TWI758419B - 標靶il-13ra2的抗體及其應用 - Google Patents
標靶il-13ra2的抗體及其應用 Download PDFInfo
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Abstract
本發明涉及抗IL-13RA2的抗體及其應用。本發明揭示了新的專一性辨識IL-13RA2的抗體。本發明的抗體可以被應用於製備標靶性抗腫瘤藥物以及診斷腫瘤的藥物。
Description
本發明涉及腫瘤免疫治療或診斷領域,更具體地,涉及專一辨識IL-13RA2的抗體及其應用。
惡性神經膠質瘤(malignant gliomas, MG),包括多形性成膠質細胞瘤和膠質母細胞瘤,在美國每年的新增病例有20000例。根據美國腦部腫瘤協會的統計,截至2010年,美國有140000人患有惡性的腦部腫瘤。儘管MG是一種罕見的疾病,但是它的惡性程度以及致死率是非常高的。現有的標準治療手段,效果非常有限,外科手術以及放射治療後的五年生存率也非常低。對於手術後復發的病人,新的治療選擇也非常少。因此,開發新的標的,新的治療手段是廣大病人的迫切需求。
白介素13受體a2 (Interleukin-13 Receptor subunit alpha 2, IL-13RA2)是專一性高表現於人神經膠質瘤等惡性腫瘤細胞表面的腫瘤專一性標誌物(Dehinski等,(1995) Clin. Cancer Res. 1, 1253-1258)。人IL-13RA2做為人神經膠質瘤的治療標的早在1988年已引起美國FDA的注意,該組織先後製備了針對人IL-13RA2治療標的的藥物IL-13-PE38和針對人IL-13RA2的單鏈抗體scFv-PE融合分子。儘管IL-13-PE38已在神經膠質瘤、頭頸部腫瘤、卵巢癌和腎癌等惡性腫瘤的治療中取得了療效並已被美國FDA批准進入臨床期治療,但由於在治療過程中,IL-13-PE38不僅與腫瘤細胞表面專一性表現的人IL-13RA2結合,也可以與表現於正常組織細胞表面的IL-13RA1結合,損傷正常組織和細胞。由於缺乏嚴格的標靶性,限制了IL-13-PE38的進一步應用。
本發明目的在於發現專一性針對IL-13RA2的抗體以及開發標靶IL-13RA2的免疫效應細胞。
本發明的目的在於提供抗IL-13RA2的抗體及其應用。
在第一方面,本發明提供了一種專一性辨識IL-13RA2的抗體,所述抗體與內源性表現IL-13RA2的U251細胞的結合相對親和力EC50
不高於100 nM,優選不高於10 nM,更優選0.01-10 nM。
在一優選例中,所述相對親和力數據的處理使用GraphPad Prism 5軟體(GraphPad Software, Inc)。
在具體的實施方式中,所述抗體選自以下的任一種: (1)抗體,其包含重鏈可變區,所述重鏈可變區包含SEQ ID NO: 9、45、46、47、48、49、50、51、63、或64所示的HCDR1,和/或包含SEQ ID NO: 10、52、53、54、55、56、57、58、65、或66所示的HCDR2,和/或包含SEQ ID NO: 11或SEQ ID NO: 12任一所示的HCDR3; (2)抗體,其包含輕鏈可變區,所述輕鏈可變區包含SEQ ID NO: 13所示的LCDR1,和/或包含SEQ ID NO: 14所示的LCDR2,和/或包含SEQ ID NO: 15或SEQ ID NO: 16任一所示的LCDR3; (3)抗體,包含(1)所述抗體的重鏈可變區及(2)所述抗體的輕鏈可變區; (4)抗體,(1)~(3)中任一項所述的抗體的變體,且具備與(1)~(3)中任一項所述的抗體相同或相似的活性。
在具體的實施方式中,所述抗體選自以下的任一種: (1)抗體,包含輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 4所示的胺基酸序列、SEQ ID NO: 8所示的胺基酸序列或SEQ ID NO: 4和SEQ ID NO: 8的變體的序列; (2)抗體,包含重鏈可變區,所述重鏈可變區具有SEQ ID NO: 2、6、29、31、33、35、37、39、41、43、59或61所示的序列、或上述序列的變體; (3)抗體,包含(1)所述抗體的重鏈可變區及(2)所述抗體的輕鏈可變區。
在具體的實施方式中,所述的抗體的輕鏈可變區包含SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15或SEQ ID NO: 16所示的LCDR3。
在具體的實施方式中,所述的抗體的輕鏈可變區具有SEQ ID NO: 4或8所示的序列,或具有與上述任一序列至少80%,例如,85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%相似性的序列。
在具體的實施方式中,所述抗體的重鏈可變區包含SEQ ID NO: 9、45、46、47、48、49、50、51、63或64所示的HCDR1,SEQ ID NO: 10、52、53、54、55、56、57、58、65或66所示的HCDR2,和SEQ ID NO: 11或SEQ ID NO: 12所示的HCDR3。
在具體的實施方式中,所述抗體的重鏈可變區具有SEQ ID NO: 2、6、29、31、33、35、37、39、41、43、59或61所示的序列,或具有與上述任一序列至少80%,更優選85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%相似性的序列。
在具體的實施方式中,所述輕鏈可變區的CDR區和所述重鏈可變區的CDR區具有下述任選的序列或其變體: (1) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO:9所示的HCDR1,SEQ ID NO: 10所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (2) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 16所示的LCDR3;SEQ ID NO: 9所示的HCDR1,SEQ ID NO: 10所示的HCDR2和SEQ ID NO: 12所示的HCDR3; (3) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 16所示的LCDR3;SEQ ID NO: 64所示的HCDR1,SEQ ID NO: 66所示的HCDR2和SEQ ID NO: 12所示的HCDR3; (4) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 45所示的HCDR1,SEQ ID NO: 52所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (5) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 16所示的LCDR3;SEQ ID NO: 63所示的HCDR1,SEQ ID NO: 65所示的HCDR2和SEQ ID NO: 12所示的HCDR3; (6) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 50所示的HCDR1,SEQ ID NO:56所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (7) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 46所示的HCDR1,SEQ ID NO: 52所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (8) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 48所示的HCDR1,SEQ ID NO: 54所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (9) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 47所示的HCDR1,SEQ ID NO: 53所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (10) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 49所示的HCDR1,SEQ ID NO: 55所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (11) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 51所示的HCDR1,SEQ ID NO: 57所示的HCDR2和SEQ ID NO: 11所示的HCDR3; (12) SEQ ID NO: 13所示的LCDR1,SEQ ID NO: 14所示的LCDR2和SEQ ID NO: 15所示的LCDR3;SEQ ID NO: 49所示的HCDR1,SEQ ID NO: 58所示的HCDR2和SEQ ID NO: 11所示的HCDR3。
在具體的實施方式中, (1)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 2所示的序列或其變體的序列; (2)所述輕鏈可變區具有SEQ ID NO: 8所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 6所示的序列或其變體的序列; (3)所述輕鏈可變區具有SEQ ID NO: 8所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 61所示的序列或其變體的序列; (4)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 29所示的序列或其變體的序列; (5)所述輕鏈可變區具有SEQ ID NO: 8所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 59所示的序列或其變體的序列; (6)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 39所示的序列或其變體的序列; (7)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 31所示的序列或其變體的序列; (8)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 35所示的序列或其變體的序列; (9)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 33所示的序列或其變體的序列; (10)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 37所示的序列或其變體的序列; (11)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 41所示的序列或其變體的序列; (12)所述輕鏈可變區具有SEQ ID NO: 4所示的序列或其變體的序列,所述重鏈可變區具有SEQ ID NO: 43所示的序列或其變體的序列。
在第二方面,本發明提供一種專一性辨識IL-13RA2的抗體,該抗體與第一方面所述的抗體辨識相同的抗原決定部位。
在第三方面,本發明提供一種專一性辨識IL-13RA2的抗體,該抗體與第一方面所述的抗體競爭性結合IL-13RA2。
在第四方面,本發明提供編碼第一-第三方面所述的抗體的核酸。
在第五方面,本發明提供一種表現載體,其包含第四方面所述的核酸。
在第六方面,本發明提供一種宿主細胞,其包含第五方面所述的表現載體或基因組中整合有第四方面所述的核酸。
在第七方面,本發明提供一種多功能免疫綴合物,所述的多功能免疫綴合物包括: 第一-第三方面所述的抗體;以及 與之連接的功能性分子;所述的功能性分子選自:標靶腫瘤表面標誌物的分子,抑制腫瘤的分子,標靶免疫細胞的表面標誌物的分子或可偵測標記物。
在具體的實施方式中,所述的標靶腫瘤表面標誌物的分子是結合除IL-13RA2外的其他腫瘤表面標誌物的抗體或配體;或 所述的抑制腫瘤的分子是抗腫瘤的細胞因子或抗腫瘤的毒素;較佳地,所述的細胞因子選自:IL-12、IL-15、I型干擾素、TNF-alpha。
在具體的實施方式中,所述的標靶免疫細胞的表面標誌物的分子是結合免疫細胞表面標誌物的抗體,優選的,所述的結合免疫細胞表面標誌物選自:CD3,CD16,CD28,更佳的,所述的結合免疫細胞表面標誌物的抗體是抗CD3抗體。
在具體的實施方式中,所述的標靶免疫細胞的表面標誌物的分子是結合T細胞表面標誌物的抗體,其與第一方面-第三方面任一所述的抗體形成T細胞參與的雙功能抗體。
在具體的實施方式中,所述多功能免疫綴合物是融合多肽,在第一方面-第三方面任一所述的抗體以及與之連接的功能性分子之間,還包括連接肽。
在第八方面,本發明提供編碼第七方面所述的多功能免疫綴合物的核酸。
在第九方面,本發明提供第一-第三方面所述的抗體的嵌合抗原受體,其特徵在於,所述的嵌合抗原受體包含順序連接的:第一-第三方面所述的抗體、跨膜區和胞內訊號區。
在具體的實施方式中,所述的胞內訊號區選自:CD3ζ、CD3γ、CD3δ、CD3ε、FcRγ(FCER1G)、FcRβ(FcεR1b)、CD79a、CD79b、FcγRIIa、DAP10和DAP12的蛋白質的功能訊號傳導結構域,或其組合。
在具體的實施方式中,所述的胞內訊號區還具有共刺激訊號傳導結構域,所述共刺激訊號傳導結構域包含選自以下蛋白的功能訊號傳導結構域:CD27、CD28、4-1BB (CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴細胞功能相關的抗原-1 (LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、專一性結合CD83的配體、CDS、ICAM-1、GITR、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRF1)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244, 2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69 、SLAMF6 (NTB-A, Ly108)、SLAM (SLAMF1, CD150, IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46和NKG2D,或其組合。
在具體的實施方式中,所述的嵌合抗原受體包括如下的順序連接的抗體、跨膜區和胞內訊號區: 第一-第三方面所述的抗體、CD8和CD3ζ; 第一-第三方面所述的抗體、CD8、CD137和CD3ζ;或 第一-第三方面所述的抗體、CD28分子的跨膜區、CD28分子的胞內訊號區和CD3ζ;或 第一-第三方面所述的抗體、CD28分子的跨膜區、CD28分子的胞內訊號區、CD137和CD3ζ。
在第十方面,本發明提供編碼第九方面所述的嵌合抗原受體的核酸。
在第十一方面,本發明提供一種表現載體,其包含第十方面所述的核酸。
在第十二方面,本發明提供一種病毒,所述病毒包含第十一方面所述的載體。
在第十三方面,本發明提供一種嵌合抗原受體修飾的免疫細胞,其轉導有第十方面所述的核酸,或第十一方面所述的表現載體或第十二方面所述的病毒;或其表面表現第九方面所述的嵌合抗原受體; 較佳地,所述的免疫細胞為:T淋巴細胞、NK細胞或者NKT淋巴細胞。 在具體的實施方式中,所述的免疫細胞還攜帶外源的細胞因子的編碼序列;或 其還表現另一種嵌合抗原受體,該受體不含有CD3ζ;或 其還表現趨化因子受體;較佳地,所述的趨化因子受體包括:CCR;或 其還表現能降低PD-1表現的siRNA或者阻斷PD-L1的蛋白;或其細胞中內源性的PD-1被基因編輯技術剔除;或 其還表現安全開關。
在第十四方面,本發明提供一種藥物組成物,其包括: 第一-第三方面所述的抗體或編碼該抗體的核酸;或 第七方面所述的免疫綴合物或編碼該綴合物的核酸;或 第九方面所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸;或 第十三方面所述的嵌合抗原受體修飾的免疫細胞; 以及藥學上可接受的載體或賦形劑。
在第十五方面,本發明提供一種套組,其包括: 容器,以及位於容器中的第十四方面所述的藥物組成物;或 容器,以及位於容器中的第一-第三方面所述的抗體或編碼該抗體的核酸;或第七方面所述的免疫綴合物或編碼該綴合物的核酸;或第九方面所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸;或第十三方面所述的嵌合抗原受體修飾的免疫細胞。
在第十六方面,本發明提供第一-第三方面所述的抗體或編碼該抗體的核酸;或第七方面所述的免疫綴合物或編碼該綴合物的核酸;或第九方面所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸;或第十三方面所述的嵌合抗原受體修飾的免疫細胞的用途,用於治療表現IL-13RA2的腫瘤, 較佳的,所述的表現IL-13RA2的腫瘤為腦癌、胰腺癌、卵巢癌、腎癌、膀胱癌、胰腺癌、胃癌、腸癌、頭頸癌、甲狀腺癌、前列腺癌、卡波氏肉瘤。更佳的,所述的腦癌選自星形細胞瘤、腦膜瘤、少突神經膠質瘤、神經膠質瘤。
應理解,在本發明範圍內中,本發明的上述各技術特徵和在下文(如實施例)中具體描述的各技術特徵之間都可以互相組合,從而構成新的或優選的技術方案。限於篇幅,在此不再一一累述。
本發明人經過深入的研究篩選,獲得了專一性辨識IL-13RA2的抗體,包括單鏈抗體和人源化抗體。本發明的抗體可以被應用於製備各種標靶性抗腫瘤藥物以及診斷腫瘤的藥物。
為了更易於理解本發明,首先定義一些術語。
本文中的術語“IL-13RA2”,也是CD213A2,是白介素-13受體複合物的一個亞單位。由380個胺基酸殘基組成的跨膜蛋白(NCBI Reference Sequence: NP_000631.1)。它與IL-13RA1 (NCBI Reference Sequence: NP_001551.1)相類似,與IL-13結合很強,但是沒有胞內訊號域。
本文中的術語“抗體”指免疫系統的抗原結合蛋白,包括具有抗原結合區域的完整的全長抗體,還包括具有“抗原結合部分”或“抗原結合區域”的片段、或其單鏈例如單鏈可變片段(scFv),還包括本文提供的抗體的變體。抗體片段包括但不限於:(i)由VL、VH、CL和CH1結構域組成的Fab片段,包括Fab’和Fab’-SH,(ii) VH和CH1結構域組成的Fd片段,(iii)由單個抗體的VL和VH結構域組成的Fv片段;(iv)由單個可變區組成的dAb片段(Ward等,1989,Nature 341: 544-546);(v) F(ab’)2片段,包含2個連接的Fab片段的二價片段;(vi)單鏈Fv分子抗原結合位址;(vii)雙專一性單鏈Fv二聚體(PCT/US92/09965);(viii)“二體”或“三體”,透過基因融合構建的多價或多專一性片段;和(ix)與相同或不同抗體遺傳融合的scFv。
本文中的術語“Fc”或“Fc區”包括包含除第一恆定區免疫球蛋白結構域以外的抗體恆定區的多肽。因而,Fc指IgA、IgD和IgG的最後兩個恆定區免疫球蛋白結構域,和IgE和IgM的最後三個恆定區免疫球蛋白結構域,和這些結構域N端的柔性鉸鏈。對於IgA和IgM,Fc可包括J鏈。對於IgG,Fc包括免疫球蛋白結構域Cγ2和Cγ3和在Cγ1和Cγ2之間的鉸鏈。雖然Fc區的邊界可以改變,但人IgG重鏈Fc區通常定義為在其羧基端包含殘基C226或P230,其中編號是根據Kabat的EU索引。對於人IgG1,Fc在本文定義為包含殘基P232至其羧基端,其中編號是根據Kabat中的EU索引。Fc可以指分離的該區域,或者位於Fc多肽,例如抗體,環境中的該區域。上述“鉸鏈”包括包含在抗體的第一和第二恆定結構域之間的胺基酸的柔性多肽。結構上,IgG CH1結構域中止於EU220位,IgG CH2結構域始於殘基EU237位。因而,對於IgG,本文中抗體鉸鏈定義為包括221 (IgG1的D221)至231 (IgG1的A231)位,其中編號是根據Kabat的EU索引。
術語“變體”指與本申請所提供的抗體的序列具有基本上相同胺基酸序列或由基本上相同的核苷酸序列編碼的一種或多種活性的多肽。所述變體與本申請實施例中所提供的抗體具有相同或相似的活性。
變體相比親代抗體,具有至少一個胺基酸修飾。在具體的實施方式中,本文中的變體序列優選的具有與親代抗體序列至少約80%,最優選至少約90%,更優選至少約95%,更優選至少約98%、最優選至少約99%的胺基酸序列相同性。變體可以指抗體本身,也可以指包含親代抗體的組成物。術語“胺基酸修飾”包括胺基酸取代、添加和/或缺失,“胺基酸取代”意指用另一種胺基酸替換親代多肽序列中特定位置上的胺基酸,“胺基酸插入”意指在親代多肽序列中的特定位置添加胺基酸,“胺基酸缺失”或“缺失”意指去除親代多肽序列中特定位置上的胺基酸。
“胺基酸修飾”可透過本領域已知的標準技術將修飾導入本發明的抗體中,例如定點誘變和PCR媒介的誘變。保守的胺基酸取代是用具有相似側鏈的胺基酸殘基替換胺基酸殘基的取代。本領域已經定義了具有相似側鏈的胺基酸殘基家族。這些家族包括含鹼性側鏈的胺基酸(例如,離胺酸、精胺酸、組胺酸)、酸性側鏈(例如,天冬胺酸、麩胺酸)、不帶電的極性側鏈(例如,甘胺酸、天冬醯胺、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸、色胺酸)、非極性側鏈(例如,丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸)、β分支側鏈(例如,蘇胺酸、纈胺酸、異亮胺酸)和芳香族側鏈(例如,酪胺酸、苯丙胺酸、色胺酸、組胺酸)。因而,可以用其他相同側鏈家族的胺基酸殘基替換本發明抗體的CDR區中或框架區中的一個或多個胺基酸殘基,並可以測試所改變的抗體(變體抗體)保留的功能。
上述術語“親代抗體”指本申請所提供的抗體或依據本申請所提供的抗體進行突變、或親和力成熟等處理後所得的抗體,優選的,指實施例所示的抗體。所述親代抗體可以是天然存在的抗體,或者天然存在的抗體的變體或改造版本。親代抗體可以指抗體本身,包含所述親代抗體的組成物,或其編碼胺基酸序列。
本文中使用的術語“抗原決定部位”又稱抗原表位,可以由IL-13RA2蛋白序列的連續序列組成,也可以由IL-13RA2蛋白序列不連續的三維結構組成。
抗
IL-13RA2
的抗體
