T細胞反應性的鑑別。
將自患者4386之左乳房腋下淋巴結切除之腫瘤切成24個片段且在細胞介素IL-2存在下培養以使TIL離體生長。藉由與用DMSO (媒劑)或突變p53-R273C肽SGNLLGRNSFEV
C VCACPGRDRRTE (SEQ ID NO: 117)脈衝之自體樹突狀細胞共培養來測試片段(編號F1至F24)之腫瘤特異性新生抗原反應性,包括突變p53。藉由ELISpot分析量測IFN-γ產生。結果展示於圖1B中。鑑別出片段編號F7含有識別p53-R273C之TIL。
基於CD3以及一或多種細胞表面標記物CD4、CD8、CD39、PD-1及TIGIT之表現來分選來自患者4386之新鮮腫瘤消化物(腫瘤1A或腫瘤1B)的T細胞。使經分選細胞群擴增且針對突變p53-R273C肽或DMSO測試反應性。藉由ELISpot分析量測IFN-γ產生。結果展示於圖1C中。鑑別出來自腫瘤1A之兩個細胞群含有識別p53-R273C: CD3
+CD4
+CD39
+PD-1
+TIGIT
+及CD3
+CD4
+CD39
+PD-1
+TIGIT
-之T細胞。
對來自患者4386之TIL進行活體外敏化以富集新生抗原反應性T細胞,接著針對DMSO或突變p53-R273C肽進行測試。藉由流動式細胞測量術量測T細胞活化標記物4-1BB及OX40。結果展示於圖1D中。
實例3
此實例展現抗p53-Y220C TCR與實例1之反應性TIL的分離。
再刺激反應性TIL且藉由4-1BB上調而分選至96孔培養盤中以供單細胞T細胞受體(TCR)定序。發現TCR,亦即4343-D TCR (TRAV12-3/TRBV27)。
藉由單細胞TCR定序鑑別TCR α及β鏈可變區之序列。α及β鏈可變區之胺基酸序列展示於表3中。CDR加底線。N端信號肽呈粗體字。
表3
實例4
TCR 名稱 | TCR 鏈 | 胺基酸序列 |
4343-D TCR | 可變α (無N端信號肽SignalP之經預測序列) | QQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP (SEQ ID NO: 8) |
可變α (無N端信號肽IMGT之經預測序列) | QKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP (SEQ ID NO: 119) | |
可變β (無N端信號肽SignalP之經預測序列) | QVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL (SEQ ID NO: 9) | |
可變β (無N端信號肽IMGT之經預測序列) | EAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL (SEQ ID NO: 120) | |
可變α (具有N端信號肽,位置2處為H) | MHKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP (SEQ ID NO: 10) | |
可變α (具有N端信號肽,位置2處為A) | MAKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP (SEQ ID NO: 121) | |
可變β (具有N端信號肽,位置2處為A) | MAPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL (SEQ ID NO: 11) | |
可變β (具有N端信號肽,位置2處為H) | MHPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL (SEQ ID NO: 122) | |
可變α (具有WT N端信號肽) | MMKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP (SEQ ID NO: 12) | |
可變β (具有WT N端信號肽) | MGPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL (SEQ ID NO: 13) |
此實例展現抗p53-R273C TCR與實例2之反應性TIL的分離。
再刺激反應性TIL且藉由4-1BB上調而分選至96孔培養盤中以供單細胞T細胞受體(TCR)定序。發現四種TCR,亦即4386-F TCR (TRAV13-2 / TRBV4-3)、4386-G TCR (TRAV3 / TRBV20-1)、4386-H TCR (TRAV23 / TRBV7-2)及4386-O TCR (TRAV13-2 / TRBV7-3)。
藉由單細胞TCR定序鑑別TCR α及β鏈可變區之序列。α及β鏈可變區之胺基酸序列展示於表4中。CDR加底線。N端信號肽呈粗體字。
表4
實例5
TCR 名稱 | TCR 鏈 | 胺基酸序列 |
4386-F TCR | 可變α (無N端信號肽SignalP之經預測序列) | ESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP (SEQ ID NO: 27) |
可變α (無N端信號肽IMGT之經預測序列) | GESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP (SEQ ID NO: 123) | |
可變β (無N端信號肽SignalP之經預測序列) | METGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL (SEQ ID NO: 28) | |
可變β (無N端信號肽IMGT之經預測序列) | ETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL (SEQ ID NO: 124) | |
可變α (具有N端信號肽,位置2處為H) | MHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP (SEQ ID NO: 29) | |
可變α (具有N端信號肽,位置2處為A) | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP (SEQ ID NO: 125) | |
可變β (具有N端信號肽,位置2處為A) | MACRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL (SEQ ID NO: 30) | |
可變β (具有N端信號肽,位置2處為H) | MHCRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL (SEQ ID NO: 126) | |
可變α (具有WT N端信號肽) | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP (SEQ ID NO: 31) | |
可變β (具有WT N端信號肽) | MGCRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL (SEQ ID NO: 32) | |
4386-G TCR | 可變α (無N端信號肽SignalP之經預測序列) | QSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA (SEQ ID NO: 46) |
可變α (無N端信號肽IMGT之經預測序列) | AQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA (SEQ ID NO: 127) | |
可變β (無N端信號肽SignalP之經預測序列) | AVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL (SEQ ID NO: 47) | |
可變β (無N端信號肽IMGT之經預測序列) | GAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL (SEQ ID NO: 128) | |
可變α (具有N端信號肽,位置2處為H) | MHSAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA (SEQ ID NO: 48) | |
可變α (具有N端信號肽,位置2處為A) | MASAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA (SEQ ID NO: 129) | |
可變β (具有N端信號肽,位置2處為A) | MALLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL (SEQ ID NO: 49) | |
可變β (具有N端信號肽,位置2處為H) | MHLLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL (SEQ ID NO: 130) | |
可變α (具有WT N端信號肽) | MASAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA (SEQ ID NO: 50) | |
可變β (具有WT N端信號肽) | MLLLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL (SEQ ID NO: 51) | |
4386-H TCR | 可變α (無N端信號肽SignalP之經預測序列) | QQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP (SEQ ID NO: 65) |
可變α (無N端信號肽IMGT之經預測序列) | QQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP (SEQ ID NO: 131) | |
可變β (無N端信號肽SignalP之經預測序列) | GVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL (SEQ ID NO: 66) | |
可變β (無N端信號肽IMGT之經預測序列) | GAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL (SEQ ID NO: 132) | |
可變α (具有N端信號肽,位置2處為H) | MHKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP (SEQ ID NO: 67) | |
可變α (具有N端信號肽,位置2處為A) | MAKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP (SEQ ID NO: 133) | |
可變β (具有N端信號肽,位置2處為A) | MATRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL (SEQ ID NO: 68) | |
可變β (具有N端信號肽,位置2處為H) | MHTRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL (SEQ ID NO: 134) | |
可變α (具有WT N端信號肽) | MDKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP (SEQ ID NO: 69) | |
可變β (具有WT N端信號肽) | MGTRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL (SEQ ID NO: 70) | |
4386-O TCR | 可變α (無N端信號肽SignalP之經預測序列) | ESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP (SEQ ID NO: 84) |
可變α (無N端信號肽IMGT之經預測序列) | GESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP (SEQ ID NO: 135) | |
可變β (無N端信號肽SignalP之經預測序列) | GVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL (SEQ ID NO: 85) | |
可變β (無N端信號肽IMGT之經預測序列) | GAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL (SEQ ID NO: 136) | |
可變α (具有N端信號肽,位置2處為H) | MHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP (SEQ ID NO: 86) | |
可變α (具有N端信號肽,位置2處為A) | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP (SEQ ID NO: 137) | |
可變β (具有N端信號肽,位置2處為A) | MATRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL (SEQ ID NO: 87) | |
可變β (具有N端信號肽,位置2處為H) | MHTRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL (SEQ ID NO: 138) | |
可變α (具有WT N端信號肽) | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP (SEQ ID NO: 88) | |
可變β (具有WT N端信號肽) | MGTRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL (SEQ ID NO: 89) |
此實例展現實例3至4之編碼各別TCR的反轉錄病毒載體之構築。
獲得編碼表3至4之TCR之α及β鏈之可變區的核苷酸序列,且進行密碼子最佳化。使TCRβ VDJ區與小鼠TCRβ恆定鏈融合。使TCRα VJ區與小鼠TCRα恆定鏈融合。不受特定理論或機制束縛,咸信用對應鼠類恆定區置換人類TCRα及TCRβ鏈之恆定區可改良TCR表現及功能性(Cohen等人, Cancer Res., 66(17): 8878-86 (2006))。
另外,鼠類TCRα及TCRβ恆定鏈經半胱胺酸修飾。將跨膜疏水性突變引入至鼠類TCRα恆定鏈中。不受特定理論或機制束縛,咸信此等修飾使得所引入之TCR鏈優先配對且TCR表面表現及功能增強(Cohen等人, Cancer Res., 67(8):3898-903 (2007);Haga-Friedman等人, J. Immu., 188: 5538-5546 (2012))。
為了促進將TCR表現卡匣選殖至MSGV1載體5'NcoI位點中,且為樂引入Kozak序列,將TCRVα鏈之N端信號肽中之第二胺基酸變成組胺酸(H),且將TCRVβ鏈之N端信號肽中之第二胺基酸變成丙胺酸(A)。
五個TCR中之每一者之全長α及β鏈,包括對恆定區之此等修飾,展示於表5中。在表5中,CDR加底線,恆定區呈斜體字,且恆定區之經修飾胺基酸殘基加底線且呈粗體。
表5
TCR 名稱 | TCR 鏈 | 胺基酸序列 |
4343-D TCR | 經Cys取代、經LVL修飾之α鏈,具有N端信號肽 | MHKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 14) |
經Cys取代、經LVL修飾之β鏈,具有N端信號肽 | MAPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 15) | |
經Cys取代、經LVL修飾之α鏈,具有WT N端信號肽 | MMKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 16) | |
經Cys取代、經LVL修飾之β鏈,具有WT N端信號肽 | MGPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 17) | |
經Cys取代、經LVL修飾之α鏈預測序列,無N端信號肽 | QQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 18) | |
經Cys取代、經LVL修飾之β鏈預測序列,無N端信號肽 | QVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 19) | |
4386-F | 經Cys取代、經LVL修飾之α鏈,具有N端信號肽 | MHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 33) |
經Cys取代、經LVL修飾之β鏈,具有N端信號肽 | MACRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 34) | |
經Cys取代、經LVL修飾之α鏈,具有WT N端信號肽 | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 35) | |
經Cys取代、經LVL修飾之β鏈,具有WT N端信號肽 | MGCRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 36) | |
經Cys取代、經LVL修飾之α鏈預測序列,無N端信號肽 | ESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 37) | |
經Cys取代、經LVL修飾之β鏈預測序列,無N端信號肽 | METGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 38) | |
4386-G | 經Cys取代、經LVL修飾之α鏈,具有N端信號肽 | MHSAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 52) |
經Cys取代、經LVL修飾之β鏈,具有N端信號肽 | MALLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 53) | |
經Cys取代、經LVL修飾之α鏈,具有WT N端信號肽 | MASAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 54) | |
經Cys取代、經LVL修飾之β鏈,具有WT N端信號肽 | MLLLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 55) | |
經Cys取代、經LVL修飾之α鏈預測序列,無N端信號肽 | QSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 56) | |
經Cys取代、經LVL修飾之β鏈預測序列,無N端信號肽 | AVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 57) | |
4386-H | 經Cys取代、經LVL修飾之α鏈,具有N端信號肽 | MHKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 71) |
經Cys取代、經LVL修飾之β鏈,具有N端信號肽 | MATRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 72) | |
經Cys取代、經LVL修飾之α鏈,具有WT N端信號肽 | MDKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 73) | |
經Cys取代、經LVL修飾之β鏈,具有WT N端信號肽 | MGTRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 74) | |
經Cys取代、經LVL修飾之α鏈預測序列,無N端信號肽 | QQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 75) | |
經Cys取代、經LVL修飾之β鏈預測序列,無N端信號肽 | GVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 76) | |
4386-O | 經Cys取代、經LVL修飾之α鏈,具有N端信號肽 | MHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 90) |
經Cys取代、經LVL修飾之β鏈,具有N端信號肽 | MATRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 91) | |
經Cys取代、經LVL修飾之α鏈,具有WT N端信號肽 | MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 92) | |
經Cys取代、經LVL修飾之β鏈,具有WT N端信號肽 | MGTRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 93) | |
經Cys取代、經LVL修飾之α鏈預測序列,無N端信號肽 | ESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDK C VLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNL L V IV LRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 94) | |
經Cys取代、經LVL修飾之β鏈預測序列,無N端信號肽 | GVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGV C TDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS (SEQ ID NO: 95) |
將編碼表5之TCR之α及β鏈之可變區的核苷酸序列選殖至具有以下表現卡匣構形的基於MSGV1之反轉錄病毒載體中:5'NcoI-VDJβ-mCβ-弗林蛋白酶(Furin)/SerGly/P2A-VJα-mCα-EcoRI3'。
TCRβ鏈及TCRα鏈藉由弗林蛋白酶Ser/Gly P2A連接子RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 100)分離。不受特定理論或機制束縛,咸信連接子為兩個鏈提供相當之表現效率(Szymczak等人,
Nat. Biotechnol., 22(5):589-94 (2004))。
反轉錄病毒載體之TCR表現卡匣自5'至3'編碼藉由連接子分離之TCRβ及TCRα鏈。TCR表現卡匣之核苷酸序列展示於表6中。
表6
TCR 名稱 | TCR 表現卡匣 |
4343-D | SEQ ID NO: 109 |
4386-F | SEQ ID NO: 110 |
4386-G | SEQ ID NO: 111 |
4386-H | SEQ ID NO: 112 |
4386-O | SEQ ID NO: 113 |
由各各別TCR表現卡匣編碼之胺基酸序列展示於表7中。在表7中,CDR加底線,恆定區呈斜體,且連接子以粗體展示。
表7
實例6
TCR 名稱 | 由TCR 表現卡匣編碼之胺基酸序列 |
4343-D | MAPQLLGYVVLCLLGAGPLEAQVTQNPRYLITVTGKKLTVTCSQN MNHEYMSWYRQDPGLGLRQIYY SMNVEVTDKGDVPEGYKVSRKEKRNFPLILESPSPNQTSLYF CASSFISNQPQHFGDGTRLSIL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS RAKRSGSGATNFSLLKQAGDVEENPGPMHKSLRVLLVILWLQLSWVWSQQKEVEQDPGPLSVPEGAIVSLNCTYS NSAFQYFMWYRQYSRKGPELLMY TYSSGNKEDGRFTAQVDKSSKYISLFIRDSQPSDSATYL CAGGSYGKLTFGQGTILTVHP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS(SEQ ID NO: 20) |
4386-F | MACRLLCCAVLCLLGAVPMETGVTQTPRHLVMGMTNKKSLKCEQH LGHNAMYWYKQSAKKPLELMFV YSLEERVENNSVPSRFSPECPNSSHLFLHLHTLQPEDSALYL CASSRVEGSDTQYFGPGTRLTVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS RAKRSGSGATNFSLLKQAGDVEENPGPMHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKSTGNQFYFGTGTSLTVIP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS(SEQ ID NO: 39) |
4386-G | MALLLLLLGPGSGLGAVVSQHPSRVICKSGTSVKIECRSL DFQATTMFWYRQFPKQSLMLMAT SNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYI CSAIRDRSGGETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS RAKRSGSGATNFSLLKQAGDVEENPGPMHSAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYS VSGNPYLFWYVQYPNRGLQFLLK YITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYF CAVRDPTVSGTYKYIFGTGTRLKVLA NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS(SEQ ID NO: 58) |
4386-H | MATRLLFWVAFCLLGADHTGAGVSQSPSNKVTEKGKDVELRCDPI SGHTALYWYRQSLGQGLEFLIY FQGNSAPDKSGLPSDRFSAERTGGSVSTLTIQRTQQEDSAVYL CASSLGGSSETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS RAKRSGSGATNFSLLKQAGDVEENPGPMHKILGASFLVLWLQLCWVSGQQKEKSDQQQVKQSPQSLIVQKGGISIINCAYE NTAFDYFPWYQQFPGKGPALLIA IRPDVSEKKEGRFTISFNKSAKQFSLHIMDSQPGDSATYF CAAKRQGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS(SEQ ID NO: 77) |
4386-O | MATRLLCWAALCLLGADHTGAGVSQTPSNKVTEKGKYVELRCDPI SGHTALYWYRQSLGQGPEFLIY FQGTGAADDSGLPNDRFFAVRPEGSVSTLKIQRTERGDSAVYL CASSPGGSQETQYFGPGTRLLVL EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS RAKRSGSGATNFSLLKQAGDVEENPGPMHGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNSIINCAYS NSASDYFIWYKQESGKGPQFIID IRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYF CAEKRRGGSEKLVFGKGTKLTVNP NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS(SEQ ID NO: 96) |
此實例展現由實例5之反轉錄病毒載體表現之抗p53-Y220C TCR的親合力。
同種異體PBL獨立地經實例5之編碼4343-D TCR之反轉錄病毒載體轉導。以圖3A中所示之各種濃度中之一者用突變p53-Y220C 25-mer肽DRNTFRHSVVVP
C EPPEVGSDCTTI (SEQ ID NO: 115)或對應WT 25-mer肽DRNTFRHSVVVP
Y EPPEVGSDCTTI (SEQ ID NO: 114)對自體DC脈衝兩小時。將細胞洗滌兩次且以1:1之比率與經轉導T細胞共培養16小時。藉由ELISpot分析量測IFN-γ分泌。如圖3A中所示,經TCR轉導之細胞展現用p53-Y220C 25-mer肽脈衝之DC的特異性及親合識別。
不受特定理論或機制束縛,咸信存在於WT 25-mer肽(SEQ ID NO: 114)及突變p53 Y220C 25-mer肽(SEQ ID NO: 115)中之半胱胺酸殘基可能易於氧化及均二聚,可最終導致T細胞效力降低(Sachs等人,
J. Immunol., 205(2):539-549 (2020))。Y220C突變自身引入另一半胱胺酸殘基。假設另一半胱胺酸殘基可影響TCR對突變肽之識別。
藉由將野生型肽及突變肽兩者之原始序列中之半胱胺酸殘基全部修飾成不再易於氧化或二聚之AABA來測試此假設。經修飾之肽展示於表8中。
表8
含有AABA 取代之野生型25-mer | DRNTFRHSVVVP YEPPEVGSDXTTI 位置22處的X為AABA | SEQ ID NO: 150 |
含有AABA 取代之突變25-mer | DRNTFRHSVVVP XEPPEVGSDXTTI 位置13處的X為AABA 位置22處的X為AABA | SEQ ID NO: 151 |
同種異體PBL獨立地經實例5之編碼4343-D TCR之反轉錄病毒載體轉導。以圖3B至圖3C中所示之各種濃度中之一者用含有取代之突變p53-Y220C 25-mer肽(SEQ ID NO: 151)或含有AABA取代之對應WT 25-mer肽(SEQ ID NO: 150)對自體B細胞脈衝兩小時。將細胞洗滌兩次且以1:1之比率與經轉導T細胞共培養16小時。藉由流動式細胞測量術,藉由量測鼠類TCR恆定區陽性細胞中T細胞活化標記物4-1BB之上調來測試反應性。
如圖3B至圖3C中所示,結果驗證上文所描述之此實例中之假設。觀測到相對於含有AABA取代之對應WT 25-mer肽,含有AABA取代之突變p53-Y220C 25-mer肽具有對數或更大TCR效力。
實例7
此實例展現由實例5之反轉錄病毒載體表現之抗p53-R273C TCR的親合力。
同種異體PBL獨立地經實例5之編碼4386-F TCR、4386-G TCR、4386-H TCR或4386-O TCR的反轉錄病毒載體轉導。以圖3D至圖3G中所示之各種濃度中之一者用p53-R273C 25-mer肽SGNLLGRNSFEV
C VCACPGRDRRTE (SEQ ID NO: 117)或對應WT 25-mer肽SGNLLGRNSFEV
R VCACPGRDRRTE (SEQ ID NO: 116)對自體DC脈衝兩小時。將細胞洗滌兩次且以1:1之比率與經轉導T細胞共培養16小時。藉由ELISA量測IFN-γ分泌(圖3D至圖3G)。如圖3D至圖3G中所示,經TCR轉導之細胞展現用突變p53-R273C 25-mer肽脈衝之DC的特異性及親合識別。
實例8
此實例展現由實例5之反轉錄病毒載體表現之抗p53-Y220C TCR識別由HLA-DRB3*02/HLA-DRA1*01異二聚體呈現之突變p53。
使用外顯子體及mRNA定序測定由患者4343表現之II類MHC分子。所表現之II類MHC分子展示於圖2A中。
效應細胞為經實例5之編碼4343-D TCR之反轉錄病毒載體轉導的同種異體PBL。目標細胞為獨立地經圖2A中展示且用p53-Y220C 25-mer肽DRNTFRHSVVVP
C EPPEVGSDCTTI (SEQ ID NO: 115)脈衝之II類HLA異二聚體中之一者轉染的COS7細胞。
藉由流動式細胞測量術,藉由量測鼠類TCR恆定區陽性細胞中T細胞活化標記物4-1BB之上調來測試反應性。結果展示於圖2A中。如圖2A中所示,僅在將經4343-D TCR轉導之細胞與經編碼HLA-DRA1*01:01:01 / HLA-DRB3*02:02:01異二聚體之核苷酸序列轉導的負載p53-Y220C 25-mer之目標細胞共培養後,觀測到反應性。
實例9
此實例展現實例2之TIL識別由HLA-DPB1*04:02 / HLA-DPA1*01異二聚體呈現之突變p53。
使用外顯子體及mRNA定序測定由患者4386表現之II類MHC分子。所表現之II類MHC分子展示於圖2B中。
效應細胞為含有實例2中所鑑別之識別p53-R273C的T細胞的TIL。目標細胞為獨立地經圖2B中展示且用p53-R273C 25-mer肽SGNLLGRNSFEV
C VCACPGRDRRTE (SEQ ID NO: 117)脈衝之II類HLA異二聚體中之一者轉染的COS7細胞。
藉由流動式細胞測量術,藉由量測CD3陽性細胞中T細胞活化標記物4-1BB之上調來測試反應性。結果展示於圖2B中。如圖2B中所示,僅在將TIL與經編碼HLA-DPA1*01:03 / HLA-DPB1*04:02異二聚體之核苷酸序列轉導的負載p53-R273C 25-mer之目標細胞共培養後,觀測到反應性。
本文所引用之所有參考文獻(包括公開案、專利申請案及專利)以引用之方式併入本文中,該引用程度就如同個別及特定地指示各參考文獻以引用之方式併入且於本文中全文闡述一般。
除非本文另有指示或明顯與上下文矛盾,否則在描述本發明之上下文中(尤其在以下申請專利範圍的上下文中),使用術語「一」及「該」以及「至少一者」及類似提及物應解釋為涵蓋單數及複數兩者。除非本文另有指示或明顯與上下文矛盾,否則使用接一或多個項目之清單之術語「至少一者」(例如「A及B中之至少一者」)應解釋為意謂選自所列項目之一個項目(A或B)或所列項目中之兩者或更多者之任何組合(A及B)。除非另外指出,否則術語「包含」、「具有」、「包括」及「含有」應理解為開放式術語(亦即,意謂「包括但不限於」)。除非本文另有指示,否則本文之值範圍之列舉僅意欲充當個別地提及屬於該範圍內之各獨立值的簡寫方法,且各獨立值併入至本說明書中,如同在本文中單獨列舉一般。除非本文另有指示或以其他方式明顯與上下文相矛盾,否則本文所描述之所有方法可以任何適合之次序執行。除非另有主張,否則使用本文所提供之任何及所有實例或例示性語言(例如,「諸如」)僅意欲較佳地闡明本發明而不對本發明之範疇造成限制。本說明書中之語言不應理解為指示實踐本發明所必需之任何未主張要素。
本文描述本發明之較佳實施例,其包括本發明者已知用於進行本發明之最佳模式。在閱讀前述描述之後,彼等較佳實施例之變化形式對於一般熟習此項技術者可變得顯而易見。本發明人期望熟習此項技術者適當時採用該等變化形式,且本發明人意欲以不同於本文中特定描述之其他方式來實施本發明。因此,若適用法律准許,則本發明包括在隨附於本文之申請專利範圍中所敍述之主題之所有修改及等效物。此外,除非本文另有指示或以其他方式明顯與上下文矛盾,否則本發明涵蓋上文所描述之要素以其所有可能變化形式之任何組合。
圖1A為展示在將患者4343腫瘤片段編號F1至F7及F9至F24與用DMSO (媒劑)或突變p53-Y220C (圖1A)脈衝之自體性DC共培養之後量測的IFN-γ斑點(每2e4個細胞)之數目的圖表。具有突變p53反應性之片段為方形。
圖1B為展示在將患者4386腫瘤片段編號F1至F24與用DMSO (媒劑)或突變p53-R273C (圖1B)脈衝之自體性DC共培養之後量測的IFN-γ斑點(每2e4個細胞)之數目的圖表。具有突變p53反應性之片段為方形。
圖1C為展示在將自患者4386之(腫瘤1A或腫瘤1B之)新鮮腫瘤消化物的經分選T細胞與用DMSO (媒劑)或突變p53-R273C脈衝之自體性DC共培養之後量測的IFN-γ斑點(每2e4個細胞)之數目的圖表。基於指定細胞表面標記物之表現而對T細胞進行分選。具有突變p53反應性之經分選T細胞群為方形。
圖1D展示在將來自患者4386之TIL與用DMSO (媒劑)或突變p53-R273C肽脈衝之自體性DC共培養之後,表現OX40及4-1BB之T細胞之百分比,如藉由流動式細胞測量術所量測。
圖2A為展示在將目標細胞與效應細胞共培養之後,表現4-1BB之鼠類TCR恆定區陽性細胞的百分比的圖表。效應細胞經4343-D TCR轉導。目標細胞為經所示且用p53-Y220C 25-mer肽脈衝之II類HLA異二聚體中之一者轉染的COS7細胞。
圖2B為展示在將目標細胞與效應細胞共培養之後,表現4-1BB之CD3陽性細胞的百分比的圖表。效應細胞為含有識別p53-R273C之T細胞的TIL。目標細胞為經所示且用p53-R273C 25-mer肽脈衝之II類HLA異二聚體中之一者轉染的COS7細胞。
圖3A為展示在將目標細胞與效應細胞共培養之後量測的IFN-γ分泌(斑點數目/2e4個細胞)的圖表。效應細胞為經4343-D TCR轉導的T細胞。目標細胞為用所示濃度(µg/mL)的p53-Y220C 25-mer肽(正方形)或對應WT 25-mer肽(圓形)脈衝之自體DC。
