TW202313669A - Flt3之嵌合受體及其使用方法 - Google Patents
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Abstract
根據本發明揭示FLT3之抗原結合分子、嵌合受體、及經工程改造之免疫細胞。本發明進一步關於載體、組成物、及使用該FLT3抗原結合分子及經工程改造之免疫細胞治療及/或偵測之方法。
Description
急性骨髓性白血病(AML)係一種異質性血液學惡性腫瘤,其係成人中診斷的最常見的急性白血病類型。AML佔所有白血病之大致三分之一,在2013年僅在美國已報導經估計14,500例新病例,且總體存活率差。過去三十年裡,AML患者之護理標準幾乎沒有改善。然而,分子及細胞生物之最近進展已經徹底改變我們對正常及患病狀態下的人類造血作用的理解。
已鑒別出涉及疾病發病機制之若干關鍵參與者,且其可作為可執行(actionable)目標來探查。在大約30% AML中最常突變的一種此類活化「驅動子」基因係FLT3。
亦稱為胎肝激酶2 (FLK-2)、人類幹細胞激酶1 (SCK-1)、或分化抗原簇(CD135)之Fms樣酪胺酸激酶3 (FLT3)係一種造血受體酪胺酸激酶,其在20世紀90年代由兩個獨立的小組選殖。位於人類染色體13q12上之FLT3基因編碼III類受體酪胺酸激酶蛋白,其與其他III類家族成員共用同源性,該等其他III類家族成員包括幹細胞因子受體(c-KIT)、巨噬細胞群落刺激因子受體(FMS)、及血小板衍生生長因子受體(PDGFR)。
當與FLT3配位體結合時,FLT3受體經歷同源二聚化,從而實現近膜域中特異性酪胺酸殘基之自磷酸化,及經由PI3K/Akt、MAPK、及STAT5之下游活化。因此,FLT3在控制正常造血細胞之增殖、存活、及分化中起關鍵作用。
人類FLT3在CD34+CD38-造血幹細胞(HSC)以及樹狀細胞之亞組中表現。FLT3表現亦可在多能先驅細胞中檢測到,多能先驅細胞如CD34
+CD38
+CD45RA
-CD123
低共同骨髓性先驅細胞(CMP)、CD34
+CD38
+CD45RA
+CD123
低顆粒球單核球先驅細胞(GMP)、及CD34
+CD38
+CD10
+CD19
-共同淋巴性先驅細胞(CLP)。有趣的是,在CD34
+CD38
-CD45RA
-CD123
-巨核細胞紅血球先驅細胞(MEP)中幾乎不存在FLT3表現。因此,FLT3表現主要限於早期骨髓性及淋巴性先驅細胞,其中一些表現在較成熟的單核球譜系細胞中。FLT3之這種有限的表現模式與FLT3配位體之表現模式形成鮮明對比,該FLT3配位體在大多數造血組織以及前列腺、腎、肺、結腸、及心臟中表現。此等不同的表現模式,使得FLT3表現係確定FLT3傳訊途徑之組織特異性的速率限制步驟。
AML中最常見的FLT3突變係FLT3內部串聯重複(FLT3-ITD),其見於20%至38%患有細胞遺傳學正常AML的患者中。FLT3-ITD當近膜域編碼序列之一部分經複製且以頭接尾定向插入時形成。在患有慢性淋巴性白血病(CLL)、非霍奇金氏淋巴瘤、及多發性骨髓瘤之患者中尚未鑒別出表明對AML的強烈疾病特異性的FLT3突變。突變體FLT3活化通常跨所有FAB亞型觀察到,然而,其在患有FAB M5 (單核球白血病)的AML患者中顯著增加,而FAB亞型M2及M6 (顆粒球性或紅血球系白血病)顯著地不太頻繁地與FLT3活化相關,符合FLT3之正常表現模式。小百分比的AML患者(5%至7%)在FLT3酪胺酸激酶域(FLT3 TKD)中呈現有單個胺基酸突變,最常見在D835處,或在一些情況下在T842或I836處,同時甚至較少患者(約1%)在涉及殘基579、590、591、及594的FLT3近膜域中具有突變。具有FLT3-ITD突變體AML的患者具有特性在於早期復發及存活差的侵襲性形式的疾病,而總體存活及無事件存活不受FLT3-TKD突變之存在的顯著影響。此外,與具有野生型TET2或DNMT3A的FLT3-ITD突變體AML患者相比,並行TET2或DNMT3A突變的具有FLT3-ITD突變的AML患者具有不利的總體風險特徵,其強調AML之臨床及生物異質性。
FLT3-ITD及FLT3 TKD突變均誘導FLT3之配位體非依賴性活化,其導致Ras/MAPK途徑及PI3K/Akt途徑之下游活化。然而,與任一突變相關的下游傳訊途徑之主要區別在於STAT5由FLT3-ITD優先活化,從而引起增殖潛力增加及DNA修復途徑之調節異常。
與FLT3突變狀態無關,FLT3磷酸化在超過三分之二的AML患者中係明顯的,且FLT3在>80% AML母細胞中表現,且在約90%的所有AML患者中表現,使其成為以大樣品大小之形式的疾病發病機制相關的有吸引力的治療靶標。
若干小分子抑制劑已呈針對具有FLT3突變的AML患者的有吸引力的治療選項出現。第一代FLT3酪胺酸激酶抑制劑(TKI)之特性在於缺乏選擇性、效力、及不利的藥物動力學性質。已開發較新且更具選擇性的藥劑來應對這種問題;然而,其功效受出現續發性抗性(secondary resistance)的限制。
若干早期FLT3 TKI包括米哚妥林(midostaurin) (PKC412)、來他替尼(lestaurtinib) (CEP-701)、舒尼替尼(sunitinib) (SUI1248)、及索拉非尼(sorafinib) (BAY 43-9006)等。在患有復發性或難治性AML的患者中,在此等多激酶靶向藥劑之情況下I期及II期之反應速率係有限,大概歸因於其不能在沒有劑量限制性毒性之情況下達成有效的FLT3抑制。奎紮替尼(Quizartinib) (AC220)已開發為對FLT3野生型及FLT3-ITD具有高選擇性的第二代FLT3 TKI,且已經證實特別在較年輕患者群體中之周邊移植設定(peritransplant setting)方面的益處。然而,在接受奎紮替尼的復發性患者中鑒別的FLT3之續發性突變強調開發針對AML患者的更好的治療策略的需要,同時突出FLT3作為治療靶標的正確性。
若干靶向藥劑已在患有原發性(de novo)、復發性/難治性、或續發性疾病的AML患者中經測試。腫瘤抑制基因之表觀遺傳沉默在AML疾病發病機制中起重要作用,且DNA甲基轉移酶(DNMT)抑制劑(如阿紮胞苷(azacitadine)及地西他濱)已經達成一些臨床成功。此外,影響AML患者亞組中之組蛋白轉譯後修飾(例如,EZH2及ASXL1突變)或DNA甲基化(例如,DNMT3A、TET2、IDH1/2)的突變的最近鑒別已引起多種治療選項之發展,治療選項包括EZH2、DOT1L、IDH1/2抑制劑、連同HDAC與蛋白酶體抑制劑。然而,此等化合物中之許多在AML細胞中之臨床前研究表明,此等抑制劑可能改變造血分化之表現性及基因表現特性,而非造成AML母細胞之直接細胞毒性。因此,仍然有鑒別出新穎的靶標/模態以應對AML並造成AML母細胞之靶向溶解的強烈的、未滿足的醫療需要。針對AML之其他治療候選者包括Aurora激酶抑制劑(包括AMG 900)及在細胞週期進程中起重要作用的polo樣激酶之抑制劑。
當可行時,針對AML患者之護理標準仍然是化學療法與幹細胞移植。然而,大多數經治療之患者中復發性/難治性病例之出現准許另外的治療模態。若干白血病特異性抗原之鑒別及描述、連同免疫介導之移植物抗白血病效應之更明確的理解已為開發用於應對血液學惡性腫瘤的免疫調節策略做好準備,其綜述於若干文章中。
經工程改造之免疫細胞已顯示在治療性治療中(特別是在腫瘤學中)具有所要的品質。兩種主要類型的經工程改造之免疫細胞係含有嵌合抗原受體(稱為「CAR」或「CAR-T」)及T細胞受體(「TCR」)之免疫細胞。此等經工程改造之細胞經經工程改造以賦予其抗原特異性,同時保留或增強其識別並殺傷靶細胞之能力。嵌合抗原受體可包含例如:(i)抗原特異性組分(「抗原結合分子」);(ii)一或多個共刺激域;及(iii)一或多個活化域。各域皆可係異質性的,亦即,包含來源於不同蛋白質鏈的序列。嵌合抗原受體表現免疫細胞(諸如T細胞)可用於各種療法,包括癌症療法。應當理解,如本文所定義之共刺激多肽可用於增強針對靶抗原的CAR表現細胞之活化,且因此增加過繼性免疫療法之效力。
T細胞可經經工程改造以具有對一或多個所要靶標的特異性。例如,T細胞可用編碼抗原結合分子(諸如抗體之一或多個單鏈可變片段(「scFv」))的DNA或其他遺傳物質結合一或多個傳訊分子、及/或一或多個活化域(諸如CD3 ζ)轉導。
除了CAR-T細胞之識別並破壞經靶向之細胞的能力之外,成功的T細胞療法受益於CAR-T細胞之以下能力:持續且維持響應於抗原而增殖的能力。
T細胞受體(TCR)係見於T細胞表面上的分子,其負責識別作為結合至主要組織相容性複合體(MHC)分子的肽之抗原片段。TCR包含兩種不同的蛋白質鏈(在大約95%的人類TCR中),TCR由阿伐(α)及貝他(β)鏈組成。在大約5%的人類T細胞中,TCR由γ及δ (γ/δ)鏈組成。各鏈均包含兩個細胞外域:可變(V)區及恆定(C)區,兩者均屬於免疫球蛋白超家族。如在其他免疫球蛋白中一樣,TCR α鏈及β鏈(或γ及δ (γ/δ)鏈)之可變域各自具有三個高變區或互補決定區(CDR)。當TCR與抗原肽及MHC(肽/MHC)接合時,T細胞變得活化,使其能夠攻擊並破壞靶細胞。
然而,當前療法已顯示隨非所要的副作用而程度不同的有效性。因此,存在鑒別用於治療FLT3相關疾病及病症之新穎的且改善的療法的需要。
本發明係關於對FLT3具有特異性之經工程改造之免疫細胞(諸如CAR或TCR)、抗原結合分子(包括但不限於抗體、scFv、重鏈及/或輕鏈、及此等抗原結合分子之CDR)。
本發明進一步關於一種新穎的CD28序列,其可用作此等細胞中之共刺激域。
本發明之嵌合抗原受體通常包含:(i) FLT3特異性抗原結合分子;(ii)一或多個共刺激域;及(iii)一或多個活化域。應當理解,各域皆可係異質性的,因此包含來源於不同蛋白質鏈的序列。
在一些實施例中,本發明係關於一種嵌合抗原受體,其包含特異性結合至FLT3之抗原結合分子,其中該抗原結合分子包含以下項中之至少一者:(a)可變重鏈CDR1,其包含與SEQ ID NO: 17之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;(b)可變重鏈CDR2,其包含與SEQ ID NO:18或SEQ ID NO:26之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;(c)可變重鏈CDR3,其包含與SEQ ID NO SEQ ID NO: 19或SEQ ID NO:27之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;(d)可變輕鏈CDR1,其包含與SEQ ID NO:22或SEQ ID NO:30之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;(e)可變輕鏈CDR2,其包含與SEQ ID NO:23或31之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;(f)可變輕鏈CDR3,其包含與SEQ ID:24或SEQ ID NO:32之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列。
在其他實施例中,嵌合抗原受體進一步包含至少一個共刺激域。在進一步實施例中,嵌合抗原受體進一步包含至少一個活化域。
在某些實施例中,共刺激域係以下項之傳訊區:CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1、CDl-la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
在一些實施例中,共刺激域來源於4-1BB。在其他實施例中,共刺激域來源於OX40。亦參見,Hombach
等人,Oncoimmunology. 2012年7月1日; 1(4): 458–466。在又其他實施例中,共刺激域包含如Guedan
等人, 2014年8月14日; Blood: 124 (7)及Shen
等人, Journal of Hematology & Oncology (2013) 6:33中所述之ICOS。在又其他實施例中,共刺激域包含如Song
等人, Oncoimmunology. 2012年7月1日;1(4): 547–549中所述之CD27。
在某些實施例中,CD28共刺激域包含SEQ ID NO: 2、SEQ ID NO: 4、SEQ ID NO: 6、或SEQ ID NO: 8。在另外的實施例中,CD8共刺激域包含SEQ ID NO: 14。在進一步實施例中,活化域包含CD3、CD3 ζ、或具有SEQ ID NO: 10中所闡明之序列的CD3 ζ。
在其他實施例中,本發明係關於一種嵌合抗原受體,其中共刺激域包含SEQ ID NO: 2且活化域包含SEQ ID NO: 10。
本發明進一步關於編碼嵌合抗原受體之多核苷酸及包含該等多核苷酸之載體。該載體可係例如逆轉錄病毒載體、DNA載體、質體、RNA載體、腺病毒載體、腺病毒相關載體、慢病毒載體、或其任何組合。本發明進一步關於包含該等載體之免疫細胞。在一些實施例中,慢病毒載體係pGAR載體。
示範性免疫細胞包括但不限於T細胞、腫瘤浸潤淋巴球(TIL)、NK細胞、TCR表現細胞、樹狀細胞、或NK-T細胞。T細胞可係自體的、同種異體的、或異源的。在其他實施例中,本發明係關於醫藥組成物,其包含本文所述之免疫細胞。
在某些實施例中,本發明係關於抗原結合分子(及包含此等分子之嵌合抗原受體),其包含以下項中之至少一者:
(a) 與10E3之VH區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VH區及與10E3之VL區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VL區;
(b) 與2E7之VH區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VH區及與2E7之VL區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VL區;
(c) 與8B5之VH區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VH區及與8B5之VL區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VL區;
(d) 與4E9之VH區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VH區及與4E9之VL區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VL區;及
(e) 與11F11之VH區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VH區及與10E3之VL區之胺基酸序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的VL區;
且其中該(或該等)VH區及VL區由至少一個連接子連接。
在其他實施例中,本發明係關於抗原結合分子(及包含此等分子之嵌合抗原受體),其中連接子包含scFv G4S連接子及scFv Whitlow連接子中之至少一者。
在其他實施例中,本發明係關於編碼本發明之多肽的載體,且關於包含此等多肽之免疫細胞。較佳的免疫細胞包括T細胞、腫瘤浸潤淋巴球(TIL)、NK細胞、TCR表現細胞、樹狀細胞、或NK-T細胞。T細胞可係自體的、同種異體的、或異源的。
在其他實施例中,本發明係關於經分離之多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子之嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子包含可變重(V
H)鏈CDR3,該可變重(V
H)鏈CDR3包含SEQ ID NO: 19或SEQ ID NO:27之胺基酸序列。該多核苷酸可進一步包含活化域。在較佳實施例中,活化域係CD3、更佳CD3 ζ、更佳SEQ ID NO: 9中所闡明之胺基酸序列。
在其他實施例中,本發明包括共刺激域,諸如CD28、CD28T、OX40、4-1BB/CD137、CD2、CD3 (α、β、δ、ε、γ、ζ)、CD4、CD5、CD7、CD9、CD16、CD22、CD27、CD30、CD 33、CD37、CD40、CD 45、CD64、CD80、CD86、CD134、CD137、CD154、PD-1、ICOS、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD247、CD276 (B7-H3)、LIGHT (腫瘤壞死因子超家族成員14;TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF、TNFr、整聯蛋白、傳訊淋巴球活化分子、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl-ld、ITGAE、CD103、ITGAL、CDl-la、LFA-1、ITGAM、CDl-lb、ITGAX、CDl-lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、CD83配位體、或其片段或組合。下文敘述較佳共刺激域。
在進一步實施例中,本發明係關於編碼嵌合抗原受體(CAR)或T細胞受體(TCR)之經分離之多核苷酸,其中該CAR或TCR包含特異性結合至FLT3之抗原結合分子,且其中該抗原結合分子包含可變輕(V
L)鏈CDR3,該可變輕(V
L)鏈CDR3包含選自SEQ ID NO:24及SEQ ID NO:32之胺基酸序列。多核苷酸可進一步包含活化域。多核苷酸可進一步包含共刺激域。
在其他實施例中,本發明係關於經分離之多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子的嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子重鏈包含CDR1 (SEQ ID NO: 17)、CDR2 (SEQ ID NO: 18)、及CDR3 (SEQ ID NO: 19),且該抗原結合分子輕鏈包含CDR1 (SEQ ID NO: 22)、CDR2 (SEQ ID NO: 23)、及CDR3 (SEQ ID NO: 24)。
在其他實施例中,本發明係關於經分離多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子的嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子重鏈包含CDR1 (SEQ ID NO: 17)、CDR2 (SEQ ID NO: 26)及CDR3 (SEQ ID NO:27),且該抗原結合分子輕鏈包含CDR1 (SEQ ID NO: 30)、CDR2 (SEQ ID NO:31)及CDR3 (SEQ ID NO:32)。
本發明進一步關於FLT3之抗原結合分子,該抗原結合分子包含如本文所闡明之至少一個可變重鏈CDR3或可變輕鏈CDR3序列。本發明進一步關於FLT3之抗原結合分子,該抗原結合分子包含如本文所述之至少一個可變重鏈CDR1、CDR2、及CDR3序列。本發明進一步關於FLT3之抗原結合分子,該抗原結合分子包含如本文所述之至少一個可變輕鏈CDR1、CDR2、及CDR3序列。本發明進一步關於FLT3之抗原結合分子,該抗原結合分子包含如本文所述之可變重鏈CDR1、CDR2、CDR3、以及可變輕鏈CDR1、CDR2、及CDR3序列兩者。
適用於根據本發明之FLT3結合分子的另外重鏈可變域及輕鏈可變域以及CDR多核苷酸及胺基酸序列係見於2015年7月31日提交的美國臨時申請案第62/199,944號中。
本發明進一步關於治療有需要之受試者的疾病或病症之方法,該方法包含向受試者投與根據本發明之抗原結合分子、CAR、TCR、多核苷酸、載體、細胞、或組成物。合適於治療之疾病包括但不限於急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、慢性骨髓單核球白血病(CMML)、幼年型骨髓單核球白血病、非典型慢性骨髓性白血病、急性前骨髓球白血病(APL)、急性單核母細胞性白血病、急性紅血球系白血病、急性巨核母細胞性白血病、骨髓增殖異常症候群(MDS)、骨髓增生性病症、骨髓性贅生物、骨髓性肉瘤、或其組合。另外的疾病包括炎性及/或自體免疫疾病,諸如類風濕性關節炎、牛皮癬、過敏、氣喘、克羅恩氏病、IBD、IBS、纖維肌痛(fibromyalga)、肥大細胞增多症(mastocytosis)、及乳糜瀉。
應當理解,嵌合抗原受體(CAR或CAR-T)及T細胞受體(TCR)係經遺傳工程改造之受體。此等經工程改造之受體可根據此項技術中已知的技術容易地插入至免疫細胞(包括T細胞)中,且由其表現。在CAR之情況下,單個受體可經程式化以識別特異性抗原,並且當結合至該抗原時活化免疫細胞以攻擊且破壞攜帶該抗原之細胞。當此等抗原存在於腫瘤細胞上時,表現CAR之免疫細胞可靶向且殺傷腫瘤細胞。
CAR可藉由併入與所靶向之抗原相互作用的抗原結合分子來工程改造以結合至該抗原(諸如細胞表面抗原)。較佳的是,抗原結合分子係其抗體片段,且更佳的是一或多個單鏈抗體片段(「scFv」)。scFv係具有抗體之連接在一起的重鏈與輕鏈之可變區的單鏈抗體片段。參見,美國專利第7,741,465號及第6,319,494號以及Eshhar
等人, Cancer Immunol Immunotherapy (1997) 45: 131-136。scFv保留親本抗體與靶抗原特異性相互作用之能力。scFv較佳用於嵌合抗原受體,因為它們可經經工程改造以連同其他CAR組分一起表現為單鏈之一部分。
同上。亦參見,Krause
等人, J. Exp. Med., 第188卷,第4期, 1998 (619–626);Finney
等人,
Journal of Immunology,1998, 161: 2791–2797。應當理解,抗原結合分子通常容納於CAR之細胞外部分內,使得其能夠識別並結合至所關注之抗原。雙特異性CAR及多特異性CAR考慮在本發明範疇內,其對多於一個所關注之靶標具有特異性。
共刺激域。嵌合抗原受體可併入共刺激(傳訊)域以增加其效力。參見,美國專利第7,741,465號及第6,319,494號,以及Krause
等人及Finney
等人(見上文);Song
等人, Blood 119:696-706 (2012);Kalos
等人, Sci Transl. Med. 3:95 (2011);Porter
等人, N. Engl. J. Med. 365:725-33 (2011);及Gross
等人, Annu. Rev. Pharmacol. Toxicol. 56:59–83 (2016)。例如,CD28係在T細胞上天然發現的共刺激蛋白。CD28之完整原態胺基酸序列描述於NCBI參考序列:NP_006130.1中。完整原態CD28核酸序列描述於NCBI參考序列:NM_006139.1中。
某些CD28域已用於嵌合抗原受體中。根據本發明,已經發現,當用於CAR構築體時,新穎的CD28細胞外域(稱為「CD28T」)意外地提供某些益處。
CD28T分子(包括細胞外CD28T域及CD28跨膜域與細胞內域)之核苷酸序列闡明於SEQ ID NO: 1中:
CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC
對應胺基酸序列闡明於SEQ ID NO: 2中:
LDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSK RSRLLHSDYM NMTPRRPGPT RKHYQPYAPP RDFAAYRS
CD28T之細胞外部分之核苷酸序列闡明於SEQ ID NO: 3中:
CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA
CD28T細胞外域之對應胺基酸序列闡明於SEQ ID NO: 4中:LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP
CD28跨膜域之核苷酸序列闡明於SEQ ID NO: 5中:
TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTT
CD28跨膜域之胺基酸序列闡明於
SEQ ID NO: 6中:FWVLVVVGGV LACYSLLVTV AFIIFWV
CD28細胞內傳訊域之核苷酸序列闡明於SEQ ID NO: 7中:
AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC
CD28細胞內傳訊域之胺基酸序列闡明於SEQ ID NO: 8中:RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
合適用於本發明之另外的CD28序列包括SEQ ID NO: 11中所闡明之CD28核苷酸序列:
ATTGAGGTGATGTATCCACCGCCTTACCTGGATAACGAAAAGAGTAACGGTACCATCATTCACGTGAAAGGTAAACACCTGTGTCCTTCTCCCCTCTTCCCCGGGCCATCAAAGCCC
對應胺基酸序列闡明於SEQ ID NO: 12中:
IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP
其他合適之細胞外序列或跨膜序列可來源於CD8。合適之CD8細胞外域及跨膜域之核苷酸序列闡明於SEQ ID NO: 13中:
GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCTTGCCGGCTAAGCCTACTACCACACCCGCTCCACGGCCACCTACCCCAGCTCCTACCATCGCTTCACAGCCTCTGTCCCTGCGCCCAGAGGCTTGCCGACCGGCCGCAGGGGGCGCTGTTCATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGGCACCCCTGGCCGGAACCTGCGGCGTACTCCTGCTGTCCCTGGTCATCACGCTCTATTGTAATCACAGGAAC
對應胺基酸序列闡明於SEQ ID NO: 14中:
AAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN
除了其他來源之外,本發明範疇內之合適之共刺激域可來源於CD28、CD28T、OX40、4-1BB/CD137、CD2、CD3 (α、β、δ、ε、γ、ζ)、CD4、CD5、CD7、CD9、CD16、CD22、CD27、CD30、CD 33、CD37、CD40、CD 45、CD64、CD80、CD86、CD134、CD137、CD154、PD-1、ICOS、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD247、CD276 (B7-H3)、LIGHT (腫瘤壞死因子超家族成員14;TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF、TNFr、整聯蛋白、傳訊淋巴球活化分子、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl-ld、ITGAE、CD103、ITGAL、CDl-la、LFA-1、ITGAM、CDl-lb、ITGAX、CDl-lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、CD83配位體、或其片段或組合。
活化域。
CD3係原態T細胞上T細胞受體之元件,且已經顯示係CAR中重要的細胞內活化元件。在較佳實施例中,CD3係CD3 ζ,其核苷酸序列闡明於SEQ ID NO: 9中:
AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG
細胞內CD3 ζ之對應胺基酸闡明於SEQ ID NO: 10中:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR RKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
域定向
在結構上,應當理解,此等域對應於相對於免疫細胞的位置。因此,此等域可係以下之一部分:(i)「鉸鏈」域或胞外(EC)域(EC);(ii)跨膜(TM)域;及/或(iii)細胞內(細胞質)域(IC)。細胞內組分經常部分包含CD3家族之成員,較佳CD3 ζ,其能夠在抗原結合分子結合至其靶標時活化T細胞。在一個實施例中,鉸鏈域通常包含如本文所定義之至少一個共刺激域。
亦
應當理解,鉸鏈區亦可含有免疫球蛋白家族成員(諸如IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE、IgM)中之一些或全部、或其片段。
根據本發明之示範性CAR構築體闡明於表1中。
表 1
相對於細胞的域
構築體名稱 | scFv | 共刺激域 | 活化域 |
24C1 CD28T | 24C1 | CD28T | CD3 ζ |
24C1 CD28 | 24C1 | CD28 | CD3 ζ |
24C1 CD8 | 24C1 | CD8 | CD3 ζ |
24C8 CD28T | 24C8 | CD28T | CD3 ζ |
24C8 CD28 | 24C8 | CD28 | CD3 ζ |
24C8 CD8 | 24C8 | CD8 | CD3 ζ |
20C5.1 CD28T | 20C5.1 | CD28T | CD3 ζ |
20C5.1 CD28 | 20C5.1 | CD28 | CD3 ζ |
20C5.1 CD8 | 20C5.1 | CD8 | CD3 ζ |
20C5.2 CD28T | 20C5.2 | CD28T | CD3 ζ |
20C5.2 CD28 | 20C5.2 | CD28 | CD3 ζ |
20C5.2 CD8 | 20C5.2 | CD8 | CD3 ζ |
應當理解,相對於攜帶受體之細胞,本發明之經工程改造之T細胞包含抗原結合分子(諸如scFv)、細胞外域(其可包含「鉸鏈」域)、跨膜域、及細胞內域。細胞內域至少部分包含活化域,較佳包含CD3家族成員諸如CD3 ζ、CD3 ε、CD3 γ、或其部分。應當進一步理解,抗原結合分子(例如,一或多種scFv)經經工程改造,使得其位於分子/構築體之細胞外部分,使得其能夠識別並結合至其一或多個靶標。
細胞外域。細胞外域對於傳訊且對於淋巴球對抗原之有效反應係有利的。
特別用於本發明之細胞外域可來源於(
即,包含) CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1、CDl-la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。細胞外域可來源於天然來源或合成來源。
如本文所述,細胞外域常常包含鉸鏈部分。這是細胞外域之一部分,有時稱為「間隔」區。可根據本發明採用多種鉸鏈,包括如上文所述之共刺激
分子,以及免疫球蛋白(Ig)序列或其他合適之分子,以達成與靶細胞相距所要的特殊距離。在一些實施例中,整個細胞外區包含鉸鏈區。在一些實施例中,鉸鏈區包含CD28T、或CD28之EC域。
跨膜域。CAR可設計成包含融合至CAR之細胞外域的跨膜域。其可類似地融合至
CAR之細胞內域。在一個實施例中,使用與CAR中之域之一者天然締合的跨膜域。在一些情況下,跨膜域可藉由胺基酸取代經選擇或修飾,以避免此類域結合至相同或不同表面膜蛋白之跨膜域,以使與受體複合體之其他成員的相互作用最小。跨膜域可來源於天然來源或合成來源。當來源係天然的時,該域可來源於任何膜結合蛋白或跨膜蛋白。特別用於本發明之跨膜區可來源於(即,包含) CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1、CDl-la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
視情況,短連接子可在CAR之細胞外域、跨膜域、及細胞內域中之任一者或
一些之間形成鍵聯。
在一個實施例中,本發明之CAR中之跨膜域係CD8跨膜域。在一個實施例中,CD8跨膜域包含SEQ ID NO: 13之核酸序列之跨膜部分。在另一個實施例中,CD8跨膜域包含編碼SEQ ID NO: 14內所含有之跨膜胺基酸序列的核酸序列。
在某些實施例中,本發明之CAR中之跨膜域係CD28跨膜域。在一個實施例中,CD28跨膜域包含SEQ ID NO: 5之核酸序列。在一個實施例中,CD28跨膜域包含編碼SEQ ID NO: 6之胺基酸序列的核酸序列。在另一個實施例中,CD28跨膜域包含SEQ ID NO: 6之胺基酸序列。
細胞內 ( 細胞質 ) 域。本發明之經工程改造之T細胞之細胞內(細胞質)域可提供免疫細胞之正常效應物功能之至少一者之活化。例如,T細胞之效應物功能可係溶細胞活性或輔助活性,包括細胞介素之分泌。
應當理解,合適之細胞內分子包括(
即,包含)但不限於CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1、CDl-la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
在較佳實施例中,CAR之細胞質域可設計成包含CD3 ζ傳訊域本身或與在本發明之CAR之情形下可用的任何其他所要的細胞質域組合之CD3 ζ傳訊域。例如,CAR之細胞質域可包含CD3 ζ鏈部分及共刺激傳訊區。
本
發明之CAR之細胞質傳訊部分內的細胞質傳訊序列可以隨機或指定順序彼此連接。
在
一個較佳實施例中,細胞質域設計成包含CD3 ζ之傳訊域及CD28之傳訊域。在另一個實施例中,細胞質域設計成包含CD3 ζ之傳訊域及4-1BB之傳訊域。在另一個實施例中,本發明之CAR中之細胞質域設計成包含CD28及CD3 ζ之一部分,其中細胞質CD28包含SEQ ID NO: 7中所闡明之核酸序列及SEQ ID NO: 8中所闡明之胺基酸序列。CD3 ζ核酸序列闡明於SEQ ID NO: 9中,且胺基酸序列闡明SEQ ID NO: 8中。
應當
理解,根據本發明之CAR之一個較佳定向包含與共刺激域及活化域串聯的抗原結合域(諸如scFv)。共刺激域可包含細胞外部分、跨膜部分、及細胞內部分中之一或多者。應當進一步理解,可串聯利用多個共刺激域。
在一些實施例中,提供包含可操作地連接至編碼抗原結合分子、至少一種共刺激分子、及活化域之第一多核苷酸的啟動子的核酸。
在一些實施例中,核酸構築體容納於病毒載體內。在一些實施例中,病毒載體係選自由以下項所組成之群組:逆轉錄病毒載體、鼠白血病病毒載體、
SFG載體、腺病毒載體、慢病毒載體、腺相關病毒(AAV)載體、皰疹病毒載體、及牛痘病毒載體。在一些實施例中,核酸容納於質體內。
本發明進一步關於編碼嵌合抗原受體之經分離之多核苷酸及包含該等多核苷酸之載體。此項技術種已知的任何載體可合適用於本發明。在一些實施例中,載體係病毒載體。在一些實施例中,載體係逆轉錄病毒載體(諸如pMSVG1)、DNA載體、鼠白血病病毒載體、SFG載體、質體、RNA載體、腺病毒載體、桿狀病毒載體、艾司坦巴爾(Epstein Barr)病毒載體、乳多泡病毒載體、牛痘病毒載體、單純皰疹病毒載體、腺病毒相關載體(AAV)、慢病毒載體(諸如pGAR)、或其任何組合。pGAR載體圖顯示於圖12中。pGAR序列如下:
CTGACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGTCTATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAAATGAGCTGATTTAACAAAAATTTAACGCGAATTTTAACAAAATATTAACGCTTACAATTTGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGACCCGGGGATGGCGCGCCAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGGGGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGAACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTGCTGAAGCGCGCACGGCAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGCGATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAAGGCTGTAGACAAATACTGGGACAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGACCACCGCACAGCAAGCCGCCGCTGATCTTCAGACCTGGAGGAGGAGATATGAGGGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTTGGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACACTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGCTGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAGGGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGATCTCGACGGTATCGGTTAACTTTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAAATTCAAAATTTTATCGCGATCGCGGAATGAAAGACCCCACCTGTAGGTTTGGCAAGCTAGCTTAAGTAACGCCATTTTGCAAGGCATGGAAAATACATAACTGAGAATAGAGAAGTTCAGATCAAGGTTAGGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCAATAAAAGAGCCCACAACCCCTCACTCGGCGCGCCAGTCCTTCGAAGTAGATCTTTGTCGATCCTACCATCCACTCGACACACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTAATTCACGGTACCCACCATGGCCTAGGGAGACTAGTCGAATCGATATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTTCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGGTTAATTAAAGTACCTTTAAGACCAATGACTTACAAGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCGAATTCACTCCCAACGAAGACAAGATCTGCTTTTTGCTTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGGCATGCCAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTGGCGCGCCATCGTCGAGGTTCCCTTTAGTGAGGGTTAATTGCGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCAC (SEQ ID NO: 95)
合適之另外的示範性載體包括例如pBABE-puro、pBABE-neo largeTcDNA、pBABE-hygro-hTERT、pMKO.1 GFP、MSCV-IRES-GFP、pMSCV PIG (Puro IRES GFP空質體)、pMSCV-loxp-dsRed-loxp-eGFP-Puro-WPRE、MSCV IRES螢光素酶、pMIG、MDH1-PGK-GFP_2.0、TtRMPVIR、pMSCV-IRES-mCherry FP、pRetroX GFP T2A Cre、pRXTN、pLncEXP、及pLXIN-Luc。
在一些實施例中,經工程改造之免疫細胞係T細胞、腫瘤浸潤淋巴球(
TIL)、NK細胞、TCR表現細胞、樹狀細胞、或NK-T細胞。在一些實施例中,細胞係獲自周邊血或由其製備。在一些實施例中,細胞係獲自周邊血單核細胞(PBMC)或由其製備。在一些實施例中,細胞係獲自骨髓或由其製備。在一些實施例中,細胞係獲自臍帶血或由其製備。在一些實施例中,細胞係人類細胞。在一些實施例中,細胞係藉由核酸載體使用選自由以下項組成之群組的方法來轉染或轉導:電穿孔、超音波穿孔(sonoporation)、生物彈(biolistics) (例如,基因槍)、脂質轉染、聚合物轉染、奈米粒子、或聚合體(polyplex)。
在一些實施例中,嵌合抗原受體在包含本申請案之核酸的經工程改造之免疫細胞中表現。在一些實施例中,本申請案之此等嵌合抗原受體可包含(i)
抗原結合分子(諸如scFv)、(ii)跨膜區、及(iii) T細胞活化分子或區。
抗原結合分子
抗原結合分子在本發明範疇內。
如本文所用之「抗原結合分子」意指結合指定靶抗原的任何蛋白質。在本申請案中,指定靶抗原係FLT3蛋白或其片段。抗原結合分子包括但不限於抗體及其結合部分,諸如免疫學功能片段。肽抗體(
即,包含肽結合域之Fc融合分子)係合適之抗原結合分子之另一個實例。
在一些實施例中,抗原結合分子結合至腫瘤細胞上之抗原。在一些實施例中,抗原結合分子結合至涉及過度增殖性疾病的細胞上的抗原或病毒或細菌抗原。在某些實施例中,抗原結合分子結合至FLT3。在進一步實施例中,抗原結合分子係抗體或其片段,包括其互補決定區(CDR)中之一或多者。在進一步實施例中,抗原結合分子係單鏈可變片段(scFv)。
術語抗原結合分子之「免疫學功能片段」(或「片段」)係抗原結合分子之包含抗體之一部分(不管該部分係如何獲得或合成)的物質,其缺乏至少一些存在於全長鏈中的胺基酸但仍能夠特異性結合至抗原。此類片段具生物活性,因為其結合至靶抗原,且可與其他抗原結合分子(包括完整抗體)競爭結合至給定表位。在一些實施例中,片段係中和片段。在一些實施例中,片段可阻斷或降低FLT3之活性。在一個態樣中,此類片段將保留存在於全長輕鏈或重鏈中之至少一個CDR,且在一些實施例中將包含單個重鏈及/或輕鏈、或其部分。此等片段可藉由重組DNA技術產生,或可藉由抗原結合分子(包括完整抗體)之酶裂解或化學裂解產生。
免疫學功能免疫球蛋白片段包括但不限於scFv片段、Fab片段(Fab'、F(ab')
2、及其類似者)、一或多個CDR、雙功能抗體(與輕鏈可變域相同的多肽上之重鏈可變域,該重鏈可變域經由短肽連接子連接,該短肽連接子過短以致無法允許相同鏈上的兩個域之間的配對)、域抗體、及單鏈抗體。此等片段可來源於任何哺乳動物來源,包括但不限於人類、小鼠、大鼠、駱駝科、或兔。如熟習此項技術者將理解,抗原結合分子可包括非蛋白質組分。
抗原結合分子之變異體亦在本發明範疇內,例如各自與本文所述之序列之胺基酸序列具有至少70-80%、80-85%、85-90%、90-95%、95-97%、97-99%、或高於99%一致性的可變輕鏈及/或可變重鏈。在一些情況下,此類分子至少包括一個重鏈及一個輕鏈,而在其他情況下,變異體形式含有兩個一致的輕鏈及兩個一致的重鏈(或其子部分)。熟習此項技術者將能夠使用熟知的技術確定如本文所闡明之抗原結合分子之合適變異體。在某些實施例中,熟習此項技術者可鑒別分子之可藉由靶據信對於活性而言不重要的區來改變而不破壞活性的合適區域。
在某些實施例中,抗原結合分子之多肽結構係基於抗體,分別包括但不限於單株抗體、雙特異性抗體、微抗體、域抗體、合成抗體(本文中有時稱為「抗體模擬物」)、嵌合抗體、人源化抗體、人類抗體、抗體融合物(本文中有時稱為「抗體接合物」)、及其片段。在一些實施例中,抗原結合分子包含avimer或由其組成。
在一些實施例中,FLT3之抗原結合分子係單獨投與。在其他實施例中,FLT3之抗原結合分子係作為CAR、TCR、或其他免疫細胞之一部分投與。在此類免疫細胞中,FLT3之抗原結合分子可在相同啟動子區或分開的啟動子之控制下。在某些實施例中,編碼蛋白質藥劑及/或FLT3之抗原結合分子的基因可在分開的載體中。
本發明進一步提供醫藥組成物,其包含FLT3之抗原結合分子,連同醫藥學上可接受之稀釋劑、載劑、增溶劑、乳化劑、防腐劑、及/或佐劑。在某些實施例中,醫藥組成物將包括多於一種不同的FLT3之抗原結合分子。在某些實施例中,醫藥組成物將包括多於一種FLT3之抗原結合分子,其中FLT3之抗原結合分子結合多於一個表位。在一些實施例中,各種抗原結合分子將不彼此競爭結合至FLT3。
在其他實施例中,醫藥組成物可經選擇以供腸胃外傳遞、吸入、或透過消化道傳遞,諸如經口傳遞。此類醫藥學上可接受之組成物之製備係在熟習此項技術者之能力內。在某些實施例中,緩衝劑用於將組成物維持在生理pH值或略微較低pH值下,通常在約5至約8之pH值範圍內。在某些實施例中,當考慮腸胃外投與時,治療組成物可呈無熱原、腸胃外可接受之水溶液之形式,其包含在醫藥學上可接受之媒劑中所要的FLT3之抗原結合分子(其具有或不具有另外的治療劑)。在某些實施例中,用於腸胃外注射之媒劑係無菌蒸餾水,在該無菌蒸餾水中將FLT3之抗原結合分子(其具有或不具有至少一種另外的治療劑)調配為適當保存的無菌等滲溶液。在某些實施例中,製備可涉及調配所要分子與可提供然後可經由儲槽注射傳遞之產品之控制或持續釋放的聚合化合物(諸如聚乳酸或聚乙醇酸)、珠粒、或脂質體。在某些實施例中,可使用可植入藥物傳遞裝置來引入所要分子。