在本揭露中,描述了具有基於scFv的抗原結合區域的抗原結合蛋白,包括抗體。其中使用重組IL-13RA2,從人scFv噬菌體展示基因庫選擇scFv。這些分子展示精細的專一性。例如,該抗體僅辨識IL-13RA2,不辨識IL-13RA1。本發明中如果沒有特別說明,IL-13RA2指人的IL-13RA2。
在一些實施方案中,本發明包括具有scFv序列的抗體,所述scFv序列與一個或多個重鏈恆定區域融合以形成具有人免疫球蛋白Fc區的抗體以產生雙價蛋白,從而增加抗體的總體親和力和穩定性。此外,Fc部分允許將其他分子(包括但不限於螢光染料、細胞毒素、放射性同位素等)與例如用於抗原定量研究中的抗體直接綴合,以便固定抗體用於親和力測量、用於定向遞送治療藥、使用免疫效應細胞測試Fc媒介的細胞毒性和許多其它應用。
本文提供的結果突顯出本發明抗體在標靶IL-13RA2時的專一性、靈敏性和效用。
本發明的分子基於使用噬菌體展示鑑定和選擇單鏈可變片段(scFv),所述單鏈可變片段的胺基酸序列賦予分子針對IL-13RA2的專一性並且形成本揭露的全部抗原結合蛋白的基礎。因此,所述scFv可以用來設計一系列不同“抗體”分子,包括例如全長抗體、其片段如Fab和F(ab’)2、融合蛋白(包括scFv_Fc)、多價抗體、即,具有針對相同抗原或不同抗原的多於一種專一性的抗體,例如,雙專一性T細胞結合抗體(BiTE)、三抗體等(見Cuesta等人,Multivalent antibodies: when design surpasses evolution, Trends in Biotechnology 28: 355-362, 2010)。
在抗原結合蛋白是全長抗體的一個實施方案中,本發明抗體的重鏈和輕鏈可以是全長(例如,抗體可以包括至少一條並優選地兩條完整重鏈,和至少一條並優選地兩條完整輕鏈)或可以包括抗原結合部分(Fab、F(ab’)2、Fv或scFv)。在其他實施方案中,抗體重鏈恆定區選自例如IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE。抗體類型的選擇將取決於所設計的抗體欲引發的免疫效應物功能。在構建重組免疫球蛋白時,各種免疫球蛋白同種型的恆定區的適宜胺基酸序列和用於產生廣泛種類抗體的方法是熟悉本發明所屬技藝的人士已知的。
在第一方面,本發明提供了專一性辨識IL-13RA2的抗體,其與穩定轉染了人IL-13RA2的U251細胞的結合相對親和力EC50
小於100 nM,優選小於10 nM,更優選0.1-1 nM,最優選0.3-0.6 nM。
在一優選方案中,本發明提供的IL-13RA2的抗體包括:包含SEQ ID NO: 9的胺基酸序列的重鏈CDR1,和/或包含SEQ ID NO: 10的胺基酸序列的重鏈CDR2,和/或包含SEQ ID NO: 11或者12的胺基酸序列的重鏈CDR3。在另一優選方案中,本發明提供的結合IL-13RA2的抗體包括:包含SEQ ID NO: 13的胺基酸序列的輕鏈CDR1,和/或包含SEQ ID NO: 14的胺基酸序列的輕鏈CDR2,和/或包含SEQ ID NO: 15或者16的胺基酸序列的輕鏈CDR3。在另一優選方案中,本發明提供了結合IL-13RA2的抗體包括:包含SEQ ID NO: 9的胺基酸序列的重鏈CDR1,和/或包含SEQ ID NO: 10的胺基酸序列的重鏈CDR2,和/或包含SEQ ID NO: 11或者12的胺基酸序列的重鏈CDR3,以及包含SEQ ID NO: 13的胺基酸序列的輕鏈CDR1,和/或包含SEQ ID NO: 14的胺基酸序列的輕鏈CDR2,和/或包含SEQ ID NO: 15或者16的胺基酸序列的輕鏈CDR3。優選的,所述結合IL-13RA2的抗體包括:包含SEQ ID NO: 9所示的HCDR1、SEQ ID NO: 10所示的HCDR2、SEQ ID NO: 11所示的HCDR3,以及SEQ ID NO: 13所示的LCDR1、SEQ ID NO: 14所示的LCDR2、SEQ ID NO: 15所示的LCDR3;或者包含SEQ ID NO: 9所示的HCDR1、SEQ ID NO: 10所示的HCDR2、SEQ ID NO: 12所示的HCDR3,以及SEQ ID NO: 13所示的LCDR1、SEQ ID NO: 14所示的LCDR2、SEQ ID NO: 16所示的LCDR3。
更優選的,所述結合IL-13RA2的抗體包含SEQ ID NO: 9所示的HCDR1、SEQ ID NO: 10所示的HCDR2、SEQ ID NO: 12所示的HCDR3,以及SEQ ID NO: 13所示的LCDR1、SEQ ID NO: 14所示的LCDR2、SEQ ID NO: 16所示的LCDR3。
在另一方面,本發明提供了結合IL-13RA2的抗體,其重鏈可變區選自SEQ ID NO: 2或者SEQ ID NO: 6的序列,或者二者的變體的序列。
在另一方面,本發明提供了結合IL-13RA2的抗體或其片段,其包括選自SEQ ID NO: 4或者SEQ ID NO: 8的輕鏈可變區序列。
考慮到這些重鏈和輕鏈可變區序列各自可以結合IL-13RA2,可以“混合和匹配”重鏈和輕鏈可變區序列來產生本發明的抗IL-13RA2的結合分子。
在另一個方面,本發明提供了結合IL-13RA2的抗體或其片段的變體。因而本發明提供了抗體或其片段,具有與重鏈或輕鏈的可變區序列至少80%相同的重鏈和/或輕鏈可變區。優選的,重鏈和/或輕鏈可變區的胺基酸序列相同性是至少85%,更優選至少90%,最優選至少95%,特別是96%,更特別97%,甚至更特別98%,最特別99%,包括例如80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%和100%。變體可以以本申請所述的抗體為母代抗體,透過酵母庫篩選、噬菌體庫篩選、點突變等方法得到。
在另一個方面,本發明提供了與前述的抗IL-13RA2的抗體辨識相同的抗原決定部位的抗體。
抗
IL-13RA2
的抗體特性
評估抗體例如抗IL-13RA2的抗體的結合能力的標準測定是本領域已知的,包括例如ELISA、biacore、Western墨點和流式細胞儀分析。合適的測定詳細描述在實施例中。
核酸、載體和宿主細胞
本發明還提供了編碼結合IL-13RA2的抗體和其片段分離的核酸、載體以及包含所述核酸或載體的宿主細胞。核酸可位於完整細胞中、細胞裂解液中或者以部分純化的或基本純化的形式。
可以使用標準的分子生物學技術獲得本發明的核酸,例如可以透過標準的PCR擴增或cDNA轉殖技術,獲得編碼抗體的輕鏈和重鏈或者編碼VH和VL區段的cDNA。對於從免疫球蛋白基因庫獲得的抗體(例如,使用噬菌體展示技術),可以從基因庫回收編碼抗體的一種或多種核酸。向宿主細胞中導入外源核酸的方法是本領域普遍已知的,並可隨所使用的宿主細胞而變化。
優選的本發明核酸分子是編碼選自SEQ ID NO: 3或者SEQ ID NO: 7的輕鏈可變區,和/或選自SEQ ID NO: 1或者SEQ ID NO: 5的重鏈可變區的那些。更優選的是這樣的核酸分子,所述核酸分子包含SEQ ID NO: 1的重鏈序列,和包含SEQ ID NO: 3的輕鏈序列或者包含SEQ ID NO: 5的重鏈序列,和包含SEQ ID NO: 7的輕鏈序列。
為了表現蛋白質,可以將編碼本發明抗體的核酸整合到表現載體中。多種表現載體可用於蛋白質表現。表現載體可包括自我複製的染色體外載體,或整合到宿主基因組中的載體。用於本發明的表現載體包括但不限於使蛋白質能夠在哺乳動物細胞、細菌、昆蟲細胞、酵母和體外系統中表現的那些。如本領域已知的,多種表現載體是可商業或其他方式獲得的。可用於本發明中來表現抗體。
免疫綴合物
本發明還提供了多功能免疫綴合物,其包含本文所述抗體以及進一步包含至少一種其它類型的功能性分子。所述的功能性分子選自但不限於:標靶腫瘤表面標誌物的分子,抑制腫瘤的分子,標靶免疫細胞的表面標誌物的分子或可偵測標記物。所述抗體與所述功能性分子可以透過共價連接、偶聯、附著、交聯等方式構成綴合物。
作為一種優選方式,所述免疫綴合物可包含:本發明的抗體以及至少一種標靶腫瘤表面標誌物的分子或抑制腫瘤的分子。所述的抑制腫瘤的分子可以是抗腫瘤的細胞因子,或抗腫瘤的毒素;較佳地,所述的細胞因子包括(但不限於):IL-2、IL-7、IL-12、IL-15、I型IFN、TNF-alpha。在具體的實施方式中,所述的標靶腫瘤表面標誌物的分子是標靶本發明抗體所標靶的相同腫瘤的表面標誌物的分子。例如,所述的標靶腫瘤表面標誌物的分子可以是結合腫瘤表面標誌物的抗體或配體,例如可以與本發明的抗體協同作用,更精準地標靶腫瘤細胞。可選的,
作為一種優選方式,所述免疫綴合物可包含:本發明的抗體以及可偵測標記物。所述的可偵測標記物包括但不限於:螢光標記物、顯色標記物;如:酵素、輔基、螢光材料、發光材料,生物發光材料、放射性材料、正電子發射金屬以及非放射性順磁性金屬離子。也可包含一個以上的標記物。為了偵測和/或分析和/或診斷目的用於標記抗體的標記依賴於使用的特定偵測/分析/診斷技術和/或方法例如免疫組織化學染色(組織)樣品、流式細胞計量術等。對於本領域已知的偵測/分析/診斷技術和/或方法合適的標記為熟悉本發明所屬技藝的人士所熟知。
作為一種優選方式,所述免疫綴合物可包含:本發明的抗體以及標靶免疫細胞的表面標誌物的分子。所述標靶免疫細胞的表面標誌物的分子可以是結合免疫細胞表面標誌物的抗體或配體,能夠辨識免疫細胞,其攜帶本發明的抗體達到免疫細胞,同時本發明的抗體可將免疫細胞標靶於腫瘤細胞,從而引發免疫細胞專一性地殺傷腫瘤。所述的免疫細胞表面標誌物可以選自CD3、CD16、CD28,更佳的,結合免疫細胞表面標誌物的抗體是抗CD3抗體。免疫細胞可選自T細胞、NK細胞、NKT細胞。
作為透過直接或間接(例如透過轉接子)綴合而化學產生免疫綴合物的一種方式,所述免疫綴合物可以作為融合蛋白而產生,所述融合蛋白包含本發明的抗體及合適的其它蛋白。融合蛋白可以透過本領域已知方法產生,例如透過構建核酸分子以及隨後表現所述核酸分子而重組產生,所述核酸分子包含符合讀框的編碼抗體的核苷酸序列以及編碼合適標記的核苷酸序列。
本發明另一方面提供了編碼本發明的至少一種抗體、其功能變體或者免疫綴合物的核酸分子。一旦獲得了有關的序列,就可以用重組法來大批量地獲得有關序列。這通常是將其轉殖入載體,再轉入細胞,然後透過常規方法從增殖後的宿主細胞中分離得到有關序列。
在另一個方面,本發明提供了嵌合抗原受體,其包含胞外結合結構域、跨膜域和胞內域。本文所用的術語“嵌合抗原受體(Chimeric Antigen Receptor, CAR)”指一種融合到細胞內訊號傳導域的腫瘤抗原結合結構域,能活化T細胞。常見地,CAR的胞外結合結構域來源於小鼠或人源化或人的單株抗體。
胞外結合結構域為本發明所述的抗體,非限制性實例包括衍生自抗體的單鏈可變片段(scFv)、選自基因庫的片段抗原結合區(Fab)、單結構域片段或與接合其同源受體的自然配體。在一些實施方案中,胞外抗原結合區域可以包含scFv、Fab或天然配體,以及它們的任何衍生物。胞外抗原結合區可以指除完整抗體之外的分子,其可以包含完整抗體的一部分並且可以與完整抗體所結合的抗原結合。抗體片段的實例可以包括但不限於Fv、Fab、Fab’、Fab’-SH、F(ab’)2;雙功能抗體、線性抗體;單鏈抗體分子(例如scFv);和由抗體片段形成的多專一性抗體。
胞外抗原結合區,例如scFv、Fab或天然配體,可以是確定抗原專一性的CAR的一部分。胞外抗原結合區可以結合任何互補的標的。胞外抗原結合區可以衍生自已知可變區序列的抗體。胞外抗原結合區可以從獲自可獲得的小鼠融合瘤的抗體序列中得到。或者,可以從腫瘤細胞或原代細胞例如腫瘤浸潤淋巴細胞(TIL)的全外切割定序獲得胞外抗原結合區。
在一些實施方案中,胞外抗原結合區的結合專一性可以透過互補決定區或CDR,如輕鏈CDR或重鏈CDR來確定。在許多情況下,結合專一性可以透過輕鏈CDR和重鏈CDR來確定。與其他參考抗原相比,給定的重鏈CDR和輕鏈CDR的組合可以提供給定的結合袋,其可以賦予抗原更大的親和力和/或專一性。
在本文揭露的任何實施方案的某些方面,胞外抗原結合區,例如scFv可以包含對抗原專一性的輕鏈CDR。輕鏈CDR可以是抗體例如CAR的scFv輕鏈的互補決定區。輕鏈CDR可以包含連續的胺基酸殘基序列,或由非互補決定區(例如框架區)隔開的兩個或更多個連續的胺基酸殘基序列。在一些實施方案中,輕鏈CDR可以包含兩個或更多個輕鏈CDR,其可以被稱為輕鏈CDR-1,CDR-2等。在一些實施方案中,輕鏈CDR可以包含三個輕鏈CDR,其可分別稱為輕鏈CDR-1,輕鏈CDR-2和輕鏈CDR-3。在一些實例中,存在於普通輕鏈上的一組CDR可統稱為輕鏈CDR。
在本文揭露的任何實施方案的某些方面,胞外抗原結合區,例如scFv可以包含對抗原專一的重鏈CDR。重鏈CDR可以是抗體例如scFv的重鏈互補決定區。重鏈CDR可以包含胺基酸殘基的連續序列,或由非互補決定區(例如框架區)隔開的兩個或更多個胺基酸殘基的連續序列。在一些實施方案中,重鏈CDR可以包含兩個或更多個重鏈CDR,其可以稱為重鏈CDR-1,CDR-2等。在一些實施方案中,重鏈CDR可以包含三個重鏈CDR,其可分別稱為重鏈CDR-1,重鏈CDR-2和重鏈CDR-3。在一些實施方案中,存在於共同重鏈上的一組CDR可統稱為重鏈CDR。
透過使用基因工程,可以以各種方式修飾胞外抗原結合區。在一些實施方案中,可以突變胞外抗原結合區域,從而可以選擇胞外抗原結合區域以對其標的具有更高的親和力。在一些實施方案中,胞外抗原結合區域對其標的的親和力可針對可在正常組織上以低位準表現的標的進行最適化。可以進行此最適化,以儘量減少潛在的毒性。在其他情況下,對標的的膜結合形式具有更高親和力的胞外抗原結合區域的轉殖株可以優於其可溶形式的對應物。可以進行這種修飾,因為也可以偵測到不同位準的可溶形式的標的,並且它們的標靶可引起不期望的毒性。
在一些實施方案中,胞外抗原結合區域包括鉸鏈或間隔區。術語鉸鏈和間隔區可以互換使用。鉸鏈可以被認為是用於向胞外抗原結合區提供柔性的CAR的一部分。在一些實施方案中,鉸鏈可用於偵測細胞的細胞表面上的CAR,特別是當偵測胞外抗原結合區的抗體不起作用或可用時。例如,衍生自免疫球蛋白的鉸鏈的長度可能需要最適化,這取決於胞外抗原結合區域標靶靶上的表位的位置。
在一些實施方案中,鉸鏈可能不屬於免疫球蛋白,而是屬於另一種分子,如CD8α分子的天然鉸鏈。CD8α鉸鏈可以含有已知在CD8輔助受體和MHC分子的相互作用中起作用的半胱胺酸和脯胺酸殘基。所述半胱胺酸和脯胺酸殘基可影響所述CAR的性能。
CAR鉸鏈可以是尺寸可調的。免疫應答細胞和標靶細胞之間的免疫突觸的這種形貌還限定了由於細胞表面標靶分子上的膜遠端表位而不能由CAR進行功能橋接的距離,即使用短鉸鏈CAR也不能使突觸距離達到訊號能夠傳導的近似值。同樣,膜近端CAR標靶抗原表位僅在長鉸鏈CAR的背景下觀察到訊號輸出。可以根據所使用的胞外抗原結合區域來調節鉸鏈。鉸鏈可以是任何長度的。
跨膜結構域可以將CAR錨定在細胞的質膜上。CD28的天然跨膜部分可用於CAR。在其他情況下,也可以在CAR中使用CD8α的天然跨膜部分。“CD8”可以是與NCBI參考號:NP_001759或其具有刺激活性的片段具有至少85、90、95、96、97、98、99或100%相同性的蛋白質。“CD8核酸分子”可以是編碼CD8多肽的多核苷酸,在某些情況下,跨膜區可以是CD28的天然跨膜部分,“CD28”可以指與NCBI參考號:NP_006130或其具有刺激活性的片段具有至少85、90、95、96、97、98、99或100%相同性的蛋白質。“CD28核酸分子”可以是編碼CD28多肽的多核苷酸。在一些實施方案中,跨膜部分可以包含CD8α區域。
CAR的(細)胞內訊號傳導區域可以負責活化CAR已經置於其中的免疫應答細胞的效應物功能中的至少一種。CAR可以誘導T細胞的效應物功能,例如,所述效應物功能是細胞溶解活性或輔助活性,包括細胞因子的分泌。因此,術語細胞內訊號傳導區域是指轉導效應物功能訊號並引導細胞進行專一功能的蛋白質部分。雖然通常可以使用整個細胞內訊號傳導區域,但是在許多情況下,不必使用訊號結構域的整個鏈。在一些實施方案中,使用細胞內訊號傳導區的截短部分。在一些實施方案中,術語細胞內訊號傳導區域因此意在包括足以轉導效應物功能訊號的細胞內訊號傳導區的任何截短部分。
在CAR中使用的訊號結構域的優選實例可以包括T細胞受體(TCR)的細胞質序列和協同作用以在標的-受體結合之後啓動訊號傳導的共同受體,以及它們的任何衍生物或變體序列和這些序列的具有相同功能性的任何合成序列。
在一些實施方案中,所述細胞內訊號傳導區域可以含有已知的免疫受體酪胺酸活化基序(ITAM)的訊號基序。含有細胞質訊號傳導序列的ITAM的實例包括衍生自TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d的那些。然而,在優選的實施方案中,細胞內訊號結構域衍生自CD3ζ鏈。
含有一個或多個ITAM基序的T細胞訊號結構域的實例是CD3ζ結構域,也稱為T細胞受體T3ζ鏈或CD247。該結構域是T細胞受體-CD3複合物的一部分,並且在將幾種細胞內訊號傳導途徑的抗原辨識與T細胞的主效應活化相結合方面起重要作用。如本文所用,CD3ζ主要是指人類CD3ζ及其同種型,如從Swissprot條目P20963所知的,包括具有基本相同序列的蛋白質。作為嵌合抗原受體的一部分,再次重申,不需要全T細胞受體T3ζ鏈,並且其包含T細胞受體T3ζ鏈的訊號結構域的任何衍生物都是合適的,包括其任何功能等同物。
細胞內訊號傳導結構域可以選自表1的任何一個結構域。在一些實施方案中,可以修飾結構域,使得與參考結構域的相同性可以為約50%至約100%。可以修飾表1的任何一個結構域,使得修飾形式可以包含約50、60、70、80、90、95、96、97、98、99或至多約100%的相同性。
CAR的細胞內訊號傳導區可以進一步包含一個或多個共刺激結構域。細胞內訊號傳導區可以包含單個共刺激結構域,例如ζ鏈(第一代CAR)或其與CD28或4-1BB(第二代CAR)。在其他實例中,細胞內訊號傳導區可以包含兩個共刺激結構域,例如CD28/OX40或CD28/4-1BB(第三代)。
與細胞內訊號結構域如CD8一起,這些共刺激結構域可以產生激酶途徑的下游活化,從而支援基因轉錄和功能性細胞反應。CAR的共刺激結構域可以活化與CD28 (磷脂醯肌醇-4,5-二磷酸3-激酶)或4-1BB/OX40 (TNF-受體相關因子銜接蛋白)途徑以及MAPK和Akt活化相關的近端訊號蛋白。
在某些情況下,透過CAR產生的訊號可能與輔助或共刺激訊號相結合。對於共刺激訊號結構域,嵌合抗原受體樣複合物可被設計成包含若干可能的共刺激訊號結構域。如本領域眾所周知的,在初始T細胞中,T細胞受體的單獨接合不足以誘導T細胞的完全活化為細胞毒性T細胞。完整的生產性T細胞活化需要第二共刺激訊號。已經報導對T細胞活化提供共刺激的幾種受體,包括但不限於CD28、OX40、CD27、CD2、CD5、ICAM-1、LFA-1 (CD11a/CD18)、4-1BBL、MyD88和4-1BB。這些共刺激分子使用的訊號傳導途徑均能與原代T細胞受體活化訊號協同作用。這些共刺激訊號傳導區域提供的訊號可以與源自一個或多個ITAM基序(例如CD3zeta訊號傳導域)的主效應活化訊號協同作用,並且可以完成T細胞活化的要求。
嵌合抗原受體結合標靶抗原。當在體外或離體測定T細胞活化時,可以從各種來源獲得或分離標靶抗原。本文使用的標靶抗原是抗原或抗原上的免疫表位,其在哺乳動物中對於免疫識別和最終消除或控制致病因素或疾病狀態中至關重要。免疫識別可以是細胞和/或體液。在細胞內病原體和癌症的情況下,免疫識別可以是,例如T淋巴細胞反應。
在一些實施方案中,標靶抗原包括與癌前或增生狀態相關的抗原。標靶抗原也可能與癌症相關或起因於癌症。例如,在一些實施方案中,本發明的嵌合抗原受體辨識並結合包括本文前述的IL-13RA2的腫瘤抗原。
在一些實施方案中,本文的嵌合抗原受體當存在於細胞的質膜上,並且當與其標的結合並活化時,表現所述嵌合抗原受體的細胞可對攜帶所述標的的細胞產生細胞毒性。例如,在一些實施方案中,所述嵌合抗原受體存在於細胞毒性細胞上,如NK細胞或者細胞毒性T細胞,並且在被標的活化時,可以增加所述細胞毒性細胞對標靶細胞的毒性。在一些實施方案中,本文的嵌合抗原受體可增加免疫反應性細胞對表現IL-13RA2的細胞如腫瘤細胞的作用。在一些實施方案中,與不表現本文的嵌合抗原受體的細胞相比,表現本文所述嵌合抗原受體的細胞對表現IL-13RA2的細胞的細胞毒性作用提高至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少1倍、至少1.5倍、至少2倍、至少2.5倍、至少3倍、至少3.5倍、至少4倍、至少4.5倍、至少5倍、至少6倍、至少7倍、至少8倍、至少9倍、或者至少10倍。
可以將編碼目標結合抗原的受體或CAR的基因轉殖併入細胞中。例如,可將基因轉殖併入免疫應答細胞,例如T細胞。當插入細胞時,基因轉殖可以是互補DNA (cDNA)片段,其是信使RNA (mRNA)的複本;或者位於其基因組DNA原始區域的基因本身(含或不含內含子)。
編碼基因轉殖序列的核酸如DNA可以隨機插入細胞的染色體。隨機整合可以由將核酸(例如DNA)插入細胞的任何方法產生。例如,該方法可以包括但不限於電穿孔、超音波、使用基因槍、脂質體轉染、磷酸鈣轉染、使用樹枝狀大分子、顯微注射和使用包括腺病毒、AAV和反轉錄病毒載體的病毒載體、和/或II型核糖酵素。
編碼基因轉殖的DNA也可以設計成包括報導基因,從而可以透過報導基因的活化偵測基因轉殖或其表現產物的存在。可以使用任何報導基因,例如上述那些。透過在細胞培養物中選擇其中報導基因已經被活化的細胞,可以選擇含有基因轉殖的細胞。
CAR的表現可以透過表現測定法,例如qPCR或透過測量RNA的位準來驗證。表現位準也可以指示複本數。例如,如果表現位準非常高,這可以表明CAR的多於一個複本被整合到基因組中。或者,高表現可以指示基因轉殖整合在高轉錄區域中,例如高度表現的啓動子附近。也可以透過測量蛋白質位準來驗證表現,例如透過Western墨點。
在一些實施方案中,本發明的免疫應答細胞可以包含一種或多種基因轉殖。所述一種或多種基因轉殖可以表現CAR蛋白,而該CAR蛋白辨識並結合抗原上的至少一個表位或結合抗原上的突變表位。CAR可以是功能性CAR。在一些實施方案中本發明的免疫應答細胞可以包含一種或多種CAR,或者其可以包含單一CAR和二次工程化受體。
在一些實施方案中,基因轉殖可編碼自殺基因。如癌症患者的許多有效治療所證明的,CAR免疫應答細胞使得腫瘤消退但可伴隨毒性。在一些實施方案中,當標靶抗原在正常組織和腫瘤細胞中共用時,CAR免疫應答細胞可能不能區分腫瘤和正常組織(“在靶/脫靶毒性”)。在另一些情況下,可以發生免疫系統的全身擾動,稱為細胞因子釋放綜合症(CRS)。所述CRS可以包含全身炎症反應綜合症或細胞因子風暴,這可能是CAR免疫應答細胞體內快速膨脹的後果。CRS是以發熱和低血壓為特徵的病症,嚴重者可導致多器官功能衰竭。在大多數情況下,所述毒性與輸注的CAR免疫應答細胞的體內擴增相關,其可引起免疫系統的整體擾動,以及釋放高位準的促炎細胞因子,例如TNFα和IL-6。自殺基因可以誘導消除CAR免疫反應性細胞。自殺基因可以是在所述CAR免疫反應性細胞中誘導細胞凋亡的任何基因。自殺基因可以與所述結合抗原的受體一起編碼在病毒載體內。編碼自殺基因使得在特定的情況下可以緩解或者徹底中止由輸注的CAR免疫應答細胞在體內擴增引起的毒性。