圖3B至圖3C為展示在將目標細胞與效應細胞共培養之後,表現4-1BB之鼠類TCR恆定區陽性細胞的百分比的圖表。效應細胞為經4343-D TCR轉導的來自供體C (3B)或供體H (3C)的T細胞。目標細胞為用所示濃度(µg /mL)的與含有AABA取代之對應WT 25-mer肽(圓形)相對比的含有α-胺基丁酸(AABA)取代之突變p53-Y220C 25-mer肽(正方形)脈衝的自體B細胞。
圖3D至圖3G為展示在將目標細胞與效應細胞共培養之後量測的IFN-γ分泌(pg/mL)的圖表。效應細胞為分別經4386-F TCR (圖3D)、4386-G TCR (圖3E)、4386-H TCR (圖3F)或4386-O TCR(圖3G)轉導之T細胞。目標細胞為用所示濃度(ng/mL)的p53-R273C 25-mer肽(正方形)或對應WT 25-mer肽(圓形)脈衝之自體DC。
圖4展示九個p53剪接變體之胺基酸序列的比對。SP|P04637|P53_HUMAN (SEQ ID NO: 1);SP|P04637-2|P53_HUMAN (SEQ ID NO: 101);SP|P04637-3|P53_HUMAN (SEQ ID NO: 102);SP|P04637-4|P53_HUMAN (SEQ ID NO: 103);SP|P04637-5|P53_HUMAN (SEQ ID NO: 104);SP|P04637-6|P53_HUMAN (SEQ ID NO: 105);SP|P04637-7|P53_HUMAN (SEQ ID NO: 106);SP|P04637-8|P53_HUMAN (SEQ ID NO: 107);及SP|P04637-9|P53_HUMAN (SEQ ID NO: 108)。
<![CDATA[<110> 美國衛生與公眾服務部(THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, ]]> DEPARTMENT OF HEALTH AND HUMAN SERVICES) <![CDATA[<120> 識別P53中R273C或Y220C突變的T細胞受體]]> <![CDATA[<130> 757043]]> <![CDATA[<150> US 63/074,747]]> <![CDATA[<151> 2020-09-04]]> <![CDATA[<160> 151 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 393]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 <![CDATA[<210> 2]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Asn Ser Ala Phe Gln Tyr 1 5 <![CDATA[<210> 3]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Thr Tyr Ser Ser Gly Asn 1 5 <![CDATA[<210> 4]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Cys Ala Gly Gly Ser Tyr Gly Lys Leu Thr Phe 1 5 10 <![CDATA[<210> 5]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Met Asn His Glu Tyr 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Ser Met Asn Val Glu Val 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> Cys Ala Ser Ser Phe Ile Ser Asn Gln Pro Gln His Phe 1 5 10 <![CDATA[<210> 8]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 8]]> Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu 1 5 10 15 Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln 20 25 30 Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu 35 40 45 Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala 50 55 60 Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser 65 70 75 80 Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly 85 90 95 Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro 100 105 110 <![CDATA[<210> 9]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 9]]> Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly Lys Lys 1 5 10 15 Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met Ser Trp 20 25 30 Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr Ser Met 35 40 45 Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr Lys Val 50 55 60 Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser Pro Ser 65 70 75 80 Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Phe Ile Ser Asn 85 90 95 Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu 100 105 110 <![CDATA[<210> 10]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 10]]> Met His Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu 1 5 10 15 Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro 20 25 30 Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser 35 40 45 Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys 50 55 60 Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp 65 70 75 80 Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu 85 90 95 Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala 100 105 110 Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr 115 120 125 Val His Pro 130 <![CDATA[<210> 11]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 11]]> Met Ala Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu 130 <![CDATA[<210> 12]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 12]]> Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu 1 5 10 15 Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro 20 25 30 Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser 35 40 45 Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys 50 55 60 Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp 65 70 75 80 Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu 85 90 95 Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala 100 105 110 Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr 115 120 125 Val His Pro 130 <![CDATA[<210> 13]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 13]]> Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu 130 <![CDATA[<210> 14]]> <![CDATA[<211> 268]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 14]]> Met His Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu 1 5 10 15 Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro 20 25 30 Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser 35 40 45 Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys 50 55 60 Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp 65 70 75 80 Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu 85 90 95 Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala 100 105 110 Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr 115 120 125 Val His Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys 130 135 140 Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp 145 150 155 160 Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr 165 170 175 Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly 180 185 190 Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe 195 200 205 Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala 210 215 220 Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln 225 230 235 240 Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly 245 250 255 Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 <![CDATA[<210> 15]]> <![CDATA[<211> 304]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 15]]> Met Ala Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 <![CDATA[<210> 16]]> <![CDATA[<211> 268]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 16]]> Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu 1 5 10 15 Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro 20 25 30 Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser 35 40 45 Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys 50 55 60 Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp 65 70 75 80 Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu 85 90 95 Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala 100 105 110 Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr 115 120 125 Val His Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys 130 135 140 Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp 145 150 155 160 Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr 165 170 175 Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly 180 185 190 Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe 195 200 205 Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala 210 215 220 Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln 225 230 235 240 Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly 245 250 255 Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 <![CDATA[<210> 17]]> <![CDATA[<211> 304]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 17]]> Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 <![CDATA[<210> 18]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 18]]> Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu 1 5 10 15 Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln 20 25 30 Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu 35 40 45 Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala 50 55 60 Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser 65 70 75 80 Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly 85 90 95 Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro Asn Ile 100 105 110 Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln 115 120 125 Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val 130 135 140 Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu 145 150 155 160 Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser 165 170 175 Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala 180 185 190 Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys 195 200 205 Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile 210 215 220 Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met 225 230 235 240 Thr Leu Arg Leu Trp Ser Ser 245 <![CDATA[<210> 19]]> <![CDATA[<211> 283]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 19]]> Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly Lys Lys 1 5 10 15 Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met Ser Trp 20 25 30 Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr Ser Met 35 40 45 Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr Lys Val 50 55 60 Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser Pro Ser 65 70 75 80 Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Phe Ile Ser Asn 85 90 95 Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu Glu Asp 100 105 110 Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys 115 120 125 Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg 130 135 140 Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys 145 150 155 160 Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser 165 170 175 Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe 180 185 190 Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly 195 200 205 Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr 210 215 220 Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr 225 230 235 240 Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu 245 250 255 Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu 260 265 270 Val Val Met Ala Met Val Lys Arg Lys Asn Ser 275 280 <![CDATA[<210> 20]]> <![CDATA[<211> 599]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 20]]> Met Ala Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys 305 310 315 320 Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Lys Ser Leu 325 330 335 Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser Trp Val Trp Ser 340 345 350 Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu 355 360 365 Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln 370 375 380 Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu 385 390 395 400 Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala 405 410 415 Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser 420 425 430 Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly 435 440 445 Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro Asn Ile 450 455 460 Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln 465 470 475 480 Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val 485 490 495 Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu 500 505 510 Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser 515 520 525 Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala 530 535 540 Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys 545 550 555 560 Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile 565 570 575 Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met 580 585 590 Thr Leu Arg Leu Trp Ser Ser 595 <![CDATA[<210> 21]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 21]]> Asn Ser Ala Ser Asp Tyr 1 5 <![CDATA[<210> 22]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 22]]> Ile Arg Ser Asn Met Asp Lys 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 23]]> Cys Ala Glu Lys Ser Thr Gly Asn Gln Phe Tyr Phe 1 5 10 <![CDATA[<210> 24]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 24]]> Leu Gly His Asn Ala 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 25]]> Tyr Ser Leu Glu Glu Arg 1 5 <![CDATA[<210> 26]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 26]]> Cys Ala Ser Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe 1 5 10 <![CDATA[<210> 27]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 27]]> Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp 1 5 10 15 Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe 20 25 30 Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp 35 40 45 Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu 50 55 60 Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln 65 70 75 80 Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly Asn 85 90 95 Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro 100 105 110 <![CDATA[<210> 28]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 28]]> Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met 1 5 10 15 Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala 20 25 30 Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe 35 40 45 Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg 50 55 60 Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His 65 70 75 80 Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg 85 90 95 Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr 100 105 110 Val Leu <![CDATA[<210> 29]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 29]]> Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr 115 120 125 Val Ile Pro 130 <![CDATA[<210> 30]]> <![CDATA[<211> 132]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 30]]> Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu 130 <![CDATA[<210> 31]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 31]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr 115 120 125 Val Ile Pro 130 <![CDATA[<210> 32]]> <![CDATA[<211> 132]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 32]]> Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu 130 <![CDATA[<210> 33]]> <![CDATA[<211> 268]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 33]]> Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr 115 120 125 Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys 130 135 140 Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp 145 150 155 160 Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr 165 170 175 Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly 180 185 190 Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe 195 200 205 Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala 210 215 220 Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln 225 230 235 240 Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly 245 250 255 Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 <![CDATA[<210> 34]]> <![CDATA[<211> 305]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 34]]> Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser 130 135 140 Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr 145 150 155 160 Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser 165 170 175 Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro 180 185 190 Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu 195 200 205 Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys 210 215 220 Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly 225 230 235 240 Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg 245 250 255 Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser 260 265 270 Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala 275 280 285 Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn 290 295 300 Ser 305 <![CDATA[<210> 35]]> <![CDATA[<211> 268]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 35]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr 115 120 125 Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys 130 135 140 Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp 145 150 155 160 Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr 165 170 175 Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly 180 185 190 Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe 195 200 205 Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala 210 215 220 Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln 225 230 235 240 Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly 245 250 255 Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 <![CDATA[<210> 36]]> <![CDATA[<211> 305]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 36]]> Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser 130 135 140 Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr 145 150 155 160 Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser 165 170 175 Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro 180 185 190 Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu 195 200 205 Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys 210 215 220 Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly 225 230 235 240 Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg 245 250 255 Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser 260 265 270 Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala 275 280 285 Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn 290 295 300 Ser 305 <![CDATA[<210> 37]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 37]]> Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp 1 5 10 15 Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe 20 25 30 Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp 35 40 45 Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu 50 55 60 Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln 65 70 75 80 Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly Asn 85 90 95 Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro Asn Ile 100 105 110 Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln 115 120 125 Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val 130 135 140 Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu 145 150 155 160 Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser 165 170 175 Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala 180 185 190 Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys 195 200 205 Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile 210 215 220 Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met 225 230 235 240 Thr Leu Arg Leu Trp Ser Ser 245 <![CDATA[<210> 38]]> <![CDATA[<211> 287]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 38]]> Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met 1 5 10 15 Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala 20 25 30 Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe 35 40 45 Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg 50 55 60 Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His 65 70 75 80 Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg 85 90 95 Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr 100 105 110 Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe 115 120 125 Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val 130 135 140 Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp 145 150 155 160 Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala 165 170 175 Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val 180 185 190 Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val 195 200 205 Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro 210 215 220 Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp 225 230 235 240 Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr 245 250 255 Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu 260 265 270 Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 275 280 285 <![CDATA[<210> 39]]> <![CDATA[<211> 600]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 39]]> Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser 130 135 140 Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr 145 150 155 160 Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser 165 170 175 Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro 180 185 190 Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu 195 200 205 Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys 210 215 220 Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly 225 230 235 240 Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg 245 250 255 Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser 260 265 270 Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala 275 280 285 Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn 290 295 300 Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 305 310 315 320 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Gly Ile 325 330 335 Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp Trp Val Ser Arg 340 345 350 Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly 355 360 365 Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr 370 375 380 Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile 385 390 395 400 Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val 405 410 415 Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr 420 425 430 Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly 435 440 445 Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro Asn 450 455 460 Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser 465 470 475 480 Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn 485 490 495 Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val 500 505 510 Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp 515 520 525 Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn 530 535 540 Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu 545 550 555 560 Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val 565 570 575 Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu 580 585 590 Met Thr Leu Arg Leu Trp Ser Ser 595 600 <![CDATA[<210> 40]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 40]]> Val Ser Gly Asn Pro Tyr 1 5 <![CDATA[<210> 41]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 41]]> Tyr Ile Thr Gly Asp Asn Leu Val 1 5 <![CDATA[<210> 42]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 42]]> Cys Ala Val Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe 1 5 10 15 <![CDATA[<210> 43]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 43]]> Asp Phe Gln Ala Thr Thr 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 44]]> Ser Asn Glu Gly Ser Lys Ala 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 45]]> Cys Ser Ala Ile Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe 1 5 10 15 <![CDATA[<210> 46]]> <![CDATA[<211> 115]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 46]]> Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn 1 5 10 15 Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu 20 25 30 Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys 35 40 45 Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala 50 55 60 Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala 65 70 75 80 Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr 85 90 95 Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys 100 105 110 Val Leu Ala 115 <![CDATA[<210> 47]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 47]]> Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr 1 5 10 15 Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met 20 25 30 Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr 35 40 45 Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp 50 55 60 Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val 65 70 75 80 Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile 85 90 95 Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg 100 105 110 Leu Leu Val Leu 115 <![CDATA[<210> 48]]> <![CDATA[<211> 135]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 48]]> Met His Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser 1 5 10 15 Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val 20 25 30 Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly 35 40 45 Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln 50 55 60 Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr 65 70 75 80 Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys 85 90 95 Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val 100 105 110 Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly 115 120 125 Thr Arg Leu Lys Val Leu Ala 130 135 <![CDATA[<210> 49]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 49]]> Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu 130 <![CDATA[<210> 50]]> <![CDATA[<211> 135]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 50]]> Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser 1 5 10 15 Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val 20 25 30 Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly 35 40 45 Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln 50 55 60 Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr 65 70 75 80 Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys 85 90 95 Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val 100 105 110 Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly 115 120 125 Thr Arg Leu Lys Val Leu Ala 130 135 <![CDATA[<210> 51]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 51]]> Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu 130 <![CDATA[<210> 52]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 52]]> Met His Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser 1 5 10 15 Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val 20 25 30 Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly 35 40 45 Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln 50 55 60 Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr 65 70 75 80 Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys 85 90 95 Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val 100 105 110 Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly 115 120 125 Thr Arg Leu Lys Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val 130 135 140 Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe 145 150 155 160 Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly 165 170 175 Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser 180 185 190 Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys 195 200 205 Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val 210 215 220 Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn 225 230 235 240 Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu 245 250 255 Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 270 <![CDATA[<210> 53]]> <![CDATA[<211> 304]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 53]]> Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 <![CDATA[<210> 54]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 54]]> Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser 1 5 10 15 Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val 20 25 30 Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly 35 40 45 Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln 50 55 60 Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr 65 70 75 80 Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys 85 90 95 Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val 100 105 110 Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly 115 120 125 Thr Arg Leu Lys Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val 130 135 140 Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe 145 150 155 160 Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly 165 170 175 Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser 180 185 190 Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys 195 200 205 Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val 210 215 220 Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn 225 230 235 240 Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu 245 250 255 Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 270 <![CDATA[<210> 55]]> <![CDATA[<211> 304]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 55]]> Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 <![CDATA[<210> 56]]> <![CDATA[<211> 252]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 56]]> Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn 1 5 10 15 Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu 20 25 30 Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys 35 40 45 Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala 50 55 60 Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala 65 70 75 80 Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr 85 90 95 Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys 100 105 110 Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys 115 120 125 Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp 130 135 140 Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr 145 150 155 160 Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly 165 170 175 Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe 180 185 190 Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala 195 200 205 Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln 210 215 220 Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly 225 230 235 240 Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 245 250 <![CDATA[<210> 57]]> <![CDATA[<211> 289]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 57]]> Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr 1 5 10 15 Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met 20 25 30 Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr 35 40 45 Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp 50 55 60 Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val 65 70 75 80 Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile 85 90 95 Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg 100 105 110 Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser 115 120 125 Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr 130 135 140 Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser 145 150 155 160 Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro 165 170 175 Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu 180 185 190 Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys 195 200 205 Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly 210 215 220 Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg 225 230 235 240 Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser 245 250 255 Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala 260 265 270 Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn 275 280 285 Ser <![CDATA[<210> 58]]> <![CDATA[<211> 603]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 58]]> Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu 130 135 140 Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu 145 150 155 160 Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp 165 170 175 Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln 180 185 190 Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg 195 200 205 Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln 210 215 220 Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser 225 230 235 240 Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala 245 250 255 Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala 260 265 270 Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 275 280 285 Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 290 295 300 Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys 305 310 315 320 Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Ser Ala Pro 325 330 335 Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser Gly Leu Arg Ala Gln 340 345 350 Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn Pro 355 360 365 Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu Phe 370 375 380 Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys Tyr 385 390 395 400 Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala Glu 405 410 415 Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala Leu 420 425 430 Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr Val 435 440 445 Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val 450 455 460 Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp 465 470 475 480 Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser 485 490 495 Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp 500 505 510 Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala 515 520 525 Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys 530 535 540 Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr 545 550 555 560 Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn 565 570 575 Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe 580 585 590 Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 595 600 <![CDATA[<210> 59]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 59]]> Asn Thr Ala Phe Asp Tyr 1 5 <![CDATA[<210> 60]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 60]]> Ile Arg Pro Asp Val Ser Glu 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 61]]> Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe 1 5 10 <![CDATA[<210> 62]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 62]]> Ser Gly His Thr Ala 1 5 <![CDATA[<210> 63]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 63]]> Phe Gln Gly Asn Ser Ala 1 5 <![CDATA[<210> 64]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 64]]> Cys Ala Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe 1 5 10 <![CDATA[<210> 65]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 65]]> Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser Pro Gln 1 5 10 15 Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys Ala Tyr 20 25 30 Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe Pro Gly 35 40 45 Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser Glu Lys 50 55 60 Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys Gln Phe 65 70 75 80 Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr Tyr Phe 85 90 95 Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe Gly Lys 100 105 110 Gly Thr Lys Leu Thr Val Asn Pro 115 120 <![CDATA[<210> 66]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 66]]> Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp 1 5 10 15 Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp 20 25 30 Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln 35 40 45 Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser 50 55 60 Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln Arg Thr 65 70 75 80 Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Gly Gly 85 90 95 Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu 100 105 110 <![CDATA[<210> 67]]> <![CDATA[<211> 141]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 67]]> Met His Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu 1 5 10 15 Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val 20 25 30 Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile 35 40 45 Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr 50 55 60 Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro 65 70 75 80 Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys 85 90 95 Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp 100 105 110 Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys 115 120 125 Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro 130 135 140 <![CDATA[<210> 68]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 68]]> Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 69]]> <![CDATA[<211> 141]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 69]]> Met Asp Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu 1 5 10 15 Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val 20 25 30 Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile 35 40 45 Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr 50 55 60 Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro 65 70 75 80 Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys 85 90 95 Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp 100 105 110 Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys 115 120 125 Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro 130 135 140 <![CDATA[<210> 70]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 70]]> Met Gly Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 71]]> <![CDATA[<211> 278]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 71]]> Met His Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu 1 5 10 15 Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val 20 25 30 Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile 35 40 45 Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr 50 55 60 Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro 65 70 75 80 Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys 85 90 95 Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp 100 105 110 Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys 115 120 125 Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln 130 135 140 Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp 145 150 155 160 Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro 165 170 175 Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp 180 185 190 Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn 195 200 205 Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr 210 215 220 Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser 225 230 235 240 Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val 245 250 255 Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr 260 265 270 Leu Arg Leu Trp Ser Ser 275 <![CDATA[<210> 72]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 72]]> Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser 305 <![CDATA[<210> 73]]> <![CDATA[<211> 278]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 73]]> Met Asp Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu 1 5 10 15 Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val 20 25 30 Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile 35 40 45 Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr 50 55 60 Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro 65 70 75 80 Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys 85 90 95 Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp 100 105 110 Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys 115 120 125 Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln 130 135 140 Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp 145 150 155 160 Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro 165 170 175 Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp 180 185 190 Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn 195 200 205 Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr 210 215 220 Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser 225 230 235 240 Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val 245 250 255 Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr 260 265 270 Leu Arg Leu Trp Ser Ser 275 <![CDATA[<210> 74]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 74]]> Met Gly Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser 305 <![CDATA[<210> 75]]> <![CDATA[<211> 257]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 75]]> Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser Pro Gln 1 5 10 15 Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys Ala Tyr 20 25 30 Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe Pro Gly 35 40 45 Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser Glu Lys 50 55 60 Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys Gln Phe 65 70 75 80 Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr Tyr Phe 85 90 95 Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe Gly Lys 100 105 110 Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala 115 120 125 Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu 130 135 140 Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser 145 150 155 160 Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp 165 170 175 Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr 180 185 190 Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp 195 200 205 Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met 210 215 220 Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu 225 230 235 240 Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser 245 250 255 Ser <![CDATA[<210> 76]]> <![CDATA[<211> 285]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 76]]> Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp 1 5 10 15 Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp 20 25 30 Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln 35 40 45 Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser 50 55 60 Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln Arg Thr 65 70 75 80 Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Gly Gly 85 90 95 Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu 100 105 110 Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro 115 120 125 Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 130 135 140 Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn 145 150 155 160 Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys 165 170 175 Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala 180 185 190 Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe 195 200 205 His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 210 215 220 Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 225 230 235 240 Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu 245 250 255 Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser 260 265 270 Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 275 280 285 <![CDATA[<210> 77]]> <![CDATA[<211> 611]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 77]]> Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu 305 310 315 320 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Lys 325 330 335 Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu Cys Trp Val 340 345 350 Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser 355 360 365 Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys 370 375 380 Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe 385 390 395 400 Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser 405 410 415 Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys 420 425 430 Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr 435 440 445 Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe 450 455 460 Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu 465 470 475 480 Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu 485 490 495 Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met 500 505 510 Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala 515 520 525 Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser 530 535 540 Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser 545 550 555 560 Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr 565 570 575 Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile 580 585 590 Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu 595 600 605 Trp Ser Ser 610 <![CDATA[<210> 78]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 78]]> Asn Ser Ala Ser Asp Tyr 1 5 <![CDATA[<210> 79]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 79]]> Ile Arg Ser Asn Met Asp Lys 1 5 <![CDATA[<210> 80]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 80]]> Cys Ala Glu Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe 1 5 10 <![CDATA[<210> 81]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 81]]> Ser Gly His Thr Ala 1 5 <![CDATA[<210> 82]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 82]]> Phe Gln Gly Thr Gly Ala 1 5 <![CDATA[<210> 83]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 83]]> Cys Ala Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe 1 5 10 <![CDATA[<210> 84]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 84]]> Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp 1 5 10 15 Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe 20 25 30 Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp 35 40 45 Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu 50 55 60 Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln 65 70 75 80 Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly Gly 85 90 95 Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro 100 105 110 <![CDATA[<210> 85]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 85]]> Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Tyr 1 5 10 15 Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp 20 25 30 Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr Phe Gln 35 40 45 Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg Phe Phe 50 55 60 Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln Arg Thr 65 70 75 80 Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro Gly Gly 85 90 95 Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu 100 105 110 <![CDATA[<210> 86]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 86]]> Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys 115 120 125 Leu Thr Val Asn Pro 130 <![CDATA[<210> 87]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 87]]> Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 88]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 88]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys 115 120 125 Leu Thr Val Asn Pro 130 <![CDATA[<210> 89]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 89]]> Met Gly Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 90]]> <![CDATA[<211> 270]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 90]]> Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys 115 120 125 Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln 130 135 140 Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp 145 150 155 160 Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe 165 170 175 Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser 180 185 190 Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp 195 200 205 Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys 210 215 220 Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn 225 230 235 240 Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val 245 250 255 Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 270 <![CDATA[<210> 91]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 91]]> Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser 305 <![CDATA[<210> 92]]> <![CDATA[<211> 270]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 92]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys 115 120 125 Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln 130 135 140 Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp 145 150 155 160 Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe 165 170 175 Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser 180 185 190 Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp 195 200 205 Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys 210 215 220 Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn 225 230 235 240 Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val 245 250 255 Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 260 265 270 <![CDATA[<210> 93]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 93]]> Met Gly Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser 305 <![CDATA[<210> 94]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 94]]> Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp 1 5 10 15 Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe 20 25 30 Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp 35 40 45 Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu 50 55 60 Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln 65 70 75 80 Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly Gly 85 90 95 Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro 100 105 110 Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 115 120 125 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 130 135 140 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 145 150 155 160 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 165 170 175 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 180 185 190 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 195 200 205 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 210 215 220 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 225 230 235 240 Leu Met Thr Leu Arg Leu Trp Ser Ser 245 <![CDATA[<210> 95]]> <![CDATA[<211> 285]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 95]]> Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Tyr 1 5 10 15 Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp 20 25 30 Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr Phe Gln 35 40 45 Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg Phe Phe 50 55 60 Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln Arg Thr 65 70 75 80 Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro Gly Gly 85 90 95 Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu 100 105 110 Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro 115 120 125 Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 130 135 140 Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn 145 150 155 160 Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys 165 170 175 Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala 180 185 190 Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe 195 200 205 His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 210 215 220 Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 225 230 235 240 Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu 245 250 255 Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser 260 265 270 Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 275 280 285 <![CDATA[<210> 96]]> <![CDATA[<211> 603]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 96]]> Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val 130 135 140 Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala 145 150 155 160 Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu 165 170 175 Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp 180 185 190 Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg 195 200 205 Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg 210 215 220 Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu 225 230 235 240 Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly 245 250 255 Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu 260 265 270 Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr 275 280 285 Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys 290 295 300 Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu 305 310 315 320 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Gly 325 330 335 Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp Trp Val Ser 340 345 350 Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu 355 360 365 Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp 370 375 380 Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile 385 390 395 400 Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr 405 410 415 Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala 420 425 430 Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg 435 440 445 Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val 450 455 460 Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp 465 470 475 480 Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser 485 490 495 Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp 500 505 510 Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala 515 520 525 Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys 530 535 540 Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr 545 550 555 560 Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn 565 570 575 Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe 580 585 590 Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 595 600 <![CDATA[<210> 97]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 97]]> Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 98]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 98]]> Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 99]]> <![CDATA[<211> 173]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 99]]> Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro 1 5 10 15 Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 20 25 30 Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn 35 40 45 Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys 50 55 60 Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala 65 70 75 80 Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe 85 90 95 His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 100 105 110 Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 115 120 125 Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu 130 135 140 Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser 145 150 155 160 Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 165 170 <![CDATA[<210> 100]]> <![CDATA[<211> 27]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 100]]> Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys 1 5 10 15 Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro 20 25 <![CDATA[<210> 101]]> <![CDATA[<211> 341]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 101]]> Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Asp Gln Thr Ser Phe 325 330 335 Gln Lys Glu Asn Cys 340 <![CDATA[<210> 102]]> <![CDATA[<211> 346]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 102]]> Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Met Leu Leu Asp Leu 325 330 335 Arg Trp Cys Tyr Phe Leu Ile Asn Ser Ser 340 345 <![CDATA[<210> 103]]> <![CDATA[<211> 354]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 103]]> Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr 1 5 10 15 Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro 20 25 30 Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro 35 40 45 Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr 50 55 60 Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala 65 70 75 80 Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys 85 90 95 Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro 100 105 110 Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln 115 120 125 His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser 130 135 140 Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly 145 150 155 160 Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser 165 170 175 Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr 180 185 190 Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn 195 200 205 Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn 210 215 220 Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly 225 230 235 240 Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro 245 250 255 His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn 260 265 270 Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr 275 280 285 Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe Arg Glu 290 295 300 Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro 305 310 315 320 Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys Lys Gly Gln 325 330 335 Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly Pro Asp 340 345 350 Ser Asp <![CDATA[<210> 104]]> <![CDATA[<211> 302]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 104]]> Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr 1 5 10 15 Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro 20 25 30 Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro 35 40 45 Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr 50 55 60 Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala 65 70 75 80 Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys 85 90 95 Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro 100 105 110 Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln 115 120 125 His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser 130 135 140 Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly 145 150 155 160 Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser 165 170 175 Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr 180 185 190 Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn 195 200 205 Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn 210 215 220 Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly 225 230 235 240 Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro 245 250 255 His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn 260 265 270 Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr 275 280 285 Phe Thr Leu Gln Asp Gln Thr Ser Phe Gln Lys Glu Asn Cys 290 295 300 <![CDATA[<210> 105]]> <![CDATA[<211> 307]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 105]]> Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr 1 5 10 15 Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro 20 25 30 Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro 35 40 45 Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr 50 55 60 Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala 65 70 75 80 Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys 85 90 95 Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro 100 105 110 Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln 115 120 125 His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser 130 135 140 Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly 145 150 155 160 Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser 165 170 175 Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr 180 185 190 Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn 195 200 205 Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn 210 215 220 Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly 225 230 235 240 Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro 245 250 255 His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn 260 265 270 Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr 275 280 285 Phe Thr Leu Gln Met Leu Leu Asp Leu Arg Trp Cys Tyr Phe Leu Ile 290 295 300 Asn Ser Ser 305 <![CDATA[<210> 106]]> <![CDATA[<211> 261]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 106]]> Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp 1 5 10 15 Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys 20 25 30 Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu 35 40 45 Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg 50 55 60 Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe 65 70 75 80 Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp 85 90 95 Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly 100 105 110 Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser 115 120 125 Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala 130 135 140 Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys 145 150 155 160 Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu 165 170 175 Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp 180 185 190 Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met 195 200 205 Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly 210 215 220 Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys 225 230 235 240 Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu 245 250 255 Gly Pro Asp Ser Asp 260 <![CDATA[<210> 107]]> <![CDATA[<211> 209]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 107]]> Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp 1 5 10 15 Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys 20 25 30 Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu 35 40 45 Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg 50 55 60 Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe 65 70 75 80 Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp 85 90 95 Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly 100 105 110 Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser 115 120 125 Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala 130 135 140 Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys 145 150 155 160 Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu 165 170 175 Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp 180 185 190 Gly Glu Tyr Phe Thr Leu Gln Asp Gln Thr Ser Phe Gln Lys Glu Asn 195 200 205 Cys <![CDATA[<210> 108]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 108]]> Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp 1 5 10 15 Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys 20 25 30 Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu 35 40 45 Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg 50 55 60 Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe 65 70 75 80 Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp 85 90 95 Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly 100 105 110 Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser 115 120 125 Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala 130 135 140 Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys 145 150 155 160 Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu 165 170 175 Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp 180 185 190 Gly Glu Tyr Phe Thr Leu Gln Met Leu Leu Asp Leu Arg Trp Cys Tyr 195 200 205 Phe Leu Ile Asn Ser Ser 210 <![CDATA[<210> 109]]> <![CDATA[<211> 1797]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 109]]> atggcgcccc agctgctggg ctacgtggtg ctgtgcctgc tgggagcagg accactggag 60 gcacaggtga cccagaaccc cagatatctg atcaccgtga caggcaagaa gctgaccgtg 120 acatgttccc agaacatgaa tcacgagtac atgtcttggt ataggcagga ccctggcctg 180 ggcctgaggc agatctacta ttctatgaat gtggaggtga cagacaaggg cgatgtgcct 240 gagggctaca aggtgagccg gaaggagaag agaaacttcc cactgatcct ggagtctccc 300 agccctaatc agaccagcct gtatttctgc gccagctcct ttatctccaa ccagccccag 360 cactttggcg atggcacaag gctgtccatc ctggaggatc tccggaatgt gacaccccct 420 aaggtgtctc tgttcgagcc aagcaaggcc gagatcgcca acaagcagaa ggccaccctg 480 gtgtgcctgg ccagaggctt ctttcccgat cacgtggagc tgtcctggtg ggtgaatggc 540 aaggaggtgc actctggcgt gtgcaccgac cctcaggcct ataaggagtc caactactct 600 tattgtctga gctcccggct gagagtgtcc gccacattct ggcacaatcc cagaaaccac 660 ttcagatgcc aggtgcagtt tcacggcctg tccgaggagg ataagtggcc tgagggctct 720 ccaaagcccg tgacccagaa tatcagcgcc gaggcatggg gaagggcaga ctgtggaatc 780 acctccgcct cttaccagca gggcgtgctg agcgccacaa tcctgtatga gatcctgctg 840 ggcaaggcca ccctgtacgc cgtgctggtg agcacactgg tggtcatggc tatggtgaag 900 aggaagaaca gccgggccaa gcgcagcggc tccggcgcaa ccaacttctc tctgctgaag 960 caggcaggcg acgtggagga gaatcctggc ccaatgcata agagcctgcg ggtgctgctg 1020 gtcatcctgt ggctccagct gtcttgggtg tggagccagc agaaggaggt ggagcaggac 1080 cccggccctc tgagcgtgcc tgagggagcc atcgtgtccc tgaactgcac ctactccaat 1140 tctgccttcc agtacttcat gtggtacagg cagtacagcc ggaagggccc cgagctgctg 1200 atgtacacct atagctccgg caacaaggag gacggcaggt tcacagccca ggtggataag 1260 tctagcaagt acatctccct gtttatccgc gactctcagc caagcgattc cgccacctac 1320 ctgtgcgcag gaggatccta tggcaagctg acattcggcc agggcaccat cctgacagtg 1380 caccccaata ttcagaatcc cgagcccgcg gtataccagc tgaaggaccc ccggagccag 1440 gatagcaccc tgtgcctgtt cacagacttt gattctcaga tcaacgtgcc caagacaatg 1500 gagagcggca cctttatcac agacaagtgc gtgctggaca tgaaggctat ggactctaag 1560 agcaatggcg ccatcgcctg gtccaaccag acctctttca catgccagga tatctttaag 1620 gagacaaatg ccacataccc cagctccgac gtgccttgtg atgccaccct gacagagaag 1680 agcttcgaga cagacatgaa tctgaacttt cagaacctgc tggtcatcgt gctgagaatc 1740 ctgctgctga aagtggctgg cttcaacctg ctgatgaccc tgcggctgtg gagtagc 1797 <![CDATA[<210> 110]]> <![CDATA[<211> 1800]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 110]]> atggcgtgcc ggctgctgtg ctgtgccgtg ctgtgcctgc tgggagcagt gccaatggag 60 accggagtga cccagacacc caggcacctg gtcatgggca tgacaaacaa gaagtctctg 120 aagtgcgagc agcacctggg ccacaatgcc atgtactggt ataagcagtc cgccaagaag 180 cctctggagc tgatgttcgt gtactctctg gaggagcggg tggagaacaa ttccgtgcca 240 agccggttca gccccgagtg ccctaacagc tcccacctgt ttctgcacct gcacaccctc 300 cagccagagg acagcgccct gtacctgtgc gcctctagca gggtggaggg ctccgataca 360 cagtattttg gccctggcac ccgcctgaca gtgctggagg atctccggaa tgtgacaccc 420 cctaaggtgt ctctgttcga gccaagcaag gccgagatcg ccaacaagca gaaggccacc 480 ctggtgtgcc tggccagagg cttctttccc gatcacgtgg agctgtcctg gtgggtgaat 540 ggcaaggagg tgcactctgg cgtgtgcacc gaccctcagg cctataagga gtccaactac 600 tcttattgtc tgagctcccg gctgagagtg tccgccacat tctggcacaa tcccagaaac 660 cacttcagat gccaggtgca gtttcacggc ctgtccgagg aggataagtg gcctgagggc 720 tctccaaagc ccgtgaccca gaatatcagc gccgaggcat ggggaagggc agactgtgga 780 atcacctccg cctcttacca gcagggcgtg ctgagcgcca caatcctgta tgagatcctg 840 ctgggcaagg ccaccctgta cgccgtgctg gtgagcacac tggtggtcat ggctatggtg 900 aagaggaaga acagccgggc caagcgcagc ggctccggcg caaccaactt ctctctgctg 960 aagcaggcag gcgacgtgga ggagaatcct ggcccaatgc atggcatcag ggccctgttc 1020 atgtacctgt ggctccagct ggactgggtg agccggggcg agtccgtggg actgcacctg 1080 ccaaccctgt ctgtgcagga gggcgacaac agcatcatca attgcgccta tagcaactcc 1140 gcctctgatt acttcatctg gtataagcag gagagcggca agggccccca gtttatcatc 1200 gacatccggt ccaacatgga taagcggcag ggccagagag tgaccgtgct gctgaataag 1260 acagtgaagc acctgtctct ccagatcgca gcaacacagc ccggcgattc cgccgtgtac 1320 ttttgtgccg agaagtctac cggcaatcag ttctattttg gcaccggcac aagcctgaca 1380 gtgatcccta atattcagaa tcccgagccc gcggtatacc agctgaagga cccccggagc 1440 caggatagca ccctgtgcct gttcacagac tttgattctc agatcaacgt gcccaagaca 1500 atggagagcg gcacctttat cacagacaag tgcgtgctgg acatgaaggc tatggactct 1560 aagagcaatg gcgccatcgc ctggtccaac cagacctctt tcacatgcca ggatatcttt 1620 aaggagacaa atgccacata ccccagctcc gacgtgcctt gtgatgccac cctgacagag 1680 aagagcttcg agacagacat gaatctgaac tttcagaacc tgctggtcat cgtgctgaga 1740 atcctgctgc tgaaagtggc tggcttcaac ctgctgatga ccctgcggct gtggagtagc 1800 <![CDATA[<210> 111]]> <![CDATA[<211> 1809]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 111]]> atggcgctgc tgctgctgct gctgggccct ggctctggcc tgggagcagt ggtgtcccag 60 caccctagca gagtgatctg caagtctggc acaagcgtga agatcgagtg taggagcctg 120 gacttccagg ccaccacaat gttctggtac cgccagtttc ccaagcagtc cctgatgctg 180 atggccacaa gcaacgaggg ctccaaggcc acctatgagc agggcgtgga gaaggataag 240 tttctgatca atcacgcctc tctgaccctg agcaccctga cagtgacctc cgcccaccca 300 gaggacagct ccttctacat ctgctccgcc atccgggata gatctggcgg cgagacacag 360 tattttggcc ctggcaccag gctgctggtg ctggaggatc tccggaatgt gacaccccct 420 aaggtgtctc tgttcgagcc aagcaaggcc gagatcgcca acaagcagaa ggccaccctg 480 gtgtgcctgg ccagaggctt ctttcccgat cacgtggagc tgtcctggtg ggtgaatggc 540 aaggaggtgc actctggcgt gtgcaccgac cctcaggcct ataaggagtc caactactct 600 tattgtctga gctcccggct gagagtgtcc gccacattct ggcacaatcc cagaaaccac 660 ttcagatgcc aggtgcagtt tcacggcctg tccgaggagg ataagtggcc tgagggctct 720 ccaaagcccg tgacccagaa tatcagcgcc gaggcatggg gaagggcaga ctgtggaatc 780 acctccgcct cttaccagca gggcgtgctg agcgccacaa tcctgtatga gatcctgctg 840 ggcaaggcca ccctgtacgc cgtgctggtg agcacactgg tggtcatggc tatggtgaag 900 aggaagaaca gccgggccaa gcgcagcggc tccggcgcaa