在一些實施例中,抗原結合分子用作診斷或驗證工具。抗原結合分子可用於分析樣品及/或受試者中存在之FLT3之量。在一些實施例中,診斷性抗原結合分子非係中和的。在一些實施例中,本文所揭示之抗原結合分子用於或提供於用於偵測哺乳動物組織或細胞中之FLT3以篩檢/診斷與FLT3位準變化相關之疾病或病症的分析套組及/或方法中。套組可包含結合FLT3之抗原結合分子,連同用於指示抗原結合分子與FLT3之結合(若存在)及視情況FLT3蛋白位準的構件。
將鑒於下文定義及描述進一步理解抗原結合分子。
「Fc」區包含兩個重鏈片段,其包含抗體之CH1及CH2域。兩個重鏈片段藉由二或更多個二硫鍵且藉由CH3域之疏水性相互作用保持在一起。
「Fab片段」包含一條輕鏈、及一條重鏈之CH1與可變區。Fab分子之重鏈不可與另一個重鏈分子形成二硫鍵。「Fab'」「片段」包含一條輕鏈及一條重鏈之一部分,該部分含有VH域及CH1域且亦含有在CH1與CH2域之間的區,使得可在兩個Fab'片段之兩條重鏈之間形成鏈間二硫鍵以形成F(ab')
2分子。「F(ab')
2片段」含有兩條輕鏈及兩條重鏈,該兩條重鏈含有在CH1與CH2域之間的恆定區之一部分,使得在兩條重鏈之間形成鏈間二硫鍵。因此,F(ab')
2片段包含由兩條重鏈之間的二硫鍵保持在一起的兩個Fab'片段。
「Fv區」包含來自重鏈及輕鏈之可變區,但缺乏恆定區。
「單鏈可變片段」(「scFv」,亦稱為「單鏈抗體」)係指以下Fv分子,在該等Fv分子中重鏈可變區及輕鏈可變區已由撓性連接子連接以形成單個多肽鏈,該單個多肽鏈形成抗原結合區。參見,PCT申請案WO88/01649及美國專利第4,946,778號及第5,260,203號,該等專利之揭示內容以全文引用之方式併入。
「二價抗原結合分子」包含兩個抗原結合位點。在一些情況下,兩個結合位點具有相同的抗原特異性。二價抗原結合分子可係雙特異性的。「多特異性抗原結合分子」係靶向多於一種抗原或表位之分子。「雙特異性」、「雙重特異性」、或「雙功能性」抗原結合分子係分別具有兩個不同抗原結合位點的雜交抗原結合分子或抗體。雙特異性抗原結合分子之兩個結合位點將結合至可位於相同或不同蛋白質靶標上的兩個不同的表位。
當解離常數(K
d)係約1x10
-7M時,稱抗原結合分子「特異性結合」其靶抗原。抗原結合分子在K
d係1x10
-9M至5x10
-9M時,以「高親和力」特異性結合抗原,且在K
d係1x10
-10M至5x10
-10M時以「非常高的親和力」結合。在一個實施例中,抗原結合分子具有10
-9M之K
d。在一個實施例中,解離速率(off-rate)係<1x10
-5。在其他實施例中,抗原結合分子將以約10
-7M與10
-13M之間的K
d結合至人類FLT3,且在又一個實施例中,抗原結合分子將以1.0x10
-10至5x10
-10之K
d結合。
當抗原結合分子結合至一個靶標比結合至第二靶標更緊密時,稱其係「選擇性的」。
術語「抗體」係指具有任何同型之完整免疫球蛋白、或其可與完整抗體競爭特異性結合至靶抗原之片段,且包括例如嵌合抗體、人源化抗體、完全人類抗體、及雙特異性抗體。「抗體」係如本文所定義之抗原結合分子之物種。完整抗體通常將至少包含兩條全長重鏈及兩條全長輕鏈,但在一些情況下可包括較少鏈,諸如天然存在於駱駝中之抗體,其僅可包含重鏈。抗體可僅僅來源於單個來源,或可係嵌合的,亦即,抗體之不同部分可來源於如下文進一步所述之兩種不同抗體。抗原結合分子、抗體、或結合片段可藉由重組DNA技術、或藉由完整抗體之酶裂解或化學裂解來在融合瘤中產生。除非另外指示,否則除了包含兩條全長重鏈及兩條全長輕鏈的抗體之外,術語「抗體」包括其衍生物、變異體、片及突變蛋白(mutein),其實例描述於下文。此外,除非明確排除,否則抗體分別包括單株抗體、雙特異性抗體、微抗體、域抗體、合成抗體(本文中有時稱為「抗體模擬物」)、嵌合抗體、人源化抗體、人類抗體、抗體融合物(本文中有時稱為「抗體接合物」)、及其片段。
可變區通常展現3個高變區(即,「CDR」)所連接之相對保守的框架區(FR)之相同的一般結構。來自各對之兩條鏈之CDR通常藉由框架區比對,其可實現結合至特異性表位。從N端至C端,輕鏈可變區及重鏈可變區通常包含域FR1、CDR1、FR2、CDR2、FR3、CDR3、及FR4。按照慣例,重鏈中之CDR區通常稱為HC CDR1、CDR2、及CDR3。輕鏈中之CDR區通常稱為LC CDR1、CDR2、及CDR3。各域之胺基酸之指定通常根據Kabat之定義(Seqs of Proteins of Immunological Interest (NIH, Bethesda, MD (1987及1991))或Chothia (J. Mol. Biol., 196:901-917 (1987);Chothia
等人, Nature, 342:878-883 (1989))。可採用各種分析方法來鑒別或估計CDR區,不僅包括Kabat或Chothia,還包括AbM定義。
術語「輕鏈」包括全長輕鏈或其具有足以賦予結合特異性的可變區序列的片段。全長輕鏈包括可變區域V
L及恆定區域C
L。輕鏈之可變區域在多肽之胺基端處。輕鏈包括κ鏈及λ鏈。
術語「重鏈」包括全長重鏈或其具有足以賦予結合特異性的可變區序列的片段。全長重鏈包括可變區域V
H及三個恆定區域CH1、CH2、及CH3。V
H域在多肽之胺基端處,且C
H域在羧基端處,而CH3最接近多肽之羧基端。重鏈可具有任何同型,包括IgG (包括IgG1、IgG2、IgG3、及IgG4亞型)、IgA (包括IgA1及IgA2亞型)、IgM、及IgE。
術語「可變區」或「可變域」係指抗體之輕鏈及/或重鏈之一部分,通常在重鏈中包括大約120至130個胺基端胺基酸且在輕鏈中包括約100至110個胺基端胺基酸。抗體之可變區通常決定特定抗體對其靶標之特異性。
變異性非係在抗體之整個可變域中均勻分佈;其集中於重鏈可變區及輕鏈可變區之各者之子域中。此等子域稱為「高變區」或「互補決定區」(CDR)。可變域之更保守(即,非高變的)部分稱為「框架」區(FRM或FR),且為三維空間中的六個CDR提供支架以形成抗原結合表面。天然存在的重鏈及輕鏈之可變域各自包含四個FRM區域(FR1、FR2、FR3、及FR4),主要採用β褶板組態,藉由三個高變區連接,其形成環連接,且在一些情況下形成β褶板結構之一部分。各鏈中之高變區藉由FRM緊密地保持在一起,且與來自另一條鏈之高變區一起促成形成抗原結合位點(參見,Kabat等人,上文引用)。
術語「CDR」及其複數「CDR」係指互補決定區,該互補決定區中之三個構成輕鏈可變區(CDR-L1、CDR-L2、及CDR-L3)之結合特性,且三個構成重鏈可變區(CDRH1、CDR-H2、及CDR-H3)之結合特性。CDR含有負責抗體與抗原之特異性相互作用的大多數殘基,且因此促成抗體分子之功能活性:其係抗原特異性之主要決定子。
確切定義的CDR邊界及長度受制於不同的分類及編號系統。因此,CDR可藉由Kabat、Chothia、接觸、或任何其他邊界定義(包括本文所述之編號系統)來指代。儘管邊界不同,但是此等系統中之各者在構成可變序列內之所謂「高變區」中具有一定程度的重疊。因此,根據此等系統之CDR定義之長度及邊界區域相對於相鄰框架區可能不同。參見,例如,Kabat (基於交叉物種序列變異性之方法)、Chothia (基於抗原-抗體複合體之結晶學研究的方法)、及/或MacCallum (Kabat等人,上文引用;Chothia等人, J. MoI. Biol, 1987, 196: 901-917;及MacCallum等人, J. MoI. Biol, 1996, 262: 732)。用於特性化抗原結合位點之又另一個標準係Oxford Molecular之AbM抗體建模軟體所使用之AbM定義。參見,例如,抗體可變域之蛋白質序列及結構分析。在Antibody Engineering Lab Manual (編:Duebel, S.及Kontermann, R., Springer-Verlag, Heidelberg)中。在兩個殘基鑒別技術定義重疊之區而非一致區的情況下,其可經組合以定義雜交CDR。然而,根據所謂的Kabat系統之編號係較佳的。
通常,CDR形成可經分類為正則結構的環結構。術語「正則結構」係指抗原結合(CDR)環所採用之主要鏈構形。根據比較性結構研究已發現六個抗原結合環中之五個僅具有有限的一組可用構形。各正則結構可由多肽骨架之扭轉角特性化。因此,儘管環之大多數部分中之胺基酸序列變異性很高,但是抗體之間的對應環可具有非常類似的三維結構(Chothia及Lesk, J. MoI. Biol., 1987, 196: 901;Chothia等人, Nature, 1989, 342: 877;Martin及Thornton, J. MoI. Biol, 1996, 263: 800)。此外,在所採用之環結構與其周圍之胺基酸序列之間有一定關係。特定正則類別之構形係由環之長度、及存在於環內以及保守框架內(即,環之外部)的關鍵位置處的胺基酸殘基確定。因此,特定正則類別之指定可基於此等關鍵胺基酸殘基之存在來進行。
術語「正則結構」亦可包括關於抗體之線性序列的考慮,例如,如Kabat (Kabat等人,上文引用)所編目。Kabat編號方案(系統)係廣泛採用的用於以一致方式對抗體可變域之胺基酸殘基進行編號的標準,且係本發明中所應用之較佳方案,亦如本文別處所提及。另外的結構考慮亦可用於確定抗體之正則結構。例如,未藉由Kabat編號完全反映出的那些差異可藉由Chothia等人之編號系統描述,且/或藉由其他技術(例如,晶體學及二維或三維計算建模)顯示。因此,給定抗體序列可置於正則類別中,其尤其允許鑒別適當的底板(chassis)序列(例如,基於在文庫中包括多種正則結構的期望)。Kabat編號抗體胺基酸序列及結構考慮(如Chothia等人(上文引用)以及其對於解釋抗體結構之正則態樣的啟示所述)描述於文獻中。不同類別的免疫球蛋白之亞單元結構及三維組態在此項技術中是眾所周知的。對於抗體結構之綜述,參見,Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Harlow等人編, 1988。
輕鏈之CDR3及(特別是)重鏈之CDR3可在輕鏈可變區及重鏈可變區內的抗原結合中構成最重要的決定子。在一些抗體構築體中,重鏈CDR3似乎構成抗原與抗體之間的主要接觸區域。單獨改變CDR3之體外選擇方案可用於改變抗體之結合性質或確定哪些殘基有助於抗原之結合。因此,CDR3通常是抗體結合位點內分子多樣性之最大來源。例如,H3可短至兩個胺基酸殘基或大於26個胺基酸。
術語「中和」係指抗原結合分子、scFv、或抗體分別結合至配位體且防止或減小該配位體之生物效應。這可例如藉由直接阻斷配位體上之結合位點或藉由結合至配位體且透過直接手段(諸如配位體中之結構或能量改變)改變配位體結合之能力來進行。在一些實施例中,該術語亦可表示抗原結合分子防止其所結合之蛋白執行生物功能。
術語「靶標」或「抗原」係指能夠由抗原結合分子結合的分子或分子之一部分。在某些實施例中,靶標可具有一或多個表位。
當在競爭相同表位的抗原結合分子之情形下使用時,術語「競爭」意指抗原結合分子之間如藉由所測試之抗原結合分子(例如,抗體或其免疫學功能片段)防止或抑制(例如,減小)參考抗原結合分子特異性結合至抗原的分析所確定的競爭。許多類型的競爭性結合分析可用於確定一個抗原結合分子是否與另一個抗原結合分子競爭,例如:固相直接或間接放射免疫分析(RIA)、固相直接或間接酶免疫分析(EIA)、夾心競爭分析(Stahli
等人, 1983, Methods in Enzymology 9:242-253);固相直接生物素-抗生物素蛋白EIA (Kirkland
等人, 1986, J. Immunol. 137:3614-3619)、固相直接標記分析、固相直接標記夾心分析(Harlow及Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press);使用1-125標記的固相直接標記RIA (Morel
等人, 1988, Molec. Immunol. 25:7-15);固相直接生物素-抗生物素蛋白EIA (Cheung
等人, 1990, Virology 176:546-552);及直接標記RIA (Moldenhauer
等人, 1990, Scand. J. Immunol. 32:77-82)。術語「表位」包括能夠由本發明之抗原結合分子諸如scFv、抗體、或免疫細胞結合的任何決定子。表位係抗原之由靶向該抗原之抗原結合分子所結合之區,且當抗原係蛋白質時,包括直接接觸抗原結合分子之特異性胺基酸。
如本文所使用,術語「標記」或「經標記」係指例如藉由併入經放射性標記之胺基酸或連接至可藉由經標誌之抗生物素蛋白偵測的具有生物素部分之多肽(例如,含有可藉由光學法或比色法偵測的螢光標誌物或酶活性之鏈黴抗生物素蛋白)來併入可偵測標誌物。在某些實施例中,標記或標誌物亦可係治療性的。各種標記多肽及醣蛋白之方法係此項技術中已知的,且可供使用。
根據本發明,打開-關閉(on-off)或其他類型的控制開關技術可併入本文中。此等技術可採用對二聚化域及此類域二聚化之可選活化劑之使用。此等技術包括
例如由Wu
等人,
Science2014
350 (6258)所述在某些細胞中利用FKBP/Rapalog二聚化系統之技術,該文獻之內容以全文引用之方式併入本文中。另外的二聚化技術描述於
例如Fegan
等人 Chem. Rev.2010,
110,3315–3336以及美國專利第5,830,462號;第5,834,266號;第5,869,337號;及第6,165,787號中,該等文獻之內容亦以全文引用之方式併入本文中。另外的二聚化對可包括環孢素-A/親環蛋白、受體、雌激素/雌激素受體(視情況使用他莫昔芬)、糖皮質素/糖皮質素受體、四環素/四環素受體、維生素D/維生素D受體。二聚化技術之進一步實例可見於
例如WO 2014/127261、WO 2015/090229、US 2014/0286987、US 2015/0266973、US 2016/0046700、美國專利第8,486,693號、US 2014/0171649、及US 2012/0130076中,該等文獻之內容進一步以全文引用之方式併入本文中。
治療方法
使用過繼性免疫療法,原態T細胞可(i)從患者中移除;(ii)經遺傳工程改造以表現結合至至少一種腫瘤抗原的嵌合抗原受體(CAR);(iii)經
離體擴增成更大的經工程改造之T細胞群體;且(iv)重新引入患者中。參見,例如,美國專利第7,741,465號及第6,319,494號、Eshhar
等人(Cancer Immunol,同上);Krause
等人(同上)
;Finney
等人(同上)。在將經工程改造之T細胞重新引入至患者中後,其介導針對表現腫瘤抗原之細胞的免疫反應。參見,例如,Krause
等人, J. Exp. Med.,第188卷,第4期, 1998 (619–626)。此免疫反應包括T細胞分泌IL-2及其他細胞介素、識別腫瘤抗原之T細胞之選殖擴增、及T細胞介導之靶標陽性細胞之特異性殺傷。參見,Hombach
等人, Journal of Immun. 167: 6123–6131 (2001)。
在一些態樣中,本發明因此包含一種用於治療或預防患者之與非所要及/或升高的FLT3位準相關之病狀的方法,其包含向有需要之患者投與有效量之至少一種本文所揭示之經分離之抗原結合分子、CAR、或TCR。
提供用於治療疾病或病症(包括癌症)之方法。在一些實施例中,本發明係關於在受試者中產生T細胞介導之免疫反應,其包含向受試者投與有效量之本申請案之經工程改造之免疫細胞。在一些實施例中,T細胞介導之免疫反應係針對一或多種靶細胞。在一些實施例中,經工程改造之免疫細胞包含嵌合抗原受體(CAR)或T細胞受體(TCR)。在一些實施例中,靶細胞係腫瘤細胞。在一些態樣中,本發明包含一種用於治療或預防惡性腫瘤之方法,該方法包含向有需要之受試者投與有效量之至少一種本文所述之經分離之抗原結合分子。在一些態樣中,本發明包含一種用於治療或預防惡性腫瘤之方法,該方法包含向有需要之受試者投與有效量之至少一種免疫細胞,其中該免疫細胞包含至少一種如本文所述之嵌合抗原受體、T細胞受體、及/或經分離之抗原結合分子。
在一些態樣中,本發明包含一種醫藥組成物,其包含至少一種如本文所述之抗原結合分子及醫藥學上可接受之賦形劑。在一些實施例中,醫藥組成物進一步包含另外的活性劑。
本發明之抗原結合分子、CAR、TCR、免疫細胞、及類似者可用於治療骨髓性疾病,該等骨髓疾病包括但不限於急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、慢性骨髓單核球白血病(CMML)、幼年型骨髓單核球白血病、非典型慢性骨髓性白血病、急性前骨髓球白血病(APL)、急性單核母細胞性白血病、急性紅血球系白血病、急性巨核母細胞性白血病、骨髓增殖異常症候群(MDS)、骨髓增生性病症、骨髓性贅生物、骨髓性肉瘤)、或其組合另外的疾病包括炎性及/或自體免疫疾病,諸如類風濕性關節炎、牛皮癬、過敏、氣喘、克羅恩氏病、IBD、IBS、纖維肌痛、肥大細胞增多症、及乳糜瀉。
應當理解,用於CAR
+/ CAR-T
+/ TCR
+細胞之目標劑量之範圍可為1x10
6至2x10
10個細胞/kg、較佳為2x10
6個細胞/kg、更佳。應當理解,高於及低於此範圍的劑量可適合於某些受試者,且適當的劑量位準可由保健提供者根據需要來確定。另外,可根據本發明提供多個劑量的細胞。
亦提供用於減小受試者之腫瘤大小的方法,其包含向受試者投與本發明之經工程改造之細胞,其中該細胞包含嵌合抗原受體、T細胞受體、或包含結合至腫瘤上之抗原的抗原結合分子的基於T細胞受體之嵌合抗原受體。在一些實施例中,受試者具有實體瘤或諸如淋巴瘤或白血病之血液惡性腫瘤。在一些實施例中,經工程改造之細胞經傳遞至腫瘤床。在一些實施例中,癌症存在於受試者之骨髓中。
在一些實施例中,經工程改造之細胞係自體T細胞。在一些實施例中,經工程改造之細胞係同種異體T細胞。在一些實施例中,經工程改造之細胞係異源T細胞。在一些實施例中,本申請案之經工程改造之細胞係
體內轉染或轉導。在其他實施例中,經工程改造之細胞係
離體轉染或轉導。
該等方法可進一步包含投與一或多種化學治療劑。在某些實施例中,化學治療劑係淋巴球清除(預調節)化學治療劑。有益的預調節治療方案連同相關的有益的生物標誌物描述於美國臨時專利申請案62/262,143及62/167,750中,該等專利特此以全文引用之方式併入本文中。此等專利描述
例如用於調節需要T細胞療法之患者的方法,其包含向患者投與指定有益劑量的環磷醯胺(介於200 mg/m
2/天與2000 mg/m
2/天之間)及指定劑量的氟達拉濱(介於20 mg/m
2/天與900 mg/m
2/天之間)。較佳的劑量方案涉及治療患者,其包含每日向患者投與約500 mg/m
2/天的環磷醯胺及約60 mg/m
2/天的氟達拉濱持續三天,之後向患者投與治療有效量的經工程改造之T細胞。
在其他實施例中,抗原結合分子、經轉導之(或以其他方式經工程改造之)細胞(諸如CAR或TCR)、及化學治療劑各自以有效治療受試者之疾病或病狀的量投與。
在某些實施例中,包含本文所揭示之表現CAR的免疫效應細胞之組成物可結合任何數目的化學治療劑投與。化學治療劑之實例包括:烷化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXAN
TM);烷基磺酸酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)、及哌泊舒凡(piposulfan);氮丙啶類,諸如苯并多巴(benzodopa)、卡巴醌(carboquone)、麥曲多巴(meturedopa)、及左多巴(uredopa);乙烯亞胺類及甲基三聚氰胺類,包括六甲嘧胺(altretamine)、三伸乙基三聚氰胺(triethylenemelamine)、三伸乙基磷醯胺(trietylenephosphoramide)、三伸乙基硫代磷醯胺(triethylenethiophosphaoramide)、及三羥甲基三聚氰胺(trimethylolomelamine resume);氮芥類,諸如氮芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、環磷醯胺(cholophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲氮芥(mechlorethamine)、氧化甲氮芥鹽酸鹽(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼莫司汀(prednimustine)、氯乙環磷醯胺(trofosfamide)、尿嘧啶氮芥(uracil mustard));亞硝基脲類(諸如亞硝基脲氮芥(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysins)、放線菌素(actinomycin)、安麯黴素(authramycin)、重氮絲胺酸(azaserine)、博來黴素(bleomycins)、放線菌素C (cactinomycin)、卡奇黴素(calicheamicin)、卡柔比星(carabicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycin)、放線菌素D (dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、佐柔比星(zorubicin);抗代謝物,諸如甲胺蝶呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如二甲葉酸(denopterin)、甲胺蝶呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如環胞苷(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如卡魯睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、硫雄甾醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺劑,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺醣苷(aldophosphamide glycoside);胺基酮戊酸(aminolevulinic acid);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地氟法胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);埃氟米辛(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK®;雷佐生(razoxane);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2, 2',2''-三氯三乙基胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitobronitol);哌泊溴烷(pipobroman);胞嘧啶(gacytosine);阿拉伯糖苷(arabinoside,「Ara-C」);環磷醯胺;噻替派;紫杉烷類,例如太平洋紫杉醇(paclitaxel) (TAXOL
TM, Bristol-Myers Squibb)及歐洲紫衫醇(doxetaxel) (TAXOTERE
®, Rhone-Poulenc Rorer);氮芥苯丁酸;吉西他濱;6-硫鳥嘌呤;巰基嘌呤;甲胺蝶呤;鉑類似物,諸如順鉑及卡鉑;長春花鹼;鉑;依託泊苷(VP-16);異環磷醯胺;絲裂黴素C;米托蒽醌;長春新鹼;長春瑞濱;諾維本;諾安托;替尼泊苷;道諾黴素;胺基蝶呤;希羅達;伊班膦酸鹽;CPT-11;拓撲異構酶抑制劑RFS2000;二氟甲基鳥胺酸(DMFO);視黃酸衍生物,諸如Targretin
TM(蓓薩羅丁)、Panretin
TM、(阿利維A酸);ONTAK
TM(地尼白介素);卡培他濱;及以上任一者之醫藥學上可接受之鹽、酸、或衍生物。此定義中亦包括用於調控或抑制激素對腫瘤之作用之抗激素藥劑,諸如抗雌激素,包括例如他莫昔芬、雷洛昔芬、芳香酶抑制性4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬、克昔芬、LY117018、奧那司酮、及托瑞米芬(法樂通);及抗雄激素,諸如氟他胺、尼魯米特、比卡魯胺、亮丙瑞林、及戈舍瑞林;及以上任一者之醫藥學上可接受之鹽、酸、或衍生物。適當時,亦投與化學治療劑之組合,其包括但不限於CHOP,(即,環磷醯胺(Cytoxan
®))、多柔比星(羥基多柔比星)、長春新鹼(Oncovin
®)、及強的松。
在一些實施例中,化學治療劑係在投與經工程改造之細胞或核酸同時或之後一週內投與。在其他實施例中,化學治療劑係在投與經工程改造之細胞或核酸之後1至4週或1週至1個月、1週至2個月、1週至3個月、1週至6個月、1週至9個月、或1週至12個月投與。在其他實施例中,化學治療劑係在投與細胞或核酸之前至少1個月投與。在一些實施例中,該等方法進一步包含投與二或更多種化學治療劑。
多種另外的治療劑可結合本文所述之組成物使用。例如,潛在有用的另外治療劑包括PD-1抑制劑,諸如納武單抗(nivolumab) (Opdivo
®)、派姆單抗(pembrolizumab)(Keytruda
®)、派姆單抗、匹地利珠單抗(pidilizumab)、及阿特珠單抗(atezolizumab)。
合適用於與本發明組合使用之另外治療劑包括但不限於依魯替尼(ibrutinib) (Imbruvica
®)、奧法木單抗(ofatumumab) (Arzerra
®)、利妥昔單抗(rituximab) (Rituxan
®)、貝伐單抗(bevacizumab) (Avastin
®)、曲妥珠單抗(trastuzumab) (Herceptin
®)、賀癌寧(trastuzumab emtansine) (KADCYLA
®)、伊馬替尼(Gleevec
®)、西妥昔單抗(cetuximab) (Erbitux
®)、帕尼單抗(panitumumab) (Vectibix
®)、卡妥索單抗(catumaxomab)、替伊莫單抗(ibritumomab)、奧法木單抗、托西莫單抗(tositumomab)、本圖希單抗(brentuximab)、阿侖單抗(alemtuzumab)、吉妥珠單抗(gemtuzumab)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、來那替尼(neratinib)、阿昔替尼(axitinib)、馬賽替尼(masitinib)、帕唑帕尼(pazopanib)、舒尼替尼、索拉非尼(sorafenib)、托西尼布(toceranib)、來他替尼、阿昔替尼、西地尼布(cediranib)、樂伐替尼(lenvatinib)、尼達尼布(nintedanib)、帕唑帕尼、瑞格非尼(regorafenib)、司馬沙尼(semaxanib)、索拉非尼、舒尼替尼、替沃紮尼(tivozanib)、托西尼布、凡德他尼、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊馬替尼(imatinib)、達沙替尼(dasatinib)、尼羅替尼(nilotinib)、帕納替尼(ponatinib)、拉多替尼(radotinib)、博舒替尼(bosutinib)、來他替尼、魯索利替尼(ruxolitinib)、帕克替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、比美替尼(binimetinib)、艾樂替尼(alectinib)、色瑞替尼(ceritinib)、克裡唑替尼(crizotinib)、阿柏西普(aflibercept)、阿帝潑肽(adipotide)、地尼白介素(denileukin diftitox)、mTOR抑制劑諸如依維莫司(Everolimus)及西羅莫司(Temsirolimus)、刺蝟抑制劑(hedgehog inhibitor)諸如索尼德吉(sonidegib)及維莫德吉(vismodegib)、CDK抑制劑諸如CDK抑制劑(帕布昔利布(palbociclib))。
在另外的實施例中,包含含有CAR免疫之組成物可與抗炎劑一起投與。抗炎劑或藥物包括但不限於類固醇及糖皮質素(包括倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、乙酸氫化可的松(hydrocortisone acetate)、氫化可的松(hydrocortisone)、氫化可的松、甲基強的松龍(methylprednisolone)、強的松龍(prednisolone)、強的松(prednisone)、曲安西龍(triamcinolone));非類固醇抗炎藥(NSAIDS),包括阿司匹林、布洛芬(ibuprofen)、萘普生(naproxen)、甲胺蝶呤、柳氮磺胺吡啶(sulfasalazine)、來氟米特(leflunomide)、抗TNF藥物、環磷醯胺、及黴酚酸酯。示範性NSAID包括布洛芬、萘普生、萘普生鈉、Cox-2抑制劑、及唾液酸酯(sialylate)。示範性止痛劑包括乙醯酚胺(acetaminophen)、羥考酮(oxycodone)、曲馬多(tramadol)、或鹽酸普帕西芬(proporxyphene hydrochloride)。示範性糖皮質素包括可的松、地塞米松、氫化可的松、甲基強的松龍、強的松龍、或強的松。示範性生物反應修飾劑包括針對細胞表面標誌物(例如,CD4、CD5等等)之分子、細胞介素抑制劑諸如TNF拮抗劑(例如,依那西普(etanercept) (ENBREL
®)、阿達木單抗(HUMIRA
®)及英夫利昔單抗(REMICADE
®)、趨化介素抑制劑、及黏附分子抑制劑。生物反應修飾劑包括單株抗體以及重組形式的分子。示範性DMARD包括硫唑嘌呤、環磷醯胺、環孢素、甲胺蝶呤、青黴胺、來氟米特、柳氮磺胺吡啶、羥氯喹(hydroxychloroquine)、Gold (口服(金諾芬(auranofin))及肌內)、及米諾環素(minocycline)。
在某些實施例中,本文所述之組成物係結合細胞介素投與。如本文所使用之「細胞介素」係指一個細胞群體所釋放之作為細胞間介體作用於另一個細胞的蛋白質。細胞介素之實例係淋巴因子、單核因子、及傳統多肽激素。細胞介素中包括:生長激素,諸如人類生長激素、N-甲硫胺醯人類生長激素、及牛生長激素;副甲狀腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;鬆弛素原;醣蛋白激素,諸如濾泡刺激素(FSH)、甲狀腺刺激素(TSH)、及黃體成長激素(LH);肝生長因子(HGF);纖維母細胞生長因子(FGF);催乳素;胎盤生乳素;慕氏抑制物質(mullerian-inhibiting substance);小鼠促性腺素相關肽;抑制素;活化素;血管內皮生長因子;整合蛋白;血小板生成素(TPO);神經生長因子(NGF),諸如NGF-β;血小板生長因子;轉化生長因子(TGF),諸如TGF-α及TGF-β;胰島素樣生長因子-I及胰島素樣生長因子-II;紅血球生成素(EPO);骨誘導因子( osteoinductive factor);干擾素,諸如干擾素-α、干擾素-β、及干擾素-γ;群落刺激因子(CSF),諸如巨噬細胞-CSF(M-CSF);顆粒球-巨噬細胞-CSF (GM-CSF);及顆粒球-CSF (G-CSF);白介素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-15;腫瘤壞死因子,諸如TNF-α或TNF-β;及其他多肽因子,包括LIF及kit配位體(KL)。如本文所使用,術語細胞介素包括來自天然來源或重組細胞培養物之蛋白質、及生物活性當量的原態序列細胞介素。
在一些態樣中,本發明包含以小於100 pM之K
d結合至FLT3的抗原結合分子。在一些實施例中,抗原結合分子以小於10 pM之K
d結合。在其他實施例中,抗原結合分子以少於5 pM之K
d結合。
製備方法
多種已知技術可用於製備根據本發明之多核苷酸、多肽、載體、抗原結合分子、免疫細胞、組成物、及類似者。
在本文所述之免疫細胞的
體外操作或遺傳修飾之前,可自受試者獲得細胞。在一些實施例中,免疫細胞包含T細胞。T細胞可獲自許多來源,包括周邊血單核球(PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染部位之組織、腹水、胸膜滲出液、脾組織、及腫瘤。在某些實施例中,T細胞可使用熟習此項技術者已知的許多技術(諸如FICOLL
TM分離)獲自從受試者收集的單位血液。細胞可較佳藉由分離術獲自個體之循環血液。分離術產品通常含有淋巴球,包括T細胞、單核球、顆粒球、B細胞、其他有核白血球、紅血球、及血小板。在某些實施例中,藉由分離術所收集之細胞可經洗滌以移除血漿級分,且置於適當緩衝液或培養基中以進行後續加工。細胞可用PBS洗滌。如應當理解,可諸如藉由使用半自動流過離心機(semiautomated flowthrough centrifuge) (例如Cobe
TM2991細胞處理機、Baxter CytoMate
TM、或類似者)來使用洗滌步驟。洗滌後,細胞可重懸於多種生物相容性緩衝液、或具有或不具有緩衝液的其他鹽水溶液中。在某些實施例中,可移除分離術樣品之非所要組分。
在某些實施例中,T細胞係藉由溶解紅血球且清除單核球(例如經由PERCOLL
TM梯度使用離心)來從PBMC中分離。可藉由此項技術中已知的陽性或陰性選擇技術進一步分離特異性T細胞亞群體,諸如CD28
+、CD4
+、CD8
+、CD45RA
+、及CD45RO
+T細胞。例如,藉由陰性選擇富集T細胞群體可用針對經陰性選擇之細胞所特有之表面標誌物的抗體之組合完成。用於本文之一種方法係經由陰性磁性免疫黏附或流動式細胞測量術進行的細胞分選及/或選擇,其使用針對存在於經陰性選擇之細胞上的細胞表面標誌物的單株抗體之混合物(cocktail)。例如,為了藉由陰性選擇富集CD4
+細胞,單株抗體混合物通常包括CD14、CD20、CD11b、CD16、HLA-DR、及CD8之抗體。流動式細胞測量術及細胞分選亦可用於分離用於本發明中之所關注之細胞群體。
可直接使用PBMC以使用如本文所述之方法用免疫細胞(諸如CAR或TCR)進行遺傳修飾。在某些實施例中,在分離PBMC之後,可進一步分離T淋巴球,且在遺傳修飾及/或擴增之前或之後,細胞毒性T淋巴球及輔助T淋巴球均可經分選成初始T細胞、記憶T細胞、及效應T細胞亞群體。
在一些實施例中,CD8
+細胞藉由鑒別細胞表面抗原來進一步分選成初始細胞、中央記憶細胞、及效應細胞,該等細胞表面抗原與此等類型的CD8
+細胞中之各者相關。在一些實施例中,中央記憶T細胞之表型標誌物之表現包括CD45RO、CD62L、CCR7、CD28、CD3、及CD127,且對顆粒酶B係陰性的。在一些實施例中,中央記憶T細胞係CD45RO
+、CD62L
+、CD8
+T細胞。在一些實施例中,效應T細胞對CD62L、CCR7、CD28、及CD127係陰性的,且對顆粒酶B及穿孔蛋白係陽性的。在某些實施例中,CD4
+T細胞進一步分選成亞群體。例如,CD4
+T輔助細胞可藉由鑒別具有細胞表面抗原之細胞群體來分選成初始細胞、中央記憶細胞、及效應細胞。
免疫細胞(諸如T細胞)可在分離後使用已知方法來遺傳修飾,或免疫細胞可在遺傳修飾之前
體外活化且擴增(或在先驅細胞之情況下經分化)。在另一個實施例中,免疫細胞(諸如T細胞)用本文所述之嵌合抗原受體來遺傳修飾(例如,用包含編碼CAR的一或多種核苷酸序列的病毒載體轉導),然後體外活化且/或擴增。用於活化及擴增T細胞之方法係此項技術中已知的,且描述於例如在美國專利第6,905,874號;美國專利第6,867,041號;美國專利第6,797,514號;及PCT WO2012/079000中,該等專利之內容特此以全文引用之方式併入。通常,此類方法包括在具有適當細胞介素(諸如IL-2)之培養基中將PBMC或經分離之T細胞與通常連接至珠粒或其他表面的刺激藥劑及共刺激藥劑(諸如抗CD3及抗CD28抗體)接觸。連接至相同珠粒的抗CD3及抗CD28抗體用作「替代」抗原呈現細胞(APC)。一個實例係Dynabeads
®系統,即針對人類T細胞之生理活化的CD3/CD28活化劑/刺激劑系統。
在其他實施例中,T細胞可經活化且經刺激以使用諸如以下中所述之方法的方法與餵養細胞及適當抗體與細胞介素一起增殖:美國專利第6,040,177號;美國專利第5,827,642號;及WO2012129514,該等專利之內容特此以全文引用之方式併入。
用於製備本發明之構築體及經工程改造之免疫細胞的某些方法描述於PCT申請案PCT/US15/14520中,該申請案之內容特此以全文引用之方式併入。製備構築體及細胞之另外方法可見於美國臨時專利申請案第62/244036號中,該申請案之內容特此以全文引用之方式併入。
應當理解,PBMC可進一步包括其他細胞毒性淋巴球,諸如NK細胞或NKT細胞。攜帶如本文所揭示之嵌合受體之編碼序列的表現載體可引入至人類供體T細胞、NK細胞、或NKT細胞之群體中。攜帶表現載體的經成功轉導之T細胞可使用流動式細胞測量術分選,以分離CD3陽性T細胞,然後除使用抗CD3抗體及IL-2或如本文別處所述之此項技術中已知的其他方法進行細胞活化之外,經進一步增殖以增加此等CAR表現T細胞之數目。標準程序用於冷凍保存表現CAR之T細胞以供儲存及/或製備以用於人類受試者。在一個實施例中,T細胞之
體外轉導、培養、及/或擴增在不存在非人類動物衍生之產物(諸如胎牛血清(fetal calf serum及fetal bovine serum))的情況下執行。
為了選殖多核苷酸,可將載體引入至宿主細胞(經分離之宿主細胞)中,以允許載體本身之複製,從而擴增其中所含的多核苷酸之拷貝。選殖載體可含有序列組分,其通常包括但不限於複製起點、啟動子序列、轉錄起始序列、增強子序列、及可選擇標誌物。此等元件可由此項技術中之普通技術人員適當時選擇。例如,複製起點可經選擇以促進載體在宿主細胞中之自主複製。
在某些實施例中,本揭露提供含有本文所提供之載體的經分離之宿主細胞。含有載體之宿主細胞可用於載體中所含之多核苷酸之表現或選殖。合適之宿主細胞可包括但不限於原核細胞、真菌細胞、酵母細胞、或高等真核細胞,諸如哺乳動物細胞。用於此目的的合適之原核細胞包括但不限於真細菌,諸如革蘭氏陰性或革蘭氏陽性生物體,例如腸桿菌科,諸如艾氏菌屬(例如,大腸桿菌);腸桿菌屬;伊文氏桿菌屬;克留氏菌屬;變形桿菌屬;沙氏桿菌屬(例如,鼠傷寒沙氏桿菌);沙雷氏菌屬(例如,黏質沙雷氏菌);及志賀桿菌屬;以及芽孢桿菌屬(諸如,枯草芽孢桿菌及地衣芽孢桿菌)、假單胞菌屬(諸如綠膿桿菌)、及鏈黴菌屬。
載體可使用此項技術中已知的任何合適方法引入至宿主細胞,該等方法包括但不限於DEAE-葡聚糖介導之傳遞、磷酸鈣沉澱法、陽離子脂質介導之傳遞、脂質體介導之轉染、電穿孔、微粒子炸射法(microprojectile bombardment)、受體介導之基因傳遞、由聚離胺酸、組蛋白、幾丁聚糖、及肽介導之傳遞。用於轉染及轉化用於表現所關注之載體的細胞之標準方法係此項技術中眾所周知的。在進一步實施例中,不同表現載體之混合物可用於遺傳修飾免疫效應細胞之供體群體,其中各載體編碼如本文所揭示之不同CAR。所得經轉導之免疫效應細胞形成經工程改造之細胞之混合群體,其中經工程改造之細胞群體表現多於一種不同的CAR。
在一個實施例中,本發明提供一種儲存表現靶向FLT3蛋白之CAR或TCR的經遺傳工程改造之細胞的方法。此涉及冷凍保存免疫細胞,使得細胞在解凍時保持活力。一部分表現CAR之免疫細胞之可藉由此項技術中已知的方法冷凍保存,以為將來治療罹患惡性腫瘤之患者提供此類細胞之永久來源。當需要時,冷凍保存的經轉化之免疫細胞可經解凍、生長、及擴增以獲得更多此類細胞。
如本文所使用,「冷凍保存」係指藉由冷卻至零下溫度(諸如(通常) 77克耳文或-196℃(液氮之沸點))來保存細胞。冷凍保護劑常常在零下溫度下使用,以防止所保存之細胞由於在低溫下冷凍或溫至室溫而損壞。冷凍保存劑及最佳冷卻速率可防止細胞損傷。可根據本發明使用的冷凍保護劑包括但不限於:二甲亞碸(DMSO) (Lovelock & Bishop, Nature (1959); 183: 1394-1395; Ashwood-Smith, Nature (1961); 190: 1204-1205)、甘油、聚乙烯吡咯烷酮(Rinfret, Ann. N.Y. Acad. Sci. (1960); 85: 576)、及聚乙二醇(Sloviter & Ravdin, Nature (1962); 196: 48)。較佳的冷卻速率為1℃至3℃/分鐘。
術語「實質上純的」用於指示給定組分以高位準存在。組分合意地係存在於組成物中之主要組分。較佳的是,其存在的位準多於30%、多於50%、多於75%、多於90%、或甚至多於95%,該位準係在相對於所考慮的總組成物的幹重/幹重基礎上確定。在非常高的位準下(例如,在多於90%、多於95%、或多於99%之位準下),該組分可視為「純形式」。本發明之生物活性物質(包括多肽、核酸分子、抗原結合分子、部分)可以實質上不含該物質可以其他方式締合的一或多種污染物之形式提供。當組成物實質上不含給定污染物時,該污染物將在低位準下(
例如,在上文闡述的幹重/幹重基礎上,在小於10%、小於5%、或小於1%之位準下)。
在一些實施例中,細胞藉由以下來調配:首先從細胞培養基收穫細胞,然後洗滌並將細胞以治療有效量濃縮於合適於投與的介質及容器系統(「醫藥學上可接受之」載劑)中。合適之輸注介質可係任何等滲介質調配物,通常係生理鹽水、Normosol
TMR (Abbott)、或Plasma-Lyte
TMA (Baxter),但亦可利用5%右旋糖水溶液或林格氏乳酸鹽。輸注介質可補充有人類血清白蛋白。
組成物中細胞之所要治療量通常為至少2個細胞(例如,至少1個 CD8
+中央記憶T細胞及至少1個CD4
+輔助T細胞亞組)或更通常為大於10
2個細胞,且多達10
6、多達且包括10
8或10
9個細胞,且可為多於10
10個細胞。細胞之數目將取決於組成物所意欲的所要用途、及其中包括的細胞類型。所要細胞之密度通常大於10
6個細胞/ml,且通常大於10
7個細胞/ml,通常係10
8個細胞/ml或更大。臨床相關數目的免疫細胞可分配成多次輸注,其累積等於或超過10
5、10
6、10
7、10
8、10
9、10
10、10
11、或10
12個細胞。在本發明之一些態樣中,特別是因為所有輸注細胞將重定向至特定靶抗原(FLT3),所以可投與較低數目的細胞,其範圍為10
6/千克(10
6至10
11個/患者)。CAR治療可以此等範圍內的劑量投與多次。細胞可係自體的、同種異體的、或對經受療法之患者異源的。
本發明之CAR表現細胞群體可單獨投與、或作為與稀釋劑及/或其他組分(諸如IL-2或其他細胞介素或細胞群體)組合的醫藥組成物投與。本發明之醫藥組成物可包含與一或多種醫藥學上或生理學上可接受之載劑、稀釋劑、或賦形劑組合的如本文所述之CAR或TCR表現細胞群體(諸如T細胞)。此類組成物可包含:緩衝液,諸如中性緩衝鹽水、磷酸鹽緩衝鹽水、及類似者;碳水化合物,諸如葡萄糖、甘露糖、蔗糖、或葡聚糖、甘露醇;蛋白質;多肽或胺基酸,諸如甘胺酸;抗氧化劑;螯合劑,諸如EDTA或麩胱甘肽;佐劑(例如,氫氧化鋁);及防腐劑。本發明之組成物較佳調配用於靜脈內投與。
醫藥組成物(溶液、懸浮液、或類似者)可包括以下之一或多者:無菌稀釋劑諸如注射用水、鹽水溶液、較佳生理鹽水、林格氏溶液、等滲氯化鈉、不揮發油諸如可用作溶劑或懸浮介質之合成的單甘油酯或雙甘油酯、聚乙二醇、甘油、丙二醇、或其他溶劑;抗菌劑,諸如苄醇或對羥基苯甲酸甲酯;抗氧化劑,諸如抗壞血酸或亞硫酸氫鈉;螯合劑,諸如乙二胺四乙酸;緩衝液,諸如乙酸鹽、檸檬酸鹽、或磷酸鹽;以及用於調整滲性之藥劑,諸如氯化鈉或右旋糖。腸胃外製劑可封裝於由玻璃或塑膠製成之安瓿、拋棄式注射器、或多劑量小瓶中。可注射醫藥組成物較佳係無菌的。
應當理解,藉由用自殺基因轉導免疫細胞(含有一或多種CAR或TCR)可使不利事件最小化。亦可期望將可誘導型「打開」或「加速」開關併入至免疫細胞中。合適之技術包括在用本發明之CAR構築體轉導細胞之前、之後、或同時使用可誘導型半胱天冬酶-9 (美國申請案2011/0286980)或胸苷激酶。用於引入自殺基因及/或「打開」開關之另外方法包括TALENS、鋅指、RNAi、siRNA、shRNA、反義技術、及此項技術中已知的其他技術。
應當理解,本文中之描述僅係示範性及解釋性的,且不限制所主張之本發明。在本申請案中,除非另外明確說明,否則使用單數包括複數。
本文所使用之章節標題僅出於組織目的且不應解釋為限制所描述之標的物。本申請案中引用之所有文獻或文獻之部分(包括但不限於專利、專利申請案、文章、書籍、及論文)特此明確地出於任何目的以全文引用之方式併入。如根據本揭露所用,除非另外指示,否則以下術語應理解成具有以下含義:
在本申請案中,除非另外說明,否則使用「或」意謂「及/或」。此外,使用術語「包括(including)」以及其他形式(諸如「包括(includes)」及「包括(included)」)不具有限制性。同樣,除非另外明確說明,否則諸如「元件」或「組分」之術語涵蓋包含一個單元之元件及組分與包含多於一個次單元之元件及組分兩者。
術語「FLT3活性」包括FLT3之任何生物效應。在某些實施例中,FLT3活性包括FLT3與受質或受體相互作用或結合至受質或受體之能力。
術語「多核苷酸」、「核苷酸」、或「核酸」包括單鏈及雙鏈核苷酸聚合物。包含多核苷酸之核苷酸可係核糖核苷酸或去氧核糖核苷酸或任一核苷酸類型之經修飾形式。該等修飾包括:鹼基修飾(諸如,溴尿苷及肌苷衍生物);核糖修飾,諸如2',3'-二去氧核糖;及核苷酸間鍵聯修飾,諸如,硫代磷酸酯、二硫代磷酸酯、硒代磷酸酯、二硒代磷酸酯、苯胺基硫代磷酸酯(phosphoro-anilothioate)、苯胺基磷酸酯(phoshoraniladate)、及胺基磷酸酯(phosphoroamidate)。