在一些實施方案中,可以產生存在於正常組織的抗原的CAR免疫反應性細胞,使得它們瞬時表現CAR,例如在電穿孔編碼受體的mRNA之後。此外,透過包括安全開關來進一步加強CAR免疫反應性細胞的重大努力,在嚴重的在靶毒性的情況下,可以大大消除CAR免疫反應性細胞。
在一些實施方案中,編碼CAR的載體可以與諸如可誘導的半胱天冬酶-9基因(由二聚化學誘導劑活化)或截短形式的EGF受體R (由單株抗體西妥昔單抗活化)或RQR8的安全開關組合。
本文所用的一個或多個基因轉殖可以來自不同的物種。例如,一個或多個基因轉殖可以包含人基因、小鼠基因、大鼠基因、豬基因、牛基因、狗基因、貓基因、猴基因、黑猩猩基因或其任何組合。例如,基因轉殖可以來自具有人類遺傳序列的人。一個或多個基因轉殖可以包含人基因。在某些情況下,一個或多個基因轉殖不是腺病毒基因。
如上所述,基因轉殖可以以隨機或位址專一性方式插入免疫反應性細胞的基因組中。例如,可以將基因轉殖插入到免疫細胞的基因組中的隨機位址。這些基因轉殖可以是功能性的,例如,在插入到基因組中的任何地方中時是完全功能性的。例如,基因轉殖可以編碼其自身的啓動子,或者可以插入其內部啓動子控制的位置。或者,可以將基因轉殖插入基因,例如基因的內含子或基因的外顯子、啓動子或非編碼區。可以插入基因轉殖使得插入破壞基因,例如內源性免疫檢查點。
在一些實施方案中,一個以上複本的基因轉殖可以插入到基因組內的多個隨機位址。例如,可將多個複本插入基因組中的隨機位址。與基因轉殖隨機插入一次相比,這可能導致整體表現增加。或者,基因轉殖的複本可以插入到基因中,基因轉殖的另一複本可以插入到不同的基因中。可以標靶基因轉殖,使其可以插入到免疫反應性細胞的基因組中的特定位址。
在一些實施方案中,包含編碼結合抗原的受體序列的多核酸可以採取質體載體的形式。質體載體可以包含啓動子。在某些情況下,啓動子可以是組成型的。在一些實施方案中,啓動子是可誘導的。啓動子可以是或可以衍生自CMV、U6、MND或EF1a。在一些實施方案中,啓動子可以與CAR序列相鄰。在一些實施方案中,質體載體還包含剪接受體。在一些實施方案中,剪接受體可以與CAR序列相鄰。啓動子序列可以是PKG或MND啓動子。MND啓動子可以是含有骨髓增生性肉瘤病毒增強子修飾的MoMuLV LTR的U3區域的合成啓動子。
在一些實施方案中,可以設計編碼目標受體的多核苷酸,以透過非病毒技術遞送至細胞。在某些情況下,多核苷酸可以是良好的製造規範(GMP)相容試劑。
編碼目標結合抗原的受體或CAR的多核苷酸的表現可以由一種或多種啓動子控制。啓動子可以是普遍存在的,組成型(不受限制的啓動子,允許相關基因的連續轉錄),組織專一性啓動子或誘導型啓動子。可以調節插入鄰近或接近啓動子的基因轉殖的表現。例如,基因轉殖可插入到普遍存在的啓動子附近或旁邊。一些普遍存在的啓動子可以是CAGGS啓動子、hCMV啓動子、PGK啓動子、SV40啓動子或ROSA26啓動子。
啓動子可以是內源的或外源的。例如,可以將一個或多個基因轉殖插入到內源或外源ROSA26啓動子的鄰近或接近處。此外,啓動子可以是免疫反應性細胞的專一性。例如,一個或多個基因轉殖可以插入豬ROSA26啓動子的鄰近或接近。
組織專一性啓動子或細胞專一性啓動子可用於控制表現的位置。例如,可以將一個或多個基因轉殖插入組織專一性啓動子的鄰近或接近。組織專一性啓動子可以是FABP啓動子、Lck啓動子、CamKII啓動子、CD19啓動子、角蛋白啓動子、白蛋白啓動子、aP2啓動子、胰島素啓動子、MCK啓動子、MyHC啓動子、WAP啓動子、或Col2A啓動子。
也可以使用誘導型啓動子。如果需要,可以透過添加或除去誘導劑來開啓和關閉這些誘導型啓動子。預期誘導型啓動子可以是但不限於Lac、tac、trc、trp、araBAD、phoA、recA、proU、cst-1、tetA、cadA、nar、PL、cspA、T7、VHB、Mx和/或Trex。
本文所用的術語“誘導型啓動子”是一種受控的啓動子,其在所期待的條件未達成前不表現或者低表現與其可操作地連接的基因,而在所期待的條件達成的情況下表現或者高位準表現與其可操作地連接的基因。
此外,儘管不是表現必需的,但基因轉殖序列還可以包括轉錄或轉譯調控序列,例如啓動子、增強子、絕緣體、內部核糖體進入位址、編碼2A肽和/或多腺苷酸化訊號的序列。
在一些實施方案中,基因轉殖編碼目標結合抗原的受體或CAR,其中將基因轉殖插入安全港,使得表現所述結合抗原的受體。在一些實施方案中,將基因轉殖插入PD-1和/或CTLA-4基因座。在其他情況下,將基因轉殖以慢病毒遞送至細胞隨機插入,而PD-1或CTLA-4專一性核酸酶可作為mRNA提供。在一些實施方案中,基因轉殖透過病毒載體系統如反轉錄病毒、AAV或腺病毒以及編碼對於安全港專一的核酸酶(例如AAVS1、CCR5、白蛋白或HPRT)的mRNA遞送。也可以用編碼PD-1和/或CTLA-4專一性核酸酶的mRNA處理細胞。在一些實施方案中,編碼CAR的多核苷酸透過病毒遞送系統與編碼HPRT專一性核酸酶和PD-1或CTLA-4專一性核酸酶的mRNA一起提供。可以與本文揭露的方法和組成物一起使用的CAR可以包括所有類型的這些嵌合蛋白。
在一些實施方案中,可以使用反轉錄病毒載體(γ-反轉錄病毒或慢病毒載體)將基因轉殖導入免疫反應性細胞。例如,編碼CAR的基因轉殖或結合抗原的任何受體或其變體或片段可被轉殖到反轉錄病毒載體中,並且可以由其內源性啓動子、反轉錄病毒長末端重複序列、或對標靶細胞類型專一性的啓動子驅動。也可以使用非病毒載體。非病毒載體遞送系統可以包括DNA質體、裸露的核酸和與遞送載體如脂質體或泊洛沙姆複合的核酸。
已經開發了許多基於病毒的系統用於將基因轉移到哺乳動物細胞中。例如,反轉錄病毒為基因遞送系統提供了便利的平臺。可以使用本領域已知的技術將所選擇的基因插入載體並包裝在反轉錄病毒顆粒中。衍生自反轉錄病毒如慢病毒的載體是實現長期基因轉移的合適工具,因為它們允許基因轉殖的長期穩定整合及其在子細胞中的繁殖。慢病毒載體與衍生自反轉錄病毒如鼠類白血病病毒的載體相比具有附加優點,因為它們可以轉導非增殖細胞。它們還具有低免疫原性的附加優點。腺病毒載體的優點是它們不融合到標靶細胞的基因組中,從而繞過負面的整合相關事件。
可以用編碼所述結合抗原的受體的基因轉殖轉染細胞。基因轉殖濃度可以為約100皮克至約50微克。在一些實施方案中,可以改變插入細胞的核酸(例如,ssDNA、dsDNA或RNA)的量以最適化轉染效率和/或細胞可活性。例如,可以向每個細胞樣品中加入1微克dsDNA用於電穿孔。在一些實施方案中,最佳轉染效率和/或細胞可活性所需的核酸(例如,雙鏈DNA)的量根據細胞類型而不同。在一些實施方案中,用於每個樣品的核酸(例如,dsDNA)的量可以直接對應於轉染效率和/或細胞可活性。例如,一系列轉染濃度。由載體編碼的基因轉殖可以整合到細胞基因組中。在一些實施方案中,由載體編碼的基因轉殖前向整合。在其他情況下,由載體編碼的基因轉殖的反向整合。
通常透過全身給藥(例如靜脈內、腹膜內、肌內、皮下或顱內輸注)或局部應用,透過給予個體患者體內遞送載體,如下所述。或者,載體可以離體遞送到細胞,例如從個體患者(例如,淋巴細胞、T細胞、骨髓抽吸物、組織活檢)移出的細胞,然後通常在選擇併入了該載體的細胞後將細胞再植入患者體內。在選擇之前或之後,可以擴增細胞。
用於表現結合抗原的受體的合適的免疫反應性細胞可以是對於有需要的個體是自體的或非自體的細胞。
可以從個體獲得合適的免疫應答細胞的來源。在某些情況下,可以獲得T細胞。所述T細胞可以從許多來源獲得,包括PBMC、骨髓、淋巴結組織、臍帶血、胸腺組織和來自感染部位、腹水、胸腔積液、脾組織和腫瘤的組織。在某些情況下,可以使用任何數量的熟悉本發明所屬技藝的人士已知的技術,例如FicollTM分離,從自所述個體收集的血液獲得T細胞。在一些實施方案中,透過單採血獲得來自個體的循環血液的細胞。單採樣品通常含有淋巴細胞,包括T細胞、單核細胞、顆粒細胞、B細胞、其他白血球、紅血球和血小板。在一些實施方案中,可以洗滌透過單採採集收集的細胞以除去血漿部分並將細胞置於合適的緩衝液或培養基中用於隨後的加工步驟。
或者,可以從健康供體,來自診斷患有癌症的患者或診斷為感染的患者衍生細胞。在一些實施方案中,細胞可以是具有不同表型特徵的混合細胞群體的一部分。還可以根據前述方法從轉化的T細胞獲得細胞株。還可以從細胞治療庫獲得細胞。可以透過本文所述的任何方法獲得對免疫抑制治療有抗性的修飾細胞。還可以在修飾前選擇合適的細胞群。修飾後也可以選擇工程細胞群。工程細胞可用於自體移植。或者,細胞可用於同種異體移植。在一些實施方案中,將細胞施用於樣品用於鑑定癌症相關標靶序列的同一患者。在其他情況下,將細胞施用於不同於其樣本用於鑑定癌症相關標靶序列的患者。
在一些實施方案中,合適的原代細胞包括外周血單核細胞(PBMC)、外周血淋巴細胞(PBL)和其它血液細胞亞群,例如但不限於T細胞、天然殺傷細胞、單核細胞、天然殺傷劑T細胞、單核細胞前體細胞、造血幹細胞或非多能幹細胞。在一些實施方案中,細胞可以是任何免疫細胞,包括任何T細胞如腫瘤浸潤細胞(TIL),如CD3+
T細胞、CD4+
T細胞、CD8+
T細胞或任何其他類型的T細胞。T細胞還可以包括記憶T細胞、記憶幹T細胞或效應T細胞。也可以從大量群體中選擇T細胞,例如從全血中選擇T細胞。T細胞也可以從大量群體中擴增。T細胞也可能傾向於特定種群和表型。例如,T細胞可以傾向於表型包含CD45RO(-)、CCR7(+)、CD45RA(+)、CD62L(+)、CD27(+)、CD28(+)和/或IL-7Rα(+)。合適的細胞可以選自以下列表中的一種或多種標誌物:CD45RO(-)、CCR7(+)、CD45RA(+)、CD62L(+)、CD27(+)、CD28(+)和/或IL-7Rα(+)。合適的細胞還包括幹細胞,例如,胚胎幹細胞、誘導的多能幹細胞、造血幹細胞、神經元幹細胞和間充質幹細胞。合適的細胞可以包含任何數量的原代細胞,例如人細胞、非人細胞和/或小鼠細胞。合適的細胞可以是祖細胞。合適的細胞可以衍生自要治療的受試者(例如,患者)。
患者中需要的治療有效的細胞的量可以根據細胞的存活力和細胞被遺傳修飾的效率而變化(例如,基因轉殖被整合到一個或多個細胞中的效率,或者由基因轉殖編碼的蛋白質的表現位準)。在一些實施方案中,遺傳修飾後細胞存活力的產物(例如,倍增)和基因轉殖整合的效率可以對應於可用於給予受試者的細胞的治療量。在一些實施方案中,遺傳修飾後細胞存活力的增加可能對應於給予治療對患者有效的必需細胞量的減少。在一些實施方案中,基因轉殖整合到一個或多個細胞中的效率的增加可以對應於給予在患者中治療有效的必需的細胞數量的減少。在一些實施方案中,確定所需的治療有效的細胞的量可以包括確定與細胞隨時間變化相關的功能。在一些實施方案中,確定需要治療有效的細胞的量可以包括確定與根據時間相關變量將基因轉殖整合到一個或多個細胞中的效率變化相對應的功能(例如,細胞培養時間、電穿孔時間、細胞刺激時間)。在一些實施方案中,治療有效的細胞可以是細胞群,其包含在細胞表面上約30%至約100%的結合抗原的受體的表現。在一些實施方案中,透過流式細胞術測量,治療有效的細胞可以在細胞表面上表現所述結合抗原的受體約30%、35%、40%、45%、50%、55%、60%、65%、70%、75% 80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%、99.9%或超過約99.9%。
根據本發明的一個方面,本發明也包括編碼所述結合抗原的受體的核酸。本發明還涉及上述多核苷酸的變異體,其編碼與本發明有相同的胺基酸序列的多肽或多肽的片段、類似物和衍生物。
本發明還提供了包含上述編碼表現於免疫應答細胞表面的結合抗原的受體蛋白的核酸的載體。
本發明還包括包含上述載體的病毒。本發明的病毒包括包裝後的具有感染力的病毒,也包括包含包裝為具有感染力的病毒所必需成分的待包裝的病毒。本領域內已知的其它可用於將外源基因轉導入免疫應答細胞的病毒及其對應的質體載體也可用於本發明。
在另一個方面,本文提供了宿主細胞,其包含本文所述的抗體或嵌合抗原受體、以及任選的I型干擾素。在另一個方面,本文提供了宿主細胞,其包含編碼本文所述的抗體或嵌合抗原受體、以及任選的I型干擾素的核酸。
在一些實施方案中,所述宿主細胞是免疫應答細胞。在一些實施方案中,所述免疫應答細胞是T細胞、自然殺傷細胞、細胞毒性T淋巴細胞、自然殺傷T細胞、DNT細胞、和/或調節性T細胞。在一些實施方案中,所述宿主細胞是NK92細胞。
本發明所述的免疫應答細胞還可以進一步攜帶外源的細胞因子的編碼序列;所述的細胞因子包括但不限於:IL-12,IL-15或IL-21等。這些細胞因子具有進一步的免疫調節或抗腫瘤的活性,能增強效應T細胞及活化的NK細胞的功能,或直接發揮抗腫瘤作用。因此,熟悉本發明所屬技藝的人士可以理解,這些細胞因子的運用有助於所述的免疫應答細胞更好地發揮作用。
本發明所述的免疫應答細胞還可以表現除了上述結合抗原的受體以外的另一種結合抗原的受體。
本發明所述的免疫應答細胞還可以表現趨化因子受體;所述的趨化因子受體包括但不限於CCR2。熟悉本發明所屬技藝的人士可以理解,所述的CCR2趨化因子受體可以使得體內的CCR2與之競爭性結合,對於阻斷腫瘤的轉移是有利的。
本發明所述的免疫應答細胞還可以表現能降低PD-1表現的siRNA或者阻斷PD-L1的蛋白。熟悉本發明所屬技藝的人士可以理解,競爭性阻斷PD-L1與其受體PD-1的相互作用,有利於恢復抗腫瘤T細胞反應,從而抑制腫瘤生長。
本發明所述的免疫應答細胞還可以表現安全開關;較佳地,所述的安全開關包括:iCaspase-9,Truancated EGFR或RQR8。
在一些實施方案中,本發明的免疫應答細胞不表現諸如4-1BBL這類的共刺激配體。
因此,在另一方面,本文還提供了一種生成本文所述的抗體或嵌合抗原受體或者包含它們的組成物的方法,其包括在適合的條件下培養本文所述的宿主細胞。在一些實施方案中,所述方法包括分離並獲得所述宿主細胞的表現產物。
在另一方面,本文提供了一種組成物,其包含本文所述的抗體、嵌合抗原受體、或核酸。在一些實施方案中,所述組成物是包含所述抗體、嵌合抗原受體或核酸的藥物組成物。在一些實施方案中,所述藥物組成物還包含藥學可接受的載體。
在另一方面,本文提供了一種藥物組成物,其包含本文所述的宿主細胞和藥學可接受的載體。
術語“藥學上可接受的”是指當分子本體和組成物適當地給予動物或人時,它們不會產生不利的、過敏的或其它不良反應。
在一些實施方案中,所述組成物包含另一治療劑。在一些實施方案中,所述另一治療劑是化療劑,如US20140271820中記載的那些和/或其藥學上可接受的鹽或類似物。在一些實施方案中,所述治療劑包括但不限於有絲分裂抑制劑(長春花生物鹼),包括長春新鹼、長春花鹼、長春地辛和諾維賓(TM)(長春瑞濱,5’-去氫硫化氫);拓撲異構酶I抑制劑,例如喜樹鹼化合物,包括CamptosarTM
(伊立替康HCL)、HycamtinTM
(托泊替康HCL)和衍生自喜樹鹼及其類似物的其它化合物;鬼臼毒素衍生物,例如依託泊苷、替尼泊苷和米多昔佐茲;烷基化劑順鉑、環磷醯胺、氮芥、三亞甲基硫代磷醯胺、卡莫司汀、白消安、苯丁酸氮芥、布列喹嗪、尿嘧啶芥末、氯洛芬和達卡巴嗪;抗代謝物,包括阿糖胞苷、5-氟尿嘧啶、甲氨蝶呤、巰嘌呤、硫唑嘌呤和丙卡巴肼;抗生素,包括但不限於多柔比星、博來黴素、更生黴素、柔紅黴素、黴素黴素、絲裂黴素、肉瘤黴素C和道諾黴素;以及其它化療藥物,包括但不限於抗腫瘤抗體、達卡巴嗪、氮胞苷、阿姆沙康、美法侖、異環磷醯胺和米托蒽醌。在一些實施方案中,所述另外的治療劑選自表柔比星、奧沙利鉑和5-氟尿嘧啶中的一種或多種。在一些實施方案中,所述另外的治療劑包括但不限於抗血管生成劑,包括抗VEGF抗體(包括人源化和嵌合抗體、抗VEGF適體和反義寡核苷酸)以及其他血管發生抑制劑,例如血管抑素、內皮抑制素、干擾素、白細胞介素1(包括α和β)白介素12、視黃酸和金屬蛋白酶-1和-2的組織抑制劑等。
可作為藥學上可接受的載體或其組分的一些物質的具體例子是醣類,如乳糖、葡萄糖和蔗糖;澱粉,如玉米澱粉和土豆澱粉;纖維素及其衍生物,如羧甲基纖維素鈉、乙基纖維素和甲基纖維素;西黃蓍膠粉末;麥芽;明膠;滑石;固體潤滑劑,如硬脂酸和硬脂酸鎂;硫酸鈣;植物油,如花生油、棉籽油、芝麻油、橄欖油、玉米油和可可油;多元醇,如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇;海藻酸;乳化劑,如Tween;潤濕劑,如月桂基硫酸鈉;著色劑;調味劑;壓片劑、穩定劑;抗氧化劑;防腐劑;無熱原水;等滲鹽溶液;和磷酸鹽緩衝液等。
本文所述的藥物組成物可包含一種或多種藥學可接受的鹽。“藥學可接受的鹽”指這樣一種鹽,其保留親代化合物的期望生物學活性且不產生任何不利的毒物學效果(參見例如,Berge, S.M.等人, 1977, J. Pharm. Sci. 66: 1-19)。此類鹽的例子包括酸加成鹽和鹼加成鹽。
酸加成鹽包括衍生自無毒無機酸,諸如鹽酸、硝酸、磷酸、硫酸、氫溴酸、氫碘酸、亞磷酸等的鹽,以及衍生自無毒有機酸,諸如脂肪族單羧酸和二羧酸、苯基取代的鏈烷酸、羥基鏈烷酸、芳香族酸、脂肪族和芳香族磺酸等的鹽。鹼加成鹽包括衍生自鹼土金屬(諸如鈉、鉀、鎂、鈣等)的鹽,以及衍生自無毒有機胺的鹽,諸如N,N’-二苄乙二胺、N-甲基葡糖胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、普魯卡因等。
本文所述的藥物組成物還可包含抗氧化劑。抗氧化劑的實例包括但不限於:水溶性抗氧化劑,諸如抗壞血酸、鹽酸半胱胺酸、硫酸氫鈉、焦亞硫酸鈉、亞硫酸鈉等;油溶性抗氧化劑,諸如抗壞血酸棕櫚酸酯、丁基化羥基茴香醚(BHA)、丁基化羥基甲苯(BHT),卵磷脂、沒食子酸丙酯、α-生育酚等;和金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本發明的組成物可根據需要製成各種劑型,並可由醫師根據患者種類、年齡、體重和大致疾病狀況、給藥方式等因素確定對病人有益的劑量進行施用。給藥方式例如可以採用腸胃外給藥(如注射)或其它治療方式。
免疫原性組成物的“腸胃外”施用包括例如皮下(s.c.)、靜脈內(i.v.)、肌內(i.m.)或胸骨內注射或輸注技術。
給予個體的包含免疫反應性細胞群體的製劑包含有效治療和/或預防特定適應症或疾病的多個免疫反應性細胞。因此,可以向個體施用免疫反應性細胞的治療有效群體。通常,施用包含約1×104
至約1×1010
個免疫反應性細胞的製劑。在大多數情況下,製劑將包含約1×105
至約1×109
個免疫反應性細胞、約5×105
至約5×108
個免疫反應性細胞、或約1×106
至約1×107
個免疫反應性細胞。然而,根據癌症的位置、來源、身份、程度和嚴重程度、待治療的個體的年齡和身體狀況等,對個體施用的CAR免疫反應性細胞的數量將在寬的範圍之間變化。醫生將最終確定要使用的適當劑量。
在一些實施方案中,使用嵌合抗原受體來刺激免疫細胞媒介的免疫反應。例如,T細胞媒介的免疫反應是涉及T細胞活化的免疫反應。活化的抗原專一性細胞毒性T細胞能夠在表面上顯示外源抗原表位的標靶細胞中誘導細胞凋亡,例如顯示腫瘤抗原的癌細胞。在另一些實施方案中,使用嵌合抗原受體在哺乳動物中提供抗腫瘤免疫。由於T細胞媒介的免疫反應,受試者將產生抗腫瘤免疫。
在某些情況下,治療患有癌症的受試者的方法可以涉及向需要治療的受試者施用一種或多種本發明所述的免疫應答細胞。所述免疫應答細胞可結合腫瘤標靶分子並誘導癌細胞死亡。如前文所述,本發明還提供治療個體中的病原體感染的方法,包括向所述個體施用治療有效量的本發明的免疫應答細胞。
本發明的免疫反應性細胞的給藥頻率將根據包括所治療疾病的因素、特定免疫反應性細胞的元件和給藥方式。例如可以每日給藥4次、3次、2次或每日一次、每隔一天、每三天、每四天、每五天、每六天一次、每週一次、每八天一次、每九天一次、每十天、每週一次、或者每月兩次給藥。如本文所述,由於本申請的免疫應答細胞具有改善的活力,從而可以不僅以與類似的但不表現外源性I型干擾素的免疫應答細胞更低的治療有效的量給藥,並且可以以更低的頻率給藥,以獲得至少類似、並且優選更加顯著的療效。
在一些實施方案中,組成物可以是等滲的,即它們可以具有與血液和淚液相同的滲透壓。本發明組成物的期望等滲性可以使用氯化鈉或其它藥學上可接受的試劑如葡萄糖、硼酸、酒石酸鈉、丙二醇或其它無機或有機溶質來實現。如果需要,組成物的黏度可以使用藥學上可接受的增稠劑維持在選定的位準。合適的增稠劑包括,例如,甲基纖維素、黃原膠、羧甲基纖維素、羥丙基纖維素、卡波姆等。增稠劑的優選濃度將取決於所選擇的試劑。顯然,合適的載體和其它添加劑的選擇將取決於確切的給藥途徑和特定劑型的性質,例如液體劑型。
本發明還提供了包含本文所述的抗體、嵌合抗原受體、核酸或免疫應答細胞的套組。在一些實施方案中,套組可以包括含有有效量的包含一種或多種單位劑型的本文所述的抗體、嵌合抗原受體、核酸或免疫應答細胞的治療或預防組成物。在一些實施方案中,套組包含可含有治療或預防性組成物的無菌容器;這樣的容器可以是盒、安瓿、瓶、小瓶、管、袋、泡罩包裝或本領域已知的其它合適的容器形式。這種容器可以由塑膠、玻璃、層壓紙、金屬箔或其他適合於保持藥物的材料製成。在一些實施方案中,所述套組包含本文所述的抗體、嵌合抗原受體、核酸或免疫應答細胞,以及將本文所述的抗體、嵌合抗原受體、核酸或免疫應答細胞給予個體的說明書。說明書中通常包含使用本文所述的抗體、嵌合抗原受體、核酸或免疫應答細胞來治療或預防癌症或腫瘤的方法。在一些實施方案中,套組包含本文所述的宿主細胞,並且可以包括約1×104
個細胞至約1×106
個細胞。在一些實施方案中,套組可以包括至少約1×105
個細胞,至少約1×106
個細胞,至少約1×107
個細胞,至少約4×107
個細胞,至少約5×107
個細胞,至少約6×107
個細胞,至少約6×107
個細胞,8×107
個細胞,至少約9×107
個細胞,至少約1×108
個細胞,至少約2×108
個細胞,至少約3×108
個細胞,至少約4×108
個細胞,至少約5×108
個細胞,至少約6×108
個細胞,至少約6×108
細胞,至少約8×108
個細胞,至少約9×108
細胞,至少約1×109
個細胞,至少約2×109
個細胞,至少約3×109
個細胞,至少約4×109
個細胞,至少約5×109
個細胞,至少約6×109
個細胞,至少約8×109
個細胞,至少約9×109
個細胞,至少約1×1010
個細胞,至少約2×1010
個細胞,至少約3×1010
個細胞,至少約4×1010
個細胞,至少約5×1010
個細胞,至少約6×1010
個細胞,至少約7×1010
個細胞、至少約8×1010
個細胞、至少約9×1010
個細胞,至少約1×1011
個細胞,至少約2×1011
個細胞,至少約3×1011
個細胞,至少約4×1011
個細胞,至少約5×1011
個細胞,至少約8×1011
個細胞,至少約9×1011