ccaacttctc tctgctgaag 960 caggcaggcg acgtggagga gaatcctggc ccaatgcata gcgcccccat ctccatgctg 1020 gccatgctgt ttaccctgtc tggcctgagg gcacagagcg tggcacagcc agaggaccag 1080 gtgaacgtgg ccgagggcaa tcccctgacc gtgaagtgca catacagcgt gtccggcaac 1140 ccctatctgt tctggtacgt gcagtatcct aatcggggcc tccagttcct gctgaagtac 1200 atcaccggcg ataacctggt gaagggcagc tatggcttcg aggccgagtt taataagtcc 1260 cagacatctt tccacctgaa gaagccttcc gccctggtgt ctgacagcgc cctgtacttt 1320 tgtgccgtgc gggatccaac cgtgtctggc acatacaagt atatcttcgg caccggcaca 1380 agactgaagg tgctggccaa tattcagaat cccgagcccg cggtatacca gctgaaggac 1440 ccccggagcc aggatagcac cctgtgcctg ttcacagact ttgattctca gatcaacgtg 1500 cccaagacaa tggagagcgg cacctttatc acagacaagt gcgtgctgga catgaaggct 1560 atggactcta agagcaatgg cgccatcgcc tggtccaacc agacctcttt cacatgccag 1620 gatatcttta aggagacaaa tgccacatac cccagctccg acgtgccttg tgatgccacc 1680 ctgacagaga agagcttcga gacagacatg aatctgaact ttcagaacct gctggtcatc 1740 gtgctgagaa tcctgctgct gaaagtggct ggcttcaacc tgctgatgac cctgcggctg 1800 tggagtagc 1809 <![CDATA[<210> 112]]> <![CDATA[<211> 1833]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 112]]> atggcgaccc ggctgctgtt ctgggtggca ttttgcctgc tgggagcaga ccacaccgga 60 gcaggcgtgt cccagtctcc aagcaacaag gtgacagaga agggcaagga cgtggagctg 120 aggtgtgatc ccatcagcgg ccacacagcc ctgtactggt ataggcagtc cctgggacag 180 ggcctggagt tcctgatcta ctttcagggc aattctgccc ccgacaagag cggcctgcct 240 tccgatcggt tctctgccga gagaaccggc ggctccgtgt ctaccctgac aatccagcgg 300 acacagcagg aggattccgc cgtgtacctg tgcgccagct ccctgggagg atctagcgag 360 acccagtatt ttggccctgg cacaaggctg ctggtgctgg aggatctccg gaatgtgaca 420 ccccctaagg tgtctctgtt cgagccaagc aaggccgaga tcgccaacaa gcagaaggcc 480 accctggtgt gcctggccag aggcttcttt cccgatcacg tggagctgtc ctggtgggtg 540 aatggcaagg aggtgcactc tggcgtgtgc accgaccctc aggcctataa ggagtccaac 600 tactcttatt gtctgagctc ccggctgaga gtgtccgcca cattctggca caatcccaga 660 aaccacttca gatgccaggt gcagtttcac ggcctgtccg aggaggataa gtggcctgag 720 ggctctccaa agcccgtgac ccagaatatc agcgccgagg catggggaag ggcagactgt 780 ggaatcacct ccgcctctta ccagcagggc gtgctgagcg ccacaatcct gtatgagatc 840 ctgctgggca aggccaccct gtacgccgtg ctggtgagca cactggtggt catggctatg 900 gtgaagagga agaacagccg ggccaagcgc agcggctccg gcgcaaccaa cttctctctg 960 ctgaagcagg caggcgacgt ggaggagaat cctggcccaa tgcataagat cctgggcgcc 1020 tccttcctgg tgctgtggct ccagctgtgc tgggtgagcg gccagcagaa ggagaagtcc 1080 gaccagcagc aggtgaagca gagcccccag tccctgatcg tgcagaaggg cggcatctct 1140 atcatcaact gtgcctacga gaataccgcc ttcgactact ttccctggta tcagcagttc 1200 cccggcaagg gacctgccct gctgatcgca atccggcccg acgtgagcga gaagaaggag 1260 ggcagattca ccatctcttt taacaagagc gccaagcagt ttagcctgca catcatggac 1320 tcccagcctg gcgattctgc cacatatttc tgcgcagcaa agaggcaggg aggaagcgag 1380 aagctggtgt ttggcaaggg caccaagctg acagtgaatc caaatattca gaatcccgag 1440 cccgcggtat accagctgaa ggacccccgg agccaggata gcaccctgtg cctgttcaca 1500 gactttgatt ctcagatcaa cgtgcccaag acaatggaga gcggcacctt tatcacagac 1560 aagtgcgtgc tggacatgaa ggctatggac tctaagagca atggcgccat cgcctggtcc 1620 aaccagacct ctttcacatg ccaggatatc tttaaggaga caaatgccac ataccccagc 1680 tccgacgtgc cttgtgatgc caccctgaca gagaagagct tcgagacaga catgaatctg 1740 aactttcaga acctgctggt catcgtgctg agaatcctgc tgctgaaagt ggctggcttc 1800 aacctgctga tgaccctgcg gctgtggagt agc 1833 <![CDATA[<210> 113]]> <![CDATA[<211> 1809]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 113]]> atggcgacca ggctgctgtg ctgggccgcc ctgtgcctgc tgggagcaga ccacacagga 60 gcaggcgtgt cccagacccc ttctaacaag gtgacagaga agggcaagta cgtggagctg 120 cggtgcgatc caatcagcgg ccacaccgcc ctgtactggt atagacagtc cctgggacag 180 ggccccgagt tcctgatcta ttttcaggga acaggagccg ccgacgattc cggcctgccc 240 aatgacaggt tctttgccgt gcgccctgag ggatctgtga gcaccctgaa gatccagcgg 300 acagagagag gcgatagcgc cgtgtacctg tgcgccagct ccccaggcgg aagccaggag 360 acccagtatt tcggccctgg cacaagactg ctggtgctgg aggatctccg gaatgtgaca 420 ccccctaagg tgtctctgtt cgagccaagc aaggccgaga tcgccaacaa gcagaaggcc 480 accctggtgt gcctggccag aggcttcttt cccgatcacg tggagctgtc ctggtgggtg 540 aatggcaagg aggtgcactc tggcgtgtgc accgaccctc aggcctataa ggagtccaac 600 tactcttatt gtctgagctc ccggctgaga gtgtccgcca cattctggca caatcccaga 660 aaccacttca gatgccaggt gcagtttcac ggcctgtccg aggaggataa gtggcctgag 720 ggctctccaa agcccgtgac ccagaatatc agcgccgagg catggggaag ggcagactgt 780 ggaatcacct ccgcctctta ccagcagggc gtgctgagcg ccacaatcct gtatgagatc 840 ctgctgggca aggccaccct gtacgccgtg ctggtgagca cactggtggt catggctatg 900 gtgaagagga agaacagccg ggccaagcgc agcggctccg gcgcaaccaa cttctctctg 960 ctgaagcagg caggcgacgt ggaggagaat cctggcccaa tgcatggcat ccgggccctg 1020 ttcatgtacc tgtggctcca gctggactgg gtgagcaggg gcgagtccgt gggactgcac 1080 ctgccaaccc tgtctgtgca ggagggcgac aacagcatca tcaattgcgc ctatagcaac 1140 tccgcctctg attacttcat ctggtataag caggagagcg gcaagggccc ccagtttatc 1200 atcgacatcc ggtccaacat ggataagagg cagggacaga gggtgaccgt gctgctgaat 1260 aagacagtga agcacctgtc cctccagatc gcagcaacac agcccggcga ttctgccgtg 1320 tacttctgtg ccgagaagcg gagaggcggc tctgagaagc tggtgtttgg caagggcacc 1380 aagctgacag tgaatcctaa tattcagaat cccgagcccg cggtatacca gctgaaggac 1440 ccccggagcc aggatagcac cctgtgcctg ttcacagact ttgattctca gatcaacgtg 1500 cccaagacaa tggagagcgg cacctttatc acagacaagt gcgtgctgga catgaaggct 1560 atggactcta agagcaatgg cgccatcgcc tggtccaacc agacctcttt cacatgccag 1620 gatatcttta aggagacaaa tgccacatac cccagctccg acgtgccttg tgatgccacc 1680 ctgacagaga agagcttcga gacagacatg aatctgaact ttcagaacct gctggtcatc 1740 gtgctgagaa tcctgctgct gaaagtggct ggcttcaacc tgctgatgac cctgcggctg 1800 tggagtagc 1809 <![CDATA[<210> 114]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 114]]> Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro 1 5 10 15 Glu Val Gly Ser Asp Cys Thr Thr Ile 20 25 <![CDATA[<210> 115]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 115]]> Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro 1 5 10 15 Glu Val Gly Ser Asp Cys Thr Thr Ile 20 25 <![CDATA[<210> 116]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 116]]> Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala 1 5 10 15 Cys Pro Gly Arg Asp Arg Arg Thr Glu 20 25 <![CDATA[<210> 117]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 117]]> Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Cys Val Cys Ala 1 5 10 15 Cys Pro Gly Arg Asp Arg Arg Thr Glu 20 25 <![CDATA[<210> 118]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 118]]> Arg Ala Lys Arg 1 <![CDATA[<210> 119]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 119]]> Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly 1 5 10 15 Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr 20 25 30 Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met 35 40 45 Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln 50 55 60 Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln 65 70 75 80 Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly Lys 85 90 95 Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro 100 105 <![CDATA[<210> 120]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 120]]> Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly 1 5 10 15 Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met 20 25 30 Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr 35 40 45 Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr 50 55 60 Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser 65 70 75 80 Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Phe Ile 85 90 95 Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu 100 105 110 <![CDATA[<210> 121]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 121]]> Met Ala Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu 1 5 10 15 Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro 20 25 30 Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser 35 40 45 Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys 50 55 60 Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp 65 70 75 80 Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu 85 90 95 Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala 100 105 110 Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr 115 120 125 Val His Pro 130 <![CDATA[<210> 122]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 122]]> Met His Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr 20 25 30 Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His 35 40 45 Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln 50 55 60 Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro 65 70 75 80 Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile 85 90 95 Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser 100 105 110 Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu 115 120 125 Ser Ile Leu 130 <![CDATA[<210> 123]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 123]]> Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly 1 5 10 15 Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr 20 25 30 Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile 35 40 45 Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val 50 55 60 Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr 65 70 75 80 Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly 85 90 95 Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro 100 105 110 <![CDATA[<210> 124]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 124]]> Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met Thr 1 5 10 15 Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala Met 20 25 30 Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe Val 35 40 45 Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg Phe 50 55 60 Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His Thr 65 70 75 80 Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg Val 85 90 95 Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val 100 105 110 Leu <![CDATA[<210> 125]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 125]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr 115 120 125 Val Ile Pro 130 <![CDATA[<210> 126]]> <![CDATA[<211> 132]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 126]]> Met His Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala 1 5 10 15 Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met 20 25 30 Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His 35 40 45 Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu 50 55 60 Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro 65 70 75 80 Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His 85 90 95 Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser 100 105 110 Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg 115 120 125 Leu Thr Val Leu 130 <![CDATA[<210> 127]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 127]]> Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly 1 5 10 15 Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr 20 25 30 Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu 35 40 45 Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu 50 55 60 Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser 65 70 75 80 Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro 85 90 95 Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu 100 105 110 Lys Val Leu Ala 115 <![CDATA[<210> 128]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 128]]> Gly Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly 1 5 10 15 Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr 20 25 30 Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala 35 40 45 Thr Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys 50 55 60 Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr 65 70 75 80 Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala 85 90 95 Ile Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr 100 105 110 Arg Leu Leu Val Leu 115 <![CDATA[<210> 129]]> <![CDATA[<211> 135]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 129]]> Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser 1 5 10 15 Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val 20 25 30 Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly 35 40 45 Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln 50 55 60 Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr 65 70 75 80 Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys 85 90 95 Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val 100 105 110 Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly 115 120 125 Thr Arg Leu Lys Val Leu Ala 130 135 <![CDATA[<210> 130]]> <![CDATA[<211> 131]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 130]]> Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala 1 5 10 15 Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser 20 25 30 Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe 35 40 45 Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser 50 55 60 Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys 65 70 75 80 Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr 85 90 95 Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg 100 105 110 Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu 115 120 125 Leu Val Leu 130 <![CDATA[<210> 131]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 131]]> Gln Gln Gln Val Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly 1 5 10 15 Gly Ile Ser Ile Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr 20 25 30 Phe Pro Trp Tyr Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile 35 40 45 Ala Ile Arg Pro Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile 50 55 60 Ser Phe Asn Lys Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser 65 70 75 80 Gln Pro Gly Asp Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly 85 90 95 Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn 100 105 110 Pro <![CDATA[<210> 132]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 132]]> Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly 1 5 10 15 Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu 20 25 30 Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr 35 40 45 Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg 50 55 60 Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln 65 70 75 80 Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu 85 90 95 Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu 100 105 110 Val Leu <![CDATA[<210> 133]]> <![CDATA[<211> 141]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 133]]> Met Ala Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu 1 5 10 15 Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val 20 25 30 Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile 35 40 45 Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr 50 55 60 Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro 65 70 75 80 Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys 85 90 95 Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp 100 105 110 Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys 115 120 125 Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro 130 135 140 <![CDATA[<210> 134]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 134]]> Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro 65 70 75 80 Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu 85 90 95 Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 135]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 135]]> Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly 1 5 10 15 Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr 20 25 30 Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile 35 40 45 Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val 50 55 60 Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr 65 70 75 80 Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly 85 90 95 Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn 100 105 110 Pro <![CDATA[<210> 136]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 136]]> Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly 1 5 10 15 Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu 20 25 30 Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr 35 40 45 Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg 50 55 60 Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln 65 70 75 80 Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro 85 90 95 Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu 100 105 110 Val Leu <![CDATA[<210> 137]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 137]]> Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp 1 5 10 15 Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser 20 25 30 Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser 35 40 45 Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro 50 55 60 Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln 65 70 75 80 Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln 85 90 95 Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu 100 105 110 Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys 115 120 125 Leu Thr Val Asn Pro 130 <![CDATA[<210> 138]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 138]]> Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala 1 5 10 15 Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr 20 25 30 Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His 35 40 45 Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe 50 55 60 Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro 65 70 75 80 Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu 85 90 95 Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala 100 105 110 Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr 115 120 125 Arg Leu Leu Val Leu 130 <![CDATA[<210> 139]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 139]]> Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser 100 105 110 Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 140]]> <![CDATA[<211> 173]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 140]]> Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro 1 5 10 15 Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 20 25 30 Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn 35 40 45 Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys 50 55 60 Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala 65 70 75 80 Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe 85 90 95 His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 100 105 110 Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 115 120 125 Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu 130 135 140 Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser 145 150 155 160 Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 165 170 <![CDATA[<210> 141]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> X為Asn, Asp, His,或Tyr]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (48)..