術語「寡核苷酸」係指包含200個或更少核苷酸之多核苷酸。寡核苷酸可係單鏈或雙鏈的,例如,以用於構築突變基因。寡核苷酸可係有義或反義寡核苷酸。寡核苷酸可包括用於偵測分析之標記,包括放射性標記、螢光標記、半抗原、或抗原標記。寡核苷酸可用作例如PCR引子、選殖引子、或雜交探針。
術語「控制序列」係指可影響所連接之編碼序列之表現及加工的多核苷酸序列。此類控制序列之性質可取決於宿主生物體。在特定實施例中,原核生物之控制序列可包括啟動子、核糖體結合位點、及轉錄終止序列。例如,真核生物之控制序列可包括啟動子(其包含轉錄因子之一個或複數個識別位點)、轉錄增強子序列、及轉錄終止序列。「控制序列」可包括前導序列(信號肽)及/或融合搭配物序列。
如本文所使用,「可操作地連接」意指該術語所應用的組分係以允許其在合適條件下實現其固有功能的關係。
術語「載體」意指用於將蛋白質編碼資訊轉移至宿主細胞中的任何分子或實體(例如,核酸、質體、噬菌體、或病毒)。術語「表現載體」或「表現構築體」係指以下載體,該載體合適於宿主細胞之轉化且含有指導及/或控制(結合宿主細胞)可操作地連接至該載體的一或多個異源編碼區之表現的核酸序列。表現構築體可包括但不限於影響或控制轉錄、轉譯且(若內含子存在)影響可操作地連接至內含子的編碼區之RNA剪接的序列。
術語「宿主細胞」係指已經或能夠用核酸序列轉化從而表現所關注之基因的細胞。術語包括親本細胞之後代,無論該後代在形態上或在遺傳構成上是否與原始親本細胞相同,只要感興趣的基因存在即可。
術語「轉化」係指細胞遺傳特性之變化,且當細胞已經修飾以含有新的DNA或RNA時,細胞已經轉化。例如,當細胞藉由經由轉染、轉導、或其他技術引入新的遺傳物質來從其原態狀態進行遺傳修飾時,細胞係經轉化。在轉染或轉導後,轉化DNA可藉由物理整合至細胞之染色體中來與細胞之DNA重組,或可在未複製之情況下作為附加型元件瞬時地維持,或可作為質體獨立地複製。當轉化DNA隨著細胞之分裂複製時,細胞被視為已「穩定轉化」。
術語「轉染」係指由外來或外源DNA由細胞吸收。許多轉染技術在此項技術中眾所周知,且在本文中揭示。參見,
例如,Graham
等人, 1973, Virology 52:456;Sambrook
等人, 2001, Molecular Cloning: A Laboratory Manual,同上;Davis
等人, 1986, Basic Methods in Molecular Biology, Elsevier;Chu
等人, 1981, Gene 13:197。
術語「轉導」係指外來DNA經由病毒載體引入至細胞中的過程。參見,Jones
等人, (1998).Genetics: principles and analysis. Boston: Jones & Bartlett Publ。
術語「多肽」或「蛋白質」係指具有蛋白質之胺基酸序列的巨分子,其包括原態序列之一或多個胺基酸的缺失、添加、及/或取代。術語「多肽」及「蛋白質」具體涵蓋FLT3抗原結合分子、抗體、或具有抗原結合蛋白之一或多個胺基酸的缺失、添加、及/或取代的序列。術語「多肽片段」係指與全長原態蛋白相比具有胺基端缺失、羧基端缺失、及/或內部缺失之多肽。與原態蛋白相比,此類片段亦可含有經修飾之胺基酸。有用的多肽片段包括抗原結合分子之免疫學功能片段。有用的片段包括但不限於一或多個CDR區、重鏈及/或輕鏈之可變域、抗體鏈之其他部分之一部分、及類似者。
術語「經分離」意指(i)不含至少一些通常一起可見的其他蛋白質;(ii)基本上不含來自相同來源(
例如來自相同物種)之其他蛋白質;(iii)與至少約50%的多核苷酸、脂質、碳水化合物、或在自然界中與之締合的其他材料分離;(iv)與在自然界中未與之締合的多肽可操作地締合(藉由共價或非共價相互作用);或(v)在自然界中不存在。
多肽(
例如,抗原結合分子或抗體)之「變異體」包含以下胺基酸序列,在該胺基酸序列中一或多個胺基酸殘基相對於另一個多肽序列插入、缺失、及/或取代至該胺基酸序列中。變異體包括融合蛋白。
術語「一致性」係指二或更多種多肽分子或二或更多種核酸分子之序列之間的關係,如藉由比對及比較該等序列所確定。「一致性百分比」意指經比較之分子中胺基酸或核苷酸之間一致的殘基之百分比,且係基於所比較之最小分子之大小計算。對於此等計算,比對之間隙(若存在)較佳藉由特定數學模型或計算機程式(
即,「演算法」)來尋址。
為了計算一致性百分比,所比較之序列通常係以得到序列之間最大匹配的方式比對。可用於確定一致性百分比的計算機程式之一個實例係GCG程式包,其包括GAP (Devereux
等人 ,1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.)。計算機演算法GAP用於比對欲確定序列一致性百分比的兩種多肽或多核苷酸。該等序列經比對以用於其各自胺基酸或核苷酸之最佳匹配(「匹配跨度」,如藉由演算法所確定)。在某些實施例中,演算法亦使用標準比較矩陣(參見,針對PAM 250比較矩陣,Dayhoff
等人, 1978, Atlas of Protein Sequence and Structure 5:345-352;針對BLOSUM 62比較矩陣,Henikoff
等人, 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919)。
如本文所使用,二十種習知(例如,天然存在的)胺基酸及其縮寫遵循習知用法。
參見,Immunology - A Synthesis (第2版, Golub及Gren,編, Sinauer Assoc., Sunderland, Mass. (1991)),該文獻出於任何目的以引用之方式併入本文中。二十種習知胺基酸之立體異構體(例如,D-胺基酸)、非天然胺基酸諸如α-胺基酸、α-二取代胺基酸、N-烷基胺基酸、乳酸及、其他非習知胺基酸亦可為本發明之多肽之合適組分。非習知胺基酸之實例包括:4-羥脯胺酸、γ-羧基麩胺酸、ε-N,N,N-三甲基離胺酸、e-N-乙醯離胺酸、O-磷酸絲胺酸、N-乙醯絲胺酸、N-甲醯甲硫胺酸、3-甲基組胺酸、5-羥離胺酸、σ-N-甲基精胺酸、以及其他類似胺基酸及亞胺基酸(例如,4-羥脯胺酸)。在本文所使用的多肽符號中,根據標準使用及慣例,左手方向係胺基端方向,且右手方向係羧基端方向。
保守胺基酸取代可涵蓋非天然存在的胺基酸殘基,其通常藉由化學肽合成而非藉由生物系統中之合成來併入。此等胺基酸包括擬肽物及其他逆轉或反向形式的胺基酸部分。天然存在的殘基可基於共同的側鏈性質分為以下類別:
a) 疏水性:正白胺酸、Met、Ala、Val、Leu、Ile;
b) 中性親水性:Cys、Ser、Thr、Asn、Gln;
c) 酸性:Asp、Glu;
d) 鹼性:His、Lys、Arg;
e) 影響鏈定向之殘基:Gly、Pro;及
f) 芳族:Trp、Tyr、Phe。
例如,非保守取代可涉及將此等類別中一者之成員交換為來自另一類別之成員。此類經取代之殘基可例如引入至與非人類抗體同源的人類抗體區、或分子之非同源區中。
根據某些實施例,在對抗原結合分子、經工程改造之T細胞之共刺激或活化域進行改變時,可考慮胺基酸之疏水指數(hydropathic index)。已基於各胺基酸之疏水性及電荷特性來指定該等胺基酸之疏水指數。其為:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8);苯基丙胺酸(+2.8);半胱胺酸/胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸(-3.5);麩醯胺酸(-3.5);天冬胺酸酯(-3.5);天冬醯胺酸(-3.5);離胺酸(-3.9);及精胺酸(-4.5)。參見,Kyte等人, J. Mol. Biol., 157:105-131 (1982)。已知某些胺基酸可由具有相似疏水指數或分數的其他胺基酸取代,且仍保留類似的生物活性。在此項技術中亦應理解,特別是當由此產生的生物功能蛋白質或肽意欲用於免疫學實施例中時,如在當前情況下,可基於親水性有效地進行類似胺基酸之取代。示範性胺基酸取代闡明於表2中。
表 2
原始殘基 | 示範性取代 | 較佳取代 |
Ala | Val、Leu、Ile | Val |
Arg | Lys、Gln、Asn | Lys |
Asn | Gln | Gln |
Asp | Glu | Glu |
Cys | Ser、Ala | Ser |
Gln | Asn | Asn |
Glu | Asp | Asp |
Gly | Pro、Ala | Ala |
His | Asn、Gln、Lys、Arg | Arg |
Ile | Leu、Val、Met、Ala、Phe、正白胺酸 | Leu |
Leu | 正白胺酸、Ile、Val、Met、Ala、Phe | Ile |
Lys | Arg、1,4二胺基-丁酸(1,4 Diamino-butyric) | Arg |
酸、Gln、Asn | ||
Met | Leu、Phe、Ile | Leu |
Phe | Leu、Val、Ile、Ala、 | Leu |
Tyr | ||
Pro | Ala | Gly |
Ser | Thr、Ala、Cys | Thr |
Thr | Ser | Ser |
Trp | Tyr、Phe | Tyr |
Tyr | Trp、Phe、Thr、Ser | Phe |
Val | Ile、Met、Leu、Phe、 | Leu |
Ala、正白胺酸 |
術語「衍生物」係指除胺基酸(或核酸)之插入、缺失、或取代以外亦包括化學修飾的分子。在某些實施例中,衍生物包含共價修飾,其包括但不限於與聚合物、脂質、或其他有機或無機部分之化學鍵合。在某些實施例中,經化學修飾之抗原結合分子可比未經化學修飾之抗原結合分子具有更長的循環半衰期。在一些實施例中,衍生的抗原結合分子經共價修飾以包括一或多種水溶性聚合物連接,包括但不限於聚乙二醇、聚氧乙二醇、或聚丙二醇。
肽類似物通常在製藥工業中用作非肽藥物,其具有與模板肽之性質類似的性質。此等類型的非肽化合物稱為「肽模擬物」或「擬肽物」。Fauchere, J., Adv. Drug Res., 15:29 (1986);Veber及Freidinger, TINS,第392頁 (1985);及Evans
等人, J. Med. Chem., 30:1229 (1987),該等文獻出於任何目的以引用之方式併入本文中。
術語「治療有效量」係指經確定在哺乳動物中產生治療反應的FLT3抗原結合分子之量。此類治療有效量易於由此項技術中之普通技術人員確定。
術語「患者」及「受試者」可互換使用,且包括人類及非人類動物受試者、以及具有經正式診斷之病症的受試者、不具有經正式識別之病症的受試者、接受醫療照顧的受試者、處於發展病症的風險中的受試者等等。
術語「治療(treat)」及「治療(treatment)」包括減少受試者將發展病症之風險或其他風險因素的治療性治療、預防性治療、及應用。治療不需要完全治癒病症,且涵蓋減少症狀或潛在風險因素之實施例。術語「預防」不需要100%消除事件之可能性。相反,其表示事件發生之可能性在該化合物或方法之存在下降低。
標準技術可用於重組DNA、寡核苷酸合成、及組織培養及轉化(例如,電穿孔、脂轉染)。可根據製造商說明書或如此項技術中通常所達成或如本文所述來執行酶促反應及純化技術。前述技術及程序可通常根據在此項技術中眾所周知及如本說明書整篇引用及論述之各種一般性及更具體參考文獻中所述之習用方法來執行。參見,例如,Sambrook
等人, Molecular Cloning: A Laboratory Manual 第2版, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)),該文獻出於任何目的以引用之方式併入本文中。
以下序列將進一步例證本發明。
CD28T DNA細胞外、跨膜、細胞內
CTTGATAATGAAAAGTC AAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC (SEQ ID NO: 1)
CD28T AA細胞外、跨膜、細胞內:
LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP FWVLVVVGGV LACYSLLVTV AFIIFWVRSK RSRLLHSDYM NMTPRRPGPT RKHYQPYAPP RDFAAYRS(SEQ ID NO: 2)
CD28T DNA - 細胞外
CTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA(SEQ ID NO: 3)
CD28T AA - 細胞外
LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP(SEQ ID NO: 4)
CD28 DNA跨膜域
TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTT(SEQ ID NO: 5)
CD28 AA跨膜域:
FWVLVVVGGV LACYSLLVTV AFIIFWV(SEQ ID NO: 6)
CD28 DNA細胞內域:
AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC(SEQ ID NO: 7)
CD28 AA細胞內域
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO: 8)
CD3 ζ DNA
AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG(SEQ ID NO: 9)
CD3 ζ AA
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 10)
CD28 DNA
ATTGAGGTGATGTATCCACCGCCTTACCTGGATAACGAAAAGAGTAACGGTACCATCATTCACGTGAAAGGTAAACACCTGTGTCCTTCTCCCCTCTTCCCCGGGCCATCAAAGCCC(SEQ ID NO: 11)
CD28 AA
IEVMYPPPYL DNEKSNGTII HVKGKHLCPS PLFPGPSKP(SEQ ID NO: 12)
CD8 DNA細胞外及跨膜域
GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCTTGCCGGCTAAGCCTACTACCACACCCGCTCCACGGCCACCTACCCCAGCTCCTACCATCGCTTCACAGCCTCTGTCCCTGCGCCCAGAGGCTTGCCGACCGGCCGCAGGGGGCGCTGTTCATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGGCACCCCTGGCCGGAACCTGCGGCGTACTCCTGCTGTCCCTGGTCATCACGCTCTATTGTAATCACAGGAAC(SEQ ID NO: 13)
CD8 AA細胞外及跨膜域
AAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN(SEQ ID NO: 14)
殖株10E3 HC DNA
CAGGTCACCTTGAAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGAGACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCATCAATGCTAGAATGGGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTGCACACATTTTTTCGAATGCCGAAAAATCGTACAGGACATCTCTGAAGAGCAGGCTCACCATCTCCAAGGACACCTCCAAAAGCCAGGTGGTCCTTACCATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGTGCACGGATACCAGGCTACGGTGGTAACGGGGACTACCACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA(SEQ ID NO: 15)
殖株10E3 HC AA – CDR加底線
QVTLKESGPVLVKPTETLTLTCTVSGFSLI
NARMGVSWIRQPPGKALEWLA
HIFSNAEKSYRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCAR
IPGYGGNGDYHYYGMDVWGQGTTVTVSS(SEQ ID NO: 16)
殖株10E3 HC AA CDR1: NARMGVS(SEQ ID NO: 17)
殖株10E3 HC AA CDR2: HIFSNAEKSYRTSLKS(SEQ ID NO: 18)
殖株10E3 HC AA CDR3: IPGYGGNGDYHYYGMDV(SEQ ID NO: 19)
殖株10E3 LC DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTCTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTTCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAATTTCCCGTGGACGTTCGGTCAGGGAACGAAGGTGGAAATCAAACGA (SEQ ID NO: 20)
殖株10E3 LC AA (CDR加底線)
DIQMTQSPSSLSASLGDRVTITC
RASQGIRNDLGWYQQKPGKAPKRLIY
ASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYC
LQHNNFPWTFGQGTKVEIKR(SEQ ID NO: 21)
殖株10E3 LC CDR1 AA: RASQGIRNDLG (SEQ ID NO: 22)
殖株10E3 LC CDR2 AA: ASSTLQS (SEQ ID NO: 23)
殖株10E3 LC CDR3 AA: LQHNNFPWT (SEQ ID NO: 24)
殖株2E7 HC DNA
CAGGTCACCTTGAAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGAGACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCAGGAATGCTAGAATGGGTGTAAGCTGGATCCGTCAGCCTCCCGGGAAGGCCCTGGAGTGGCTTGCACACATTTTTTCGAATGACGAAAAAACCTACAGCACATCTCTGAAGAGCAGGCTCACCATCTCCAGGGACACCTCCAAAGGCCAGGTGGTCCTTACCATGACCAAGATGGACCCTGTGGACACAGCCACATATTACTGTGCACGGATACCCTACTATGGTTCGGGGAGTCATAACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO:25)
殖株2E7 HC AA (CDR加底線)
QVTLKESGPVLVKPTETLTLTCTVSGFSLR
NARMGVSWIRQPPGKALEWLA
HIFSNDEKTYSTSLKSRLTISRDTSKGQVVLTMTKMDPVDTATYYCAR
IPYYGSGSHNYGMDVWGQGTTVTVSS (SEQ ID NO:26)
殖株2E7 HC AA CDR1: NARMGVS (SEQ ID NO:17)
殖株2E7 HC AA CDR2: HIFSNDEKTYSTSLKS (SEQ ID NO:26)
殖株2E7 HC AA CDR3: IPYYGSGSHNYGMDV (SEQ ID NO:27)
殖株2E7 LC DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTCGGCTGGTATCAACAGAAACCAGGGAAAGCCCCTCAGCGCCTGCTCTATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGTATAATACTTACCCGTGGACGTTCGGTCAGGGAACGAAGGTGGAAATCAAACGA (SEQ ID NO: 28)
殖株2E7 LC AA (CDR加底線)
DIQMTQSPSSLSASVGDRVTITC
RASQDIRNDFGWYQQKPGKAPQRLLY
AASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYC
LQYNTYPWTFGQGTKVEIKR(SEQ ID NO: 29)
殖株2E7 LC AA CDR1: RASQDIRNDFG(SEQ ID NO: 30)
殖株2E7 LC AA CDR2: AASTLQS(SEQ ID NO: 31)
殖株2E7 LHC AA CDR3: LQYNTYPWT(SEQ ID NO: 32)
殖株8B5 HC DNA
CAGATACAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCACCTTCAAGAACTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGTATGATGGAAGTAATGAATACTATGGAGACCCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACTCCAAGAACATGTTGTATCTGCAAATGAACAGCCTGAGAGCCGATGACACGGCTGTGTATTACTGTGCGAGGTCGGGAATAGCAGTGGCTGGGGCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA(SEQ ID NO: 33)
殖株8B5 HC AA (CDR加底線)
QIQLVESGGGVVQPGRSLRLSCVASGFTFK
NYGMHWVRQAPGKGLEWVA
VIWYDGSNEYYGDPVKGRFTISRDNSKNMLYLQMNSLRADDTAVYYCAR
SGIAVAGAFDYWGQGTLVTVSS(SEQ ID NO: 34)
殖株8B5 HC AA CDR1: NYGMH (SEQ ID NO: 34)
殖株8B5 HC AA CDR2: VIWYDGSNEYYGDPVKG (SEQ ID NO: 35)
殖株8B5 HC AA CDR3: SGIAVAGAFDY (SEQ ID NO: 36)
殖株8B5 LC DNA
GAAATTGTGTTGACGCAGTCTCCAGACACCCTGTCTTTGTCTCCAGGGGAAAAAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTCTTGGCCTGGTACCAGCAGAAACCTGGACAGGCTCCCAGTCTCCTCATCTATGTTGCATCCAGAAGGGCCGCTGGCATCCCTGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGGAATGTTTTACTGTCAACACTATGGTAGGACACCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGA(SEQ ID NO: 37)
殖株8B5 LC AA (CDR加底線)
EIVLTQSPDTLSLSPGEKATLSC
RASQSVSSSFLAWYQQKPGQAPSLLIY
VASRRAAGIPDRFSGSGSGTDFTLTISRLEPEDFGMFYC
QHYGRTPFTFGPGTKVDIKR (SEQ ID NO:41)
殖株8B5 LC AA CDR1: RASQSVSSSFLA (SEQ ID NO: 38)
殖株8B5 LC AA CDR2: VASRRAA (SEQ ID NO: 39)
殖株8B5 LC AA CDR3: QHYGRTPFT (SEQ ID NO: 40)
殖株4E9 HC DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATACACTGGGTGCGACAGGCCCCTGAACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGGCCAGGGACACGTCCATCAGCACAGTTTACATGGACCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAATACGCGGTGGTAACTCGGTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA(SEQ ID NO: 41)
殖株4E9 HC AA (CDR加底線)
QVQLVQSGAEVKKPGASVKVSCKASGYTFT
GYYIHWVRQAPEQGLEWMG
WINPNSGGTNYAQKFQGRVTMARDTSISTVYMDLSRLRSDDTAVYYCAR
IRGGNSVFDYWGQGTLVTVSS(SEQ ID NO: 42)
殖株4E9 HC AA CDR1: GYYIH (SEQ ID NO: 43)
殖株4E9 HC AA CDR2: WINPNSGGTNYAQKFQG (SEQ ID NO: 44)
殖株4E9 HC AA CDR3: IRGGNSVFDY (SEQ ID NO: 45)
殖株4E9 LC DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCACCCAGAGTATTTTATACACCTCCAACAATAAGAACTTCTTAGCTTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGCTCATTTCCTGGGCATCTATCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCGCTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAACAATATTTTAGTACTATGTTCAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGA(SEQ ID NO: 46)
殖株4E9 LC AA (CDR加底線)
DIVMTQSPDSLAVSLGERATINC
KSTQSILYTSNNKNFLAWYQQKPGQPPKLLIS
WASIRESGVPDRFSGSGSGTDFALTISSLQAEDVAVYYCQ
QYFSTMFSFGQGTKLEIKR(SEQ ID NO: 47)
殖株4E9 LC AA CDR1: KSTQSILYTSNNKNFLA(SEQ ID NO: 48)
殖株4E9 LC AA CDR2: WASIRES (SEQ ID NO: 49)
殖株4E9 LC AA CDR3: QQYFSTMFS (SEQ ID NO: 50)
殖株11F11 HC DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTGGTGCATACTACTGGACTTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCCATTACAGTGGGAGCACCTACTCCAACCCGTCCCTCAAGAGTCGAATTACCATATCGTTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAACTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGACAAGAGGACTACGGTGGTTTGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTTTCCTCA(SEQ ID NO: 51)
殖株11F11 HC AA (CDR加底線)
QVQLQESGPGLVKPSQTLSLTCTVSGGSIS
SGAYYWTWIRQHPGKGLEWIG
YIHYSGSTYSNPSLKSRITISLDTSKNQFSLKLNSVTAADTAVYYCAR
QEDYGGLFDYWGQGTLVTVSS(SEQ ID NO: 52)
殖株11F11 HC AA CDR1: SGAYYWT (SEQ ID NO: 53)
殖株11F1 HC AA CDR2: YIHYSGSTYSNPSLKS (SEQ ID NO: 54)
殖株11F1 HC AA CDR3: QEDYGGLFDY (SEQ ID NO: 55)
殖株11F11 LC DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAATCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCACCGACTTAGCCTGGTACCAGCAGATGCCTGGACAGGCTCCCCGGCTCCTCATCTATGATGCTTCCACCAGGGCCACTGGTTTCCCAGCCAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACGCTCACCATCAGCAGCCTGCAGGCTGAAGATTTTGCAGTTTATTACTGTCAACATTATAAAACCTGGCCTCTCACTTTCGGCGGAGGGACTAAGGTGGAGATCAAACGA(SEQ ID NO: 56)
殖株11F11 LC AA (CDR加底線)
EIVMTQSPATLSVSPGERITLSC
RASQSVTTDLAWYQQMPGQAPRLLIY
DASTRATGFPARFSGSGSGTDFTLTISSLQAEDFAVYYC
QHYKTWPLTFGGGTKVEIKR(SEQ ID NO: 57)
殖株11F11 LC AA CDR1: RASQSVTTDLA (SEQ ID NO: 58)
殖株11F1 LC AA CDR2: DASTRAT (SEQ ID NO: 59)
殖株11F1 LC AA CDR3: QHYKTWPLT (SEQ ID NO: 60)
構築體10E3 CD28 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTGACCCTCAAAGAGTCTGGACCCGTGCTCGTAAAACCTACGGAGACCCTGACACTCACCTGCACAGTCTCCGGCTTCAGCCTCATCAATGCCAGGATGGGAGTTTCCTGGATCAGGCAACCGCCCGGAAAGGCCCTGGAATGGCTCGCACATATTTTCAGTAACGCTGAAAAAAGCTATCGGACTTCTCTGAAAAGTCGGCTCACGATTAGTAAGGACACATCCAAGAGCCAAGTGGTGCTTACGATGACTAACATGGACCCTGTGGATACTGCAACCTATTACTGTGCTCGAATCCCTGGTTATGGCGGAAATGGGGACTACCACTACTACGGTATGGATGTCTGGGGCCAAGGGACCACGGTTACTGTTTCAAGCGGAGGGGGAGGGAGTGGGGGTGGCGGATCTGGCGGAGGAGGCAGCGATATCCAGATGACGCAGTCCCCTAGTTCACTTTCCGCATCCCTGGGGGATCGGGTTACCATTACATGCCGCGCGTCACAGGGTATCCGGAATGATCTGGGATGGTACCAGCAGAAGCCGGGAAAGGCTCCTAAGCGCCTCATCTACGCCAGCTCCACCCTGCAGAGTGGAGTGCCCTCCCGGTTTTCAGGCAGTGGCTCCGGTACGGAGTTTACTCTTACAATTAGCAGCCTGCAGCCAGAAGATTTTGCAACTTACTACTGTTTGCAGCATAATAATTTCCCCTGGACCTTTGGTCAGGGCACCAAGGTGGAGATCAAAAGAGCAGCCGCCATCGAAGTAATGTATCCCCCCCCGTACCTTGACAATGAGAAGTCAAATGGAACCATTATCCATGTTAAGGGCAAACACCTCTGCCCTTCTCCACTGTTCCCTGGCCCTAGTAAGCCGTTTTGGGTGCTGGTGGTAGTCGGTGGGGTGCTGGCTTGTTACTCTCTTCTCGTGACCGTCGCCTTTATAATCTTTTGGGTCAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 61)
構築體10E3 CD28 AA (信號序列為粗體;CDR加底線)
MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLI
NARMGVSWIRQPPGKALEWLA
HIFSNAEKSYRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCAR
IPGYGGNGDYHYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITC
RASQGIRNDLGWYQQKPGKAPKRLIY
ASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYC
LQHNNFPWTFGQGTKVEIKRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 62)
構築體10E3 CD28T DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAAGTTACTTTGAAGGAGTCTGGACCTGTACTGGTGAAGCCAACCGAGACACTGACACTCACGTGTACAGTGAGTGGTTTTTCCTTGATCAACGCAAGGATGGGCGTCAGCTGGATCAGGCAACCCCCTGGCAAGGCTCTGGAATGGCTCGCTCACATATTCAGCAATGCCGAAAAAAGCTACCGGACAAGCCTGAAATCCCGCCTGACTATTTCCAAGGACACTTCTAAGTCTCAGGTGGTGCTGACCATGACCAACATGGACCCGGTGGACACCGCCACCTATTACTGCGCAAGAATCCCTGGGTATGGTGGGAATGGTGACTACCATTATTATGGGATGGATGTGTGGGGGCAAGGCACAACCGTAACGGTCTCAAGCGGTGGGGGAGGCTCAGGGGGCGGAGGCTCCGGAGGTGGCGGCTCCGACATTCAGATGACCCAAAGCCCGTCCAGCCTGTCCGCCAGCCTGGGAGATAGAGTGACAATCACGTGTAGAGCTTCCCAAGGGATAAGAAATGATCTCGGGTGGTATCAGCAGAAGCCCGGCAAAGCCCCCAAAAGGCTTATATATGCTAGTAGTACACTGCAGTCTGGAGTTCCTTCCCGATTTTCAGGTAGCGGCTCCGGTACAGAGTTCACCCTCACGATAAGCTCACTCCAGCCTGAGGATTTCGCAACGTACTACTGCCTCCAGCACAACAATTTTCCCTGGACTTTCGGCCAGGGCACCAAGGTGGAGATCAAGAGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 63)
構築體10E3 CD28T AA (信號序列為粗體;CDR加底線)
MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLI
NARMGVSWIRQPPGKALEWLA
HIFSNAEKSYRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCAR
IPGYGGNGDYHYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITC
RASQGIRNDLGWYQQKPGKAPKRLIY
ASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYC
LQHNNFPWTFGQGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 64)
構築體10E3 CD8 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTGACACTCAAGGAATCAGGGCCCGTACTGGTGAAACCTACTGAGACCCTGACACTGACTTGCACCGTGTCTGGGTTCTCTCTGATTAACGCTCGAATGGGTGTGAGTTGGATACGCCAGCCTCCAGGGAAGGCTCTGGAGTGGTTGGCCCACATTTTCTCCAACGCCGAGAAGAGCTACAGGACTAGTCTGAAGTCCAGACTTACCATTTCCAAAGACACAAGTAAATCACAGGTGGTGCTGACAATGACAAACATGGACCCGGTTGATACTGCTACCTATTATTGTGCCCGCATTCCCGGCTACGGCGGCAATGGCGACTATCACTATTATGGTATGGATGTCTGGGGGCAGGGGACCACTGTTACCGTGTCCAGCGGGGGTGGTGGCAGCGGAGGTGGAGGGAGCGGTGGTGGGGGGAGTGATATTCAGATGACCCAGAGCCCTAGCTCTCTTTCCGCTTCTCTGGGCGATAGAGTCACCATCACCTGCCGGGCCTCTCAAGGCATCCGGAACGATCTTGGATGGTATCAGCAGAAGCCCGGCAAGGCACCAAAAAGGCTGATCTACGCATCAAGCACCCTGCAATCTGGGGTGCCGTCCCGGTTTTCTGGTTCTGGTAGTGGGACCGAGTTTACTCTGACTATTTCTTCCCTGCAGCCTGAGGACTTTGCTACGTACTATTGTCTGCAGCATAACAACTTCCCCTGGACGTTCGGGCAGGGTACGAAAGTGGAAATTAAGCGCGCCGCCGCCCTGTCCAACTCCATTATGTATTTCTCTCATTTTGTCCCAGTGTTCCTGCCCGCTAAACCCACAACTACTCCGGCGCCCCGACCGCCAACTCCCGCACCTACCATCGCAAGCCAGCCATTGAGCCTCCGACCTGAGGCATGTAGACCAGCAGCCGGCGGTGCCGTGCACACAAGGGGACTGGATTTCGCCTGCGACATATATATTTGGGCCCCTCTGGCTGGAACCTGTGGGGTTCTGCTGCTCTCTCTCGTTATTACACTGTATTGCAATCATCGCAATAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 65)
構築體10E3 CD8 AA (信號序列為粗體;CDR加底線)
MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLI
NARMGVSWIRQPPGKALEWLA
HIFSNAEKSYRTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCAR
IPGYGGNGDYHYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITC
RASQGIRNDLGWYQQKPGKAPKRLIY
ASSTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYC
LQHNNFPWTFGQGTKVEIKRAAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 66)
構築體8B5 CD28 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGATCCAGTTGGTGGAATCAGGGGGCGGTGTGGTGCAGCCGGGTAGGAGCCTGAGACTGTCATGCGTGGCGTCTGGCTTCACATTCAAGAACTACGGCATGCACTGGGTGCGACAGGCCCCCGGAAAGGGTTTGGAGTGGGTCGCCGTGATCTGGTACGACGGATCTAATGAGTATTACGGAGATCCTGTGAAGGGAAGGTTCACCATCTCCCGCGACAATAGCAAAAATATGCTCTACCTGCAAATGAACTCACTCAGGGCGGATGATACGGCGGTCTACTATTGCGCTCGCTCAGGGATTGCTGTGGCCGGCGCATTCGATTACTGGGGACAGGGTACCCTGGTGACAGTATCAAGCGGAGGCGGCGGCTCTGGCGGCGGCGGATCTGGCGGGGGGGGAAGTGAGATTGTGTTGACACAGTCTCCCGATACCCTGTCACTGTCACCCGGCGAGAAGGCAACGCTGAGTTGCAGAGCAAGCCAGTCAGTCTCCTCTTCTTTTCTGGCCTGGTATCAGCAAAAACCAGGTCAGGCACCATCTCTCCTGATTTACGTTGCCAGCAGACGGGCGGCTGGCATTCCCGACAGGTTCTCTGGAAGCGGATCTGGGACCGATTTTACCCTGACAATTAGCCGCTTGGAGCCCGAAGACTTTGGTATGTTTTACTGCCAGCACTACGGAAGGACACCTTTCACATTTGGCCCGGGCACGAAAGTCGATATAAAACGCGCAGCCGCCATTGAAGTAATGTACCCACCACCTTATTTGGACAATGAAAAGTCCAATGGTACCATTATTCACGTCAAGGGAAAGCATCTCTGTCCAAGCCCTCTGTTCCCCGGCCCCTCCAAACCATTCTGGGTGCTGGTGGTCGTCGGCGGAGTTCTGGCCTGCTATTCTCTGCTCGTGACTGTTGCATTCATCATTTTCTGGGTGAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 67)
構築體8B5 CD28 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQIQLVESGGGVVQPGRSLRLSCVASGFTFKNYGMHWVRQAPGKGLEWVAVIWYDGSNEYYGDPVKGRFTISRDNSKNMLYLQMNSLRADDTAVYYCARSGIAVAGAFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPDTLSLSPGEKATLSCRASQSVSSSFLAWYQQKPGQAPSLLIYVASRRAAGIPDRFSGSGSGTDFTLTISRLEPEDFGMFYCQHYGRTPFTFGPGTKVDIKRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 68)
構築體8B5 CD28T DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGATTCAGCTCGTGGAGTCAGGTGGTGGCGTGGTTCAGCCCGGACGGTCCCTGCGACTCTCTTGTGTGGCAAGCGGATTTACCTTTAAGAACTATGGCATGCACTGGGTGAGGCAGGCCCCTGGAAAAGGACTGGAGTGGGTTGCTGTGATCTGGTACGACGGGTCCAACGAATATTATGGCGATCCTGTGAAGGGACGGTTTACAATCTCACGCGATAACTCAAAGAACATGCTGTACCTGCAAATGAACTCTCTGCGCGCTGATGACACTGCCGTGTATTATTGCGCTCGGAGTGGTATCGCCGTCGCAGGAGCATTTGATTATTGGGGGCAAGGGACCCTCGTGACAGTGAGTTCCGGAGGGGGAGGTTCTGGTGGAGGCGGCTCTGGTGGGGGAGGCAGCGAGATCGTTCTGACCCAGTCTCCTGACACACTGTCACTGTCCCCTGGTGAAAAGGCCACACTGTCTTGTAGAGCGTCCCAGAGCGTTTCCAGTTCCTTCCTTGCATGGTATCAACAAAAACCCGGGCAGGCTCCAAGCTTGCTGATCTACGTGGCCAGCCGCCGGGCCGCAGGCATCCCTGATAGGTTTAGCGGTTCTGGGAGCGGGACGGACTTCACCTTGACAATATCACGGCTGGAACCCGAAGACTTCGGAATGTTTTATTGCCAGCACTACGGAAGAACTCCATTCACCTTTGGCCCGGGAACGAAGGTAGACATCAAGAGAGCAGCAGCCCTCGACAACGAGAAATCCAATGGAACCATTATCCATGTGAAGGGGAAACATCTCTGCCCTTCACCATTGTTCCCTGGACCCAGCAAGCCTTTTTGGGTTCTGGTCGTGGTGGGGGGCGTCCTGGCTTGTTACTCCCTCCTCGTTACAGTCGCCTTCATAATCTTTTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 69)