個細胞,或至少約1×1012
個細胞。例如,可以在套組中包括大約5×1010
個細胞。在另一個實例中,套組可以包括3×106
個細胞;細胞可以擴增至約5×1010
個細胞並施用於受試者。
在一些實施方案中,套組可以包括同種異體細胞。在一些實施方案中,套組可以包括可以包含基因組修飾的細胞。在一些實施方案中,套組可以包含“現成的”細胞。在一些實施方案中,套組可以包括可以擴展用於臨床使用的細胞。在某些情況下,套組可能包含用於研究目的的內容物。
在一些實施方案中,說明書包括以下中的至少一個:治療劑的描述;用於治療或預防腫瘤或其症狀的劑量方案和給藥;預防措施、警示、禁忌症、過量資訊、不良反應、動物藥理學、臨床研究、和/或引用文獻。說明書可以直接列印在容器上(如果有的話),或作為容器上的標簽,或作為容器內或容器中提供的單獨的紙張、小冊子、卡片或檔夾列印。在一些實施方案中,說明書提供施用本發明所述的免疫應答細胞用於治療或預防腫瘤的方法。在某些情況下,說明書提供了施用化學治療劑之前、之後或同時給予本發明的免疫反應性細胞的方法。
在另一方面,本文還提供了一種誘導包含IL-13RA2的細胞死亡的方法,所述方法包括使所述細胞與本文所述的抗體、本文所述的嵌合抗原受體、本文所述的組成物、或本文所述的宿主細胞接觸。在一些實施方案中,所述接觸是在體外接觸。在一些實施方案中,所述接觸是在體內接觸。
在一些實施方案中,所述細胞是腫瘤細胞。在一些實施方案中,所述細胞是腦瘤,更具體的,可以是星形細胞瘤、腦膜瘤、神經膠質瘤。
在另一方面,本文提供了一種治療有需要的個體的腫瘤的方法,所述方法包括向所述個體給予有效量的本文所述的抗體、嵌合抗原受體、組成物、載體或者宿主細胞。
在一些實施方案中,受試者可以給予免疫反應性細胞,其中可以施用的免疫反應性細胞可以是約1至約35天齡。例如,所施用的細胞可以是1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34或最多約40天。可以從刺激時起計算CAR免疫反應性細胞的年齡。可以從血液採集的時間開始計算免疫反應性細胞的年齡。可以從轉導時起計算免疫反應性細胞的年齡。在一些實施方案中,可以給予受試者的免疫反應性細胞為約10至約14或約20天齡。在一些實施方案中,免疫反應性細胞的“年齡”可以透過端粒長度來確定。例如,“年輕”的免疫反應性細胞可以具有比“耗盡”或“老”的免疫反應性細胞更長的端粒長度。不受特定理論的束縛,可以認為免疫反應性細胞在培養物中每週丟失約0.8 kb的估計端粒長度,並且年輕的免疫反應性細胞培養物可以具有比約44天的免疫反應性細胞長約1.4 kb的端粒。不受特定理論的束縛,人們認為更長的端粒長度可以與患者中的陽性客觀臨床反應和體內細胞的持久性相關聯。
在移植之前、之後和/或期間,細胞(例如,工程細胞或工程化的原代T細胞)可以是功能性的。例如,移植的細胞可以是在移植後至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18,19、20、21、22、23、24、25、6、27、28、29、30、40、50、60、70、80、90或100天起作用。移植細胞可以在移植後至少約1、2、3、4、5、6、7、8、9、10、11或12個月起作用。移植細胞可以在移植後至少約1、2、3、4、5、6、7、8、9、10、15、20、25或30年起作用。在一些實施方案中,移植細胞可以在接受者的壽命期間起作用。
此外,移植細胞可以以其正常預期功能的100%起作用。移植細胞還可以發揮其正常預期功能約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、或高達約100%的功能。
移植細胞也可以發揮其正常預期功能的超過100%的作用。例如,移植的細胞可以起到正常預期功能的約110、120、130、140、150、160、170、180、190、200、250、300、400、500、600、700、800、900、1000或至多約5000%的功能。
移植可以透過任何類型的移植。局部可以包括但不限於肝囊下空間、脾囊下空間、腎囊下空間、網膜、胃或腸黏膜下層、小腸血管節段、靜脈囊、睪丸、腦、脾或角膜。例如,移植可以是囊下移植。移植也可以是肌內移植。移植可以是門靜脈移植。
與當一個或多個野生型細胞被移植到接受者之時相比,採用本發明的免疫應答細胞治療之後可以改善移植排斥反應。例如,移植排斥可以是超急性排斥反應。移植排斥也可以是急性排斥反應。其他類型的排斥可能包括慢性排斥反應。移植排斥也可以是細胞媒介的排斥反應或T細胞媒介的排斥反應。移植排斥也可以是自然殺傷細胞媒介的排斥反應。
改善移植可能意味著減輕超急性排斥反應,其可以包括減少、減輕或降低不良作用或症狀。移植可以指細胞產品的過繼性移植。
移植成功的另一個跡象可以是接受者不需要免疫抑制治療的天數。例如,在提供本發明的免疫應答細胞之後,接受者可以不要求至少約1、2、3、4、5、6、7、8、9、10或更多天的免疫抑制治療。這可以表明移植成功。這也可以表明移植的細胞,組織和/或器官沒有排斥。
在一些實施方案中,本文所述的抗體、嵌合抗原受體、組成物、載體或者宿主細胞可以與另一治療劑聯合給藥。在一些實施方案中,所述另一治療劑是化療劑,如US20140271820中記載的那些。可以與本發明的免疫應答細胞聯合應用的化療藥物包括但不限於有絲分裂抑制劑(長春花生物鹼),包括長春新鹼、長春花鹼、長春地辛和諾維賓(TM)(長春瑞濱,5’-去氫硫化氫);拓撲異構酶I抑制劑,例如喜樹鹼化合物,包括CamptosarTM
(伊立替康HCL)、HycamtinTM
(托泊替康HCL)和衍生自喜樹鹼及其類似物的其它化合物;鬼臼毒素衍生物,例如依託泊苷、替尼泊苷和米多昔佐茲;烷基化劑順鉑、環磷醯胺、氮芥、三亞甲基硫代磷醯胺、卡莫司汀、白消安、苯丁酸氮芥、布列喹嗪、尿嘧啶芥末、氯洛芬和達卡巴嗪;抗代謝物,包括阿糖胞苷、5-氟尿嘧啶、甲氨蝶呤、巰嘌呤、硫唑嘌呤和丙卡巴肼;抗生素,包括但不限於多柔比星、博來黴素、更生黴素、柔紅黴素、黴素黴素、絲裂黴素、肉瘤黴素C和道諾黴素;以及其它化療藥物,包括但不限於抗腫瘤抗體、達卡巴嗪、氮胞苷、阿姆沙康、美法侖、異環磷醯胺和米托蒽醌。在一些實施方案中,所述額外的治療劑選自表柔比星、奧沙利鉑和5-氟尿嘧啶中的一種或多種。
在一些實施方案中,可以與本發明的免疫應答細胞聯合應用的化療藥物包括但不限於抗血管生成劑,包括抗VEGF抗體(包括人源化和嵌合抗體、抗VEGF適體和反義寡核苷酸)以及其他血管發生抑制劑,例如血管抑素、內皮抑制素、干擾素、白細胞介素1(包括α和β)白介素12、視黃酸和金屬蛋白酶-1和-2的組織抑制劑。
本發明還涉及包含上述的適當DNA序列以及適當啓動子或者控制序列的載體。這些載體可以用於轉化適當的宿主細胞,以使其能夠表現蛋白質。宿主細胞可以是原核細胞,如細菌細胞;或是低等真核細胞,如酵母細胞;或是高等真核細胞,如哺乳動物細胞。
下面結合具體實施例,進一步闡述本發明。應理解,這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未註明具體條件的實驗方法,通常按照常規條件如J.薩姆布魯克等編著,分子克隆實驗指南,第三版,科學出版社,2002中所述的條件,或按照製造廠商所建議的條件。實施例 1. IL-13RA2 和 IL-13RA1 重組蛋白的製備
a. IL-13RA2_huFc,IL-13RA1_huFc表現質體的構建
體外合成人IL-13RA2的胞外段Asp27-Arg343 (SEQ ID NO: 18)基因(SEQ ID NO: 17),將該基因插入含有人IgG1重鏈恆定區的Fc段Asp104-Lys330的真核表現質體中,中間以“GS”相連接,形成融合表現蛋白IL-13RA2_huFc (SEQ ID NO: 22),相對應的基因序列如SEQ ID NO: 11所示。或者將IL-13RA1胞外段基因(SEQ ID NO: 19)插入含有人IgG1重鏈恆定區的Fc段Asp104-Lys330的真核表現質體中,中間以“GS”相連接,形成融合表現蛋白IL-13RA1_huFc (SEQ ID NO: 24),相對應的基因序列如SEQ ID NO: 23所示。 b. 瞬時轉染表現IL-13RA2_huFc、IL-13RA1_huFc (1) 轉染前一天,接種6~7×105
/mL 293F細胞於125 mL培養瓶中 (2) 轉染當天,調整3×107
細胞於28 mL FreeStyleTM 293 expression medium (3) 按照下面的操作步驟製備lipid-DNA複合物: 用Opti-MEM I稀釋30 μg DNA,終體積1 mL,充分混勻 用Opti-MEM I稀釋60 μL 293fectinTM
,終體積1 mL,充分混勻 室溫培育5分鐘, (4) 將稀釋好的DNA與293fectinTM
混合,於室溫培育20分鐘 (5) 將2 mL DNA-293fectinTM
複合物加入28 mL細胞中,37度,8% CO2
,125 rpm培養3~4天,收取上澄液 c. IL-13RA2_huFc、IL-13RA1_huFc的純化 (1) 13000 rpm離心培養上澄液15 min (2) 採用protein A填料進行親和純化,具體操作步驟如下: 平衡:10個柱體積的平衡buffer平衡protein A填料。 上樣:0.45 μm濾膜處理好的樣品全部上樣。 洗滌:20個柱體積平衡buffer洗滌,直至流出液無物質流出。 洗提:加入10個柱體積的洗提buffer洗提目標蛋白(收集管中事先加入6%的中和buffer)。 溶液配方 平衡buffer:PBS pH 7.4 洗提buffer:0.1 M甘胺酸pH 2.6 中和buffer:1 M Tris (3) 洗提用0.22 μm的膜過濾後,使用截流量為10 KD的millipore超濾管進行濃縮,濃縮至體積1 mL以內,使用PD-Midi脫鹽柱脫鹽,收集1.5 mL樣品。透過OD280/1.47測蛋白濃度 取2 μg跑SDS-PAGE,結果如圖1所示。實施例 2. 使用全人噬菌體展示基因庫篩選針對 IL-13RA2 專一的 scFv
本發明使用的噬菌體展示基因庫為本公司構建的全人的天然的scFv噬菌體基因庫,庫容為1E+11。利用熟悉本發明所屬技藝的人士已知的篩選方法得到針對IL-13RA2高度專一的scFv片段。簡言之,分別塗佈10 μg/mL抗原IL-13RA2_huFc和IL-13RA1_huFc於免疫管。為了篩選到專一性結合IL-13RA2的抗體,將噬菌體基因庫加入塗佈了IL-13RA1_huFc的免疫管中結合1 hr。取上澄液加入塗佈IL-13RA2_huFc的免疫管中結合1.5小時,隨後將非專一性的噬菌體洗掉,將結合的噬菌體洗提下來並感染對數生長期的大腸桿菌TG1。擴大培養洗提下來得噬菌體並使用PEG/NaCl沉澱純化擴大後的噬菌體基因庫用於下一輪的篩選。將淘選進行3-4個循環以富集與IL-13RA2專一性結合的scFv噬菌體轉殖株。透過針對IL-13RA2_huFc的標準ELISA方法確定陽性轉殖株。ELISA使用IL-13RA1_huFc做為無關抗原來驗證抗體的專一性。一共篩選了3420個轉殖株,其中44個轉殖株ELISA實驗專一性的結合IL-13RA2_huFc,不結合IL-13RA1_huFc。經定序,得到5個單一的序列。表現純化這5個轉殖株,其中只有2個專一性的結合表現IL-13RA2的U251細胞(購自中國科學院細胞庫)(圖2、4),轉殖株名稱為31C2、32H4。
31C2的重鏈可變區的胺基酸序列如SEQ ID NO: 2所示,輕鏈可變區的胺基酸序列如SEQ ID NO: 4所示;32H4的重鏈可變區的胺基酸序列如SEQ ID NO: 6所示,輕鏈可變區的胺基酸序列如SEQ ID NO: 8所示。31C2的HDCR1的胺基酸序列如SEQ ID NO: 9所示、HDCR2的胺基酸序列如SEQ ID NO: 10所示、HDCR3的胺基酸序列如SEQ ID NO: 11所示、LDCR1的胺基酸序列如SEQ ID NO: 13所示、LDCR2的胺基酸序列如SEQ ID NO: 14所示、LDCR3的胺基酸序列如SEQ ID NO: 15所示;32H4的HDCR1的胺基酸序列如SEQ ID NO: 9所示、HDCR2的胺基酸序列如SEQ ID NO: 10所示、HDCR3的胺基酸序列如SEQ ID NO: 12所示、LDCR1的胺基酸序列如SEQ ID NO: 13所示、LDCR2的胺基酸序列如SEQ ID NO: 14所示、LDCR3的胺基酸序列如SEQ ID NO: 16所示。實施例 3. ELISA 結合試驗
透過標準的ELISA偵測抗體31C2,32H4的種屬專一性。鼠IL-13RA2購自Sino Biological Inc公司。塗佈5 μg/mL,100 μL/井鼠IL-13RA2與ELISA板,4度過夜。用PBS洗三遍塗佈好的ELISA板。加入200 μL/井的含2%脫脂奶粉的PBS室溫封閉1 hr。用PBS洗三遍。加入梯度稀釋的抗體,起始濃度10 μg/mL,3倍稀釋,室溫培育1 hr。PBST洗三遍,PBS洗三遍。加入HRP標記的羊抗人Fc,室溫培育1 hr。PBST洗三遍,PBS洗三遍。加入TMB顯色15分鐘後,加入硫酸終止反應並在微量培養盤讀取儀上讀數。結果如圖3所示。抗體31C2能結合鼠IL-13RA2,32H4不結合鼠IL-13RA2。實施例 4. 抗 IL-13RA2 scFv_Fc 融合抗體的構建及其在真核細胞中的瞬轉表現純化、活性鑑定
分別針對31C2,32H4的VH和VL片段設計引子,插入由15個柔性胺基酸(GGGGSGGGGSGGGGS)組成的linker連接組成scFv;在VH上游插入合適的限制酶切割位址和保護鹼基,在VL的下游插入合適的限制酶切割位址和保護鹼基。1%瓊脂糖凝膠電泳分析PCR產物並純化回收。限制酶切割後連接入合適的真核表現載體。採用293fectin™ Transfection reagent (Invitrogen, 12347-019)或者聚乙烯亞胺(PEI)(Sigma-Aldrich, 408727)瞬時轉染對數生長期的293F細胞。轉染5-7天後收集培養上澄液透過Protein A進行親和純化。
透過流式細胞術測試抗體與內源性表現IL-13RA2的U251細胞的結合,293T細胞作為陰性細胞對照。FACs偵測的具體方法如下:收取細胞,用生長培養基洗滌細胞一次,重新懸浮於PBS中,調整細胞濃度為4E+5細胞/mL。在冰上將稀釋的scFv_Fc融合抗體與細胞培育30分鐘,抗體的濃度為111 nM。其後與FITC標記的抗人IgG第二抗體培育。兩次洗滌步驟之後,使用Guava easyCyteTM HT System儀器偵測。圖4顯示了抗體31C2,32H4 scFv_Fc融合形式和U251以及293T細胞結合的情況。這兩個抗體都專一性的結合內源性表現IL-13RA2的U251細胞,不結合陰性細胞293T。實施例 5. 利用表面等離子共振技術 (SPR) 測定抗體的親和力
不同抗體針對IL-13RA2的親和力是使用biacoreT200測定的。具體做法如下:
將IL-13RA2_huFc透過氨基偶聯的方式塗佈在CM5晶片上,塗佈至500 RU左右,梯度稀釋的抗體作為流動相以30 μL/min的流速透過塗佈抗原的通道。運行緩衝液為HBS-N,溫度為25度。實驗資料透過BIAevaluation3.2進行分析,動力學曲線使用1:1的langmuir模型進行擬合。其中31C2 (scFv_Fc)的KD為1.79 nM,32H4 (scFv_Fc)的KD為3.76 nM(見圖5)。實施例 6. 利用 FACs 測定抗體與 U251 細胞的結合 EC50
收取細胞,用生長培養基洗滌細胞一次,重新懸浮於PBS中,調整細胞濃度為4E+5細胞/mL。在冰上將梯度稀釋的scFv_Fc融合抗體與細胞溫培育30分鐘,抗體的起始濃度為500 nM,5倍稀釋,8個梯度。其後與FITC標記的抗人IgG第二抗體培育。兩次洗滌步驟之後,使用Guava easyCyteTM HT System儀器偵測。結果如圖6所示,其中兩個抗體都和U251細胞有濃度梯度依賴的結合,31C2 (ScFv_Fc)的EC50為2.8 nM,32H4 (ScFv_Fc)的EC50
為1 nM。實施例 7. 抗體的親和力成熟
利用噬菌體展示技術進行親和力成熟。
以31C2和32H4為親代抗體,分別構建兩個噬菌體基因庫,一個隨機化輕鏈的CDR1以及CDR2,另一個隨機化重鏈的CDR2以及CDR2。然後針對抗原進行淘選,透過SPR技術等篩選出高親和力的抗體,即31C2和32H4的變體。引子資訊如圖7所示。
首先基於抗體31C2 (scFv)(胺基酸序列SEQ ID NO: 25,核酸序列SEQ ID NO: 26)構建範本質體。對於輕鏈CDR1和CDR2隨機化的噬菌體基因庫,使用引子LMF和IL1R,PCR擴增片段1;使用引子IL2F和FdR,PCR擴增片段2;然後透過橋式PCR連接片段1和片段2得到含有隨機化序列的scFv全長,然後用NcoI和NotI限制酶切割全長片段,透過T4連接酶連接入同樣限制酶切割的範本質體中,並電轉化至TG1感受態細胞中,庫容為1.68E+9。對於重鏈CDR1和CDR2隨機化的噬菌體基因庫,使用引子LMF和BH1R,PCR擴增片段3;使用引子BH2F和FdR,PCR擴增片段4;然後透過橋式PCR連接片段3和片段4得到含有隨機化序列的scFv全長,然後用NcoI和NotI限制酶切割全長片段,透過T4連接酶連接入同樣限制酶切割的範本質體中,並電轉化至TG1勝任細胞中,庫容為1.75E+9。
抗體32H4親和力成熟基因庫的構建與31C2類似,基於抗體32H4 (scFv)(胺基酸序列SEQ ID NO: 26,核酸序列SEQ ID NO: 27)構建範本質體。使用與31C2相同的引子隨機化輕鏈的CDR1和CDR2,得到的噬菌體基因庫庫容為2.1E+9。類似地使用與31C2相同的引子隨機化重鏈的CDR1和CDR2,得到的噬菌體基因庫庫容為1.5E+9。實施例 8. 噬菌體基因庫的篩選
參照本專利實施例2中方法。抗原IL-13RA2_huFc的起始濃度為50 nM,2倍梯度稀釋進行下一輪篩選。將淘選進行2-3個循環以富集與IL-13RA2_huFc專一性結合的scFv噬菌體轉殖株。透過針對IL-13RA2_huFc的標準ELISA方法確定陽性轉殖株。ELISA使用人IL-13RA1_huFc段作為無關抗原來驗證抗體的專一性。一共挑取111個ELISA陽性的轉殖株,重新誘導以後透過biacore測定誘導上澄液的解離常數Kd。其中有10個轉殖株的解離常數Kd比母代轉殖株低10倍以上,如圖8所示。
經定序,轉殖株2C7、2D3、1D11、1B11、2A5、2D4、1H7、1D8的輕鏈與31C2一樣(胺基酸序列SEQ ID NO: 4,核酸序列SEQ ID NO: 3)。圖9A比較了轉殖株2C7 (胺基酸序列SEQ ID NO: 29,核酸序列SEQ ID NO: 30),2D3 (胺基酸序列SEQ ID NO: 31,核酸序列SEQ ID NO: 32),1D11 (胺基酸序列SEQ ID NO: 33,核酸序列SEQ ID NO: 34),1B11 (胺基酸序列SEQ ID NO: 35,核酸序列SEQ ID NO: 36),2A5 (胺基酸序列SEQ ID NO: 37,核酸序列SEQ ID NO: 38),2D4 (胺基酸序列SEQ ID NO: 39,核酸序列SEQ ID NO: 40),1H7 (胺基酸序列SEQ ID NO: 41,核酸序列SEQ ID NO: 42),1D8 (胺基酸序列SEQ ID NO: 43,核酸序列SEQ ID NO: 44)及31C2 (胺基酸序列SEQ ID NO: 2,核酸序列SEQ ID NO: 1)的重鏈胺基酸序列。
其中,31C2的親和力成熟轉殖株的HCDR1的序列分別如SEQ ID NO: 45-51所示,HCDR2的序列分別如SEQ ID NO: 52-58所示,具體見圖9B。
與親代抗體31C2的VH相比,2C7有4個位址的突變,相似性為96.7%;2D3有5個位址的突變,相似性為95.8%;1D11有6個位址的突變,相似性為95%;1B11有5個位址的突變,相似性為95.8%;2A5有4個位址的突變,相似性為96.7%;2D4有5個位址的突變,相似性為95.8%;1H7有4個位址的突變,相似性為96.7%;1D8有4個位址的突變,相似性為96.7%。
經定序,轉殖株5G3,5D7的輕鏈與32H4一樣(胺基酸序列SEQ ID NO: 8,核酸序列SEQ ID NO: 7)。圖9C比較了轉殖株5G3(胺基酸序列SEQ ID NO: 59,核酸序列SEQ ID NO: 60),5D7 (胺基酸序列SEQ ID NO: 61,核酸序列SEQ ID NO: 62)及32H4 (胺基酸序列SEQ ID NO: 6,核酸序列SEQ ID NO: 5)的重鏈胺基酸序列。
其中,32H4的親和力成熟轉殖株的HCDR1的序列分別如SEQ ID NO: 63、64所示,HCDR2的序列分別如SEQ ID NO: 65、66所示,具體見圖9D。
與親代抗體32H4的VH相比,5G3有5個位址的突變,相似性為95.7%;2D3有5個位址的突變,相似性為95.8%;5D7有8個位址的突變,相似性為95%;1B11有5個位址的突變,相似性為93.2%。實施例 9. scFv 的表現純化
將含有抗體基因的TG1劃線培養,以挑取單個轉殖株接種於2xTY-Amp-5% Glucose培養基中,37℃,220 rpm培養至OD600nm=0.8~0.9,加入終濃度為1 mM IPTG,25度220 rpm過夜培養,誘導scFv的表現。
離心收集菌體,用30 mM Tris HCl、20%蔗糖、1 mM EDTA pH 8.0 (按每克菌體80 mL計)懸浮後冰浴,4度,8000 g離心,取上澄液A,沉澱用5 mM MgSO4
8 mL懸浮後冰浴,輕輕振盪10分鐘,4度,8000 g離心,取上澄液B。合併上澄液A和上澄液B,12000 g離心15分鐘,取上澄液即為cold osmotic shock fluid。
使用鎳柱進行親和純化,採用biacoreT200測定親和力,親和力成熟的抗體結合解離常數如圖10A所示。
參照實施例3的方法,透過標準的ELISA偵測抗體5D7、2C7、5G3、2D4、2D3、1B11的專一性。結果如圖10B所示。其中來自母代抗體31C2的轉殖株1B11、2C7、2D3、2D4專一性的結合人IL-13RA2,不結合人IL-13RA1,並且和鼠IL-13RA2有交叉反應。來自母代抗體32H4的轉殖株5D7、5G3專一性的結合人IL-13RA2,不結合人IL-13RA1,不結合鼠IL-13RA2。實施例 10. 抗體 scFv_Fc 形式的表現及親和力測定
挑取其中親和力較高的六個抗體5D7、2C7、5G3、2D4、2D3、1B11進行scFv_Fc融合形式的構建。