(48)]]> <![CDATA[<223> X為Thr或Cys]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (112)..(112)]]> <![CDATA[<223> X為Ser, Ala, Val, Leu, Ile, Pro, Phe, Met,或Trp]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (114)..(114)]]> <![CDATA[<223> X為Met, Ala, Val, Leu, Ile, Pro, Phe,或Trp]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (115)..(115)]]> <![CDATA[<223> X為Gly, Ala, Val, Leu, Ile, Pro, Phe, Met,或Trp]]> <![CDATA[<400> 141]]> Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Xaa 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Xaa 100 105 110 Val Xaa Xaa Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 142]]> <![CDATA[<211> 173]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (57)..(57)]]> <![CDATA[<223> X為Ser或Cys]]> <![CDATA[<400> 142]]> Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro 1 5 10 15 Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 20 25 30 Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn 35 40 45 Gly Lys Glu Val His Ser Gly Val Xaa Thr Asp Pro Gln Ala Tyr Lys 50 55 60 Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala 65 70 75 80 Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe 85 90 95 His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 100 105 110 Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 115 120 125 Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu 130 135 140 Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser 145 150 155 160 Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser 165 170 <![CDATA[<210> 143]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> X為Asn, Asp, His,或Tyr]]> <![CDATA[<400> 143]]> Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 144]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> X為Asn, Asp, His,或Tyr]]> <![CDATA[<400> 144]]> Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 145]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 145]]> Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 146]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 146]]> Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu 100 105 110 Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 147]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> X為Asn, Asp, His,或Tyr]]> <![CDATA[<400> 147]]> Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser 100 105 110 Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 148]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 148]]> Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser 100 105 110 Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 149]]> <![CDATA[<211> 137]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 149]]> Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg 1 5 10 15 Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile 20 25 30 Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys 35 40 45 Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala 50 55 60 Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr 65 70 75 80 Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr 85 90 95 Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser 100 105 110 Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 115 120 125 Leu Met Thr Leu Arg Leu Trp Ser Ser 130 135 <![CDATA[<210> 150]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (22)..(22)]]> <![CDATA[<223> X為α-胺基丁酸(AABA)]]> <![CDATA[<400> 150]]> Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro 1 5 10 15 Glu Val Gly Ser Asp Xaa Thr Thr Ile 20 25 <![CDATA[<210> 151]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (13)..(13)]]> <![CDATA[<223> X為α-胺基丁酸(AABA)]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<222> (22)..(22)]]> <![CDATA[<223> X為α-胺基丁酸(AABA)]]> <![CDATA[<400> 151]]> Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Xaa Glu Pro Pro 1 5 10 15 Glu Val Gly Ser Asp Xaa Thr Thr Ile 20 25
Claims (49)
- 一種經分離或經純化T細胞受體(TCR),其對人類p53 R273C或人類p53 Y220C胺基酸序列具有抗原特異性,其中該TCR包含以下胺基酸序列: (1) SEQ ID NO: 2-7全部; (2) SEQ ID NO: 21-26全部; (3) SEQ ID NO: 40-45全部; (4) SEQ ID NO: 59-64全部;或 (5) SEQ ID NO: 78-83全部。
- 如請求項1之TCR,其中該TCR包含: (1)與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列兩者; (2)與胺基酸序列SEQ ID NO: 10至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列兩者; (3)與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列兩者; (4)與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列兩者; (5)與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列兩者; (6)與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 122至少95%一致之胺基酸序列兩者; (7)與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列兩者; (8)與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列兩者; (9)與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列兩者; (10)與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列兩者; (11)與胺基酸序列SEQ ID NO: 29至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列兩者; (12)與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列兩者; (13)與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列兩者; (14)與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列兩者; (15)與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 126至少95%一致之胺基酸序列兩者; (16)與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列兩者; (17)與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列兩者; (18)與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列兩者; (19)與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列兩者; (20)與胺基酸序列SEQ ID NO: 48至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列兩者; (21)與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列兩者; (22)與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列兩者; (23)與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列兩者; (24)與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 130至少95%一致之胺基酸序列兩者; (25)與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列兩者; (26)與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列兩者; (27)與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列兩者; (28)與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列兩者; (29)與胺基酸序列SEQ ID NO: 67至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列兩者; (30)與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列兩者; (31)與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列兩者; (32)與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列兩者; (33)與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 134至少95%一致之胺基酸序列兩者; (34)與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列兩者; (35)與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列兩者; (36)與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列兩者; (37)與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列兩者; (38)與胺基酸序列SEQ ID NO: 86至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列兩者; (39)與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列兩者; (40)與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列兩者; (41)與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列兩者; (42)與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 138至少95%一致之胺基酸序列兩者; (43)與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列兩者; (44)與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列兩者;或 (45)與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列兩者。
- 如請求項1之TCR,其中該TCR包含以下胺基酸序列: (1) SEQ ID NO: 8及9兩者; (2) SEQ ID NO: 10及11兩者; (3) SEQ ID NO: 12及13兩者; (4) SEQ ID NO: 12及11兩者; (5) SEQ ID NO: 121及13兩者; (6) SEQ ID NO: 121及122兩者; (7) SEQ ID NO: 8及120兩者; (8) SEQ ID NO: 119及9兩者; (9) SEQ ID NO: 119及120兩者; (10) SEQ ID NO: 27及28兩者; (11) SEQ ID NO: 29及30兩者; (12) SEQ ID NO: 31及32兩者; (13) SEQ ID NO: 31及30兩者; (14) SEQ ID NO: 125及32兩者; (15) SEQ ID NO: 125及126兩者; (16) SEQ ID NO: 27及124兩者; (17) SEQ ID NO: 123及28兩者; (18) SEQ ID NO: 123及124兩者; (19) SEQ ID NO: 46及47兩者; (20) SEQ ID NO: 48及49兩者; (21) SEQ ID NO: 50及51兩者; (22) SEQ ID NO: 50及49兩者; (23) SEQ ID NO: 129及51兩者; (24) SEQ ID NO: 129及130兩者; (25) SEQ ID NO: 46及128兩者; (26) SEQ ID NO: 127及47兩者; (27) SEQ ID NO: 127及128兩者; (28) SEQ ID NO: 65及66兩者; (29) SEQ ID NO: 67及68兩者; (30) SEQ ID NO: 69及70兩者; (31) SEQ ID NO: 69及68兩者; (32) SEQ ID NO: 133及70兩者; (33) SEQ ID NO: 133及134兩者; (34) SEQ ID NO: 65及132兩者; (35) SEQ ID NO: 131及66兩者; (36) SEQ ID NO: 131及132兩者; (37) SEQ ID NO: 84及85兩者; (38) SEQ ID NO: 86及87兩者; (39) SEQ ID NO: 88及89兩者; (40) SEQ ID NO: 88及87兩者; (41) SEQ ID NO: 137及89兩者; (42) SEQ ID NO: 137及138兩者; (43) SEQ ID NO: 84及136兩者; (44) SEQ ID NO: 135及85兩者;或 (45) SEQ ID NO: 135及136兩者。
- 如請求項1至3中任一項之TCR,其進一步包含: (a) α鏈恆定區,其包含與胺基酸序列SEQ ID NO: 141至少95%一致之胺基酸序列,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該α鏈恆定區包含與胺基酸序列SEQ ID NO: 97或145至少95%一致之胺基酸序列; (b) β鏈恆定區,其包含與胺基酸序列SEQ ID NO: 142至少95%一致之胺基酸序列,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該β鏈恆定區包含與胺基酸序列SEQ ID NO: 99或140至少95%一致之胺基酸序列;或 (c) (a)及(b)兩者。
- 如請求項1至3中任一項之TCR,其進一步包含: (a) α鏈恆定區,其包含胺基酸序列SEQ ID NO: 141,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該α鏈恆定區包含胺基酸序列SEQ ID NO: 97或145; (b) β鏈恆定區,其包含胺基酸序列SEQ ID NO: 142,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該β鏈恆定區包含胺基酸序列SEQ ID NO: 99或140;或 (c) (a)及(b)兩者。
- 如請求項1至5中任一項之TCR,其中該TCR包含: (1)與胺基酸序列SEQ ID NO: 14至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 15至少95%一致之胺基酸序列兩者; (2)與胺基酸序列SEQ ID NO: 16至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 17至少95%一致之胺基酸序列兩者; (3)與胺基酸序列SEQ ID NO: 18至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 19至少95%一致之胺基酸序列兩者; (4)與胺基酸序列SEQ ID NO: 33至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 34至少95%一致之胺基酸序列兩者; (5)與胺基酸序列SEQ ID NO: 35至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 36至少95%一致之胺基酸序列兩者; (6)與胺基酸序列SEQ ID NO: 37至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 38至少95%一致之胺基酸序列兩者; (7)與胺基酸序列SEQ ID NO: 52至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 53至少95%一致之胺基酸序列兩者; (8)與胺基酸序列SEQ ID NO: 54至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 55至少95%一致之胺基酸序列兩者; (9)與胺基酸序列SEQ ID NO: 56至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 57至少95%一致之胺基酸序列兩者; (10)與胺基酸序列SEQ ID NO: 71至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 72至少95%一致之胺基酸序列兩者; (11)與胺基酸序列SEQ ID NO: 73至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 74至少95%一致之胺基酸序列兩者; (12)與胺基酸序列SEQ ID NO: 75至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 76至少95%一致之胺基酸序列兩者; (13)與胺基酸序列SEQ ID NO: 90至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 91至少95%一致之胺基酸序列兩者; (14)與胺基酸序列SEQ ID NO: 92至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 93至少95%一致之胺基酸序列兩者;或 (15)與胺基酸序列SEQ ID NO: 94至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 95至少95%一致之胺基酸序列兩者。
- 如請求項1至5中任一項之TCR,其中該TCR包含以下胺基酸序列: (1) SEQ ID NO: 14及15兩者; (2) SEQ ID NO: 16及17兩者; (3) SEQ ID NO: 18及19兩者; (4) SEQ ID NO: 33及34兩者; (5) SEQ ID NO: 35及36兩者; (6) SEQ ID NO: 37及38兩者; (7) SEQ ID NO: 52及53兩者; (8) SEQ ID NO: 54及55兩者; (9) SEQ ID NO: 56及57兩者; (10) SEQ ID NO: 71及72兩者; (11) SEQ ID NO: 73及74兩者; (12) SEQ ID NO: 75及76兩者; (13) SEQ ID NO: 90及91兩者; (14) SEQ ID NO: 92及93兩者;或 (15) SEQ ID NO: 94及95兩者。
- 如請求項1至7中任一項之TCR,其中該人類p53 R273C胺基酸序列為SGNLLGRNSFEV C VCACPGRDRRTE (SEQ ID NO: 117)。
- 如請求項1至7中任一項之TCR,其中該人類p53 Y220C胺基酸序列為DRNTFRHSVVVP C EPPEVGSDCTTI (SEQ ID NO: 115)。
- 如請求項1至8中任一項之TCR,其中該TCR對野生型人類p53胺基酸序列SGNLLGRNSFEV R VCACPGRDRRTE (SEQ ID NO: 116)不具有抗原特異性。
- 如請求項1至7及9中任一項之TCR,其中該TCR對野生型人類p53胺基酸序列DRNTFRHSVVVP Y EPPEVGSDCTTI (SEQ ID NO: 114)不具有抗原特異性。
- 一種經分離或經純化多肽,其包含如請求項1至11中任一項之TCR之功能部分,其中該多肽包含以下胺基酸序列: (1) SEQ ID NO: 2-7全部; (2) SEQ ID NO: 21-26全部; (3) SEQ ID NO: 40-45全部; (4) SEQ ID NO: 59-64全部;或 (5) SEQ ID NO: 78-83全部。
- 如請求項12之多肽,其中該多肽包含: (1)與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列兩者; (2)與胺基酸序列SEQ ID NO: 10至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列兩者; (3)與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列兩者; (4)與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列兩者; (5)與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列兩者; (6)與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 122至少95%一致之胺基酸序列兩者; (7)與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列兩者; (8)與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列兩者; (9)與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列兩者; (10)與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列兩者; (11)與胺基酸序列SEQ ID NO: 29至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列兩者; (12)與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列兩者; (13)與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列兩者; (14)與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列兩者; (15)與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 126至少95%一致之胺基酸序列兩者; (16)與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列兩者; (17)與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列兩者; (18)與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列兩者; (19)與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列兩者; (20)與胺基酸序列SEQ ID NO: 48至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列兩者; (21)與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列兩者; (22)與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列兩者; (23)與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列兩者; (24)與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 130至少95%一致之胺基酸序列兩者; (25)與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列兩者; (26)與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列兩者; (27)與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列兩者; (28)與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列兩者; (29)與胺基酸序列SEQ ID NO: 67至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列兩者; (30)與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列兩者; (31)與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列兩者; (32)與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列兩者; (33)與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 134至少95%一致之胺基酸序列兩者; (34)與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列兩者; (35)與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列兩者; (36)與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列兩者; (37)與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列兩者; (38)與胺基酸序列SEQ ID NO: 86至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列兩者; (39)與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列兩者; (40)與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列兩者; (41)與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列兩者; (42)與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 138至少95%一致之胺基酸序列兩者; (43)與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列兩者; (44)與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列兩者;或 (45)與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列兩者。