構築體8B5 CD28T AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQIQLVESGGGVVQPGRSLRLSCVASGFTFKNYGMHWVRQAPGKGLEWVAVIWYDGSNEYYGDPVKGRFTISRDNSKNMLYLQMNSLRADDTAVYYCARSGIAVAGAFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPDTLSLSPGEKATLSCRASQSVSSSFLAWYQQKPGQAPSLLIYVASRRAAGIPDRFSGSGSGTDFTLTISRLEPEDFGMFYCQHYGRTPFTFGPGTKVDIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 70)
構築體8B5 CD8 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGATACAGCTTGTCGAATCCGGTGGCGGGGTGGTGCAGCCTGGACGCAGCCTGCGGCTTTCTTGCGTGGCCAGCGGATTTACCTTCAAGAACTACGGGATGCATTGGGTCCGCCAGGCACCCGGCAAAGGCCTTGAGTGGGTTGCAGTGATCTGGTACGACGGCAGTAACGAGTATTATGGCGACCCCGTGAAGGGAAGGTTTACTATTTCAAGAGATAATAGTAAGAACATGTTGTATCTGCAAATGAACAGTCTGAGAGCGGACGACACTGCCGTGTACTACTGTGCTCGCTCCGGCATCGCTGTGGCAGGGGCCTTTGACTACTGGGGTCAGGGGACGCTGGTCACGGTTAGTTCCGGGGGCGGTGGTTCCGGAGGAGGCGGTTCCGGCGGCGGCGGATCAGAAATCGTTCTTACTCAGAGTCCCGATACGCTGTCCTTGTCTCCGGGAGAAAAAGCCACACTGAGCTGCCGAGCCTCACAGTCAGTAAGTTCTTCATTCCTCGCCTGGTACCAGCAAAAACCGGGGCAGGCCCCTTCCCTGCTTATCTACGTGGCCTCTAGGAGAGCCGCCGGTATTCCTGACCGGTTCAGCGGAAGTGGTTCCGGGACTGATTTTACGCTCACGATCTCCCGATTGGAGCCCGAGGATTTCGGGATGTTCTACTGTCAGCATTATGGAAGAACGCCCTTTACCTTCGGTCCGGGAACTAAGGTTGATATTAAGCGGGCTGCTGCCCTTAGCAACTCCATCATGTATTTTTCTCACTTCGTGCCAGTATTCCTGCCAGCCAAACCGACCACAACCCCAGCACCTAGACCTCCTACTCCCGCTCCCACCATAGCTTCACAGCCGCTGAGTTTGAGGCCAGAGGCCTGTCGGCCTGCTGCAGGCGGAGCAGTTCACACCAGGGGACTTGACTTTGCATGTGACATCTATATTTGGGCTCCACTGGCGGGAACCTGCGGGGTGCTCCTTTTGTCACTCGTTATCACACTGTATTGCAATCATAGGAATAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 71)
構築體8B5 CD8 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQIQLVESGGGVVQPGRSLRLSCVASGFTFKNYGMHWVRQAPGKGLEWVAVIWYDGSNEYYGDPVKGRFTISRDNSKNMLYLQMNSLRADDTAVYYCARSGIAVAGAFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPDTLSLSPGEKATLSCRASQSVSSSFLAWYQQKPGQAPSLLIYVASRRAAGIPDRFSGSGSGTDFTLTISRLEPEDFGMFYCQHYGRTPFTFGPGTKVDIKRAAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 72)
構築體4E9 CD28 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGCAGAGTGGGGCAGAAGTAAAGAAGCCTGGTGCCTCTGTCAAAGTTAGTTGCAAAGCATCTGGGTATACTTTCACCGGTTACTATATCCATTGGGTTCGGCAGGCCCCGGAGCAGGGACTGGAGTGGATGGGCTGGATCAACCCAAATTCAGGCGGCACTAACTATGCTCAAAAGTTCCAGGGCAGGGTCACAATGGCCCGGGATACTTCAATTAGCACCGTCTATATGGATCTTAGTCGGCTGCGCAGTGACGATACCGCTGTCTACTATTGCGCAAGGATCAGGGGCGGCAATTCTGTTTTTGACTATTGGGGCCAGGGAACACTGGTGACCGTCTCCTCTGGTGGAGGCGGTAGTGGTGGAGGCGGGTCCGGAGGAGGGGGCTCCGATATAGTGATGACTCAAAGTCCCGATAGCTTGGCAGTATCTCTTGGGGAACGCGCCACTATTAACTGTAAATCCACCCAGTCCATTCTCTATACCTCTAACAACAAGAATTTCCTCGCGTGGTATCAGCAAAAACCCGGGCAGCCACCTAAACTGCTTATATCCTGGGCCAGCATCAGGGAGTCCGGCGTCCCTGATCGGTTCAGCGGTAGTGGCAGCGGGACAGACTTCGCTCTGACCATCAGTAGCCTCCAGGCTGAAGATGTCGCAGTGTATTATTGCCAGCAGTACTTCAGCACGATGTTTAGCTTCGGGCAGGGAACCAAGCTGGAAATAAAGAGAGCTGCAGCAATCGAGGTGATGTACCCACCTCCATATCTGGACAATGAAAAGTCCAATGGCACTATCATACACGTGAAGGGCAAACACCTGTGTCCATCTCCACTTTTCCCGGGCCCGTCTAAACCTTTCTGGGTGCTGGTGGTGGTGGGCGGAGTTCTGGCCTGTTATTCACTGCTGGTCACCGTGGCTTTCATCATTTTTTGGGTAAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 73)
構築體4E9 CD28 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPEQGLEWMGWINPNSGGTNYAQKFQGRVTMARDTSISTVYMDLSRLRSDDTAVYYCARIRGGNSVFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSTQSILYTSNNKNFLAWYQQKPGQPPKLLISWASIRESGVPDRFSGSGSGTDFALTISSLQAEDVAVYYCQQYFSTMFSFGQGTKLEIKRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 74)
構築體4E9 CD28T DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTACAGCTGGTGCAGAGCGGGGCCGAGGTCAAAAAGCCCGGGGCTTCAGTTAAGGTTAGCTGCAAGGCTTCCGGCTACACCTTTACCGGTTACTATATTCACTGGGTTAGACAGGCACCTGAGCAAGGACTGGAGTGGATGGGGTGGATTAACCCCAATAGCGGTGGGACCAACTACGCCCAGAAGTTTCAAGGCCGAGTGACAATGGCACGAGACACCTCCATTTCCACTGTGTACATGGACTTGAGCCGCCTCAGGTCAGACGACACCGCAGTGTACTACTGTGCGCGAATCCGCGGCGGAAACAGCGTGTTTGACTACTGGGGTCAGGGCACGTTGGTGACCGTGTCTTCCGGAGGGGGGGGATCTGGTGGCGGGGGCTCCGGCGGAGGCGGTAGTGATATTGTGATGACTCAGTCACCGGACAGTCTTGCTGTTTCACTTGGTGAGAGGGCCACCATAAATTGTAAAAGCACCCAGAGCATTCTCTACACATCTAACAACAAAAATTTCCTGGCCTGGTACCAGCAGAAGCCCGGACAGCCACCCAAATTGCTGATTAGCTGGGCCAGCATTCGAGAATCTGGGGTTCCGGACCGCTTTTCCGGGTCTGGCTCTGGGACCGACTTCGCTTTGACCATAAGCTCTCTTCAGGCCGAAGACGTCGCAGTATACTATTGTCAACAGTATTTTTCTACCATGTTTTCCTTCGGCCAGGGAACTAAGTTGGAGATCAAGAGAGCAGCTGCATTGGATAATGAGAAGTCCAATGGCACTATTATCCACGTGAAAGGTAAACACCTGTGTCCCTCACCCCTGTTTCCAGGACCTAGTAAACCATTCTGGGTCTTGGTTGTAGTCGGGGGCGTTTTGGCATGTTATTCCCTTCTTGTGACAGTCGCCTTTATCATTTTCTGGGTGAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 75)
構築體4E9 CD28T AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPEQGLEWMGWINPNSGGTNYAQKFQGRVTMARDTSISTVYMDLSRLRSDDTAVYYCARIRGGNSVFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSTQSILYTSNNKNFLAWYQQKPGQPPKLLISWASIRESGVPDRFSGSGSGTDFALTISSLQAEDVAVYYCQQYFSTMFSFGQGTKLEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 76)
構築體4E9 CD8 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAAGTTCAGCTTGTGCAGAGCGGAGCTGAGGTGAAAAAACCAGGCGCCTCCGTTAAGGTGTCTTGCAAAGCCAGCGGATACACATTTACCGGGTACTATATTCACTGGGTGAGGCAGGCCCCTGAACAGGGCCTTGAATGGATGGGGTGGATCAATCCAAATTCCGGGGGAACCAATTATGCTCAGAAATTTCAGGGCAGAGTGACAATGGCCAGGGACACCTCAATCAGCACAGTCTACATGGACCTGAGCCGCCTGAGGTCTGATGACACAGCCGTCTACTACTGTGCCCGGATCAGAGGGGGAAACAGTGTCTTCGACTATTGGGGGCAGGGAACCCTGGTGACTGTCTCCTCCGGGGGAGGGGGTAGCGGGGGAGGCGGCAGCGGCGGGGGTGGTTCTGACATTGTTATGACCCAATCCCCAGACTCTCTGGCCGTGAGCCTGGGTGAGAGAGCCACCATCAATTGCAAGTCCACCCAGAGCATACTCTATACGTCAAACAATAAGAATTTCCTGGCGTGGTATCAGCAAAAGCCGGGTCAACCACCCAAGTTGTTGATTAGCTGGGCATCAATTCGAGAATCTGGCGTCCCTGATAGGTTTAGCGGGAGCGGTAGTGGAACCGACTTTGCGCTGACCATTTCATCCCTTCAGGCAGAGGACGTGGCTGTGTATTACTGTCAACAGTACTTCAGCACGATGTTTTCTTTCGGCCAGGGGACGAAGCTGGAGATAAAGCGGGCCGCAGCACTCAGCAACAGCATCATGTACTTTTCTCATTTCGTCCCAGTTTTTCTCCCCGCCAAACCCACCACTACCCCTGCTCCTAGGCCTCCCACTCCCGCACCCACCATTGCTTCCCAACCTCTGTCATTGAGGCCCGAAGCCTGCAGACCTGCCGCAGGAGGGGCTGTGCACACCCGCGGTCTGGATTTTGCTTGTGATATCTACATTTGGGCCCCTTTGGCCGGAACCTGCGGAGTGTTGTTGCTGAGCCTTGTTATCACGTTGTACTGTAATCACAGAAACAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 77)
構築體4E9 CD8 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPEQGLEWMGWINPNSGGTNYAQKFQGRVTMARDTSISTVYMDLSRLRSDDTAVYYCARIRGGNSVFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSTQSILYTSNNKNFLAWYQQKPGQPPKLLISWASIRESGVPDRFSGSGSGTDFALTISSLQAEDVAVYYCQQYFSTMFSFGQGTKLEIKRAAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 78)
構築體11F11 CD28 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTGCAGCTCCAAGAGTCAGGACCAGGACTTGTCAAACCAAGCCAGACCCTCAGCCTTACCTGCACCGTCAGCGGGGGCTCCATCAGCTCTGGGGCTTACTACTGGACATGGATACGACAGCATCCCGGTAAAGGTCTGGAGTGGATCGGGTACATACACTATAGTGGTTCCACATATTCTAATCCATCTCTTAAGAGTCGAATTACAATTTCACTCGATACTTCAAAGAATCAGTTCAGCTTGAAACTGAACTCCGTGACCGCGGCTGACACCGCCGTGTACTACTGTGCACGCCAAGAGGATTATGGCGGACTGTTCGATTATTGGGGGCAGGGAACTCTCGTGACAGTGAGCTCCGGCGGGGGCGGCAGCGGTGGGGGTGGAAGTGGTGGAGGGGGCAGCGAGATCGTGATGACCCAGAGTCCTGCCACACTGTCAGTGAGTCCTGGGGAGCGAATCACACTTTCCTGTCGAGCGTCTCAGTCCGTGACCACGGACCTGGCGTGGTACCAGCAGATGCCAGGCCAGGCGCCAAGACTCCTGATCTACGACGCTTCTACCCGCGCTACTGGTTTCCCCGCCAGATTCTCCGGAAGCGGGTCCGGGACGGATTTTACACTTACCATCTCTTCATTGCAGGCTGAGGATTTTGCCGTGTACTACTGTCAGCATTACAAAACCTGGCCCCTCACTTTCGGGGGCGGAACAAAAGTGGAAATTAAACGGGCAGCAGCTATTGAGGTGATGTACCCACCCCCCTACCTGGACAACGAGAAATCCAATGGCACCATCATCCACGTTAAGGGTAAGCACTTGTGTCCCTCACCACTCTTCCCTGGGCCTAGCAAGCCATTCTGGGTCCTGGTGGTCGTGGGAGGCGTGCTGGCCTGCTATTCCCTCCTGGTTACCGTTGCCTTTATCATATTTTGGGTCAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 79)
構築體11F11 CD28 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQTLSLTCTVSGGSISSGAYYWTWIRQHPGKGLEWIGYIHYSGSTYSNPSLKSRITISLDTSKNQFSLKLNSVTAADTAVYYCARQEDYGGLFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERITLSCRASQSVTTDLAWYQQMPGQAPRLLIYDASTRATGFPARFSGSGSGTDFTLTISSLQAEDFAVYYCQHYKTWPLTFGGGTKVEIKRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 80)
構築體11F11_CD28T_DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTGCAGTTGCAGGAGAGCGGGCCAGGCCTGGTGAAGCCCAGCCAAACACTGAGCCTCACCTGTACTGTGTCCGGTGGTAGCATTTCCAGCGGGGCGTATTATTGGACATGGATACGCCAACACCCTGGAAAAGGGTTGGAGTGGATTGGATACATCCATTATTCTGGGTCCACCTATAGTAACCCTTCTCTCAAGTCTCGCATTACTATTAGTTTGGATACCTCTAAGAATCAGTTTAGTCTGAAGCTGAACAGTGTAACCGCCGCCGACACCGCGGTCTACTACTGTGCTAGGCAGGAGGATTACGGGGGACTGTTCGATTACTGGGGCCAGGGGACATTGGTCACCGTTTCAAGCGGGGGCGGCGGATCTGGCGGAGGGGGATCTGGAGGCGGAGGCTCTGAGATCGTAATGACTCAGAGCCCAGCCACCCTGTCCGTCTCTCCCGGCGAACGCATCACTCTGAGCTGTAGGGCATCACAGTCTGTTACCACAGATCTGGCTTGGTATCAACAAATGCCTGGGCAGGCCCCGCGACTGTTGATTTATGACGCCTCTACGCGGGCCACAGGATTTCCTGCCCGGTTCTCCGGGTCTGGTTCTGGCACCGATTTTACCTTGACAATCAGTAGCTTGCAGGCAGAAGATTTCGCTGTGTATTACTGCCAACATTATAAGACATGGCCTTTGACATTCGGCGGGGGAACCAAAGTGGAGATCAAACGCGCCGCAGCCCTGGACAATGAGAAGTCTAATGGGACCATCATTCACGTCAAAGGGAAACACCTGTGCCCCTCTCCTCTGTTCCCAGGCCCTTCTAAGCCCTTCTGGGTTCTCGTGGTGGTGGGCGGTGTCCTGGCCTGCTATTCCCTTCTTGTGACAGTGGCCTTTATCATTTTTTGGGTGAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 81)
構築體11F11 CD28T AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQTLSLTCTVSGGSISSGAYYWTWIRQHPGKGLEWIGYIHYSGSTYSNPSLKSRITISLDTSKNQFSLKLNSVTAADTAVYYCARQEDYGGLFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERITLSCRASQSVTTDLAWYQQMPGQAPRLLIYDASTRATGFPARFSGSGSGTDFTLTISSLQAEDFAVYYCQHYKTWPLTFGGGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 82)
構築體11F11 CD8 DNA (信號序列為粗體)
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCGCAGGTACAGTTGCAGGAAAGCGGCCCCGGCCTTGTAAAACCAAGCCAGACTCTCAGTTTGACTTGCACCGTCTCAGGAGGAAGCATTTCCAGTGGGGCTTATTATTGGACTTGGATTCGGCAGCATCCTGGGAAAGGGTTGGAATGGATCGGTTATATTCATTATAGCGGTAGCACCTATTCCAATCCGTCTTTGAAAAGCAGAATCACTATTTCACTCGACACCTCTAAGAACCAGTTCAGTCTCAAACTGAACTCCGTGACAGCGGCCGACACAGCTGTGTACTACTGTGCACGGCAAGAAGATTATGGGGGGCTGTTCGATTATTGGGGCCAAGGCACACTGGTGACAGTATCAAGCGGTGGAGGAGGCTCCGGGGGCGGAGGAAGTGGAGGCGGGGGGAGCGAAATTGTGATGACCCAGTCTCCAGCCACGCTGTCAGTGTCTCCGGGAGAACGCATAACCCTCTCCTGCCGGGCCAGTCAGTCCGTCACGACCGATTTGGCTTGGTATCAACAGATGCCTGGGCAGGCCCCCCGCTTGCTGATCTATGACGCCTCCACCAGAGCAACTGGTTTCCCCGCCCGGTTCAGCGGATCTGGAAGCGGTACAGATTTTACACTTACCATCTCATCATTGCAAGCTGAGGATTTTGCCGTGTACTACTGCCAGCACTACAAGACCTGGCCTTTGACGTTCGGCGGCGGAACAAAAGTGGAGATTAAAAGAGCCGCTGCCCTCAGTAACTCAATCATGTACTTTAGTCACTTTGTGCCTGTGTTTCTGCCAGCAAAGCCAACAACCACACCAGCACCCCGCCCTCCAACGCCTGCCCCAACCATCGCCTCCCAGCCTCTGAGCTTGAGGCCTGAGGCTTGTCGCCCAGCTGCTGGAGGTGCTGTGCATACACGAGGACTGGATTTCGCCTGCGATATCTATATCTGGGCACCACTTGCCGGTACTTGTGGTGTGTTGCTGCTCTCACTGGTCATCACGCTGTACTGTAACCATAGGAATAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCCGAGTGAAATTTTCTAGATCAGCTGATGCTCCCGCCTATCAGCAGGGACAGAATCAACTTTACAATGAGCTGAACCTGGGTCGCAGAGAAGAGTACGACGTTTTGGACAAACGCCGGGGCCGAGATCCTGAGATGGGGGGGAAGCCGAGAAGGAAGAATCCTCAAGAAGGCCTGTACAACGAGCTTCAAAAAGACAAAATGGCTGAGGCGTACTCTGAGATCGGCATGAAGGGCGAGCGGAGACGAGGCAAGGGTCACGATGGCTTGTATCAGGGCCTGAGTACAGCCACAAAGGACACCTATGACGCCCTCCACATGCAGGCACTGCCCCCACGCTAG(SEQ ID NO: 83)
構築體11F11 CD8 AA (信號序列為粗體)
MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQTLSLTCTVSGGSISSGAYYWTWIRQHPGKGLEWIGYIHYSGSTYSNPSLKSRITISLDTSKNQFSLKLNSVTAADTAVYYCARQEDYGGLFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERITLSCRASQSVTTDLAWYQQMPGQAPRLLIYDASTRATGFPARFSGSGSGTDFTLTISSLQAEDFAVYYCQHYKTWPLTFGGGTKVEIKRAAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 84)
人類FLT3 NM_004119 AA
MPALARDGGQLPLLVVFSAMIFGTITNQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNISFYATIGVCLLFIVVLTLLICHKYKKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYDLKWEFPRENLEFGKVLGSGAFGKVMNATAYGISKTGVSIQVAVKMLKEKADSSEREALMSELKMMTQLGSHENIVNLLGACTLSGPIYLIFEYCCYGDLLNYLRSKREKFHRTWTEIFKEHNFSFYPTFQSHPNSSMPGSREVQIHPDSDQISGLHGNSFHSEDEIEYENQKRLEEEEDLNVLTFEDLLCFAYQVAKGMEFLEFKSCVHRDLAARNVLVTHGKVVKICDFGLARDIMSDSNYVVRGNARLPVKWMAPESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYKLIQNGFKMDQPFYATEEIYIIMQSCWAFDSRKRPSFPNLTSFLGCQLADAEEAMYQNVDGRVSECPHTYQNRRPFSREMDLGLLSPQAQVEDS (SEQ ID NO: 85)
CAR信號肽DNA
ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCCCG (SEQ ID NO: 86)
CAR信號肽: MALPVTALLLPLALLLHAARP (SEQ ID NO: 87)
scFv G4S連接子DNA
GGCGGTGGAGGCTCCGGAGGGGGGGGCTCTGGCGGAGGGGGCTCC (SEQ ID NO: 88)
scFv G4s連接子:GGGGSGGGGSGGGGS (SEQ ID NO: 89)
scFv Whitlow連接子DNA
GGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGG (SEQ ID NO: 90)
scFv Whitlow連接子: GSTSGSGKPGSGEGSTKG (SEQ ID NO: 91)
4-1BB核酸序列(細胞內域)
AAGCGCGGCAGGAAGAAGCTCCTCTACATTTTTAAGCAGCCTTTTATGAGGCCCGTACAGACAACACAGGAGGAAGATGGCTGTAGCTGCAGATTTCCCGAGGAGGAGGAAGGTGGGTGCGAGCTG(SEQ ID NO: 92)
4-1BB AA (細胞內域)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO: 93)
OX40 AA
RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI (SEQ ID NO: 94)
以引用方式併入
本說明書中提及之所有公開案、專利及專利申請案均以引用之方式併入本文,達到如同明確及個別地指示將各個個別公開案、專利或專利申請案以引用之方式併入的相同程度。然而,本文對參考文獻之引用不應解釋為承認此類參考文獻為本發明之先前技術。在以引用之方式併入的參考文獻中所提供之任何定義或術語與在本文中所提供之術語及討論不同的情況下,以本發明術語及定義為準。
等同物
認為前述書面說明係足以能夠使熟習此項技術者來實踐本發明。前述描述及實例詳述本發明之某些較佳實施例,且描述由發明人所考慮的最佳模式。然而,應當理解,無論前述以文本形式表現得如何詳細,本發明仍可以許多方式實踐,且應根據隨附申請專利範圍及其任何等同物解釋本發明。
僅出於說明目的提供以下實例(包括進行之實驗及達成之結果)且其不欲解釋為限制本發明。
實例 1
將Namalwa、MV4;11、及HL60細胞(ATCC)以及EoL1細胞(Sigma-Aldrich)培養於RPMI1640 (Lonza) + 10% FBS (Corning) + 1X青黴素鏈黴素L-麩醯胺(Corning) (R10)培養基中,且維持在0.5至2.0 x 106個細胞/ml之細胞密度。為了檢查細胞表面FLT3表現,將細胞在4℃下用抗FLT3抗體(BD Pharmingen)或IgG1同型對照抗體(BD Pharmingen)於染色緩衝液(BD Pharmingen)中培育30分鐘。然後將細胞洗滌且重懸浮於具有碘化丙啶(BD Pharmingen)之染色緩衝液中,之後進行數據收集。靶細胞上之FLT3表現顯示於圖1中。
實例 2
藉由用EcoRI及BamHI (NEB)隔夜消化10 µg DNA,將編碼T7啟動子、CAR構築體、及β球蛋白穩定序列之質體線性化。然後將DNA在50℃下用經苯酚/氯仿純化之蛋白酶K (Thermo Fisher, 600 U/ml)消化2小時,且藉由加入乙酸鈉及兩體積的乙醇來沉澱。然後將團塊乾燥,重懸浮於不含RNAse/DNAse的水中,且使用NanoDrop定量。然後按照製造商的說明書,使用mMESSAGE mMACHINE T7 Ultra (Thermo Fisher)將1 µg線性DNA用於體外轉錄。將RNA按照製造商的說明書使用MEGAClear Kit (Thermo Fisher)進一步純化,且使用NanoDrop定量。使用在瓊脂糖凝膠上的遷移率評估mRNA完整性。根據製造商的說明書,使用ficoll-paque密度離心從健康供體leukopak (Hemacare)中分離PBMC。在R10培養基+ IL-2 (300 IU/ml, Proleukin®, Prometheus® Therapeutics and Diagnostics)中使用OKT3 (50 ng/ml, Miltenyi Biotec)刺激PBMC。刺激後7天,將T細胞在Opti-MEM培養基(Thermo Fisher Scientific)中洗滌兩次,且以2.5x107個細胞/ml之最終濃度重懸浮於Opti-MEM培養基中。每次電穿孔使用10 µg mRNA。使用Gemini X2系統(Harvard Apparatus BTX)執行細胞之電穿孔以在2 mm光析管(Harvard Apparatus BTX)中傳遞單個400 V脈衝持續0.5 ms。將細胞立即轉移至R10 + IL-2培養基,且使其恢復6小時。為了檢查CAR表現,將T細胞在4℃下在染色緩衝液(BD Pharmingen)中用FLT-=3-HIS (Sino Biological公司)或生物素化蛋白L (Thermo Scientific)染色30分鐘。然後將細胞洗滌,且在4℃下在染色緩衝液中用抗HIS-PE (Miltenyi Biotec)或PE鏈黴抗生物素蛋白(BD Pharmingen)染色30分鐘。然後將細胞洗滌且重懸浮於具有碘化丙啶(BD Pharmingen)之染色緩衝液中,之後進行數據收集。經電穿孔之T細胞中FLT3 CAR之表現顯示於圖2中。
實例 3
為了檢查經電穿孔之FLT3 CAR T細胞中的溶細胞活性,將效應細胞與靶細胞以1:1 E:T比率培養於R10培養基中。共培養後16小時,藉由Luminex (EMD Millipore)分析上澄液,且藉由流動式細胞測量術分析CD3-陰性細胞之碘化丙啶(PI)攝取評估靶細胞活力。經電穿孔之CAR T細胞之溶細胞活性顯示於圖3中,且細胞介素產生顯示於圖4中。
實例 4
將含有不同CAR構築體之第三代慢病毒轉移載體連同ViraPower Lentiviral Packaging Mix (Life Technologies)一起使用以產生慢病毒上澄液。簡言之,藉由將15 µg DNA及22.5 µl聚乙烯亞胺(polyethileneimine) (Polysciences, 1 mg/ml)在600 µl OptiMEM培養基中混合來產生轉染混合物。在室溫下,將混合物培育5分鐘。同時,對293T細胞(ATCC)進行胰蛋白酶消化、計數,且將總計10x106個總細胞連同轉染混合物一起鋪板於T75燒瓶中。轉染後三天,將上澄液收集且透過0.45 µm過濾器過濾,且在-80℃下儲存直至使用。根據製造商的說明書,使用ficoll-paque密度離心從健康供體leukopak (Hemacare)中分離PBMC。在R10培養基+ IL-2 (300 IU/ml, Proleukin®, Prometheus® Therapeutics and Diagnostics)中使用OKT3 (50 ng/ml, Miltenyi Biotec)刺激PBMC。刺激後48小時,在MOI = 10下使用慢病毒轉導細胞。將細胞維持在0.5至2.0 x 106個細胞/ml,之後用於活性分析中。為了檢查CAR表現,將T細胞在4℃下在染色緩衝液(BD Pharmingen)中用FLT-3-HIS (Sino Biological公司)或生物素化蛋白L (Thermo Scientific)染色30分鐘。然後將細胞洗滌,且在4℃下在染色緩衝液中用抗HIS-PE (Miltenyi Biotec)或PE鏈黴抗生物素蛋白(BD Pharmingen)染色30分鐘。然後將細胞洗滌且重懸浮於具有碘化丙啶(BD Pharmingen)之染色緩衝液中,之後進行數據收集。來自兩個健康供體之T細胞中FLT3 CAR之表現顯示於圖5中。
實例 5
為了檢查經慢病毒轉導之FLT3 CAR T細胞中的溶細胞活性,將效應細胞與靶細胞以1:1 E:T比率培養於R10培養基中。共培養後16小時,藉由Luminex (EMD Millipore)分析上澄液,且藉由流動式細胞測量術分析CD3-陰性細胞之碘化丙啶(PI)攝取評估靶細胞活力。來自兩個健康供體之經慢病毒轉導之CAR T細胞之平均溶細胞活性顯示於圖6中,且來自各健康供體之CAR T細胞之細胞介素產生顯示於圖7中。
實例 6
為了評估響應於表現FLT3的靶細胞之CAR T細胞增殖,將T細胞用CFSE標記,之後與靶細胞以1:1 E:T比率共培養於R10培養基中。五天後,藉由流動式細胞測量術分析CFSE稀釋物評估T細胞增殖。FLT3 CAR T細胞之增殖顯示於圖8中。
實例 7
為了檢查體內抗白血病活性,產生FLT3 CAR T細胞,以用於人類AML之異種模型中。人類AML之異種模型中所使用之各種效應細胞株(effector line)之CAR表現顯示於圖9中。將經螢光素酶標記之MV4;11細胞(2x106個/動物)靜脈內注射至5至6週齡雌性NSG小鼠中。6天後,靜脈內注射含6x106個T細胞(約50% CAR+)之200 µl PBS,且每週使用生物發光成像測量動物之腫瘤負荷(tumor burden)。如圖10中所示,注射表現10E3-CD28T及8B5-CD28T的CAR T細胞顯著減少在所有時間點檢查之之腫瘤負荷。如圖11中所示,此情況用存活分析進一步證實,其中注射表現10E3-CD28T或8B5-CD28T的CAR T細胞賦予優於接受經模擬轉導之細胞或表現10E3-CD28或10E3-CD8構築體的CAR T細胞之動物的顯著的存活優勢。就功效而言,在10E3-CD28T與8B5-CD28T構築體之間未觀察到顯著差異。
圖1繪示對人類細胞株進行的FLT3細胞表面表現之流動式細胞測量術分析。
圖2繪示用編碼各種CAR之mRNA電穿孔之原代人類T細胞中的CAR表現。
圖3繪示共培養16小時後經電穿孔之CAR T細胞相對於多種細胞株之溶細胞活性。
圖4 (包含圖3A及圖3B)繪示與所指示之靶細胞株共培養16小時後經電穿孔之CAR T細胞的IFNγ、IL-2、及TNFα產生。
圖5繪示來自兩個健康供體的經慢病毒轉導之原代人類T細胞中之CAR表現。
圖6繪示與各種靶細胞株共培養、表現所指示的CAR、來自兩個健康供體的細胞隨時間推移的平均溶細胞活性。
圖7 (包含圖7A、圖7B、及圖7C)繪示與所指示的靶細胞株共培養16小時後來自兩個健康供體之經慢病毒轉導之CAR T細胞的IFNγ、TNFα、及IL-2產生。
圖8繪示與CD3-CD28珠粒或所指示的靶細胞株共培養5天後來自兩個健康供體之經CFSE標記的慢病毒轉導之CAR T細胞之增殖。
圖9繪示用於體內研究的經慢病毒轉導之原代人類T細胞中之CAR表現。
圖10繪示將CAR T細胞靜脈內注射於異種模型中後經標記之急性骨髓性白血病細胞之生物發光成像。
圖11繪示注射CAR T細胞的小鼠之存活曲線。
圖12繪示pGAR載體圖。
<![CDATA[<110> 美商安美基公司(AMGEN INC.)]]> <![CDATA[<120> FLT3之嵌合受體及其使用方法]]> <![CDATA[<130> TW 106111460]]> <![CDATA[<150> US 62/317,219]]> <![CDATA[<151> 2016-04-01]]> <![CDATA[<160> 98 ]]> <![CDATA[<170> PatentIn 版本3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 294]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> cttgataatg aaaagtcaaa cggaacaatc attcacgtga agggcaagca cctctgtccg 60 tcacccttgt tccctggtcc atccaagcca ttctgggtgt tggtcgtagt gggtggagtc 120 ctcgcttgtt actctctgct cgtcaccgtg gcttttataa tcttctgggt tagatccaaa 180 agaagccgcc tgctccatag cgattacatg aatatgactc cacgccgccc tggccccaca 240 aggaaacact accagcctta cgcaccacct agagatttcg ctgcctatcg gagc 294 <![CDATA[<210> 2]]> <![CDATA[<211> 98]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys 1 5 10 15 His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp 20 25 30 Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val 35 40 45 Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu 50 55 60 Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr 65 70 75 80 Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr 85 90 95 Arg Ser <![CDATA[<210> 3]]> <![CDATA[<211> 90]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> cttgataatg aaaagtcaaa cggaacaatc attcacgtga agggcaagca cctctgtccg 60 tcacccttgt tccctggtcc atccaagcca 90 <![CDATA[<210> 4]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys 1 5 10 15 His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro 20 25 30 <![CDATA[<210> 5]]> <![CDATA[<211> 81]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> ttctgggtgt tggtcgtagt gggtggagtc ctcgcttgtt actctctgct cgtcaccgtg 60 gcttttataa tcttctgggt t 81 <![CDATA[<210> 6]]> <![CDATA[<211> 27]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 1 5 10 15 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 25 <![CDATA[<210> 7]]> <![CDATA[<211> 123]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> agatccaaaa gaagccgcct gctccatagc gattacatga atatgactcc acgccgccct 60 ggccccacaa ggaaacacta ccagccttac gcaccaccta gagatttcgc tgcctatcgg 120 agc 123 <![CDATA[<210> 8]]> <![CDATA[<211> 41]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 8]]> Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40 <![CDATA[<210> 9]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 9]]> agggtgaagt tttccagatc tgcagatgca ccagcgtatc agcagggcca gaaccaactg 60 tataacgagc tcaacctggg acgcagggaa gagtatgacg ttttggacaa gcgcagagga 120 cgggaccctg agatgggtgg caaaccaaga cgaaaaaacc cccaggaggg tctctataat 180 gagctgcaga aggataagat ggctgaagcc tattctgaaa taggcatgaa aggagagcgg 240 agaaggggaa aagggcacga cggtttgtac cagggactca gcactgctac gaaggatact 300 tatgacgctc tccacatgca agccctgcca cctagg 336 <![CDATA[<210> 10]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 10]]> Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 50 55 60 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 65 70 75 80 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 85 90 95 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 100 105 110 <![CDATA[<210> 11]]> <![CDATA[<211> 117]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 11]]> attgaggtga tgtatccacc gccttacctg gataacgaaa agagtaacgg taccatcatt 60 cacgtgaaag gtaaacacct gtgtccttct cccctcttcc ccgggccatc aaagccc 117 <![CDATA[<210> 12]]> <![CDATA[<211> 39]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 12]]> Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn 1 5 10 15 Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu 20 25 30 Phe Pro Gly Pro Ser Lys Pro 35 <![CDATA[<210> 13]]> <![CDATA[<211> 288]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 13]]> gctgcagcat tgagcaactc aataatgtat tttagtcact ttgtaccagt gttcttgccg 60 gctaagccta ctaccacacc cgctccacgg