參照實施例4所示,在VH上游插入合適的限制酶切割位址和保護鹼基,在VL的下游插入合適的限制酶切割位址和保護鹼基。1%瓊脂糖凝膠電泳分析PCR產物並純化回收。限制酶切割後連接入含有人Fc段的真核表現載體V152中(購自上海銳勁生物技術有限公司)。透過293Fectin瞬時轉染至30 mL 293F細胞中並表現。轉染5-7天後收集培養上澄液透過Protein A進行親和純化。透過SEC分析抗體的聚集情況。結果如圖11所示。
參照實施例5的方法使用biacoreT200測定親和力,結果如圖11B-11G所示。經過親和力成熟以後的抗體,親和力與母代抗體相比有3~10倍的提高。抗體結合解離常數如圖11F所示。實施例 11. 抗體的 scFv_Fc 形式的與 U251 細胞結合 EC50 的測定
參照實施例6的方法,收取細胞,用生長培養基洗滌細胞一次,重懸於PBS中,調整細胞濃度為4E+5細胞/mL。在冰上將梯度稀釋的scFv_Fc融合抗體與細胞培育30分鐘,抗體的起始濃度為2000 nM,5倍稀釋,11個梯度。其後與FITC標記的抗人IgG第二抗體培育。兩次洗滌步驟之後,使用Guava easyCyteTM HT System儀器偵測。結果如圖12所示:抗體5D7、2C7、5G3、2D4、2D3、1B11的scFv_Fc形式的與U251細胞結合EC50
分別為0.56 nM、0.57 nM、0.53 nM、0.37 nM、0.33 nM、0.47 nM。與母代抗體相比也有2~8倍的提高。實施例 12. CAR-T 細胞的製備
選擇2D4和5G3進行CAR-T細胞製備和抗腫瘤活性研究。 1. 慢病毒包裝質體pRRL-hu8E3-28Z的構建
以PRRLSIN-cPPT.EF-1α為載體,構建了表現抗體2D4和5G3的嵌合抗原受體的慢病毒質體,包括PRRLSIN-cPPT.EF-1α-2D4-28Z、PRRLSIN-cPPT.EF-1α-2D4-BBZ、PRRLSIN-cPPT.EF-1α-2D4-28BBZ以及PRRLSIN-cPPT.EF-1α-5G3-28Z、PRRLSIN-cPPT.EF-1α-5G3-BBZ、PRRLSIN-cPPT.EF-1α-5G3-28BBZ。
2D4-28Z序列由CD8α訊號肽(SEQ ID NO: 68)、2D4scFv (SEQ ID NO: 67)、CD8 hinge (SEQ ID NO: 69)、CD28跨膜區(SEQ ID NO: 70)和胞內訊號傳導結構域(SEQ ID NO: 71)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。
2D4-BBZ序列由CD8α訊號肽(SEQ ID NO: 68)、2D4scFv (SEQ ID NO: 67)、CD8 hinge (SEQ ID NO: 69)、CD8跨膜區(SEQ ID NO: 73)、CD137的胞內訊號傳導結構域(SEQ ID NO: 74)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。
2D4-28BBZ序列由CD8α訊號肽(SEQ ID NO: 68)、2D4scFv (SEQ ID NO: 67)、CD8 hinge (SEQ ID NO: 69)、CD28跨膜區(SEQ ID NO: 70)和胞內訊號傳導結構域(SEQ ID NO: 71)、CD137的胞內訊號傳導結構域(SEQ ID NO: 74)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。
5G3-28Z序列由CD8α訊號肽(SEQ ID NO: 68)、5G3scFv (SEQ ID NO: 75)、CD8 hinge (SEQ ID NO: 69)、CD28跨膜區(SEQ ID NO: 70)和胞內訊號傳導結構域(SEQ ID NO: 71)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。
5G3-BBZ序列由CD8α訊號肽(SEQ ID NO: 68)、5G3scFv (SEQ ID NO: 75)、CD8 hinge (SEQ ID NO: 69)、CD8跨膜區(SEQ ID NO: 73)、CD137的胞內訊號傳導結構域(SEQ ID NO: 74)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。
5G3-28BBZ序列由CD8α訊號肽(SEQ ID NO: 68)、5G3scFv (SEQ ID NO: 75)、CD8 hinge (SEQ ID NO: 69)、CD28跨膜區(SEQ ID NO: 70)和胞內訊號傳導結構域(SEQ ID NO: 71)、CD137的胞內訊號傳導結構域(SEQ ID NO: 74)以及CD3的胞內段CD3ξ (SEQ ID NO: 72)組成。 2. 標靶IL-13RA2 CAR慢病毒載體的慢病毒包裝、病毒濃縮及效價測定
以1.7×107
的密度接種293T細胞於15 cm培養皿中,培養基為含10%胎牛血清(BioWest)的DMEM。分別將目標基因質體PRRLSIN-2D4-28Z、PRRLSIN-2D4-BBZ、PRRLSIN-2D4-28BBZ、PRRLSIN-5G3-28Z、PRRLSIN-5G3-BBZ、PRRLSIN-5G3-28BBZ質體13.73 μg與包裝質體pRsv-REV 16.4 μg、RRE-PMDLg 16.4 μg、Vsvg 6.4 μg溶入2048 μL空白DMEM培養液,混勻。
將158.4 μg PEI (1 μg/μL)溶解於2048 μL的無血清DMEM培養液中,混勻室溫培育。將質體混合液加入PEI混合液中,混勻室溫下培育20 min。將轉染複合物4.096 mL滴加入含20 mL DMEM培養基的15 cm培養皿中,4-5小時後,用10% FBS的DMEM培養基給轉染的293T細胞換液,37℃培育72 h,收集病毒液上澄液並濃縮,測定病毒效價,濃縮後的病毒效價分別為: 2D4-28Z: 3.89E×108
U/mL 2D4-BBZ: 3.08E×108
U/mL 2D4-28BBZ: 2.72E×108
U/mL 5G3-28Z: 3.7E×108
U/mL 5G3-BBZ: 1.88E×108
U/mL 5G3-28BBZ: 3.11E×108
U/mL 3. 慢病毒轉導T淋巴細胞------CAR陽性的T淋巴細胞的製備
T淋巴細胞活化:以約5×105
/mL密度加入淋巴細胞培養基液培養,並按照磁珠:細胞比例為2:1加入同時塗佈有抗CD3和CD28抗體的磁珠(Invitrogen)和終濃度500 U/mL的重組人IL-2 (上海華新生物高技術有限公司)刺激培養24-48 h;
Retronectin塗佈24井培養盤:每井加入380 μL 5 μg/mL的retronectin溶液(PBS),4℃培育過夜。棄去24井培養盤中的retronectin溶液(PBS),1 mL PBS洗兩次,培養基洗一次(井保持濕潤);將細胞接種於塗佈了retronectin的24井培養盤內,每井細胞數目5×105
,培養液體積500 μL;按照MOI=15在PBMC細胞中加入濃縮後的慢病毒,32℃,1200 g,離心60 min後,轉移至細胞培養箱中,感染病毒24 h後,低速離心換液(300 rpm,10 min,大型離心機)。感染後3~4天可以去磁珠。 4. T淋巴細胞嵌合抗原受體表現
慢病毒感染的T淋巴細胞在培養第7天,取1×106
的T細胞,二等分,4度、5000 rpm,離心5 min,棄上澄液,PBS洗兩次。對照組細胞加入50 μL PE-SA (1:200稀釋)抗體冰上培育45 min,PBS (2% NBS)洗兩次,重新懸浮後作為對照;偵測組細胞+50 μL 1:50稀釋的biotin-Goat anti human IgG,F(ab’)2抗體,冰上培育45 min;PBS (2% NBS)洗兩次;加入50 μL PE-SA (1:200稀釋)抗體冰上培育45 min;加入2 mL PBS (2% NBS)重新懸浮細胞,4℃,5000 rpm/min,離心5分鐘棄上澄液;重複兩次;流式細胞儀偵測CAR陽性的T細胞比例。 5. 標靶IL-13RA2 CAR-T細胞的細胞毒性測定
在比較UTD、2D4-28Z、2D4-BBZ、2D4-28BBZ、5G3-28Z、5G3-BBZ、5G3-28BBZ CAR-T細胞的體外殺傷活性時,六種CAR-T細胞的感染陽性率分別為66.0%、26.3%、34.8%、59.9%、35.5%以及23.8%。
三塊E-Plate 16中分別加入50 μL RPMI+10%胎牛血清(Gibco)+雙抗,置於即時監測儀上調整基線。 標靶細胞:分別接種50 μL 1×104
/mL的U251細胞於E-Plate 16板,靜置30-40 min,置於即時監測儀開始監測; 效應細胞:18小時後,按效靶比3:1、1:1或1:3加UTD及表現不同嵌合抗原受體的CAR-T細胞;
各組均設2個複井,取2個複井的平均值。偵測時間為第38 h。 其中各實驗組和各對照組如下: 各實驗組:各標靶細胞+表現不同嵌合抗原受體的CAR-T; 對照組1:標靶細胞 對照組2:空白培養基;
細胞毒性計算公式為:%細胞毒性=[(實驗組-效應細胞自發組-標靶細胞自發組)/(標靶細胞最大-標靶細胞自發)]*100
實驗結果如圖13所示,各表現不同嵌合抗原受體的CAR-T細胞對IL-13RA2陽性的細胞均有顯著的體外殺傷活性。
在本發明提及的所有文獻都在本申請中引用作為參考,就如同每一篇文獻被單獨引用作為參考那樣。此外應理解,在閱讀了本發明的上述講授內容之後,熟悉本發明所屬技藝的人士可以對本發明作各種改動或修改,這些等價形式同樣落於本申請所附申請專利範圍所限定的範圍。
圖1顯示了IL-13RA2_huFc、IL-13RA1_huFc的SDS電泳圖(還原條件);
圖2顯示了ELISA偵測31C2,32H4與IL-13RA2以及IL-13RA1的結合;
圖3顯示了ELISA偵測抗體31C2,32H4與鼠的IL-13RA2的結合;
圖4顯示了FACs偵測抗體31C2,32H4與U251 (IL-13RA2陽性)以及293T (IL-13RA2陰性)細胞的結合;
圖5顯示了Biacore測定抗體31C2,32H4 (scFv_Fc)的親和力;
圖6顯示了FACs偵測抗體31C2,32H4結合U251細胞的EC50
;
圖7顯示了親和力成熟的引子資訊;
圖8顯示了親和力成熟後篩選的10個轉殖株的解離常數Kd;
圖9A顯示了31C2的親和力成熟轉殖株重鏈序列比對,圖9B顯示了31C2的親和力成熟轉殖株的HCDR1和HCDR2的序列,圖9C顯示了32H4的親和力成熟轉殖株重鏈序列比對,圖9D顯示了32H4的親和力成熟轉殖株的HCDR1和HCDR2的序列;
圖10A顯示了親和力成熟的抗體結合解離常數;圖10B顯示了抗體5D7、2C7、5G3、2D4、2D3、1B11的專一性鑑定結果;
圖11A顯示了親和力成熟後,抗體的scFv_Fc形式在30 mL表現體系的產出以及純化產物的聚集程度測定結果;圖11B-G顯示了抗體的scFv_Fc形式的親和力;圖11H為抗體結合解離常數結果;
圖12顯示了抗體5D7、2C7、5G3、2D4、2D3、1B11的scFv_Fc形式的與U251細胞結合的EC50
;
圖13顯示了不同CAR-T細胞的體外殺傷活性。
<110> 佧琺藥業有限公司(CAFA THERAPEUTICS LIMITED) <120> 標靶IL-13RA2的抗體及其應用 <130> P2017-2623 <150> 201710087299.2 <151> 2017-02-17 <160> 75 <170> PatentIn version 3.5 <210> 1 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 31C2 VH <400> 1 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agttatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 2 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2 VH <400> 2 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 324 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 31C2 VL <400> 3 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga ccgtgtcacc 60 atcacttgcc gtgccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180 cgtttcagcg gcagtggatc cgggacagaa ttcactctca ccatcagcag cttgcagcct 240 gatgattttg caacttatta ctgccaacag tacgatacct acccaccaat cacgtttggc 300 cagggcacca aagtcgagat caag 324 <210> 4 <211> 108 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2VL <400> 4 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu 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 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Thr Tyr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 5 <211> 354 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 32H4 VH <400> 5 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agttatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gcgtgttgca 300 ttctctggtt ctttcgacta ctggggccaa ggaaccctgg tcaccgtctc gagt 354 <210> 6 <211> 118 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 32H4 VH <400> 6 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ala Phe Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 7 <211> 321 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 32H4 VL <400> 7 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga ccgtgtcacc 60 atcacttgcc gtgccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180 cgtttcagcg gcagtggatc cgggacagaa ttcactctca ccatcagcag cttgcagcct 240 gatgattttg caacttatta ctgccaacag agaaacagat acccaccaac gtttggccag 300 ggcaccaaag tcgagatcaa g 321 <210> 8 <211> 107 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 32H4 VL <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu 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 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Asn Arg Tyr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 9 <211> 5 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2&32H4 HCDR1 <400> 9 Ser Tyr Ala Met Ser 1 5 <210> 10 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2&32H4 HCDR2 <400> 10 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 11 <211> 12 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2 HCDR3 <400> 11 Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr 1 5 10 <210> 12 <211> 9 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 32H4 HCDR3 <400> 12 Val Ala Phe Ser Gly Ser Phe Asp Tyr 1 5 <210> 13 <211> 11 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2&32H4 LCDR1 <400> 13 Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala 1 5 10 <210> 14 <211> 7 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2&32H4 LCDR2 <400> 14 Asp Ala Ser Ser Leu Glu Ser 1 5 <210> 15 <211> 10 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2 LCDR3 <400> 15 Gln Gln Tyr Asp Thr Tyr Pro Pro Ile Thr 1 5 10 <210> 16 <211> 9 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 32H4 LCDR3 <400> 16 Gln Gln Arg Asn Arg Tyr Pro Pro Thr 1 5 <210> 17 <211> 951 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA2 ECD <400> 17 gacaccgaga taaaagttaa ccctcctcag gattttgaga tagtggatcc cggatactta 60 ggttatctct atttgcaatg gcaaccccca ctgtctctgg atcattttaa ggaatgcaca 120 gtggaatatg aactaaaata ccgaaacatt ggtagtgaaa catggaagac catcattact 180 aagaatctac attacaaaga tgggtttgat cttaacaagg gcattgaagc gaagatacac 240 acgcttttac catggcaatg cacaaatgga tcagaagttc aaagttcctg ggcagaaact 300 acttattgga tatcaccaca aggaattcca gaaactaaag ttcaggatat ggattgcgta 360 tattacaatt ggcaatattt actctgttct tggaaacctg gcataggtgt acttcttgat 420 accaattaca acttgtttta ctggtatgag ggcttggatc atgcattaca gtgtgttgat 480 tacatcaagg ctgatggaca aaatatagga tgcagatttc cctatttgga ggcatcagac 540 tataaagatt tctatatttg tgttaatgga tcatcagaga acaagcctat cagatccagt 600 tatttcactt ttcagcttca aaatatagtt aaacctttgc cgccagtcta tcttactttt 660 actcgggaga gttcatgtga aattaagctg aaatggagca tacctttggg acctattcca 720 gcaaggtgtt ttgattatga aattgagatc agagaagatg atactacctt ggtgactgct 780 acagttgaaa atgaaacata caccttgaaa acaacaaatg aaacccgaca attatgcttt 840 gtagtaagaa gcaaagtgaa tatttattgc tcagatgacg gaatttggag tgagtggagt 900 gataaacaat gctgggaagg tgaagaccta tcgaagaaaa ctttgctacg t 951 <210> 18 <211> 317 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA2 ECD <400> 18 Asp Thr Glu Ile Lys Val Asn Pro Pro Gln Asp Phe Glu Ile Val Asp 1 5 10 15 Pro Gly Tyr Leu Gly Tyr Leu Tyr Leu Gln Trp Gln Pro Pro Leu Ser 20 25 30 Leu Asp His Phe Lys Glu Cys Thr Val Glu Tyr Glu Leu Lys Tyr Arg 35 40 45 Asn Ile Gly Ser Glu Thr Trp Lys Thr Ile Ile Thr Lys Asn Leu His 50 55 60 Tyr Lys Asp Gly Phe Asp Leu Asn Lys Gly Ile Glu Ala Lys Ile His 65 70 75 80 Thr Leu Leu Pro Trp Gln Cys Thr Asn Gly Ser Glu Val Gln Ser Ser 85 90 95 Trp Ala