- 如請求項12之多肽,其中該多肽包含以下胺基酸序列: (1) SEQ ID NO: 8及9兩者; (2) SEQ ID NO: 10及11兩者; (3) SEQ ID NO: 12及13兩者; (4) SEQ ID NO: 12及11兩者; (5) SEQ ID NO: 121及13兩者; (6) SEQ ID NO: 121及122兩者; (7) SEQ ID NO: 8及120兩者; (8) SEQ ID NO: 119及9兩者; (9) SEQ ID NO: 119及120兩者; (10) SEQ ID NO: 27及28兩者; (11) SEQ ID NO: 29及30兩者; (12) SEQ ID NO: 31及32兩者; (13) SEQ ID NO: 31及30兩者; (14) SEQ ID NO: 125及32兩者; (15) SEQ ID NO: 125及126兩者; (16) SEQ ID NO: 27及124兩者; (17) SEQ ID NO: 123及28兩者; (18) SEQ ID NO: 123及124兩者; (19) SEQ ID NO: 46及47兩者; (20) SEQ ID NO: 48及49兩者; (21) SEQ ID NO: 50及51兩者; (22) SEQ ID NO: 50及49兩者; (23) SEQ ID NO: 129及51兩者; (24) SEQ ID NO: 129及130兩者; (25) SEQ ID NO: 46及128兩者; (26) SEQ ID NO: 127及47兩者; (27) SEQ ID NO: 127及128兩者; (28) SEQ ID NO: 65及66兩者; (29) SEQ ID NO: 67及68兩者; (30) SEQ ID NO: 69及70兩者; (31) SEQ ID NO: 69及68兩者; (32) SEQ ID NO: 133及70兩者; (33) SEQ ID NO: 133及134兩者; (34) SEQ ID NO: 65及132兩者; (35) SEQ ID NO: 131及66兩者; (36) SEQ ID NO: 131及132兩者; (37) SEQ ID NO: 84及85兩者; (38) SEQ ID NO: 86及87兩者; (39) SEQ ID NO: 88及89兩者; (40) SEQ ID NO: 88及87兩者; (41) SEQ ID NO: 137及89兩者; (42) SEQ ID NO: 137及138兩者; (43) SEQ ID NO: 84及136兩者; (44) SEQ ID NO: 135及85兩者;或 (45) SEQ ID NO: 135及136兩者。
- 如請求項12至14中任一項之多肽,其進一步包含: (a) α鏈恆定區,其包含與胺基酸序列SEQ ID NO: 141至少95%一致之胺基酸序列,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該α鏈恆定區包含與胺基酸序列SEQ ID NO: 97或145至少95%一致之胺基酸序列; (b) β鏈恆定區,其包含與胺基酸序列SEQ ID NO: 142至少95%一致之胺基酸序列,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該β鏈恆定區包含與胺基酸序列SEQ ID NO: 99或140至少95%一致之胺基酸序列;或 (c) (a)及(b)兩者。
- 如請求項12至14中任一項之多肽,其進一步包含: (a) α鏈恆定區,其包含胺基酸序列SEQ ID NO: 141,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該α鏈恆定區包含胺基酸序列SEQ ID NO: 97或145; (b) β鏈恆定區,其包含胺基酸序列SEQ ID NO: 142,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該β鏈恆定區包含胺基酸序列SEQ ID NO: 99或140;或 (c) (a)及(b)兩者。
- 如請求項12至16中任一項之多肽,其中該多肽包含: (1)與胺基酸序列SEQ ID NO: 14至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 15至少95%一致之胺基酸序列兩者; (2)與胺基酸序列SEQ ID NO: 16至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 17至少95%一致之胺基酸序列兩者; (3)與胺基酸序列SEQ ID NO: 18至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 19至少95%一致之胺基酸序列兩者; (4)與胺基酸序列SEQ ID NO: 33至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 34至少95%一致之胺基酸序列兩者; (5)與胺基酸序列SEQ ID NO: 35至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 36至少95%一致之胺基酸序列兩者; (6)與胺基酸序列SEQ ID NO: 37至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 38至少95%一致之胺基酸序列兩者; (7)與胺基酸序列SEQ ID NO: 52至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 53至少95%一致之胺基酸序列兩者; (8)與胺基酸序列SEQ ID NO: 54至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 55至少95%一致之胺基酸序列兩者; (9)與胺基酸序列SEQ ID NO: 56至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 57至少95%一致之胺基酸序列兩者; (10)與胺基酸序列SEQ ID NO: 71至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 72至少95%一致之胺基酸序列兩者; (11)與胺基酸序列SEQ ID NO: 73至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 74至少95%一致之胺基酸序列兩者; (12)與胺基酸序列SEQ ID NO: 75至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 76至少95%一致之胺基酸序列兩者; (13)與胺基酸序列SEQ ID NO: 90至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 91至少95%一致之胺基酸序列兩者; (14)與胺基酸序列SEQ ID NO: 92至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 93至少95%一致之胺基酸序列兩者;或 (15)與胺基酸序列SEQ ID NO: 94至少95%一致之胺基酸序列及與胺基酸序列SEQ ID NO: 95至少95%一致之胺基酸序列兩者。
- 如請求項12至16中任一項之多肽,其中該多肽包含以下胺基酸序列: (1) SEQ ID NO: 14及15兩者; (2) SEQ ID NO: 16及17兩者; (3) SEQ ID NO: 18及19兩者; (4) SEQ ID NO: 33及34兩者; (5) SEQ ID NO: 35及36兩者; (6) SEQ ID NO: 37及38兩者; (7) SEQ ID NO: 52及53兩者; (8) SEQ ID NO: 54及55兩者; (9) SEQ ID NO: 56及57兩者; (10) SEQ ID NO: 71及72兩者; (11) SEQ ID NO: 73及74兩者; (12) SEQ ID NO: 75及76兩者; (13) SEQ ID NO: 90及91兩者; (14) SEQ ID NO: 92及93兩者;或 (15) SEQ ID NO: 94及95兩者。
- 一種經分離或經純化蛋白質,其包含: (1)包含胺基酸序列SEQ ID NO: 2-4中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 5-7中全部的第二多肽鏈; (2)包含胺基酸序列SEQ ID NO: 21-23中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 24-26中全部的第二多肽鏈; (3)包含胺基酸序列SEQ ID NO: 40-42中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 43-45中全部的第二多肽鏈; (4)包含胺基酸序列SEQ ID NO: 59-61中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 62-64中全部的第二多肽鏈;或 (5)包含胺基酸序列SEQ ID NO: 78-80中全部的第一多肽鏈及包含胺基酸序列SEQ ID NO: 81-83中全部的第二多肽鏈。
- 如請求項19之蛋白質,其中: (1)第一多肽鏈包含與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列; (2)第一多肽鏈包含與胺基酸序列SEQ ID NO: 10至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列; (3)第一多肽鏈包含與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列; (4)第一多肽鏈包含與胺基酸序列SEQ ID NO: 12至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 11至少95%一致之胺基酸序列; (5)第一多肽鏈包含與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 13至少95%一致之胺基酸序列; (6)第一多肽鏈包含與胺基酸序列SEQ ID NO: 121至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 122至少95%一致之胺基酸序列; (7)第一多肽鏈包含與胺基酸序列SEQ ID NO: 8至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列; (8)第一多肽鏈包含與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 9至少95%一致之胺基酸序列; (9)第一多肽鏈包含與胺基酸序列SEQ ID NO: 119至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 120至少95%一致之胺基酸序列; (10)第一多肽鏈包含與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列; (11)第一多肽鏈包含與胺基酸序列SEQ ID NO: 29至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列; (12)第一多肽鏈包含與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列; (13)第一多肽鏈包含與胺基酸序列SEQ ID NO: 31至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 30至少95%一致之胺基酸序列; (14)第一多肽鏈包含與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 32至少95%一致之胺基酸序列; (15)第一多肽鏈包含與胺基酸序列SEQ ID NO: 125至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 126至少95%一致之胺基酸序列; (16)第一多肽鏈包含與胺基酸序列SEQ ID NO: 27至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列; (17)第一多肽鏈包含與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 28至少95%一致之胺基酸序列; (18)第一多肽鏈包含與胺基酸序列SEQ ID NO: 123至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 124至少95%一致之胺基酸序列; (19)第一多肽鏈包含與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列; (20)第一多肽鏈包含與胺基酸序列SEQ ID NO: 48至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列; (21)第一多肽鏈包含與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列; (22)第一多肽鏈包含與胺基酸序列SEQ ID NO: 50至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 49至少95%一致之胺基酸序列; (23)第一多肽鏈包含與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 51至少95%一致之胺基酸序列; (24)第一多肽鏈包含與胺基酸序列SEQ ID NO: 129至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 130至少95%一致之胺基酸序列; (25)第一多肽鏈包含與胺基酸序列SEQ ID NO: 46至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列; (26)第一多肽鏈包含與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 47至少95%一致之胺基酸序列; (27)第一多肽鏈包含與胺基酸序列SEQ ID NO: 127至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 128至少95%一致之胺基酸序列; (28)第一多肽鏈包含與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列; (29)第一多肽鏈包含與胺基酸序列SEQ ID NO: 67至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列; (30)第一多肽鏈包含與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列; (31)第一多肽鏈包含與胺基酸序列SEQ ID NO: 69至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 68至少95%一致之胺基酸序列; (32)第一多肽鏈包含與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 70至少95%一致之胺基酸序列; (33)第一多肽鏈包含與胺基酸序列SEQ ID NO: 133至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 134至少95%一致之胺基酸序列; (34)第一多肽鏈包含與胺基酸序列SEQ ID NO: 65至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列; (35)第一多肽鏈包含與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 66至少95%一致之胺基酸序列; (36)第一多肽鏈包含與胺基酸序列SEQ ID NO: 131至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 132至少95%一致之胺基酸序列; (37)第一多肽鏈包含與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列; (38)第一多肽鏈包含與胺基酸序列SEQ ID NO: 86至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列; (39)第一多肽鏈包含與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列; (40)第一多肽鏈包含與胺基酸序列SEQ ID NO: 88至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 87至少95%一致之胺基酸序列; (41)第一多肽鏈包含與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 89至少95%一致之胺基酸序列; (42)第一多肽鏈包含與胺基酸序列SEQ ID NO: 137至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 138至少95%一致之胺基酸序列; (43)第一多肽鏈包含與胺基酸序列SEQ ID NO: 84至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列; (44)第一多肽鏈包含與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 85至少95%一致之胺基酸序列;或 (45)第一多肽鏈包含與胺基酸序列SEQ ID NO: 135至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 136至少95%一致之胺基酸序列。
- 如請求項19之蛋白質,其中: (1)第一多肽鏈包含胺基酸序列SEQ ID NO: 8及第二多肽鏈包含胺基酸序列SEQ ID NO: 9; (2)第一多肽鏈包含胺基酸序列SEQ ID NO: 10及第二多肽鏈包含胺基酸序列SEQ ID NO: 11; (3)第一多肽鏈包含胺基酸序列SEQ ID NO: 12及第二多肽鏈包含胺基酸序列SEQ ID NO: 13; (4)第一多肽鏈包含胺基酸序列SEQ ID NO: 12及第二多肽鏈包含胺基酸序列SEQ ID NO: 11; (5)第一多肽鏈包含胺基酸序列SEQ ID NO: 121及第二多肽鏈包含胺基酸序列SEQ ID NO: 13; (6)第一多肽鏈包含胺基酸序列SEQ ID NO: 121及第二多肽鏈包含胺基酸序列SEQ ID NO: 122; (7)第一多肽鏈包含胺基酸序列SEQ ID NO: 8及第二多肽鏈包含胺基酸序列SEQ ID NO: 120; (8)第一多肽鏈包含胺基酸序列SEQ ID NO: 119及第二多肽鏈包含胺基酸序列SEQ ID NO: 9; (9)第一多肽鏈包含胺基酸序列SEQ ID NO: 119及第二多肽鏈包含胺基酸序列SEQ ID NO: 120; (10)第一多肽鏈包含胺基酸序列SEQ ID NO: 27及第二多肽鏈包含胺基酸序列SEQ ID NO: 28; (11)第一多肽鏈包含胺基酸序列SEQ ID NO: 29及第二多肽鏈包含胺基酸序列SEQ ID NO: 30; (12)第一多肽鏈包含胺基酸序列SEQ ID NO: 31及第二多肽鏈包含胺基酸序列SEQ ID NO: 32; (13)第一多肽鏈包含胺基酸序列SEQ ID NO: 31及第二多肽鏈包含胺基酸序列SEQ ID NO: 30; (14)第一多肽鏈包含胺基酸序列SEQ ID NO: 125及第二多肽鏈包含胺基酸序列SEQ ID NO: 32; (15)第一多肽鏈包含胺基酸序列SEQ ID NO: 125及第二多肽鏈包含胺基酸序列SEQ ID NO: 126; (16)第一多肽鏈包含胺基酸序列SEQ ID NO: 27及第二多肽鏈包含胺基酸序列SEQ ID NO: 124; (17)第一多肽鏈包含胺基酸序列SEQ ID NO: 123及第二多肽鏈包含胺基酸序列SEQ ID NO: 28; (18)第一多肽鏈包含胺基酸序列SEQ ID NO: 123及第二多肽鏈包含胺基酸序列SEQ ID NO: 124; (19)第一多肽鏈包含胺基酸序列SEQ ID NO: 46及第二多肽鏈包含胺基酸序列SEQ ID NO: 47; (20)第一多肽鏈包含胺基酸序列SEQ ID NO: 48及第二多肽鏈包含胺基酸序列SEQ ID NO: 49; (21)第一多肽鏈包含胺基酸序列SEQ ID NO: 50及第二多肽鏈包含胺基酸序列SEQ ID NO: 51; (22)第一多肽鏈包含胺基酸序列SEQ ID NO: 50及第二多肽鏈包含胺基酸序列SEQ ID NO: 49; (23)第一多肽鏈包含胺基酸序列SEQ ID NO: 129及第二多肽鏈包含胺基酸序列SEQ ID NO: 51; (24)第一多肽鏈包含胺基酸序列SEQ ID NO: 129及第二多肽鏈包含胺基酸序列SEQ ID NO: 130; (25)第一多肽鏈包含胺基酸序列SEQ ID NO: 46及第二多肽鏈包含胺基酸序列SEQ ID NO: 128; (26)第一多肽鏈包含胺基酸序列SEQ ID NO: 127及第二多肽鏈包含胺基酸序列SEQ ID NO: 47; (27)第一多肽鏈包含胺基酸序列SEQ ID NO: 127及第二多肽鏈包含胺基酸序列SEQ ID NO: 128; (28)第一多肽鏈包含胺基酸序列SEQ ID NO: 65及第二多肽鏈包含胺基酸序列SEQ ID NO: 66; (29)第一多肽鏈包含胺基酸序列SEQ ID NO: 67及第二多肽鏈包含胺基酸序列SEQ ID NO: 68; (30)第一多肽鏈包含胺基酸序列SEQ ID NO: 69及第二多肽鏈包含胺基酸序列SEQ ID NO: 70; (31)第一多肽鏈包含胺基酸序列SEQ ID NO: 69及第二多肽鏈包含胺基酸序列SEQ ID NO: 68; (32)第一多肽鏈包含胺基酸序列SEQ ID NO: 133及第二多肽鏈包含胺基酸序列SEQ ID NO: 70; (33)第一多肽鏈包含胺基酸序列SEQ ID NO: 133及第二多肽鏈包含胺基酸序列SEQ ID NO: 134; (34)第一多肽鏈包含胺基酸序列SEQ ID NO: 65及第二多肽鏈包含胺基酸序列SEQ ID NO: 132; (35)第一多肽鏈包含胺基酸序列SEQ ID NO: 131及第二多肽鏈包含胺基酸序列SEQ ID NO: 66; (36)第一多肽鏈包含胺基酸序列SEQ ID NO: 131及第二多肽鏈包含胺基酸序列SEQ ID NO: 132; (37)第一多肽鏈包含胺基酸序列SEQ ID NO: 84及第二多肽鏈包含胺基酸序列SEQ ID NO: 85; (38)第一多肽鏈包含胺基酸序列SEQ ID NO: 86及第二多肽鏈包含胺基酸序列SEQ ID NO: 87; (39)第一多肽鏈包含胺基酸序列SEQ ID NO: 88及第二多肽鏈包含胺基酸序列SEQ ID NO: 89; (40)第一多肽鏈包含胺基酸序列SEQ ID NO: 88及第二多肽鏈包含胺基酸序列SEQ ID NO: 87; (41)第一多肽鏈包含胺基酸序列SEQ ID NO: 137及第二多肽鏈包含胺基酸序列SEQ ID NO: 89; (42)第一多肽鏈包含胺基酸序列SEQ ID NO: 137及第二多肽鏈包含胺基酸序列SEQ ID NO: 138; (43)第一多肽鏈包含胺基酸序列SEQ ID NO: 84及第二多肽鏈包含胺基酸序列SEQ ID NO: 136; (44)第一多肽鏈包含胺基酸序列SEQ ID NO: 135及第二多肽鏈包含胺基酸序列SEQ ID NO: 85;或 (45)第一多肽鏈包含胺基酸序列SEQ ID NO: 135及第二多肽鏈包含胺基酸序列SEQ ID NO: 136。
- 如請求項19至21中任一項之蛋白質,其中: (a)第一多肽鏈包含含有與胺基酸序列SEQ ID NO: 141至少95%一致之胺基酸序列的α鏈恆定區,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該第一多肽鏈包含含有與胺基酸序列SEQ ID NO: 97或145至少95%一致之胺基酸序列的α鏈恆定區;且 (b)第二多肽鏈包含含有與胺基酸序列SEQ ID NO: 142至少95%一致之胺基酸序列的β鏈恆定區,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該第二多肽鏈包含含有與胺基酸序列SEQ ID NO: 99或140至少95%一致之胺基酸序列的β鏈恆定區。
- 如請求項19至21中任一項之蛋白質,其進一步包含: (a)第一多肽鏈,其包含含有胺基酸序列SEQ ID NO: 141之α鏈恆定區,其中: (i) SEQ ID NO: 141之位置1處的X為Asn、Asp、His或Tyr; (ii) SEQ ID NO: 141之位置48處的X為Thr或Cys; (iii) SEQ ID NO: 141之位置112處的X為Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; (iv) SEQ ID NO: 141之位置114處的X為Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且 (v) SEQ ID NO: 141之位置115處的X為Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp; 其中視情況,該第一多肽鏈包含含有胺基酸序列SEQ ID NO: 97或145之α鏈恆定區;及 (b)第二多肽鏈,其包含含有胺基酸序列SEQ ID NO: 142之β鏈恆定區,其中SEQ ID NO: 142之位置57處的X為Ser或Cys; 其中視情況,該第二多肽鏈包含含有胺基酸序列SEQ ID NO: 99或140之β鏈恆定區。
- 如請求項19至23中任一項之蛋白質,其中: (1)第一多肽鏈包含與胺基酸序列SEQ ID NO: 14至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 15至少95%一致之胺基酸序列; (2)第一多肽鏈包含與胺基酸序列SEQ ID NO: 16至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 17至少95%一致之胺基酸序列; (3)第一多肽鏈包含與胺基酸序列SEQ ID NO: 18至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 19至少95%一致之胺基酸序列; (4)第一多肽鏈包含與胺基酸序列SEQ ID NO: 33至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 34至少95%一致之胺基酸序列; (5)第一多肽鏈包含與胺基酸序列SEQ ID NO: 35至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 36至少95%一致之胺基酸序列; (6)第一多肽鏈包含與胺基酸序列SEQ ID NO: 37至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 38至少95%一致之胺基酸序列; (7)第一多肽鏈包含與胺基酸序列SEQ ID NO: 52至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 53至少95%一致之胺基酸序列; (8)第一多肽鏈包含與胺基酸序列SEQ ID NO: 54至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 55至少95%一致之胺基酸序列; (9)第一多肽鏈包含與胺基酸序列SEQ ID NO: 56至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 57至少95%一致之胺基酸序列; (10)第一多肽鏈包含與胺基酸序列SEQ ID NO: 71至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 72至少95%一致之胺基酸序列; (11)第一多肽鏈包含與胺基酸序列SEQ ID NO: 73至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 74至少95%一致之胺基酸序列; (12)第一多肽鏈包含與胺基酸序列SEQ ID NO: 75至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 76至少95%一致之胺基酸序列; (13)第一多肽鏈包含與胺基酸序列SEQ ID NO: 90至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 91至少95%一致之胺基酸序列; (14)第一多肽鏈包含與胺基酸序列SEQ ID NO: 92至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 93至少95%一致之胺基酸序列;或 (15)第一多肽鏈包含與胺基酸序列SEQ ID NO: 94至少95%一致之胺基酸序列及第二多肽鏈包含與胺基酸序列SEQ ID NO: 95至少95%一致之胺基酸序列。
- 如請求項19至23中任一項之蛋白質,其中: (1)第一多肽鏈包含胺基酸序列SEQ ID NO: 14及第二多肽鏈包含胺基酸序列SEQ ID NO: 15; (2)第一多肽鏈包含胺基酸序列SEQ ID NO: 16及第二多肽鏈包含胺基酸序列SEQ ID NO: 17; (3)第一多肽鏈包含胺基酸序列SEQ ID NO: 18及第二多肽鏈包含胺基酸序列SEQ ID NO: 19; (4)第一多肽鏈包含胺基酸序列SEQ ID NO: 33及第二多肽鏈包含胺基酸序列SEQ ID NO: 34; (5)第一多肽鏈包含胺基酸序列SEQ ID NO: 35及第二多肽鏈包含胺基酸序列SEQ ID NO: 36; (6)第一多肽鏈包含胺基酸序列SEQ ID NO: 37及第二多肽鏈包含胺基酸序列SEQ ID NO: 38; (7)第一多肽鏈包含胺基酸序列SEQ ID NO: 52及第二多肽鏈包含胺基酸序列SEQ ID NO: 53; (8)第一多肽鏈包含胺基酸序列SEQ ID NO: 54及第二多肽鏈包含胺基酸序列SEQ ID NO: 55; (9)第一多肽鏈包含胺基酸序列SEQ ID NO: 56及第二多肽鏈包含胺基酸序列SEQ ID NO: 57; (10)第一多肽鏈包含胺基酸序列SEQ ID NO: 71及第二多肽鏈包含胺基酸序列SEQ ID NO: 72; (11)第一多肽鏈包含胺基酸序列SEQ ID NO: 73及第二多肽鏈包含胺基酸序列SEQ ID NO: 74; (12)第一多肽鏈包含胺基酸序列SEQ ID NO: 75及第二多肽鏈包含胺基酸序列SEQ ID NO: 76; (13)第一多肽鏈包含胺基酸序列SEQ ID NO: 90及第二多肽鏈包含胺基酸序列SEQ ID NO: 91; (14)第一多肽鏈包含胺基酸序列SEQ ID NO: 92及第二多肽鏈包含胺基酸序列SEQ ID NO: 93;或 (15)第一多肽鏈包含胺基酸序列SEQ ID NO: 94及第二多肽鏈包含胺基酸序列SEQ ID NO: 95。
- 一種經分離或經純化核酸,其包含編碼以下之核苷酸序列:如請求項1至11中任一項之TCR、如請求項12至18中任一項之多肽或如請求項19至25中任一項之蛋白質。
- 一種經分離或經純化核酸,其自5'至3'包含第一核苷酸序列及第二核苷酸序列,其中該第一及第二核苷酸序列分別編碼以下胺基酸序列:SEQ ID NO: 8及9;9及8;10及11;11及10;12及13;13及12;12及11;11及12;121及13;13及121;121及122;122及121;8及120;120及8;119及9;9及119;119及120;120及119;14及15;15及14;16及17;17及16;18及19;19及18;27及28;28及27;29及30;30及29;31及32;32及31;31及30;30及31;125及32;32及125;125及126;126及125;27及124;124及27;123及28;28及123;123及124;124及123;33及34;34及33;35及36;36及35;37及38;38及37;46及47;47及46;48及49;49及48;50及51;51及50;50及49;49及50;129及51;51及129;129及130;130及129;46及128;128及46;127及47;47及127;127及128;128及127;52及53;53及52;54及55;55及54;56及57;57及56;65及66;66及65;67及68;68及67;69及70;70及69;69及68;68及69;133及70;70及133;133及134;134及133;65及132;132及65;131及66;66及131;131及132;132及131;71及72;72及71;73及74;74及73;75及76;76及75;84及85;85及84;86及87;87及86;88及89;89及88;88及87;87及88;137及89;89及137;137及138;138及137;84及136;136及84;135及85;85及135;135及136;136及135;90及91;91及90;92及93;93及92;94及95;或95及94。
- 如請求項27之經分離或經純化核酸,其進一步包含插入於該第一與第二核苷酸序列之間的第三核苷酸序列,其中該第三核苷酸序列編碼可裂解連接子肽。
- 如請求項28之經分離或經純化核酸,其中該可裂解連接子肽包含胺基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 100)。
- 如請求項29之經分離或經純化核酸,其編碼選自由以下組成之群的胺基酸序列:SEQ ID NO: 20、39、58、77及96。
- 一種重組表現載體,其包含如請求項26至30中任一項之核酸。
- 如請求項31之重組表現載體,其為轉位子或慢病毒載體。
- 一種經分離或經純化TCR、多肽或蛋白質,其由如請求項26至30中任一項之核酸或如請求項31或32之載體編碼。
- 一種經分離或經純化TCR、多肽或蛋白質,其由如請求項26至30中任一項之核酸或如請求項31或32之載體在細胞中的表現所產生。
- 一種產生表現TCR之宿主細胞的方法,該TCR對肽DRNTFRHSVVVP C EPPEVGSDCTTI (SEQ ID NO: 115)或SGNLLGRNSFEV C VCACPGRDRRTE (SEQ ID NO: 117)具有抗原特異性,該方法包含使細胞與如請求項31或32之載體在允許將該載體引入至該細胞中的條件下接觸。
- 一種經分離或經純化宿主細胞,其包含如請求項26至30中任一項之核酸或如請求項31或32之重組表現載體。
- 如請求項36之宿主細胞,其中該細胞為人類淋巴球。
- 如請求項36之宿主細胞,其中該細胞係選自由以下組成之群:T細胞、自然殺手T (NKT)細胞、恆定型自然殺手T (iNKT)細胞及自然殺手(NK)細胞。
- 一種經分離或經純化細胞群,其包含如請求項36至38中任一項之宿主細胞。
- 一種產生如請求項1至11、33或34中任一項之TCR、如請求項12至18、33或34中任一項之多肽或如請求項19至25、33或34中任一項之蛋白質的方法,該方法包含培養如請求項36至38中任一項之宿主細胞或如請求項39之宿主細胞群,以使得產生該TCR、多肽或蛋白質。
- 一種醫藥組合物,其包含:(a)如請求項1至11、33或34中任一項之TCR,如請求項12至18、33或34中任一項之多肽,如請求項19至25、33或34中任一項之蛋白質,如請求項26至30中任一項之核酸,如請求項31或32之重組表現載體,如請求項36至38中任一項之宿主細胞,或如請求項39之細胞群;及(b)醫藥學上可接受之載劑。
- 一種偵測哺乳動物中癌症之存在的方法,該方法包含: (a)使包含該癌症之細胞的樣本與以下接觸,從而形成複合體:如請求項1至11、33或34中任一項之TCR,如請求項12至18、33或34中任一項之多肽,如請求項19至25、33或34中任一項之蛋白質,如請求項26至30中任一項之核酸,如請求項31或32之重組表現載體,如請求項36至38中任一項之宿主細胞,如請求項39之細胞群,或如請求項41之醫藥組合物;以及 (b)偵測該複合體, 其中該複合體之偵測指示該哺乳動物中癌症之存在。
- 一種如請求項1至11、33或34中任一項之TCR、如請求項12至18、33或34中任一項之多肽、如請求項19至25、33或34中任一項之蛋白質、如請求項26至30中任一項之核酸、如請求項31或32之重組表現載體、如請求項36至38中任一項之宿主細胞、如請求項39之細胞群或如請求項41之醫藥組合物的用途,其用於製造供誘導針對哺乳動物之癌症的免疫反應的藥物。
- 一種如請求項1至11、33或34中任一項之TCR、如請求項12至18、33或34中任一項之多肽、如請求項19至25、33或34中任一項之蛋白質、如請求項26至30中任一項之核酸、如請求項31或32之重組表現載體、如請求項36至38中任一項之宿主細胞、如請求項39之細胞群或如請求項41之醫藥組合物的用途,其用於製造供治療或預防哺乳動物之癌症的藥物。
- 如請求項43或44之用途,其中該細胞群對於該哺乳動物為自體的。
- 如請求項43或44之用途,其中該細胞群對於該哺乳動物為同種異體的。
- 如請求項43至46中任一項之用途,其中該癌症為上皮癌。
- 如請求項43至46中任一項之用途,其中該癌症為膽管癌、黑色素瘤、大腸癌、直腸癌、卵巢癌、子宮內膜癌、非小細胞肺癌(NSCLC)、神經膠母細胞瘤、子宮頸癌、頭頸癌、乳癌、胰臟癌或膀胱癌。
- 如請求項43至48中任一項之用途,其中已知該癌症包含人類p53中之R273C或Y220C突變。
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