ccacctaccc cagctcctac catcgcttca 120 cagcctctgt ccctgcgccc agaggcttgc cgaccggccg cagggggcgc tgttcatacc 180 agaggactgg atttcgcctg cgatatctat atctgggcac ccctggccgg aacctgcggc 240 gtactcctgc tgtccctggt catcacgctc tattgtaatc acaggaac 288 <![CDATA[<210> 14]]> <![CDATA[<211> 96]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 14]]> Ala Ala Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro 1 5 10 15 Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 20 25 30 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 35 40 45 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 50 55 60 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 65 70 75 80 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn 85 90 95 <![CDATA[<210> 15]]> <![CDATA[<211> 381]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 15]]> caggtcacct tgaaggagtc tggtcctgtg ctggtgaaac ccacagagac cctcacgctg 60 acctgcaccg tctctgggtt ctcactcatc aatgctagaa tgggtgtgag ctggatccgt 120 cagcccccag ggaaggccct ggagtggctt gcacacattt tttcgaatgc cgaaaaatcg 180 tacaggacat ctctgaagag caggctcacc atctccaagg acacctccaa aagccaggtg 240 gtccttacca tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggata 300 ccaggctacg gtggtaacgg ggactaccac tactacggta tggacgtctg gggccaaggg 360 accacggtca ccgtctcctc a 381 <![CDATA[<210> 16]]> <![CDATA[<211> 127]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 16]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Ala Glu Lys Ser Tyr Arg Thr Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Pro Gly Tyr Gly Gly Asn Gly Asp Tyr His Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 17]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 17]]> Asn Ala Arg Met Gly Val Ser 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 18]]> His Ile Phe Ser Asn Ala Glu Lys Ser Tyr Arg Thr Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 19]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 19]]> Ile Pro Gly Tyr Gly Gly Asn Gly Asp Tyr His Tyr Tyr Gly Met Asp 1 5 10 15 Val <![CDATA[<210> 20]]> <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 20]]> gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctctaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct tcatccactt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagag ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataataatt tcccgtggac gttcggtcag 300 ggaacgaagg tggaaatcaa acga 324 <![CDATA[<210> 21]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 21]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 22]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 22]]> Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly 1 5 10 <![CDATA[<210> 23]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 23]]> Ala Ser Ser Thr Leu Gln Ser 1 5 <![CDATA[<210> 24]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 24]]> Leu Gln His Asn Asn Phe Pro Trp Thr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 25]]> caggtcacct tgaaggagtc tggtcctgtg ctggtgaaac ccacagagac cctcacgctg 60 acctgcaccg tctctgggtt ctcactcagg aatgctagaa tgggtgtaag ctggatccgt 120 cagcctcccg ggaaggccct ggagtggctt gcacacattt tttcgaatga cgaaaaaacc 180 tacagcacat ctctgaagag caggctcacc atctccaggg acacctccaa aggccaggtg 240 gtccttacca tgaccaagat ggaccctgtg gacacagcca catattactg tgcacggata 300 ccctactatg gttcggggag tcataactac ggtatggacg tctggggcca agggaccacg 360 gtcaccgtct cctca 375 <![CDATA[<210> 26]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 26]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Arg Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Thr Tyr Ser Thr Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Arg Asp Thr Ser Lys Gly Gln Val 65 70 75 80 Val Leu Thr Met Thr Lys Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Pro Tyr Tyr Gly Ser Gly Ser His Asn Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 27]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 27]]> Ile Pro Tyr Tyr Gly Ser Gly Ser His Asn Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> ]]>28 <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 28]]> gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggacattaga aatgatttcg gctggtatca acagaaacca 120 gggaaagccc ctcagcgcct gctctatgct gcatccactt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag tataatactt acccgtggac gttcggtcag 300 ggaacgaagg tggaaatcaa acga 324 <![CDATA[<210> 29]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 29]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Asp 20 25 30 Phe Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Arg Leu Leu 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Thr Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 30]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 30]]> Arg Ala Ser Gln Asp Ile Arg Asn Asp Phe Gly 1 5 10 <![CDATA[<210> 31]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 31]]> Ala Ala Ser Thr Leu Gln Ser 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 32]]> Leu Gln Tyr Asn Thr Tyr Pro Trp Thr 1 5 <![CDATA[<210> 33]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 33]]> cagatacaac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgtag cgtctggatt caccttcaag aactatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atttggtatg atggaagtaa tgaatactat 180 ggagaccccg tgaagggccg attcaccatc tccagagaca actccaagaa catgttgtat 240 ctgcaaatga acagcctgag agccgatgac acggctgtgt attactgtgc gaggtcggga 300 atagcagtgg ctggggcctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360 <![CDATA[<210> 34]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 34]]> Gln Ile Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Lys Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Glu Tyr Tyr Gly Asp Pro Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Ile Ala Val Ala Gly Ala Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 35]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 35]]> Val Ile Trp Tyr Asp Gly Ser Asn Glu Tyr Tyr Gly Asp Pro Val Lys 1 5 10 15 Gly <![CDATA[<210> 36]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 36]]> Ser Gly Ile Ala Val Ala Gly Ala Phe Asp Tyr 1 5 10 <![CDATA[<210> 37]]> <![CDATA[<211> 327]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 37]]> gaaattgtgt tgacgcagtc tccagacacc ctgtctttgt ctccagggga aaaagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagcttct tggcctggta ccagcagaaa 120 cctggacagg ctcccagtct cctcatctat gttgcatcca gaagggccgc tggcatccct 180 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttggaatgtt ttactgtcaa cactatggta ggacaccatt cactttcggc 300 cctgggacca aagtggatat caaacga 327 <![CDATA[<210> 38]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 38]]> Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala 1 5 10 <![CDATA[<210> 39]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 39]]> Val Ala Ser Arg Arg Ala Ala 1 5 <![CDATA[<210> 40]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 40]]> Gln His Tyr Gly Arg Thr Pro Phe Thr 1 5 <![CDATA[<210> 41]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 41]]> Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Lys Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu 35 40 45 Ile Tyr Val Ala Ser Arg Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Gly Met Phe Tyr Cys Gln His Tyr Gly Arg Thr Pro 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105 <![CDATA[<210> 42]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 42]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Glu Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser Ile Ser Thr Val Tyr 65 70 75 80 Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Arg Gly Gly Asn Ser Val Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 43]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 43]]> Gly Tyr Tyr Ile His 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 44]]> Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 45]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 45]]> Ile Arg Gly Gly Asn Ser Val Phe Asp Tyr 1 5 10 <![CDATA[<210> 46]]> <![CDATA[<211> 342]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 46]]> gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccaccca gagtatttta tacacctcca acaataagaa cttcttagct 120 tggtaccagc agaaaccagg gcagcctcct aaactgctca tttcctgggc atctatccgg 180 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cgctctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcaacaata ttttagtact 300 atgttcagtt ttggccaggg gaccaagctg gagatcaaac ga 342 <![CDATA[<210> 47]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 47]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Thr Gln Ser Ile Leu Tyr Thr 20 25 30 Ser Asn Asn Lys Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Ile Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Thr Met Phe Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg <![CDATA[<210> 48]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 48]]> Lys Ser Thr Gln Ser Ile Leu Tyr Thr Ser Asn Asn Lys Asn Phe Leu 1 5 10 15 Ala <![CDATA[<210> 49]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 49]]> Trp Ala Ser Ile Arg Glu Ser 1 5 <![CDATA[<210> 50]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 50]]> Gln Gln Tyr Phe Ser Thr Met Phe Ser 1 5 <![CDATA[<210> 51]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 51]]> caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60 acctgcactg tctctggtgg ctccatcagt agtggtgcat actactggac ttggatccgc 120 cagcacccag ggaagggcct ggagtggatt gggtacatcc attacagtgg gagcacctac 180 tccaacccgt ccctcaagag tcgaattacc atatcgttag acacgtctaa gaaccagttc 240 tccctgaagc tgaactctgt gactgccgcg gacacggccg tgtattactg tgcgagacaa 300 gaggactacg gtggtttgtt tgactactgg ggccagggaa ccctggtcac cgtttcctca 360 <![CDATA[<210> 52]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 52]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Ala Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Ser Thr Tyr Ser Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gln Glu Asp Tyr Gly Gly Leu Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 53]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 53]]> Ser Gly Ala Tyr Tyr Trp Thr 1 5 <![CDATA[<210> 54]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 54]]> Tyr Ile His Tyr Ser Gly Ser Thr Tyr Ser Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 55]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 55]]> Gln Glu Asp Tyr Gly Gly Leu Phe Asp Tyr 1 5 10 <![CDATA[<210> 56]]> <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 56]]> gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagaatcacc 60 ctctcctgca gggccagtca gagtgttacc accgacttag cctggtacca gcagatgcct 120 ggacaggctc cccggctcct catctatgat gcttccacca gggccactgg tttcccagcc 180 agattcagtg gcagtgggtc tgggacagac ttcacgctca ccatcagcag cctgcaggct 240 gaagattttg cagtttatta ctgtcaacat tataaaacct ggcctctcac tttcggcgga 300 gggactaagg tggagatcaa acga 324 <![CDATA[<210> 57]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 57]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ile Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Thr Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Met Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Arg Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Lys Thr Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 58]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 58]]> Arg Ala Ser Gln Ser Val Thr Thr Asp Leu Ala 1 5 10 <![CDATA[<210> 59]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 59]]> Asp Ala Ser Thr Arg Ala Thr 1 5 <![CDATA[<210> 60]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 60]]> Gln His Tyr Lys Thr Trp Pro Leu Thr 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 1482]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 61]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtga ccctcaaaga gtctggaccc gtgctcgtaa aacctacgga gaccctgaca 120 ctcacctgca cagtctccgg cttcagcctc atcaatgcca ggatgggagt ttcctggatc 180 aggcaaccgc ccggaaaggc cctggaatgg ctcgcacata ttttcagtaa cgctgaaaaa 240 agctatcgga cttctctgaa aagtcggctc acgattagta aggacacatc caagagccaa 300 gtggtgctta cgatgactaa catggaccct gtggatactg caacctatta ctgtgctcga 360 atccctggtt atggcggaaa tggggactac cactactacg gtatggatgt ctggggccaa 420 gggaccacgg ttactgtttc aagcggaggg ggagggagtg ggggtggcgg atctggcgga 480 ggaggcagcg atatccagat gacgcagtcc cctagttcac tttccgcatc cctgggggat 540 cgggttacca ttacatgccg cgcgtcacag ggtatccgga atgatctggg atggtaccag 600 cagaagccgg gaaaggctcc taagcgcctc atctacgcca gctccaccct gcagagtgga 660 gtgccctccc ggttttcagg cagtggctcc ggtacggagt ttactcttac aattagcagc 720 ctgcagccag aagattttgc aacttactac tgtttgcagc ataataattt cccctggacc 780 tttggtcagg gcaccaaggt ggagatcaaa agagcagccg ccatcgaagt aatgtatccc 840 cccccgtacc ttgacaatga gaagtcaaat ggaaccatta tccatgttaa gggcaaacac 900 ctctgccctt ctccactgtt ccctggccct agtaagccgt tttgggtgct ggtggtagtc 960 ggtggggtgc tggcttgtta ctctcttctc gtgaccgtcg cctttataat cttttgggtc 1020 agatccaaaa gaagccgcct gctccatagc gattacatga atatgactcc acgccgccct 1080 ggccccacaa ggaaacacta ccagccttac gcaccaccta gagatttcgc tgcctatcgg 1140 agccgagtga aattttctag atcagctgat gctcccgcct atcagcaggg acagaatcaa 1200 ctttacaatg agctgaacct gggtcgcaga gaagagtacg acgttttgga caaacgccgg 1260 ggccgagatc ctgagatggg ggggaagccg agaaggaaga atcctcaaga aggcctgtac 1320 aacgagcttc aaaaagacaa aatggctgag gcgtactctg agatcggcat gaagggcgag 1380 cggagacgag gcaagggtca cgatggcttg tatcagggcc tgagtacagc cacaaaggac 1440 acctatgacg ccctccacat gcaggcactg cccccacgct ag 1482 <![CDATA[<210> 62]]> <![CDATA[<211> 493]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 62]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu 20 25 30 Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe 35 40 45 Ser Leu Ile Asn Ala Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro 50 55 60 Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Ala Glu Lys 65 70 75 80 Ser Tyr Arg Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr 85 90 95 Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp 100 105 110 Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Pro Gly Tyr Gly Gly Asn Gly 115 120 125 Asp Tyr His Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 130 135 140 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 165 170 175 Ser Leu Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile 180 185 190 Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 195 200 205 Arg Leu Ile Tyr Ala Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg 210 215 220 Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser 225 230 235 240 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn 245 250 255 Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala 260 265 270 Ala Ala Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys 275 280 285 Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser 290 295 300 Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val 305 310 315 320 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 325 330 335 Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr 340 345 350 Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln 355 360 365 Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys 370 375 380 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 385 390 395 400 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 405 410 415 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 420 425 430 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 435 440 445 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 450 455 460 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 465 470 475 480 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 <![CDATA[<210> 63]]> <![CDATA[<211> 1455]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 63]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaagtta ctttgaagga gtctggacct gtactggtga agccaaccga gacactgaca 120 ctcacgtgta cagtgagtgg tttttccttg atcaacgcaa ggatgggcgt cagctggatc 180 aggcaacccc ctggcaaggc tctggaatgg ctcgctcaca tattcagcaa tgccgaaaaa 240 agctaccgga caagcctgaa atcccgcctg actatttcca aggacacttc taagtctcag 300 gtggtgctga ccatgaccaa catggacccg gtggacaccg ccacctatta ctgcgcaaga 360 atccctgggt atggtgggaa tggtgactac cattattatg ggatggatgt gtgggggcaa 420 ggcacaaccg taacggtctc aagcggtggg ggaggctcag ggggcggagg ctccggaggt 480 ggcggctccg acattcagat gacccaaagc ccgtccagcc tgtccgccag cctgggagat 540 agagtgacaa tcacgtgtag agcttcccaa gggataagaa atgatctcgg gtggtatcag 600 cagaagcccg gcaaagcccc caaaaggctt atatatgcta gtagtacact gcagtctgga 660 gttccttccc gattttcagg tagcggctcc ggtacagagt tcaccctcac gataagctca 720 ctccagcctg aggatttcgc aacgtactac tgcctccagc acaacaattt tccctggact 780 ttcggccagg gcaccaaggt ggagatcaag agggccgctg cccttgataa tgaaaagtca 840 aacggaacaa tcattcacgt gaagggcaag cacctctgtc cgtcaccctt gttccctggt 900 ccatccaagc cattctgggt gttggtcgta gtgggtggag tcctcgcttg ttactctctg 960 ctcgtcaccg tggcttttat aatcttctgg gttagatcca aaagaagccg cctgctccat 1020 agcgattaca tgaatatgac tccacgccgc cctggcccca caaggaaaca ctaccagcct 1080 tacgcaccac ctagagattt cgctgcctat cggagccgag tgaaattttc tagatcagct 1140 gatgctcccg cctatcagca gggacagaat caactttaca atgagctgaa cctgggtcgc 1200 agagaagagt acgacgtttt ggacaaacgc cggggccgag atcctgagat gggggggaag 1260 ccgagaagga agaatcctca agaaggcctg tacaacgagc ttcaaaaaga caaaatggct 1320 gaggcgtact ctgagatcgg catgaagggc gagcggagac gaggcaaggg tcacgatggc 1380 ttgtatcagg gcctgagtac agccacaaag gacacctatg acgccctcca catgcaggca 1440 ctgcccccac gctag 1455 <![CDATA[<210> 64]]> <![CDATA[<211> 484]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 64]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu 20 25 30 Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe 35 40 45 Ser Leu Ile Asn Ala Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro 50 55 60 Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Ala Glu Lys 65 70 75 80 Ser Tyr Arg Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr 85 90 95 Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp 100 105 110 Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Pro Gly Tyr Gly Gly Asn Gly 115 120 125 Asp Tyr His Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 130 135 140 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 165 170 175 Ser Leu Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile 180 185 190 Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 195 200 205 Arg Leu Ile Tyr Ala Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg 210 215 220 Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser 225 230 235 240 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn 245 250 255 Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala 260 265 270 Ala Ala Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys 275 280 285 Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro 290 295 300 Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 305 310 315 320 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser 325 330 335 Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly 340 345 350 Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala 355 360 365 Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 370 375 380 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 385 390 395 400 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 405 410 415 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg <![CDATA[<210> 65]]> <![CDATA[<211> 1563]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 65]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtga cactcaagga atcagggccc gtactggtga aacctactga gaccctgaca 120 ctgacttgca ccgtgtctgg gttctctctg attaacgctc gaatgggtgt gagttggata 180 cgccagcctc cagggaaggc tctggagtgg ttggcccaca ttttctccaa cgccgagaag 240 agctacagga ctagtctgaa gtccagactt accatttcca aagacacaag taaatcacag 300 gtggtgctga caatgacaaa catggacccg gttgatactg ctacctatta ttgtgcccgc 360 attcccggct acggcggcaa tggcgactat cactattatg gtatggatgt ctgggggcag 420 gggaccactg ttaccgtgtc cagcgggggt ggtggcagcg gaggtggagg gagcggtggt 480 ggggggagtg atattcagat gacccagagc cctagctctc tttccgcttc tctgggcgat 540 agagtcacca tcacctgccg ggcctctcaa ggcatccgga acgatcttgg atggtatcag 600 cagaagcccg gcaaggcacc aaaaaggctg atctacgcat caagcaccct