Glu Thr Thr Tyr Trp Ile Ser Pro Gln Gly Ile Pro Glu Thr 100 105 110 Lys Val Gln Asp Met Asp Cys Val Tyr Tyr Asn Trp Gln Tyr Leu Leu 115 120 125 Cys Ser Trp Lys Pro Gly Ile Gly Val Leu Leu Asp Thr Asn Tyr Asn 130 135 140 Leu Phe Tyr Trp Tyr Glu Gly Leu Asp His Ala Leu Gln Cys Val Asp 145 150 155 160 Tyr Ile Lys Ala Asp Gly Gln Asn Ile Gly Cys Arg Phe Pro Tyr Leu 165 170 175 Glu Ala Ser Asp Tyr Lys Asp Phe Tyr Ile Cys Val Asn Gly Ser Ser 180 185 190 Glu Asn Lys Pro Ile Arg Ser Ser Tyr Phe Thr Phe Gln Leu Gln Asn 195 200 205 Ile Val Lys Pro Leu Pro Pro Val Tyr Leu Thr Phe Thr Arg Glu Ser 210 215 220 Ser Cys Glu Ile Lys Leu Lys Trp Ser Ile Pro Leu Gly Pro Ile Pro 225 230 235 240 Ala Arg Cys Phe Asp Tyr Glu Ile Glu Ile Arg Glu Asp Asp Thr Thr 245 250 255 Leu Val Thr Ala Thr Val Glu Asn Glu Thr Tyr Thr Leu Lys Thr Thr 260 265 270 Asn Glu Thr Arg Gln Leu Cys Phe Val Val Arg Ser Lys Val Asn Ile 275 280 285 Tyr Cys Ser Asp Asp Gly Ile Trp Ser Glu Trp Ser Asp Lys Gln Cys 290 295 300 Trp Glu Gly Glu Asp Leu Ser Lys Lys Thr Leu Leu Arg 305 310 315 <210> 19 <211> 964 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA1 ECD <400> 19 gggcgggggc gccgcgccta cggaaactca gccacctgtg acaaatttga gtgtctctgt 60 tgaaaacctc tgcacagtaa tatggacatg gaatccaccc gagggagcca gctcaaattg 120 tagtctatgg tattttagtc attttggcga caaacaagat aagaaaatag ctccggaaac 180 tcgtcgttca atagaagtac ccctgaatga gaggatttgt ctgcaagtgg ggtcccagtg 240 tagcaccaat gagagtgaga agcctagcat tttggttgaa aaatgcatct cacccccaga 300 aggtgatcct gagtctgctg tgactgagct tcaatgcatt tggcacaacc tgagctacat 360 gaagtgttct tggctccctg gaaggaatac cagtcccgac actaactata ctctctacta 420 ttggcacaga agcctggaaa aaattcatca atgtgaaaac atctttagag aaggccaata 480 ctttggttgt tcctttgatc tgaccaaagt gaaggattcc agttttgaac aacacagtgt 540 ccaaataatg gtcaaggata atgcaggaaa aattaaacca tccttcaata tagtgccttt 600 aacttcccgt gtgaaacctg atcctccaca tattaaaaac ctctccttcc acaatgatga 660 cctatatgtg caatgggaga atccacagaa ttttattagc agatgcctat tttatgaagt 720 agaagtcaat aacagccaaa ctgagacaca taatgttttc tacgtccaag aggctaaatg 780 tgagaatcca gaatttgaga gaaatgtgga gaatacatct tgtttcatgg tccctggtgt 840 tcttcctgat actttgaaca cagtcagaat aagagtcaaa acaaataagt tatgctatga 900 ggatgacaaa ctctggagta attggagcca agaaatgagt ataggtaaga agcgcaattc 960 caca 964 <210> 20 <211> 322 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA1 ECD <400> 20 Gly Gly Gly Gly Ala Ala Pro Thr Glu Thr Gln Pro Pro Val Thr Asn 1 5 10 15 Leu Ser Val Ser Val Glu Asn Leu Cys Thr Val Ile Trp Thr Trp Asn 20 25 30 Pro Pro Glu Gly Ala Ser Ser Asn Cys Ser Leu Trp Tyr Phe Ser His 35 40 45 Phe Gly Asp Lys Gln Asp Lys Lys Ile Ala Pro Glu Thr Arg Arg Ser 50 55 60 Ile Glu Val Pro Leu Asn Glu Arg Ile Cys Leu Gln Val Gly Ser Gln 65 70 75 80 Cys Ser Thr Asn Glu Ser Glu Lys Pro Ser Ile Leu Val Glu Lys Cys 85 90 95 Ile Ser Pro Pro Glu Gly Asp Pro Glu Ser Ala Val Thr Glu Leu Gln 100 105 110 Cys Ile Trp His Asn Leu Ser Tyr Met Lys Cys Ser Trp Leu Pro Gly 115 120 125 Arg Asn Thr Ser Pro Asp Thr Asn Tyr Thr Leu Tyr Tyr Trp His Arg 130 135 140 Ser Leu Glu Lys Ile His Gln Cys Glu Asn Ile Phe Arg Glu Gly Gln 145 150 155 160 Tyr Phe Gly Cys Ser Phe Asp Leu Thr Lys Val Lys Asp Ser Ser Phe 165 170 175 Glu Gln His Ser Val Gln Ile Met Val Lys Asp Asn Ala Gly Lys Ile 180 185 190 Lys Pro Ser Phe Asn Ile Val Pro Leu Thr Ser Arg Val Lys Pro Asp 195 200 205 Pro Pro His Ile Lys Asn Leu Ser Phe His Asn Asp Asp Leu Tyr Val 210 215 220 Gln Trp Glu Asn Pro Gln Asn Phe Ile Ser Arg Cys Leu Phe Tyr Glu 225 230 235 240 Val Glu Val Asn Asn Ser Gln Thr Glu Thr His Asn Val Phe Tyr Val 245 250 255 Gln Glu Ala Lys Cys Glu Asn Pro Glu Phe Glu Arg Asn Val Glu Asn 260 265 270 Thr Ser Cys Phe Met Val Pro Gly Val Leu Pro Asp Thr Leu Asn Thr 275 280 285 Val Arg Ile Arg Val Lys Thr Asn Lys Leu Cys Tyr Glu Asp Asp Lys 290 295 300 Leu Trp Ser Asn Trp Ser Gln Glu Met Ser Ile Gly Lys Lys Arg Asn 305 310 315 320 Ser Thr <210> 21 <211> 1638 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA2 ECD_huFc <400> 21 gacaccgaga taaaagttaa ccctcctcag gattttgaga tagtggatcc cggatactta 60 ggttatctct atttgcaatg gcaaccccca ctgtctctgg atcattttaa ggaatgcaca 120 gtggaatatg aactaaaata ccgaaacatt ggtagtgaaa catggaagac catcattact 180 aagaatctac attacaaaga tgggtttgat cttaacaagg gcattgaagc gaagatacac 240 acgcttttac catggcaatg cacaaatgga tcagaagttc aaagttcctg ggcagaaact 300 acttattgga tatcaccaca aggaattcca gaaactaaag ttcaggatat ggattgcgta 360 tattacaatt ggcaatattt actctgttct tggaaacctg gcataggtgt acttcttgat 420 accaattaca acttgtttta ctggtatgag ggcttggatc atgcattaca gtgtgttgat 480 tacatcaagg ctgatggaca aaatatagga tgcagatttc cctatttgga ggcatcagac 540 tataaagatt tctatatttg tgttaatgga tcatcagaga acaagcctat cagatccagt 600 tatttcactt ttcagcttca aaatatagtt aaacctttgc cgccagtcta tcttactttt 660 actcgggaga gttcatgtga aattaagctg aaatggagca tacctttggg acctattcca 720 gcaaggtgtt ttgattatga aattgagatc agagaagatg atactacctt ggtgactgct 780 acagttgaaa atgaaacata caccttgaaa acaacaaatg aaacccgaca attatgcttt 840 gtagtaagaa gcaaagtgaa tatttattgc tcagatgacg gaatttggag tgagtggagt 900 gataaacaat gctgggaagg tgaagaccta tcgaagaaaa ctttgctacg tggatccgac 960 aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 1020 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1080 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1140 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1200 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1260 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1320 cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1380 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1440 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1500 ggctccttct tcctctatag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1560 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1620 tccctgtctc cgggtaaa 1638 <210> 22 <211> 546 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA2 ECD_huFc <400> 22 Asp Thr Glu Ile Lys Val Asn Pro Pro Gln Asp Phe Glu Ile Val Asp 1 5 10 15 Pro Gly Tyr Leu Gly Tyr Leu Tyr Leu Gln Trp Gln Pro Pro Leu Ser 20 25 30 Leu Asp His Phe Lys Glu Cys Thr Val Glu Tyr Glu Leu Lys Tyr Arg 35 40 45 Asn Ile Gly Ser Glu Thr Trp Lys Thr Ile Ile Thr Lys Asn Leu His 50 55 60 Tyr Lys Asp Gly Phe Asp Leu Asn Lys Gly Ile Glu Ala Lys Ile His 65 70 75 80 Thr Leu Leu Pro Trp Gln Cys Thr Asn Gly Ser Glu Val Gln Ser Ser 85 90 95 Trp Ala Glu Thr Thr Tyr Trp Ile Ser Pro Gln Gly Ile Pro Glu Thr 100 105 110 Lys Val Gln Asp Met Asp Cys Val Tyr Tyr Asn Trp Gln Tyr Leu Leu 115 120 125 Cys Ser Trp Lys Pro Gly Ile Gly Val Leu Leu Asp Thr Asn Tyr Asn 130 135 140 Leu Phe Tyr Trp Tyr Glu Gly Leu Asp His Ala Leu Gln Cys Val Asp 145 150 155 160 Tyr Ile Lys Ala Asp Gly Gln Asn Ile Gly Cys Arg Phe Pro Tyr Leu 165 170 175 Glu Ala Ser Asp Tyr Lys Asp Phe Tyr Ile Cys Val Asn Gly Ser Ser 180 185 190 Glu Asn Lys Pro Ile Arg Ser Ser Tyr Phe Thr Phe Gln Leu Gln Asn 195 200 205 Ile Val Lys Pro Leu Pro Pro Val Tyr Leu Thr Phe Thr Arg Glu Ser 210 215 220 Ser Cys Glu Ile Lys Leu Lys Trp Ser Ile Pro Leu Gly Pro Ile Pro 225 230 235 240 Ala Arg Cys Phe Asp Tyr Glu Ile Glu Ile Arg Glu Asp Asp Thr Thr 245 250 255 Leu Val Thr Ala Thr Val Glu Asn Glu Thr Tyr Thr Leu Lys Thr Thr 260 265 270 Asn Glu Thr Arg Gln Leu Cys Phe Val Val Arg Ser Lys Val Asn Ile 275 280 285 Tyr Cys Ser Asp Asp Gly Ile Trp Ser Glu Trp Ser Asp Lys Gln Cys 290 295 300 Trp Glu Gly Glu Asp Leu Ser Lys Lys Thr Leu Leu Arg Gly Ser Asp 305 310 315 320 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 325 330 335 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 340 345 350 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 355 360 365 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 370 375 380 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 385 390 395 400 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 405 410 415 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 420 425 430 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 435 440 445 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 450 455 460 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 465 470 475 480 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 485 490 495 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 500 505 510 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 515 520 525 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 530 535 540 Gly Lys 545 <210> 23 <211> 1653 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA1 ECD_huFc <400> 23 gggggcgggg gcgccgcgcc tacggaaact cagccacctg tgacaaattt gagtgtctct 60 gttgaaaacc tctgcacagt aatatggaca tggaatccac ccgagggagc cagctcaaat 120 tgtagtctat ggtattttag tcattttggc gacaaacaag ataagaaaat agctccggaa 180 actcgtcgtt caatagaagt acccctgaat gagaggattt gtctgcaagt ggggtcccag 240 tgtagcacca atgagagtga gaagcctagc attttggttg aaaaatgcat ctcaccccca 300 gaaggtgatc ctgagtctgc tgtgactgag cttcaatgca tttggcacaa cctgagctac 360 atgaagtgtt cttggctccc tggaaggaat accagtcccg acactaacta tactctctac 420 tattggcaca gaagcctgga aaaaattcat caatgtgaaa acatctttag agaaggccaa 480 tactttggtt gttcctttga tctgaccaaa gtgaaggatt ccagttttga acaacacagt 540 gtccaaataa tggtcaagga taatgcagga aaaattaaac catccttcaa tatagtgcct 600 ttaacttccc gtgtgaaacc tgatcctcca catattaaaa acctctcctt ccacaatgat 660 gacctatatg tgcaatggga gaatccacag aattttatta gcagatgcct attttatgaa 720 gtagaagtca ataacagcca aactgagaca cataatgttt tctacgtcca agaggctaaa 780 tgtgagaatc cagaatttga gagaaatgtg gagaatacat cttgtttcat ggtccctggt 840 gttcttcctg atactttgaa cacagtcaga ataagagtca aaacaaataa gttatgctat 900 gaggatgaca aactctggag taattggagc caagaaatga gtataggtaa gaagcgcaat 960 tccacaggat ccgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 1020 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 1080 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1140 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1200 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1260 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1320 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1380 gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1440 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1500 gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1560 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1620 acgcagaaga gcctctccct gtctccgggt aaa 1653 <210> 24 <211> 551 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> IL-13RA1 ECD_huFc <400> 24 Gly Gly Gly Gly Ala Ala Pro Thr Glu Thr Gln Pro Pro Val Thr Asn 1 5 10 15 Leu Ser Val Ser Val Glu Asn Leu Cys Thr Val Ile Trp Thr Trp Asn 20 25 30 Pro Pro Glu Gly Ala Ser Ser Asn Cys Ser Leu Trp Tyr Phe Ser His 35 40 45 Phe Gly Asp Lys Gln Asp Lys Lys Ile Ala Pro Glu Thr Arg Arg Ser 50 55 60 Ile Glu Val Pro Leu Asn Glu Arg Ile Cys Leu Gln Val Gly Ser Gln 65 70 75 80 Cys Ser Thr Asn Glu Ser Glu Lys Pro Ser Ile Leu Val Glu Lys Cys 85 90 95 Ile Ser Pro Pro Glu Gly Asp Pro Glu Ser Ala Val Thr Glu Leu Gln 100 105 110 Cys Ile Trp His Asn Leu Ser Tyr Met Lys Cys Ser Trp Leu Pro Gly 115 120 125 Arg Asn Thr Ser Pro Asp Thr Asn Tyr Thr Leu Tyr Tyr Trp His Arg 130 135 140 Ser Leu Glu Lys Ile His Gln Cys Glu Asn Ile Phe Arg Glu Gly Gln 145 150 155 160 Tyr Phe Gly Cys Ser Phe Asp Leu Thr Lys Val Lys Asp Ser Ser Phe 165 170 175 Glu Gln His Ser Val Gln Ile Met Val Lys Asp Asn Ala Gly Lys Ile 180 185 190 Lys Pro Ser Phe Asn Ile Val Pro Leu Thr Ser Arg Val Lys Pro Asp 195 200 205 Pro Pro His Ile Lys Asn Leu Ser Phe His Asn Asp Asp Leu Tyr Val 210 215 220 Gln Trp Glu Asn Pro Gln Asn Phe Ile Ser Arg Cys Leu Phe Tyr Glu 225 230 235 240 Val Glu Val Asn Asn Ser Gln Thr Glu Thr His Asn Val Phe Tyr Val 245 250 255 Gln Glu Ala Lys Cys Glu Asn Pro Glu Phe Glu Arg Asn Val Glu Asn 260 265 270 Thr Ser Cys Phe Met Val Pro Gly Val Leu Pro Asp Thr Leu Asn Thr 275 280 285 Val Arg Ile Arg Val Lys Thr Asn Lys Leu Cys Tyr Glu Asp Asp Lys 290 295 300 Leu Trp Ser Asn Trp Ser Gln Glu Met Ser Ile Gly Lys Lys Arg Asn 305 310 315 320 Ser Thr Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 325 330 335 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 340 345 350 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 355 360 365 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 370 375 380 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 385 390 395 400 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 405 410 415 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 420 425 430 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 435 440 445 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 450 455 460 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 465 470 475 480 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 485 490 495 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 500 505 510 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 515 520 525 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 530 535 540 Leu Ser Leu Ser Pro Gly Lys 545 550 <210> 25 <211> 245 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 31C2(scFv) <400> 25 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Thr Tyr Pro Pro Ile Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 Val Glu Ile Lys Arg 245 <210> 26 <211> 735 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 31C2(scFv) <400> 26 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agttatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agtggtggag gcggttcagg cggaggtggt tctggcggtg gcggatcgga catccagatg 420 acccagtctc cttccaccct gtctgcatct gtaggagacc gtgtcaccat cacttgccgt 480 gccagtcaga gtattagtag ctggttggcc tggtatcagc agaaaccagg gaaagcccct 540 aagctcctga tctatgatgc ctccagtttg gaaagtgggg tcccatcacg tttcagcggc 600 agtggatccg ggacagaatt cactctcacc atcagcagct tgcagcctga tgattttgca 660 acttattact gccaacagta cgatacctac ccaccaatca cgtttggcca gggcaccaaa 720 gtcgagatca agcgt 735 <210> 27 <211> 241 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 32H4(scFv) <400> 27 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ala Phe Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu 130 135 140 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 145 150 155 160 Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro 180 185 190 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 195 200 205 Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg 210 215 220 Asn Arg Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 225 230 235 240 Arg <210> 28 <211> 723 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 32H4(scFv) <400> 28 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agttatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gcgtgttgca 300 ttctctggtt ctttcgacta ctggggccaa ggaaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ttctggcggt ggcggatcgg acatccagat gacccagtct 420 ccttccaccc tgtctgcatc tgtaggagac cgtgtcacca tcacttgccg tgccagtcag 480 agtattagta gctggttggc ctggtatcag cagaaaccag ggaaagcccc taagctcctg 540 atctatgatg cctccagttt ggaaagtggg gtcccatcac gtttcagcgg cagtggatcc 600 gggacagaat tcactctcac catcagcagc ttgcagcctg atgattttgc aacttattac 660 tgccaacaga gaaacagata cccaccaacg tttggccagg gcaccaaagt cgagatcaag 720 cgt 723 <210> 29 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2C7 VH <400> 29 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Leu Pro 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 30 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 2C7 VH <400> 30 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttaaa ctgccggcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagca attactggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 31 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D3 VH <400> 31 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Pro 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 32 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 2D3 VH <400> 32 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttcgc agacctgcca tgacatgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagca attacaggta gtggtggtag tacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgt gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 33 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1D11 VH <400> 33 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Thr Ile 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 34 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 1D11 VH <400> 34 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttgga acaattccca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcatcc attagtggta gtgctggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 35 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1B11 VH <400> 35 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Asp 20 25 30 Ala Leu Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 36 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 1B11 VH <400> 36 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agggatgctt tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacattttac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 37 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2A5 VH <400> 37 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ala Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 38 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 2A5 VH <400> 38 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc aggtatgcca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtgcta gtggtggtgg gacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 39 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D4 VH <400> 39 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Lys Tyr 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Val Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 40 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 2D4 VH <400> 40 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttcgc aagtatgcca tgggctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaggt attagtggta gtgttggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 41 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1H7 VH <400> 41 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 42 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 1H7 VH <400> 42 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttcgt cgctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaggt attagcggga gtggtggtgg gacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 43 <211> 121 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1D8 VH <400> 43 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 44 <211> 363 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 1D8 VH <400> 44 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agatacgcca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attaatgcaa gtggaggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagttcgt 300 tacggttggg gtgcaggtgc attcgactac tggggccaag gaaccctggt caccgtctcg 360 agt 363 <210> 45 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2C7 HCDR1 <400> 45 Lys Leu Pro Ala Met Ser 1 5 <210> 46 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D3 HCDR1 <400> 46 Arg Arg Pro Ala Met Thr 1 5 <210> 47 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1D11 HCDR1 <400> 47 Gly Thr Ile Pro Met Ser 1 5 <210> 48 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1B11 HCDR1 <400> 48 Ser Arg Asp Ala Leu Asn 1 5 <210> 49 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2A5&1D8 HCDR1 <400> 49 Ser Arg Tyr Ala Met Asn 1 5 <210> 50 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D4 HCDR1 <400> 50 Arg Lys Tyr Ala Met Gly 1 5 <210> 51 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1H7 HCDR1 <400> 51 Arg Arg Tyr Ala Met Ser 1 5 <210> 52 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2C7&2D3 HCDR2 <400> 52 Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 53 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1D11 HCDR2 <400> 53 Ser Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 54 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1B11 HCDR2 <400> 54 Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 