gcaatctggg 660 gtgccgtccc ggttttctgg ttctggtagt gggaccgagt ttactctgac tatttcttcc 720 ctgcagcctg aggactttgc tacgtactat tgtctgcagc ataacaactt cccctggacg 780 ttcgggcagg gtacgaaagt ggaaattaag cgcgccgccg ccctgtccaa ctccattatg 840 tatttctctc attttgtccc agtgttcctg cccgctaaac ccacaactac tccggcgccc 900 cgaccgccaa ctcccgcacc taccatcgca agccagccat tgagcctccg acctgaggca 960 tgtagaccag cagccggcgg tgccgtgcac acaaggggac tggatttcgc ctgcgacata 1020 tatatttggg cccctctggc tggaacctgt ggggttctgc tgctctctct cgttattaca 1080 ctgtattgca atcatcgcaa tagatccaaa agaagccgcc tgctccatag cgattacatg 1140 aatatgactc cacgccgccc tggccccaca aggaaacact accagcctta cgcaccacct 1200 agagatttcg ctgcctatcg gagccgagtg aaattttcta gatcagctga tgctcccgcc 1260 tatcagcagg gacagaatca actttacaat gagctgaacc tgggtcgcag agaagagtac 1320 gacgttttgg acaaacgccg gggccgagat cctgagatgg gggggaagcc gagaaggaag 1380 aatcctcaag aaggcctgta caacgagctt caaaaagaca aaatggctga ggcgtactct 1440 gagatcggca tgaagggcga gcggagacga ggcaagggtc acgatggctt gtatcagggc 1500 ctgagtacag ccacaaagga cacctatgac gccctccaca tgcaggcact gcccccacgc 1560 tag 1563 <![CDATA[<210> 66]]> <![CDATA[<211> 520]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 66]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu 20 25 30 Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe 35 40 45 Ser Leu Ile Asn Ala Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro 50 55 60 Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Ala Glu Lys 65 70 75 80 Ser Tyr Arg Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr 85 90 95 Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp 100 105 110 Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Pro Gly Tyr Gly Gly Asn Gly 115 120 125 Asp Tyr His Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 130 135 140 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 165 170 175 Ser Leu Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile 180 185 190 Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 195 200 205 Arg Leu Ile Tyr Ala Ser Ser Thr Leu Gln Ser Gly Val Pro Ser Arg 210 215 220 Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser 225 230 235 240 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Asn 245 250 255 Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala 260 265 270 Ala Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val 275 280 285 Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr 290 295 300 Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala 305 310 315 320 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe 325 330 335 Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val 340 345 350 Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg 355 360 365 Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro 370 375 380 Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro 385 390 395 400 Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala 405 410 415 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 420 425 430 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 435 440 445 Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu 450 455 460 Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser 465 470 475 480 Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 485 490 495 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu 500 505 510 His Met Gln Ala Leu Pro Pro Arg 515 520 <![CDATA[<210> 67]]> <![CDATA[<211> 1464]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 67]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcagatcc agttggtgga atcagggggc ggtgtggtgc agccgggtag gagcctgaga 120 ctgtcatgcg tggcgtctgg cttcacattc aagaactacg gcatgcactg ggtgcgacag 180 gcccccggaa agggtttgga gtgggtcgcc gtgatctggt acgacggatc taatgagtat 240 tacggagatc ctgtgaaggg aaggttcacc atctcccgcg acaatagcaa aaatatgctc 300 tacctgcaaa tgaactcact cagggcggat gatacggcgg tctactattg cgctcgctca 360 gggattgctg tggccggcgc attcgattac tggggacagg gtaccctggt gacagtatca 420 agcggaggcg gcggctctgg cggcggcgga tctggcgggg ggggaagtga gattgtgttg 480 acacagtctc ccgataccct gtcactgtca cccggcgaga aggcaacgct gagttgcaga 540 gcaagccagt cagtctcctc ttcttttctg gcctggtatc agcaaaaacc aggtcaggca 600 ccatctctcc tgatttacgt tgccagcaga cgggcggctg gcattcccga caggttctct 660 ggaagcggat ctgggaccga ttttaccctg acaattagcc gcttggagcc cgaagacttt 720 ggtatgtttt actgccagca ctacggaagg acacctttca catttggccc gggcacgaaa 780 gtcgatataa aacgcgcagc cgccattgaa gtaatgtacc caccacctta tttggacaat 840 gaaaagtcca atggtaccat tattcacgtc aagggaaagc atctctgtcc aagccctctg 900 ttccccggcc cctccaaacc attctgggtg ctggtggtcg tcggcggagt tctggcctgc 960 tattctctgc tcgtgactgt tgcattcatc attttctggg tgagatccaa aagaagccgc 1020 ctgctccata gcgattacat gaatatgact ccacgccgcc ctggccccac aaggaaacac 1080 taccagcctt acgcaccacc tagagatttc gctgcctatc ggagccgagt gaaattttct 1140 agatcagctg atgctcccgc ctatcagcag ggacagaatc aactttacaa tgagctgaac 1200 ctgggtcgca gagaagagta cgacgttttg gacaaacgcc ggggccgaga tcctgagatg 1260 ggggggaagc cgagaaggaa gaatcctcaa gaaggcctgt acaacgagct tcaaaaagac 1320 aaaatggctg aggcgtactc tgagatcggc atgaagggcg agcggagacg aggcaagggt 1380 cacgatggct tgtatcaggg cctgagtaca gccacaaagg acacctatga cgccctccac 1440 atgcaggcac tgcccccacg ctag 1464 <![CDATA[<210> 68]]> <![CDATA[<211> 487]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 68]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Glu Ser Gly Gly Gly Val 20 25 30 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe 35 40 45 Thr Phe Lys Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys 50 55 60 Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Glu Tyr 65 70 75 80 Tyr Gly Asp Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 85 90 95 Lys Asn Met Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Ile Ala Val Ala Gly Ala Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly Glu Lys Ala Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp 180 185 190 Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu Ile Tyr Val Ala 195 200 205 Ser Arg Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe 225 230 235 240 Gly Met Phe Tyr Cys Gln His Tyr Gly Arg Thr Pro Phe Thr Phe Gly 245 250 255 Pro Gly Thr Lys Val Asp Ile Lys Arg Ala Ala Ala Ile Glu Val Met 260 265 270 Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile 275 280 285 His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro 290 295 300 Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys 305 310 315 320 Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser 325 330 335 Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg 340 345 350 Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg 355 360 365 Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp 370 375 380 Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn 385 390 395 400 Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg 405 410 415 Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly 420 425 430 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 435 440 445 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 450 455 460 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 465 470 475 480 Met Gln Ala Leu Pro Pro Arg 485 <![CDATA[<210> 69]]> <![CDATA[<211> 1437]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 69]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcagattc agctcgtgga gtcaggtggt ggcgtggttc agcccggacg gtccctgcga 120 ctctcttgtg tggcaagcgg atttaccttt aagaactatg gcatgcactg ggtgaggcag 180 gcccctggaa aaggactgga gtgggttgct gtgatctggt acgacgggtc caacgaatat 240 tatggcgatc ctgtgaaggg acggtttaca atctcacgcg ataactcaaa gaacatgctg 300 tacctgcaaa tgaactctct gcgcgctgat gacactgccg tgtattattg cgctcggagt 360 ggtatcgccg tcgcaggagc atttgattat tgggggcaag ggaccctcgt gacagtgagt 420 tccggagggg gaggttctgg tggaggcggc tctggtgggg gaggcagcga gatcgttctg 480 acccagtctc ctgacacact gtcactgtcc cctggtgaaa aggccacact gtcttgtaga 540 gcgtcccaga gcgtttccag ttccttcctt gcatggtatc aacaaaaacc cgggcaggct 600 ccaagcttgc tgatctacgt ggccagccgc cgggccgcag gcatccctga taggtttagc 660 ggttctggga gcgggacgga cttcaccttg acaatatcac ggctggaacc cgaagacttc 720 ggaatgtttt attgccagca ctacggaaga actccattca cctttggccc gggaacgaag 780 gtagacatca agagagcagc agccctcgac aacgagaaat ccaatggaac cattatccat 840 gtgaagggga aacatctctg cccttcacca ttgttccctg gacccagcaa gcctttttgg 900 gttctggtcg tggtgggggg cgtcctggct tgttactccc tcctcgttac agtcgccttc 960 ataatctttt gggttagatc caaaagaagc cgcctgctcc atagcgatta catgaatatg 1020 actccacgcc gccctggccc cacaaggaaa cactaccagc cttacgcacc acctagagat 1080 ttcgctgcct atcggagccg agtgaaattt tctagatcag ctgatgctcc cgcctatcag 1140 cagggacaga atcaacttta caatgagctg aacctgggtc gcagagaaga gtacgacgtt 1200 ttggacaaac gccggggccg agatcctgag atggggggga agccgagaag gaagaatcct 1260 caagaaggcc tgtacaacga gcttcaaaaa gacaaaatgg ctgaggcgta ctctgagatc 1320 ggcatgaagg gcgagcggag acgaggcaag ggtcacgatg gcttgtatca gggcctgagt 1380 acagccacaa aggacaccta tgacgccctc cacatgcagg cactgccccc acgctag 1437 <![CDATA[<210> 70]]> <![CDATA[<211> 478]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 70]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Glu Ser Gly Gly Gly Val 20 25 30 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe 35 40 45 Thr Phe Lys Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys 50 55 60 Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Glu Tyr 65 70 75 80 Tyr Gly Asp Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 85 90 95 Lys Asn Met Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Ile Ala Val Ala Gly Ala Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly Glu Lys Ala Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp 180 185 190 Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu Ile Tyr Val Ala 195 200 205 Ser Arg Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe 225 230 235 240 Gly Met Phe Tyr Cys Gln His Tyr Gly Arg Thr Pro Phe Thr Phe Gly 245 250 255 Pro Gly Thr Lys Val Asp Ile Lys Arg Ala Ala Ala Leu Asp Asn Glu 260 265 270 Lys Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro 275 280 285 Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val 290 295 300 Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe 305 310 315 320 Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp 325 330 335 Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr 340 345 350 Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val 355 360 365 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 370 375 380 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 385 390 395 400 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 405 410 415 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 420 425 430 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 435 440 445 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 450 455 460 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 465 470 475 <![CDATA[<210> 71]]> <![CDATA[<211> 1545]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 71]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcagatac agcttgtcga atccggtggc ggggtggtgc agcctggacg cagcctgcgg 120 ctttcttgcg tggccagcgg atttaccttc aagaactacg ggatgcattg ggtccgccag 180 gcacccggca aaggccttga gtgggttgca gtgatctggt acgacggcag taacgagtat 240 tatggcgacc ccgtgaaggg aaggtttact atttcaagag ataatagtaa gaacatgttg 300 tatctgcaaa tgaacagtct gagagcggac gacactgccg tgtactactg tgctcgctcc 360 ggcatcgctg tggcaggggc ctttgactac tggggtcagg ggacgctggt cacggttagt 420 tccgggggcg gtggttccgg aggaggcggt tccggcggcg gcggatcaga aatcgttctt 480 actcagagtc ccgatacgct gtccttgtct ccgggagaaa aagccacact gagctgccga 540 gcctcacagt cagtaagttc ttcattcctc gcctggtacc agcaaaaacc ggggcaggcc 600 ccttccctgc ttatctacgt ggcctctagg agagccgccg gtattcctga ccggttcagc 660 ggaagtggtt ccgggactga ttttacgctc acgatctccc gattggagcc cgaggatttc 720 gggatgttct actgtcagca ttatggaaga acgcccttta ccttcggtcc gggaactaag 780 gttgatatta agcgggctgc tgcccttagc aactccatca tgtatttttc tcacttcgtg 840 ccagtattcc tgccagccaa accgaccaca accccagcac ctagacctcc tactcccgct 900 cccaccatag cttcacagcc gctgagtttg aggccagagg cctgtcggcc tgctgcaggc 960 ggagcagttc acaccagggg acttgacttt gcatgtgaca tctatatttg ggctccactg 1020 gcgggaacct gcggggtgct ccttttgtca ctcgttatca cactgtattg caatcatagg 1080 aatagatcca aaagaagccg cctgctccat agcgattaca tgaatatgac tccacgccgc 1140 cctggcccca caaggaaaca ctaccagcct tacgcaccac ctagagattt cgctgcctat 1200 cggagccgag tgaaattttc tagatcagct gatgctcccg cctatcagca gggacagaat 1260 caactttaca atgagctgaa cctgggtcgc agagaagagt acgacgtttt ggacaaacgc 1320 cggggccgag atcctgagat gggggggaag ccgagaagga agaatcctca agaaggcctg 1380 tacaacgagc ttcaaaaaga caaaatggct gaggcgtact ctgagatcgg catgaagggc 1440 gagcggagac gaggcaaggg tcacgatggc ttgtatcagg gcctgagtac agccacaaag 1500 gacacctatg acgccctcca catgcaggca ctgcccccac gctag 1545 <![CDATA[<210> 72]]> <![CDATA[<211> 514]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 72]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Glu Ser Gly Gly Gly Val 20 25 30 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe 35 40 45 Thr Phe Lys Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys 50 55 60 Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Glu Tyr 65 70 75 80 Tyr Gly Asp Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 85 90 95 Lys Asn Met Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ser Gly Ile Ala Val Ala Gly Ala Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly Glu Lys Ala Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu Ala Trp 180 185 190 Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu Ile Tyr Val Ala 195 200 205 Ser Arg Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe 225 230 235 240 Gly Met Phe Tyr Cys Gln His Tyr Gly Arg Thr Pro Phe Thr Phe Gly 245 250 255 Pro Gly Thr Lys Val Asp Ile Lys Arg Ala Ala Ala Leu Ser Asn Ser 260 265 270 Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro 275 280 285 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 290 295 300 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 305 310 315 320 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 325 330 335 Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val 340 345 350 Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Ser Lys Arg Ser Arg Leu 355 360 365 Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr 370 375 380 Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr 385 390 395 400 Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 405 410 415 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 420 425 430 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 435 440 445 Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 450 455 460 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 465 470 475 480 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 485 490 495 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 500 505 510 Pro Arg <![CDATA[<210> 73]]> <![CDATA[<211> 1476]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 73]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtgc agctggtgca gagtggggca gaagtaaaga agcctggtgc ctctgtcaaa 120 gttagttgca aagcatctgg gtatactttc accggttact atatccattg ggttcggcag 180 gccccggagc agggactgga gtggatgggc tggatcaacc caaattcagg cggcactaac 240 tatgctcaaa agttccaggg cagggtcaca atggcccggg atacttcaat tagcaccgtc 300 tatatggatc ttagtcggct gcgcagtgac gataccgctg tctactattg cgcaaggatc 360 aggggcggca attctgtttt tgactattgg ggccagggaa cactggtgac cgtctcctct 420 ggtggaggcg gtagtggtgg aggcgggtcc ggaggagggg gctccgatat agtgatgact 480 caaagtcccg atagcttggc agtatctctt ggggaacgcg ccactattaa ctgtaaatcc 540 acccagtcca ttctctatac ctctaacaac aagaatttcc tcgcgtggta tcagcaaaaa 600 cccgggcagc cacctaaact gcttatatcc tgggccagca tcagggagtc cggcgtccct 660 gatcggttca gcggtagtgg cagcgggaca gacttcgctc tgaccatcag tagcctccag 720 gctgaagatg tcgcagtgta ttattgccag cagtacttca gcacgatgtt tagcttcggg 780 cagggaacca agctggaaat aaagagagct gcagcaatcg aggtgatgta cccacctcca 840 tatctggaca atgaaaagtc caatggcact atcatacacg tgaagggcaa acacctgtgt 900 ccatctccac ttttcccggg cccgtctaaa cctttctggg tgctggtggt ggtgggcgga 960 gttctggcct gttattcact gctggtcacc gtggctttca tcattttttg ggtaagatcc 1020 aaaagaagcc gcctgctcca tagcgattac atgaatatga ctccacgccg ccctggcccc 1080 acaaggaaac actaccagcc ttacgcacca cctagagatt tcgctgccta tcggagccga 1140 gtgaaatttt ctagatcagc tgatgctccc gcctatcagc agggacagaa tcaactttac 1200 aatgagctga acctgggtcg cagagaagag tacgacgttt tggacaaacg ccggggccga 1260 gatcctgaga tgggggggaa gccgagaagg aagaatcctc aagaaggcct gtacaacgag 1320 cttcaaaaag acaaaatggc tgaggcgtac tctgagatcg gcatgaaggg cgagcggaga 1380 cgaggcaagg gtcacgatgg cttgtatcag ggcctgagta cagccacaaa ggacacctat 1440 gacgccctcc acatgcaggc actgccccca cgctag 1476 <![CDATA[<210> 74]]> <![CDATA[<211> 491]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 74]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Thr Phe Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Glu Gln 50 55 60 Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn 65 70 75 80 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser 85 90 95 Ile Ser Thr Val Tyr Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ile Arg Gly Gly Asn Ser Val Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr 145 150 155 160 Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile 165 170 175 Asn Cys Lys Ser Thr Gln Ser Ile Leu Tyr Thr Ser Asn Asn Lys Asn 180 185 190 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 195 200 205 Ile Ser Trp Ala Ser Ile Arg Glu Ser Gly Val Pro Asp Arg Phe Ser 210 215 220 Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser Leu Gln 225 230 235 240 Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Thr Met 245 250 255 Phe Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala 260 265 270 Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn 275 280 285 Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu 290 295 300 Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly 305 310 315 320 Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe 325 330 335 Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn 340 345 350 Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr 355 360 365 Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser 370 375 380 Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 385 390 395 400 Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 405 410 415 Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn 420 425 430 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 435 440 445 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 450 455 460 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 465 470 475 480 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 <![CDATA[<210> 75]]> <![CDATA[<211> 1449]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 75]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtac agctggtgca gagcggggcc gaggtcaaaa agcccggggc ttcagttaag 120 gttagctgca aggcttccgg ctacaccttt accggttact atattcactg ggttagacag 180 gcacctgagc aaggactgga gtggatgggg tggattaacc ccaatagcgg tgggaccaac 240 tacgcccaga agtttcaagg ccgagtgaca atggcacgag acacctccat ttccactgtg 300 tacatggact tgagccgcct caggtcagac gacaccgcag tgtactactg tgcgcgaatc 360 cgcggcggaa acagcgtgtt tgactactgg ggtcagggca cgttggtgac cgtgtcttcc 420 ggaggggggg gatctggtgg cgggggctcc ggcggaggcg gtagtgatat tgtgatgact 480 cagtcaccgg acagtcttgc tgtttcactt ggtgagaggg ccaccataaa ttgtaaaagc 540 acccagagca ttctctacac atctaacaac aaaaatttcc tggcctggta ccagcagaag 600 cccggacagc cacccaaatt gctgattagc tgggccagca ttcgagaatc tggggttccg 660 gaccgctttt ccgggtctgg ctctgggacc gacttcgctt tgaccataag ctctcttcag 720 gccgaagacg tcgcagtata ctattgtcaa cagtattttt ctaccatgtt ttccttcggc 780 cagggaacta agttggagat caagagagca gctgcattgg ataatgagaa gtccaatggc 840 actattatcc acgtgaaagg taaacacctg tgtccctcac ccctgtttcc aggacctagt 900 aaaccattct gggtcttggt tgtagtcggg ggcgttttgg catgttattc ccttcttgtg 960 acagtcgcct ttatcatttt ctgggtgaga tccaaaagaa gccgcctgct ccatagcgat 1020 tacatgaata tgactccacg ccgccctggc cccacaagga aacactacca gccttacgca 1080 ccacctagag atttcgctgc ctatcggagc cgagtgaaat tttctagatc agctgatgct 1140 cccgcctatc agcagggaca gaatcaactt tacaatgagc tgaacctggg tcgcagagaa 1200 gagtacgacg ttttggacaa acgccggggc cgagatcctg agatgggggg gaagccgaga 1260 aggaagaatc ctcaagaagg cctgtacaac gagcttcaaa aagacaaaat ggctgaggcg 1320 tactctgaga tcggcatgaa gggcgagcgg agacgaggca agggtcacga tggcttgtat 1380 cagggcctga gtacagccac aaaggacacc tatgacgccc tccacatgca ggcactgccc 1440 ccacgctag 1449 <![CDATA[<210> 76]]> <![CDATA[<211> 482]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 76]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Thr Phe Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Glu Gln 50 55 60 Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn 65 70 75 80 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser 85 90 95 Ile Ser Thr Val Tyr Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ile Arg Gly Gly Asn Ser Val Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr 145 150 155 160 Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile 165 170 175 Asn Cys Lys Ser Thr Gln Ser Ile Leu Tyr Thr Ser Asn Asn Lys Asn 180 185 190 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 195 200 205 Ile Ser Trp Ala Ser Ile Arg Glu Ser Gly Val Pro Asp Arg Phe Ser 210 215 220 Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser Leu Gln 225 230 235 240 Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Thr Met 245 250 255 Phe Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala 260 265 270 Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys 275 280 285 His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp 290 295 300 Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val 305 310 315 320 Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu 325 330 335 Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr 340 345 350 Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr 355 360 365 Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 370 375 380 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 385 390 395 400 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 405 410 415 Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 420 425 430 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 435 440 445 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 450 455 460 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 465 470 475 480 Pro Arg <![CDATA[<210> 77]]> <![CDATA[<211> 1557]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 77]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaagttc agcttgtgca gagcggagct gaggtgaaaa aaccaggcgc ctccgttaag 120 gtgtcttgca aagccagcgg atacacattt accgggtact atattcactg ggtgaggcag 180 gcccctgaac agggccttga atggatgggg tggatcaatc caaattccgg gggaaccaat 240 tatgctcaga aatttcaggg cagagtgaca atggccaggg acacctcaat cagcacagtc 300 tacatggacc tgagccgcct gaggtctgat gacacagccg tctactactg tgcccggatc 360 agagggggaa acagtgtctt cgactattgg gggcagggaa ccctggtgac tgtctcctcc 420 gggggagggg gtagcggggg aggcggcagc ggcgggggtg gttctgacat tgttatgacc 480 caatccccag actctctggc cgtgagcctg ggtgagagag ccaccatcaa ttgcaagtcc 540 acccagagca tactctatac gtcaaacaat aagaatttcc tggcgtggta tcagcaaaag 600 ccgggtcaac cacccaagtt gttgattagc tgggcatcaa ttcgagaatc tggcgtccct 660 gataggttta gcgggagcgg tagtggaacc gactttgcgc tgaccatttc atcccttcag 720 gcagaggacg tggctgtgta ttactgtcaa cagtacttca gcacgatgtt ttctttcggc 780 caggggacga agctggagat aaagcgggcc gcagcactca gcaacagcat catgtacttt 840 tctcatttcg tcccagtttt tctccccgcc aaacccacca ctacccctgc tcctaggcct 900 cccactcccg cacccaccat tgcttcccaa cctctgtcat tgaggcccga agcctgcaga 960 cctgccgcag gaggggctgt gcacacccgc ggtctggatt ttgcttgtga tatctacatt 1020 tgggcccctt tggccggaac ctgcggagtg ttgttgctga gccttgttat cacgttgtac 1080 tgtaatcaca gaaacagatc caaaagaagc cgcctgctcc atagcgatta catgaatatg 1140 actccacgcc gccctggccc cacaaggaaa cactaccagc cttacgcacc acctagagat 1200 ttcgctgcct atcggagccg agtgaaattt tctagatcag ctgatgctcc cgcctatcag 1260 cagggacaga atcaacttta caatgagctg aacctgggtc gcagagaaga gtacgacgtt 1320 ttggacaaac gccggggccg agatcctgag atggggggga agccgagaag gaagaatcct 1380 caagaaggcc tgtacaacga gcttcaaaaa gacaaaatgg ctgaggcgta ctctgagatc 1440 ggcatgaagg gcgagcggag acgaggcaag ggtcacgatg gcttgtatca gggcctgagt 1500 acagccacaa aggacaccta tgacgccctc cacatgcagg cactgccccc acgctag 1557 <![CDATA[<210> 78]]> <![CDATA[<211> 518]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 78]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Thr Phe Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Glu Gln 50 55 60 Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn 65 70 75 80 Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser 85 90 95 Ile Ser Thr Val Tyr Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Ile Arg Gly Gly Asn Ser Val Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr 145 150 155 160 Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile 165 170 175 Asn Cys Lys Ser Thr Gln Ser Ile Leu Tyr Thr Ser Asn Asn Lys Asn 180 185 190 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 195 200 205 Ile Ser Trp Ala Ser Ile Arg Glu Ser Gly Val Pro Asp Arg Phe Ser 210 215 220 Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser Leu Gln 225 230 235 240 Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Thr Met 245 250 255 Phe Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala 260 265 270 Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu 275 280 285 Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 290 295 300 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 305 310 315 320 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 325 330 335 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 340 345 350 Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Ser Lys 355 360 365 Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg 370 375 380 Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp 385 390 395 400 Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 405 410 415 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 420 425 430 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 435 440 445 Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 450 455 460 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile 465 470 475 480 Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 485 490 495 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met 500 505 510 Gln Ala Leu Pro Pro Arg 515 <![CDATA[<210> 79]]> <![CDATA[<211> 1461]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 79]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtgc agctccaaga gtcaggacca ggacttgtca aaccaagcca gaccctcagc 120 cttacctgca ccgtcagcgg gggctccatc agctctgggg cttactactg gacatggata 180 cgacagcatc ccggtaaagg tctggagtgg atcgggtaca tacactatag tggttccaca 240 tattctaatc catctcttaa gagtcgaatt acaatttcac tcgatacttc aaagaatcag 300 ttcagcttga aactgaactc cgtgaccgcg gctgacaccg ccgtgtacta ctgtgcacgc 360 caagaggatt atggcggact gttcgattat tgggggcagg gaactctcgt gacagtgagc 420 tccggcgggg gcggcagcgg tgggggtgga agtggtggag ggggcagcga gatcgtgatg 480 acccagagtc ctgccacact gtcagtgagt cctggggagc gaatcacact ttcctgtcga 540 gcgtctcagt ccgtgaccac ggacctggcg tggtaccagc agatgccagg ccaggcgcca 600 agactcctga tctacgacgc ttctacccgc gctactggtt tccccgccag attctccgga 660 agcgggtccg ggacggattt tacacttacc atctcttcat tgcaggctga ggattttgcc 720 gtgtactact gtcagcatta caaaacctgg cccctcactt tcgggggcgg aacaaaagtg 780 gaaattaaac gggcagcagc tattgaggtg atgtacccac ccccctacct ggacaacgag 840 aaatccaatg gcaccatcat ccacgttaag ggtaagcact tgtgtccctc accactcttc 900 cctgggccta gcaagccatt ctgggtcctg gtggtcgtgg gaggcgtgct ggcctgctat 960 tccctcctgg ttaccgttgc ctttatcata ttttgggtca gatccaaaag aagccgcctg 1020 ctccatagcg attacatgaa tatgactcca cgccgccctg gccccacaag gaaacactac 1080 cagccttacg caccacctag agatttcgct gcctatcgga gccgagtgaa attttctaga 1140 tcagctgatg ctcccgccta tcagcaggga cagaatcaac tttacaatga gctgaacctg 1200 ggtcgcagag aagagtacga cgttttggac aaacgccggg gccgagatcc tgagatgggg 1260 gggaagccga gaaggaagaa tcctcaagaa ggcctgtaca acgagcttca aaaagacaaa 1320 atggctgagg cgtactctga gatcggcatg aagggcgagc ggagacgagg caagggtcac 1380 gatggcttgt atcagggcct gagtacagcc acaaaggaca cctatgacgc cctccacatg 1440 caggcactgc ccccacgcta g 1461 <![CDATA[<210> 80]]> <![CDATA[<211> 486]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 80]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 20 25 30 Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 35 40 45 Ser Ile Ser Ser Gly Ala Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro 50 55 60 Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile His Tyr Ser Gly Ser Thr 65 70 75 80 Tyr Ser Asn Pro Ser Leu Lys Ser Arg Ile Thr Ile Ser Leu Asp Thr 85 90 95 Ser Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Gln Glu Asp Tyr Gly Gly Leu Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met 145 150 155 160 Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ile Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Thr Asp Leu Ala Trp Tyr 180 185 190 Gln Gln Met Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser 195 200 205 Thr Arg Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Phe Ala 225 230 235 240 Val Tyr Tyr Cys Gln His Tyr Lys Thr Trp Pro Leu Thr Phe Gly Gly 245 250 255 Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala Ile Glu Val Met Tyr 260 265 270 Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His 275 280 285 Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser 290 295 300 Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr 305 310 315 320 Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys 325 330 335 Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg 340 345 350 Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp 355 360 365 Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 370 375 380 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 385 390 395 400 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 405 410 415 Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 420 425 430 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile 435 440 445 Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 450 455 460 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met 465 470 475 480 Gln Ala Leu Pro Pro Arg 485 <![CDATA[<210> 81]]> <![CDATA[<211> 1434]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 81]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtgc agttgcagga gagcgggcca ggcctggtga agcccagcca aacactgagc 120 ctcacctgta ctgtgtccgg tggtagcatt tccagcgggg cgtattattg gacatggata 180 cgccaacacc ctggaaaagg gttggagtgg attggataca tccattattc tgggtccacc 240 tatagtaacc cttctctcaa gtctcgcatt actattagtt tggatacctc taagaatcag 300 tttagtctga agctgaacag tgtaaccgcc gccgacaccg cggtctacta ctgtgctagg 360 caggaggatt acgggggact gttcgattac tggggccagg ggacattggt caccgtttca 420 agcgggggcg gcggatctgg cggaggggga tctggaggcg gaggctctga gatcgtaatg 480 actcagagcc cagccaccct gtccgtctct cccggcgaac gcatcactct gagctgtagg 540 gcatcacagt ctgttaccac agatctggct tggtatcaac aaatgcctgg gcaggccccg 600 cgactgttga tttatgacgc ctctacgcgg gccacaggat ttcctgcccg gttctccggg 660 tctggttctg gcaccgattt taccttgaca atcagtagct tgcaggcaga agatttcgct 720 gtgtattact gccaacatta taagacatgg cctttgacat tcggcggggg aaccaaagtg 780 gagatcaaac gcgccgcagc cctggacaat gagaagtcta atgggaccat cattcacgtc 840 aaagggaaac acctgtgccc ctctcctctg ttcccaggcc cttctaagcc cttctgggtt 900 ctcgtggtgg tgggcggtgt cctggcctgc tattcccttc ttgtgacagt ggcctttatc 960 attttttggg tgagatccaa aagaagccgc ctgctccata gcgattacat gaatatgact 1020 ccacgccgcc ctggccccac aaggaaacac taccagcctt acgcaccacc tagagatttc 1080 gctgcctatc ggagccgagt gaaattttct agatcagctg atgctcccgc ctatcagcag 1140 ggacagaatc aactttacaa tgagctgaac ctgggtcgca gagaagagta cgacgttttg 1200 gacaaacgcc ggggccgaga tcctgagatg ggggggaagc cgagaaggaa gaatcctcaa 1260 gaaggcctgt acaacgagct tcaaaaagac aaaatggctg aggcgtactc tgagatcggc 1320 atgaagggcg agcggagacg aggcaagggt cacgatggct tgtatcaggg cctgagtaca 1380 gccacaaagg acacctatga cgccctccac atgcaggcac tgcccccacg ctag 1434 <![CDATA[<210> 82]]> <![CDATA[<211> 477]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 82]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 20 25 30 Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 35 40 45 Ser Ile Ser Ser Gly Ala Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro 50 55 60 Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile His Tyr Ser Gly Ser Thr 65 70 75 80 Tyr Ser Asn Pro Ser Leu Lys Ser Arg Ile Thr Ile Ser Leu Asp Thr 85 90 95 Ser Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Gln Glu Asp Tyr Gly Gly Leu Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met 145 150 155 160 Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ile Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Thr Asp Leu Ala Trp Tyr 180 185 190 Gln Gln Met Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser 195 200 205 Thr Arg Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Phe Ala 225 230 235 240 Val Tyr Tyr Cys Gln His Tyr Lys Thr Trp Pro Leu Thr Phe Gly Gly 245 250 255 Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala Leu Asp Asn Glu Lys 260 265 270 Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser 275 280 285 Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr 325 330 335 Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln 340 345 350 Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys 355 360 365 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 370 375 380 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 385 390 395 400 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 405 410 415 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 420 425 430 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 435 440 445 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 450 455 460 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 465 470 475 <![CDATA[<210> 83]]> <![CDATA[<211> 1542]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 83]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccgcaggtac agttgcagga aagcggcccc ggccttgtaa aaccaagcca gactctcagt 120 ttgacttgca ccgtctcagg aggaagcatt tccagtgggg cttattattg gacttggatt 180 cggcagcatc ctgggaaagg gttggaatgg atcggttata ttcattatag cggtagcacc 240 tattccaatc cgtctttgaa aagcagaatc actatttcac tcgacacctc taagaaccag 300 ttcagtctca aactgaactc cgtgacagcg gccgacacag ctgtgtacta ctgtgcacgg 360 caagaagatt atggggggct gttcgattat tggggccaag gcacactggt gacagtatca 420 agcggtggag gaggctccgg gggcggagga agtggaggcg gggggagcga aattgtgatg 480 acccagtctc cagccacgct gtcagtgtct ccgggagaac gcataaccct ctcctgccgg 540 gccagtcagt ccgtcacgac cgatttggct tggtatcaac agatgcctgg gcaggccccc 600 cgcttgctga tctatgacgc ctccaccaga gcaactggtt tccccgcccg gttcagcgga 660 tctggaagcg gtacagattt tacacttacc atctcatcat tgcaagctga ggattttgcc 720 gtgtactact gccagcacta caagacctgg cctttgacgt tcggcggcgg aacaaaagtg 780 gagattaaaa gagccgctgc cctcagtaac tcaatcatgt actttagtca ctttgtgcct 840 gtgtttctgc cagcaaagcc aacaaccaca ccagcacccc gccctccaac gcctgcccca 900 accatcgcct cccagcctct gagcttgagg cctgaggctt gtcgcccagc tgctggaggt 960 gctgtgcata cacgaggact ggatttcgcc tgcgatatct atatctgggc accacttgcc 1020 ggtacttgtg gtgtgttgct gctctcactg gtcatcacgc tgtactgtaa ccataggaat 1080 agatccaaaa gaagccgcct gctccatagc gattacatga atatgactcc acgccgccct 1140 ggccccacaa ggaaacacta ccagccttac gcaccaccta gagatttcgc tgcctatcgg 1200 agccgagtga aattttctag atcagctgat gctcccgcct atcagcaggg acagaatcaa 1260 ctttacaatg agctgaacct gggtcgcaga gaagagtacg acgttttgga caaacgccgg 1320 ggccgagatc ctgagatggg ggggaagccg agaaggaaga atcctcaaga aggcctgtac 1380 aacgagcttc aaaaagacaa aatggctgag gcgtactctg agatcggcat gaagggcgag 1440 cggagacgag gcaagggtca cgatggcttg tatcagggcc tgagtacagc cacaaaggac 1500 acctatgacg ccctccacat gcaggcactg cccccacgct ag 1542 <![CDATA[<210> 84]]> <![CDATA[<211> 513]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 84]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 20 25 30 Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 35 40 45 Ser Ile Ser Ser Gly Ala Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro 50 55 60 Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile His Tyr Ser Gly Ser Thr 65 70 75 80 Tyr Ser Asn Pro Ser Leu Lys Ser Arg Ile Thr Ile Ser Leu Asp Thr 85 90 95 Ser Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Gln Glu Asp Tyr Gly Gly Leu Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met 145 150 155 160 Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ile Thr 165 170 175 Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Thr Asp Leu Ala Trp Tyr 180 185 190 Gln Gln Met Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser 195 200 205 Thr Arg Ala Thr Gly Phe Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Phe Ala 225 230 235 240 Val Tyr Tyr Cys Gln His Tyr Lys Thr Trp Pro Leu Thr Phe Gly Gly 245 250 255 Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala Leu Ser Asn Ser Ile 260 265 270 Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr 275 280 285 Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 290 295 300 Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 305 310 315 320 Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 325 330 335 Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 340 345 350 Thr Leu Tyr Cys Asn His Arg Asn Arg Ser Lys Arg Ser Arg Leu Leu 355 360 365 His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg 370 375 380 Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg 385 390 395 400 Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 405 410 415 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 420 425 430 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 435 440 445 Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 450 455 460 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 465 470 475 480 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 485 490 495 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 500 505 510 Arg <![CDATA[<210> 85]]> <![CDATA[<211> 993]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 85]]> Met Pro Ala Leu Ala Arg Asp Gly Gly Gln Leu Pro Leu Leu Val Val 1 5 10 15 Phe Ser Ala Met Ile Phe Gly Thr Ile Thr Asn Gln Asp Leu Pro Val 20 25 30 Ile Lys Cys Val Leu Ile Asn His Lys Asn Asn Asp Ser Ser Val Gly 35 40 45 Lys Ser Ser Ser Tyr Pro Met Val Ser Glu Ser Pro Glu Asp Leu Gly 50 55 60 Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr Val Tyr Glu Ala Ala Ala 65 70 75 80 Val Glu Val Asp Val Ser Ala Ser Ile Thr Leu Gln Val Leu Val Asp 85 90 95 Ala Pro Gly Asn Ile Ser Cys Leu Trp Val Phe Lys His Ser Ser Leu 100 105 110 Asn Cys Gln Pro His Phe Asp Leu Gln Asn Arg Gly Val Val Ser Met 115 120 125 Val Ile Leu Lys Met Thr Glu Thr Gln Ala Gly Glu Tyr Leu Leu Phe 130 135 140 Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile Leu Phe Thr Val Ser Ile 145 150 155 160 Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg Pro Tyr Phe Arg Lys Met 165 170 175 Glu Asn Gln Asp Ala Leu Val Cys Ile Ser Glu Ser Val Pro Glu Pro 180 185 190 Ile Val Glu Trp Val Leu Cys Asp Ser Gln Gly Glu Ser Cys Lys Glu 195 200 205 Glu Ser Pro Ala Val Val Lys Lys Glu Glu Lys Val Leu His Glu Leu 210 215 220 Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg Asn Glu Leu Gly Arg Glu 225 230 235 240 Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn Gln Thr Pro Gln Thr Thr 245 250 255 Leu Pro Gln Leu Phe Leu Lys Val Gly Glu Pro Leu Trp Ile Arg Cys 260 265 270 Lys Ala Val His Val Asn His Gly Phe Gly Leu Thr Trp Glu Leu Glu 275 280 285 Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe Glu Met Ser Thr Tyr Ser 290 295 300 Thr Asn Arg Thr Met Ile Arg Ile Leu Phe Ala Phe Val Ser Ser Val 305 310 315 320 Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys Ser Ser Ser Lys His Pro 325 330 335 Ser Gln Ser Ala Leu Val Thr Ile Val Glu Lys Gly Phe Ile Asn Ala 340 345 350 Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp Gln Tyr Glu Glu Phe Cys 355 360 365 Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln Ile Arg Cys Thr Trp Thr 370 375 380 Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln Lys Gly Leu Asp Asn Gly 385 390 395 400 Tyr Ser Ile Ser Lys Phe Cys Asn His Lys His Gln Pro Gly Glu Tyr 405 410 415 Ile Phe His Ala Glu Asn Asp Asp Ala Gln Phe Thr Lys Met Phe Thr 420 425 430 Leu Asn Ile Arg Arg Lys Pro Gln Val Leu Ala Glu Ala Ser Ala Ser 435 440 445 Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro Leu Pro Ser Trp Thr Trp 450 455 460 Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys Thr Glu Glu Ile Thr Glu 465 470 475 480 Gly Val Trp Asn Arg Lys Ala Asn Arg Lys Val Phe Gly Gln Trp Val 485 490 495 Ser Ser Ser Thr Leu Asn Met Ser Glu Ala Ile Lys Gly Phe Leu Val 500 505 510 Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr Ser Cys Glu Thr Ile Leu 515 520 525 Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile Gln Asp Asn Ile Ser Phe 530 535 540 Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe Ile Val Val Leu Thr Leu 545 550 555 560 Leu Ile Cys His Lys Tyr Lys Lys Gln Phe Arg Tyr Glu Ser Gln Leu 565 570 575 Gln Met Val Gln Val Thr Gly Ser Ser Asp Asn Glu Tyr Phe Tyr Val 580 585 590 Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys Trp Glu Phe Pro Arg Glu 595 600 605 Asn Leu Glu Phe Gly Lys Val Leu Gly Ser Gly Ala Phe Gly Lys Val 610 615 620 Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys Thr Gly Val Ser Ile Gln 625 630 635 640 Val Ala Val Lys Met Leu Lys Glu Lys Ala Asp Ser Ser Glu Arg Glu 645 650 655 Ala Leu Met Ser Glu Leu Lys Met Met Thr Gln Leu Gly Ser His Glu 660 665 670 Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Leu Ser Gly Pro Ile Tyr 675 680 685 Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Tyr Leu Arg 690 695 700 Ser Lys Arg Glu Lys Phe His Arg Thr Trp Thr Glu Ile Phe Lys Glu 705 710 715 720 His Asn Phe Ser Phe Tyr Pro Thr Phe Gln Ser His Pro Asn Ser Ser 725 730 735 Met Pro Gly Ser Arg Glu Val Gln Ile His Pro Asp Ser Asp Gln Ile 740 745 750 Ser Gly Leu His Gly Asn Ser Phe His Ser Glu Asp Glu Ile Glu Tyr 755 760 765 Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu Asp Leu Asn Val Leu Thr 770 775 780 Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln Val Ala Lys Gly Met Glu 785 790 795 800 Phe Leu Glu Phe Lys Ser Cys Val His Arg Asp Leu Ala Ala Arg Asn 805 810 815 Val Leu Val Thr His Gly Lys Val Val Lys Ile Cys Asp Phe Gly Leu 820 825 830 Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg Gly Asn Ala 835 840 845 Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Leu Phe Glu Gly Ile 850 855 860 Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr Gly Ile Leu Leu Trp Glu 865 870 875 880 Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro Gly Ile Pro Val Asp Ala 885 890 895 Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe Lys Met Asp Gln Pro Phe 900 905 910 Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met Gln Ser Cys Trp Ala Phe 915 920 925 Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn Leu Thr Ser Phe Leu Gly 930 935 940 Cys Gln Leu Ala Asp Ala Glu Glu Ala Met Tyr Gln Asn Val Asp Gly 945 950 955 960 Arg Val Ser Glu Cys Pro His Thr Tyr Gln Asn Arg Arg Pro Phe Ser 965 970 975 Arg Glu Met Asp Leu Gly Leu Leu Ser Pro Gln Ala Gln Val Glu Asp 980 985 990 Ser <![CDATA[<210> 86]]> <![CDATA[<211> 63]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 86]]> atggcactcc ccgtaactgc tctgctgctg ccgttggcat tgctcctgca cgccgcacgc 60 ccg 63 <![CDATA[<210> 87]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 87]]> Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro 20 <![CDATA[<210> 88]]> <![CDATA[<211> 45]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 88]]> ggcggtggag gctccggagg ggggggctct ggcggagggg gctcc 45 <![CDATA[<210> 89]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 89]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <![CDATA[<210> 90]]> <![CDATA[<211> 54]]> <![CDATA[<21]]>2> DNA]]> <br/><![CDATA[<213> 智人]]> <br/> <br/><![CDATA[<400> 90]]> <br/><![CDATA[gggtctacat ccggctccgg gaagcccgga agtggcgaag gtagtacaaa gggg 54 <![CDATA[<210> 91]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 91]]> Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr 1 5 10 15 Lys Gly <![CDATA[<210> 92]]> <![CDATA[<211> 126]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 92]]> Ala Ala Gly Cys Gly Cys Gly Gly Cys Ala Gly Gly Ala Ala Gly Ala 1 5 10 15 Ala Gly Cys Thr Cys Cys Thr Cys Thr Ala Cys Ala Thr Thr Thr Thr 20 25 30 Thr Ala Ala Gly Cys Ala Gly Cys Cys Thr Thr Thr Thr Ala Thr Gly 35 40 45 Ala Gly Gly Cys Cys Cys Gly Thr Ala Cys Ala Gly Ala Cys Ala Ala 50 55 60 Cys Ala Cys Ala Gly Gly Ala Gly Gly Ala Ala Gly Ala Thr Gly Gly 65 70 75 80 Cys Thr Gly Thr Ala Gly Cys Thr Gly Cys Ala Gly Ala Thr Thr Thr 85 90 95 Cys Cys Cys Gly Ala Gly Gly Ala Gly Gly Ala Gly Gly Ala Ala Gly 100 105 110 Gly Thr Gly Gly Gly Thr Gly Cys Gly Ala Gly Cys Thr Gly 115 120 125 <![CDATA[<210> 93]]> <![CDATA[<211> 42]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 93]]> Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 <![CDATA[<210> 94]]> <![CDATA[<211> 37]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 94]]> Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly 1 5 10 15 Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser 20 25 30 Thr Leu Ala Lys Ile 35 <![CDATA[<210> 95]]> <![CDATA[<211> 6762]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 質體載體]]> <![CDATA[<400> 95]]> ctgacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga 60 ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg 120 ccacgttcgc cggctttccc cgtcaagctc taaatcgggg gctcccttta gggttccgat 180 ttagtgcttt acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg 240 ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata 300 gtggactctt gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt 360 tataagggat tttgccgatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat 420 ttaacgcgaa ttttaacaaa atattaacgc ttacaatttg ccattcgcca ttcaggctgc 480 gcaactgttg ggaagggcga tcggtgcggg cctcttcgct attacgccag ctggcgaaag 540 ggggatgtgc tgcaaggcga ttaagttggg taacgccagg gttttcccag tcacgacgtt 600 gtaaaacgac ggccagtgaa ttgtaatacg actcactata gggcgacccg gggatggcgc 660 gccagtaatc aattacgggg tcattagttc atagcccata tatggagttc cgcgttacat 720 aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa 780 taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg 840 agtatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc 900 cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct 960 tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt accatgctga 1020 tgcggttttg gcagtacatc aatgggcgtg gatagcggtt tgactcacgg ggatttccaa 1080 gtctccaccc cattgacgtc aatgggagtt tgttttggca ccaaaatcaa cgggactttc 1140 caaaatgtcg taacaactcc gccccattga cgcaaatggg cggtaggcgt gtacggtggg 1200 aggtctatat aagcagagct ggtttagtga accggggtct ctctggttag accagatctg 1260 agcctgggag ctctctggct aactagggaa cccactgctt aagcctcaat aaagcttgcc 1320 ttgagtgctt caagtagtgt gtgcccgtct gttgtgtgac tctggtaact agagatccct 1380 cagacccttt tagtcagtgt ggaaaatctc tagcagtggc gcccgaacag ggacttgaaa 1440 gcgaaaggga aaccagagga gctctctcga cgcaggactc ggcttgctga agcgcgcacg 1500 gcaagaggcg aggggcggcg actggtgagt acgccaaaaa ttttgactag cggaggctag 1560 aaggagagag atgggtgcga gagcgtcagt attaagcggg ggagaattag atcgcgatgg 1620 gaaaaaattc ggttaaggcc agggggaaag aaaaaatata aattaaaaca tatagtatgg 1680 gcaagcaggg agctagaacg attcgcagtt aatcctggcc tgttagaaac atcagaaggc 1740 tgtagacaaa tactgggaca gctacaacca tcccttcaga caggatcaga agaacttaga 1800 tcattatata atacagtagc aaccctctat tgtgtgcatc aaaggataga gataaaagac 1860 accaaggaag ctttagacaa gatagaggaa gagcaaaaca aaagtaagac caccgcacag 1920 caagccgccg ctgatcttca gacctggagg aggagatatg agggacaatt ggagaagtga 1980 attatataaa tataaagtag taaaaattga accattagga gtagcaccca ccaaggcaaa 2040 gagaagagtg gtgcagagag aaaaaagagc agtgggaata ggagctttgt tccttgggtt 2100 cttgggagca gcaggaagca ctatgggcgc agcgtcaatg acgctgacgg tacaggccag 2160 acaattattg tctggtatag tgcagcagca gaacaatttg ctgagggcta ttgaggcgca 2220 acagcatctg ttgcaactca cagtctgggg catcaagcag ctccaggcaa gaatcctggc 2280 tgtggaaaga tacctaaagg atcaacagct cctggggatt tggggttgct ctggaaaact 2340 catttgcacc actgctgtgc cttggaatgc tagttggagt aataaatctc tggaacagat 2400 ttggaatcac acgacctgga tggagtggga cagagaaatt aacaattaca caagcttaat 2460 acactcctta attgaagaat cgcaaaacca gcaagaaaag aatgaacaag aattattgga 2520 attagataaa tgggcaagtt tgtggaattg gtttaacata acaaattggc tgtggtatat 2580 aaaattattc ataatgatag taggaggctt ggtaggttta agaatagttt ttgctgtact 2640 ttctatagtg aatagagtta ggcagggata ttcaccatta tcgtttcaga cccacctccc 2700 aaccccgagg ggacccgaca ggcccgaagg aatagaagaa gaaggtggag agagagacag 2760 agacagatcc attcgattag tgaacggatc tcgacggtat cggttaactt ttaaaagaaa 2820 aggggggatt ggggggtaca gtgcagggga aagaatagta gacataatag caacagacat 2880 acaaactaaa gaattacaaa aacaaattac aaaattcaaa attttatcgc gatcgcggaa 2940 tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 3000 ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 3060 gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 3120 acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 3180 ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 3240 cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 3300 cctcactcgg cgcgccagtc cttcgaagta gatctttgtc gatcctacca tccactcgac 3360 acacccgcca gcggccgctg ccaagcttcc gagctctcga attaattcac ggtacccacc 3420 atggcctagg gagactagtc gaatcgatat caacctctgg attacaaaat ttgtgaaaga 3480 ttgactggta ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg 3540 cctttgtatc atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc 3600 tggttgctgt ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc 3660 actgtgtttg ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt 3720 tccgggactt tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt 3780 gcccgctgct ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg 3840 aagctgacgt ccttttcatg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg 3900 tccttctgct acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg 3960 ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt 4020 tgggccgcct ccccgcctgg ttaattaaag tacctttaag accaatgact tacaaggcag 4080 ctgtagatct tagccacttt ttaaaagaaa aggggggact ggaagggcga attcactccc 4140 aacgaagaca agatctgctt tttgcttgta ctgggtctct ctggttagac cagatctgag 4200 cctgggagct ctctggctaa ctagggaacc cactgcttaa gcctcaataa agcttgcctt 4260 gagtgcttca agtagtgtgt gcccgtctgt tgtgtgactc tggtaactag agatccctca 4320 gaccctttta gtcagtgtgg aaaatctcta gcaggcatgc cagacatgat aagatacatt 4380 gatgagtttg gacaaaccac aactagaatg cagtgaaaaa aatgctttat ttgtgaaatt 4440 tgtgatgcta ttgctttatt tgtaaccatt ataagctgca ataaacaagt taacaacaac 4500 aattgcattc attttatgtt tcaggttcag ggggaggtgt gggaggtttt ttggcgcgcc 4560 atcgtcgagg ttccctttag tgagggttaa ttgcgagctt ggcgtaatca tggtcatagc 4620 tgtttcctgt gtgaaattgt tatccgctca caattccaca caacatacga gccggaagca 4680 taaagtgtaa agcctggggt gcctaatgag tgagctaact cacattaatt gcgttgcgct 4740 cactgcccgc tttccagtcg ggaaacctgt cgtgccagct gcattaatga atcggccaac 4800 gcgcggggag aggcggtttg cgtattgggc gctcttccgc ttcctcgctc actgactcgc 4860 tgcgctcggt cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt 4920 tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg 4980 ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg 5040 agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat 5100 accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta 5160 ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcat agctcacgct 5220 gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc 5280 ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa 5340 gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg 5400 taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact agaagaacag 5460 tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt 5520 gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta 5580 cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc 5640 agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca 5700 cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa 5760 cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcagcg atctgtctat 5820 ttcgttcatc catagttgcc tgactccccg tcgtgtagat aactacgata cgggagggct 5880 taccatctgg ccccagtgct gcaatgatac cgcgagaccc acgctcaccg gctccagatt 5940 tatcagcaat aaaccagcca gccggaaggg ccgagcgcag aagtggtcct gcaactttat 6000 ccgcctccat ccagtctatt aattgttgcc gggaagctag agtaagtagt tcgccagtta 6060 atagtttgcg caacgttgtt gccattgcta caggcatcgt ggtgtcacgc tcgtcgtttg 6120 gtatggcttc attcagctcc ggttcccaac gatcaaggcg agttacatga tcccccatgt 6180 tgtgcaaaaa agcggttagc tccttcggtc ctccgatcgt tgtcagaagt aagttggccg 6240 cagtgttatc actcatggtt atggcagcac tgcataattc tcttactgtc atgccatccg 6300 taagatgctt ttctgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgc 6360 ggcgaccgag ttgctcttgc ccggcgtcaa tacgggataa taccgcgcca catagcagaa 6420 ctttaaaagt gctcatcatt ggaaaacgtt cttcggggcg aaaactctca aggatcttac 6480 cgctgttgag atccagttcg atgtaaccca ctcgtgcacc caactgatct tcagcatctt 6540 ttactttcac cagcgtttct gggtgagcaa aaacaggaag gcaaaatgcc gcaaaaaagg 6600 gaataagggc gacacggaaa tgttgaatac tcatactctt cctttttcaa tattattgaa 6660 gcatttatca gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata 6720 aacaaatagg ggttccgcgc acatttcccc gaaaagtgcc ac 6762 <![CDATA[<210> 96]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 96]]> Ile Pro Tyr Tyr Gly Ser Gly Ser His Asn Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> 97]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 97]]> Asn Tyr Gly Met His 1 5 <![CDATA[<210> 98]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 98]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggata caccttcacc ggctactata tacactgggt gcgacaggcc 120 cctgaacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180 gcacagaagt ttcagggcag ggtcaccatg gccagggaca cgtccatcag cacagtttac 240 atggacctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaatacgc 300 ggtggtaact cggtctttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357
Claims (78)
- 一種嵌合抗原受體,其包含特異性結合至FLT3之抗原結合分子,其中該抗原結合分子包含: a) 可變重鏈CDR1,其包含與SEQ ID NO: 17之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 b) 可變重鏈CDR2,其包含與SEQ ID NO:18或SEQ ID NO:26之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 c) 可變重鏈CDR3,其包含與SEQ ID NO SEQ ID NO: 19或SEQ ID NO:27之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 d) 可變輕鏈CDR1,其包含與SEQ ID NO:22或SEQ ID NO:30之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 e) 可變輕鏈CDR2,其包含與SEQ ID NO:23或31之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 f) 可變輕鏈CDR3,其包含與SEQ ID:24或SEQ ID NO:32之胺基酸序列相差不多於3、2、1、或0個胺基酸殘基的胺基酸序列;或 g) 可變重鏈CDR1,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變重鏈CDR1序列之胺基酸序列;或 h) 可變重鏈CDR2,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變重鏈CDR2序列之胺基酸序列;或 i) 可變重鏈CDR3,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變重鏈CDR3序列之胺基酸序列;或 j) 可變輕鏈CDR1,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變輕鏈CDR1序列之胺基酸序列;或 k) 可變輕鏈CDR2,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變輕鏈CDR2序列之胺基酸序列;或 l) 可變輕鏈CDR3,其包含殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變輕鏈CDR3序列之胺基酸序列;或 m) 可變重鏈序列,其與殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變重鏈序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個殘基;或 n) 可變輕鏈序列,其與殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變輕鏈序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個殘基。
- 如請求項1之嵌合抗原受體,其進一步包含至少一個共刺激域。
- 如請求項1之嵌合抗原受體,其進一步包含至少一個活化域。
- 如請求項2之嵌合抗原受體,其中該共刺激域係以下項之傳訊區:CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
- 如請求項4之嵌合抗原受體,其中該共刺激域包含CD28。
- 如請求項5之嵌合抗原受體,其中該CD28共刺激域包含與SEQ ID NO: 2、SEQ ID NO: 4、SEQ ID NO: 6、或SEQ ID NO: 8之序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的序列。
- 如請求項3之嵌合抗原受體,其中該CD8共刺激域包含與SEQ ID NO: 14之序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的序列。
- 如請求項3之嵌合抗原受體,其中該活化域包含CD3。
- 如請求項7之嵌合抗原受體,其中該CD3包含CD3 ζ。
- 如請求項8之嵌合抗原受體,其中該CD3 ζ包含與SEQ ID NO: 10之序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的序列。
- 如請求項1之嵌合抗原受體,其中該共刺激域包含與SEQ ID NO: 2之序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個胺基酸殘基的序列,且該活化域包含與SEQ ID NO: 10之序列相差不多於10、9、10、8、7、6、5、4、3、2、1、或0個胺基酸殘基的序列。
- 一種多核苷酸,其編碼如請求項1之嵌合抗原受體。
- 一種載體,其包含如請求項12之多核苷酸。
- 如請求項13之載體,其係逆轉錄病毒載體、DNA載體、質體、RNA載體、腺病毒載體、腺病毒相關載體、慢病毒載體、或其任何組合。
- 一種免疫細胞,其包含如請求項13之載體。
- 如請求項15之免疫細胞,其中該免疫細胞係T細胞、腫瘤浸潤樹狀淋巴球(TIL)、NK細胞、TCR表現細胞、細胞、或NK-T細胞。
- 如請求項16之免疫細胞,其中該細胞係自體T細胞。
- 如請求項16之免疫細胞,其中該細胞係同種異體T細胞。
- 如請求項15之免疫細胞,其中該載體係引入至從患者身體分離或從取自患者身體之樣品生長的細胞中。
- 如請求項15之免疫細胞,其中該載體係引入至從予體身體分離或從取自患者身體之樣品生長的細胞中。
- 一種醫藥組成物,其包含如請求項15之免疫細胞。
- 一種嵌合抗原受體,其包含: (a) 殖株10E3之VH區及殖株10E3之VL區; (b) 殖株2E7之VH區及殖株2E7之VL區; (c) 殖株8B5之VH區及殖株8B5之VL區; (d) 殖株4E9之VH區及殖株4E9之VL區;或 (e) 殖株11F11之VH區和殖株11F11之VL區, 其中該VH及VL區係由至少一個連接子連接。
- 如請求項22之嵌合抗原受體,其中該連接子包含scFv G4S連接子或scFv Whitlow連接子。
- 如請求項22之嵌合抗原受體,其進一步包含共刺激域。
- 如請求項22之嵌合抗原受體,其進一步包含活化域。
- 如請求項24之嵌合抗原受體,其中該共刺激域係以下項之傳訊區:CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
- 一種免疫細胞,其包含如請求項22之嵌合抗原受體。
- 如請求項27之免疫細胞,其中該免疫細胞係T細胞、腫瘤浸潤樹狀淋巴球(TIL)、NK細胞、TCR表現細胞、細胞、或NK-T細胞。
- 如請求項28之T細胞,其係自體T細胞。
- 如請求項29之T細胞,其係同種異體T細胞。
- 一種醫藥組成物,其包含如請求項27之細胞。
- 一種經分離之多核苷酸,其包含編碼如請求項22之嵌合抗原受體的序列。
- 一種載體,其包含如請求項32之多核苷酸。
- 一種免疫細胞,其包含如請求項33之載體。
- 如請求項34之免疫細胞,其中該免疫細胞係T細胞、腫瘤浸潤樹狀淋巴球(TIL)、NK細胞、TCR表現細胞、細胞、或NK-T細胞。
- 如請求項35之T細胞,其係自體T細胞。
- 如請求項35之T細胞,其係同種異體T細胞。
- 一種經分離之多肽,其包含以下項之胺基酸序列:構築體10E3 CD28、構築體10E3 CD28T、構築體10E3 CD8、構築體2E7 CD28、構築體2E7 CD28T、構築體2E7 CD8、構築體8B5 CD28、構築體8B5 CD28T、構築體8B5 CD8、構築體4E9 CD28、構築體4E9 CD28T、構築體4E9 CD8、構築體11F11 CD28、構築體11F11 CD28T、或構築體11F11 CD8。
- 一種載體,其編碼如請求項38之多肽。
- 一種免疫細胞,其包含如請求項38之多肽。
- 如請求項40之免疫細胞,其中該免疫細胞係T細胞、腫瘤浸潤樹狀淋巴球(TIL)、NK細胞、TCR表現細胞、細胞、或NK-T細胞。
- 如請求項41之T細胞,其係自體T細胞。
- 如請求項41之T細胞,其係同種異體T細胞。
- 一種經分離之多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子之嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子包含可變重鏈CDR3,該可變重鏈CDR3包含殖株10E3、殖株2E7、殖株8B5之可變重鏈CDR3之胺基酸序列。
- 如請求項44之多核苷酸,其進一步包含活化域。
- 如請求項45之多核苷酸,其中該活化域係CD3。
- 如請求項46之多核苷酸,其中該CD3係CD3 ζ。
- 如請求項47之多核苷酸,其中該CD3 ζ包含SEQ ID NO: 9中所闡明之胺基酸序列。
- 如請求項44之多核苷酸,其進一步包含共刺激域。
- 如請求項49之多核苷酸,其中該共刺激域係以下項之傳訊區:CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
- 如請求項50之多核苷酸,其中該CD28共刺激域編碼SEQ ID NO 2中所闡明之胺基酸序列。
- 一種載體,其包含如請求項41之多核苷酸。
- 一種免疫細胞,其包含如請求項49之載體。
- 如請求項50之免疫細胞,其中該免疫細胞係T細胞、腫瘤浸潤淋巴球(TIL)、NK細胞、TCR表現細胞、樹狀細胞、或NK-T細胞。
- 如請求項51之T細胞,其係自體T細胞。
- 如請求項51之T細胞,其係同種異體T細胞。
- 一種經分離之多核苷酸,其編碼嵌合抗原受體(CAR)或T細胞受體(TCR),該CAR或TCR包含特異性結合至FLT3之抗原結合分子,其中該抗原結合分子包含: a. 可變重鏈序列,其與殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變重鏈序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個殘基;及/或 b. 可變輕鏈序列,其與殖株10E3、殖株2E7、殖株8B5、殖株4E9、或殖株11F11之可變輕鏈序列相差不多於10、9、8、7、6、5、4、3、2、1、或0個殘基。
- 如請求項54之多核苷酸,其進一步包含活化域。
- 如請求項55之多核苷酸,其中該活化域係CD3。
- 如請求項56之多核苷酸,其中該CD3係CD3 ζ。
- 如請求項60之多核苷酸,其中該CD3 ζ包含SEQ ID NO: 9中所闡明之胺基酸序列。
- 如請求項57之多核苷酸,其進一步包含共刺激域。
- 如請求項62之多核苷酸,其中該共刺激域係以下項之傳訊區:CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡-1 (PD-1)、可誘導型T細胞共刺激因子(ICOS)、淋巴球功能相關抗原-1 (LFA-1 (CDl la/CD18)、CD3 γ、CD3 δ、CD3 ε、CD247、CD276 (B7-H3)、LIGHT、(TNFSF14)、NKG2C、Ig α (CD79a)、DAP-10、Fc γ受體、MHC I類分子、TNF受體蛋白、免疫球蛋白蛋白質、細胞介素受體、整聯蛋白、傳訊淋巴球活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2R γ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Lyl08)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體、或其任何組合。
- 如請求項63之多核苷酸,其中該CD28共刺激域包含SEQ ID NO 3中所闡明之核苷酸序列。
- 如請求項64之多核苷酸,其中該CD28共刺激域包含SEQ ID NO 1中所闡明之核苷酸序列。
- 一種經分離之多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子的嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子重鏈包含CDR1 (SEQ ID NO: 17)、CDR2 (SEQ ID NO: 18)、及CDR3 (SEQ ID NO: 19),且該抗原結合分子輕鏈包含CDR1 (SEQ ID NO: 22)、CDR2 (SEQ ID NO: 23)、及CDR3 (SEQ ID NO: 24)。
- 一種經分離之多核苷酸,其編碼包含特異性結合至FLT3之抗原結合分子的嵌合抗原受體(CAR)或T細胞受體(TCR),其中該抗原結合分子重鏈包含CDR1 (SEQ ID NO:17)、CDR2 (SEQ ID NO:26)、及CDR3 (SEQ ID NO:27),且該抗原結合分子輕鏈包含CDR1 (SEQ ID NO:30)、CDR2 (SEQ ID NO:31)、及CDR3 (SEQ ID NO:32)。
- 一種治療有需要之受試者之疾病或病症之方法,其包含向該受試者投與如請求項12、44、57、66、或67之多核苷酸。
- 一種治療有需要之受試者之疾病或病症之方法,其包含向該受試者投與如請求項38之多肽。
- 一種治療有需要之受試者之疾病或病症之方法,其包含向該受試者投與如請求項1或22之嵌合抗原受體。
- 一種治療有需要之受試者之疾病或病症之方法,其包含向該受試者投與如請求項15、27、34、40、或53之細胞。
- 一種治療有需要之受試者之疾病或病症之方法,其包含向該受試者投與如請求項21或31之醫藥組成物。
- 如請求項68、69、70、71、或72中任一項之方法,其中該疾病或病症係癌症。
- 如請求項73之方法,其中該癌症係白血病、淋巴瘤、或骨髓瘤。
- 如請求項73之方法,其中該癌症係AML。
- 如請求項68、69、70、71、或72中任一項之方法,其中該疾病或病症係以下項中之至少一者:急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、慢性骨髓單核球白血病(CMML)、幼年型骨髓單核球白血病、非典型慢性骨髓性白血病、急性前骨髓球白血病(APL)、急性單核母細胞性白血病、急性紅血球系白血病、急性巨核母細胞性白血病、骨髓增殖異常症候群(MDS)、骨髓增生性病症、骨髓性贅生物、骨髓性肉瘤、及炎性/自體免疫疾病。
- 如請求項76之方法,其中該炎性/自體免疫疾病係以下項中之至少一者:類風濕性關節炎、牛皮癬、過敏、氣喘、克羅恩氏病、IBD、IBS、纖維肌痛、肥大細胞增多症、及乳糜瀉。
- 如請求項14之慢病毒載體,其中該慢病毒載體係pGAR載體。
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