55 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2A5 HCDR2 <400> 55 Ala Ile Ser Ala Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 56 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D4 HCDR2 <400> 56 Gly Ile Ser Gly Ser Val Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 57 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1H7 HCDR2 <400> 57 Gly Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 58 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 1D8 HCDR2 <400> 58 Ala Ile Asn Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 59 <211> 118 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5G3 VH <400> 59 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Val Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Arg Gly Ser Ala Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ala Phe Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 60 <211> 354 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 5G3 VH <400> 60 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc agttacgtcc tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagca attaggggta gtgctggtaa cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gcgtgttgca 300 ttctctggtt ctttcgacta ctggggccaa ggaaccctgg tcaccgtctc gagt 354 <210> 61 <211> 118 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5D7 VH <400> 61 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Arg Ser Ser Gly Gly Arg Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ala Phe Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 62 <211> 354 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> 5D7 VH <400> 62 gaggtgcaat tgctggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttagc aactatgcaa tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaggc attcgtagta gtggtggtcg cacattctac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcagatga acagcctgag agccgaggac acggccgtat attactgtgc gcgtgttgca 300 ttctctggtt ctttcgacta ctggggccaa ggaaccctgg tcaccgtctc gagt 354 <210> 63 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5G3 HCDR1 <400> 63 Ser Ser Tyr Val Leu Ser 1 5 <210> 64 <211> 6 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5D7 HCDR1 <400> 64 Ser Asn Tyr Ala Met Ser 1 5 <210> 65 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5G3 HCDR2 <400> 65 Ala Ile Arg Gly Ser Ala Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 66 <211> 17 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5D7 HCDR2 <400> 66 Gly Ile Arg Ser Ser Gly Gly Arg Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 67 <211> 245 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 2D4 scFv <400> 67 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Lys Tyr 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Val Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Arg Tyr Gly Trp Gly Ala Gly Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Thr Tyr Pro Pro Ile Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 Val Glu Ile Lys Arg 245 <210> 68 <211> 63 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD8α signal peptite <400> 68 atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60 ccg 63 <210> 69 <211> 135 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD8 hinge <400> 69 accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60 tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120 gacttcgcct gtgat 135 <210> 70 <211> 81 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD28 transmembrane domain <400> 70 ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 60 gcctttatta ttttctgggt g 81 <210> 71 <211> 123 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD28 intracellular domain <400> 71 aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60 gggccaaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120 tcc 123 <210> 72 <211> 339 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD3Z domain <400> 72 agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120 cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 180 aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240 cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300 acctacgacg cccttcacat gcaggccctg ccccctcgc 339 <210> 73 <211> 63 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD8 transmembrane <400> 73 atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60 acc 63 <210> 74 <211> 126 <212> DNA <213> 人工序列(Artificial Sequence) <220> <223> CD137 intracellular signaling <400> 74 aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60 actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120 gaactg 126 <210> 75 <211> 241 <212> PRT <213> 人工序列(Artificial Sequence) <220> <223> 5G3 scFv <400> 75 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Val Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Arg Gly Ser Ala Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ala Phe Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu 130 135 140 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 145 150 155 160 Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro 180 185 190 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 195 200 205 Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg 210 215 220 Asn Arg Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 225 230 235 240 Arg
Claims (30)
- 一種專一性辨識IL-13RA2的抗體,其特徵在於,所述輕鏈可變區的CDR區和所述重鏈可變區的CDR區具有下述任選的序列:(1)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:9所示的HCDR1,SEQ ID NO:10所示的HCDR2和SEQ ID NO:11所示的HCDR3;(2)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:16所示的LCDR3;SEQ ID NO:9所示的HCDR1,SEQ ID NO:10所示的HCDR2和SEQ ID NO:12所示的HCDR3;(3)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:16所示的LCDR3;SEQ ID NO:64所示的HCDR1,SEQ ID NO:66所示的HCDR2和SEQ ID NO:12所示的HCDR3;(4)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:45所示的HCDR1,SEQ ID NO:52所示的HCDR2和SEQ ID NO:11所示的HCDR3;(5)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:16所示的LCDR3;SEQ ID NO:63所示的HCDR1,SEQ ID NO:65所示的HCDR2和SEQ ID NO:12所示的HCDR3; (6)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:50所示的HCDR1,SEQ ID NO:56所示的HCDR2和SEQ ID NO:11所示的HCDR3;(7)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:46所示的HCDR1,SEQ ID NO:52所示的HCDR2和SEQ ID NO:11所示的HCDR3;(8)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:48所示的HCDR1,SEQ ID NO:54所示的HCDR2和SEQ ID NO:11所示的HCDR3;(9)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:47所示的HCDR1,SEQ ID NO:53所示的HCDR2和SEQ ID NO:11所示的HCDR3;(10)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:49所示的HCDR1,SEQ ID NO:55所示的HCDR2和SEQ ID NO:11所示的HCDR3;(11)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:51所示的HCDR1,SEQ ID NO:57所示的HCDR2和SEQ ID NO:11所示的HCDR3; (12)SEQ ID NO:13所示的LCDR1,SEQ ID NO:14所示的LCDR2和SEQ ID NO:15所示的LCDR3;SEQ ID NO:49所示的HCDR1,SEQ ID NO:58所示的HCDR2和SEQ ID NO:11所示的HCDR3。
- 如請求項1所述的抗體,其特徵在於,(1)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:2所示的序列;(2)所述輕鏈可變區具有SEQ ID NO:8所示的序列,所述重鏈可變區具有SEQ ID NO:6所示的序列;(3)所述輕鏈可變區具有SEQ ID NO:8所示的序列,所述重鏈可變區具有SEQ ID NO:61所示的序列;(4)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:29所示的序列;(5)所述輕鏈可變區具有SEQ ID NO:8所示的序列,所述重鏈可變區具有SEQ ID NO:59所示的序列;(6)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:39所示的序列;(7)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:31所示的序列;(8)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:35所示的序列;(9)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:33所示的序列; (10)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:37所示的序列;(11)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:41所示的序列;(12)所述輕鏈可變區具有SEQ ID NO:4所示的序列,所述重鏈可變區具有SEQ ID NO:43所示的序列。
- 編碼請求項1或2所述的抗體的核酸。
- 一種表現載體,其包含請求項3所述的核酸。
- 一種宿主細胞,其包含請求項4所述的表現載體或基因組中整合有請求項3所述的核酸。
- 一種多功能免疫綴合物,其特徵在於,所述的多功能免疫綴合物包括:請求項1或2所述的抗體;以及與之連接的功能性分子;所述的功能性分子選自:標靶腫瘤表面標誌物的分子、抑制腫瘤的分子、標靶免疫細胞的表面標誌物的分子或可偵測標記物。
- 如請求項6所述的多功能免疫綴合物,其特徵在於,所述的標靶腫瘤表面標誌物的分子是結合除IL-13RA2外的其他腫瘤表面標誌物的抗體或配體;或所述的抑制腫瘤的分子是抗腫瘤的細胞因子或抗腫瘤的毒素。
- 如請求項7所述的多功能免疫綴合物,其特徵在於,所述的細胞因子選自:IL-12、IL-15、I型干擾素、TNF-alpha。
- 如請求項6所述的多功能免疫綴合物,其特徵在於,所述的標靶免疫細胞的表面標誌物的分子是結合免疫細胞表面標誌物的抗體。
- 如請求項9所述的多功能免疫綴合物,其特徵在於,所述的結合免疫細胞表面標誌物選自:CD3、CD16、CD28。
- 如請求項10所述的多功能免疫綴合物,其特徵在於,所述的結合免疫細胞表面標誌物的抗體是抗CD3抗體。
- 如請求項9所述的多功能免疫綴合物,其特徵在於,所述的標靶免疫細胞的表面標誌物的分子是結合T細胞表面標誌物的抗體,其與請求項1或2所述的抗體形成T細胞參與的雙功能抗體。
- 如請求項9所述的多功能免疫綴合物,其特徵在於,其是融合多肽,在請求項1或2所述的抗體以及與之連接的功能性分子之間,還包括連接肽。
- 編碼請求項6-13中任一所述的多功能免疫綴合物的核酸。
- 包含請求項1或2所述的抗體的嵌合抗原受體,其特徵在於,所述的嵌合抗原受體包含順序連接的:請求項1或2所述的抗體、跨膜區和胞內訊號區。
- 如請求項15所述的嵌合抗原受體,其特徵在於,所述的胞內訊號區選自:CD3ζ、CD3γ、CD3δ、CD3ε、FcRγ(FCER1G)、FcRβ(FcεR1b)、CD79a、CD79b、FcγRIIa、DAP10和DAP12的蛋白質的功能訊號傳導結構域,或其組合。
- 如請求項16所述的嵌合抗原受體,其特徵在於,所述的胞內訊號區還具有共刺激訊號傳導結構域,所述共刺激訊號傳導結構域包含選自以下蛋白的功能訊號傳導結構域:CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴細胞功能相關的抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、專一性結合CD83的配體、CDS、ICAM-1、GITR、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRF1)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244,2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A,Ly108)、SLAM(SLAMF1,CD150,IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46和NKG2D,或其組合。
- 如請求項15所述的嵌合抗原受體,其特徵在於,所述的嵌合抗原受體包括如下的順序連接的抗體、跨膜區和胞內訊號區: 請求項1或2所述的抗體、CD8和CD3ζ;請求項1或2所述的抗體、CD8、CD137和CD3ζ;或請求項1或2所述的抗體、CD28分子的跨膜區、CD28分子的胞內訊號區和CD3ζ;或請求項1或2所述的抗體、CD28分子的跨膜區、CD28分子的胞內訊號區、CD137和CD3ζ。
- 編碼請求項15-18中任一所述的嵌合抗原受體的核酸。
- 一種表現載體,其特徵在於,其包含請求項19所述的核酸。
- 一種病毒,其特徵在於,所述的病毒包含請求項20所述載體。
- 一種嵌合抗原受體修飾的免疫細胞,其特徵在於,其轉導有請求項19所述的核酸,或請求項20所述的表現載體或請求項21所述的病毒;或其表面表現請求項15-18任一所述的嵌合抗原受體。
- 如請求項22所述的免疫細胞,其特徵在於,所述的免疫細胞為:T淋巴細胞、NK細胞或者NKT淋巴細胞。
- 如請求項22所述的免疫細胞,其特徵在於,其還攜帶外源的細胞因子的編碼序列;或其還表現另一種嵌合抗原受體,該受體不含有CD3ζ;或其還表現趨化因子受體;或其還表現能降低PD-1表現的siRNA或者阻斷PD-L1的蛋白;或其細胞中內源性的PD-1被基因編輯技術剔除;或其還表現安全開關。
- 如請求項24所述的免疫細胞,其特徵在於,所述的趨化因子受體包括:CCR。
- 一種藥物組成物,其特徵在於,其包括:請求項1或2所述的抗體或編碼該抗體的核酸;或請求項6-13任一所述的免疫綴合物或編碼該綴合物的核酸;或請求項15-18任一所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸;或請求項22-24任一所述的嵌合抗原受體修飾的免疫細胞;以及藥學上可接受的載體或賦形劑。
- 一種套組,其特徵在於,其包括:容器,以及位於容器中的請求項26所述的藥物組成物;或容器,以及位於容器中的請求項1或2所述的抗體或編碼該抗體的核酸;或請求項6-13任一所述的免疫綴合物或編碼該綴合物的核酸;或請求項15-18任一所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸;或請求項22-24任一所述的嵌合抗原受體修飾的免疫細胞。
- 一種請求項1或2所述的抗體或編碼該抗體的核酸、請求項6-13任一所述的免疫綴合物或編碼該綴合物的核酸、請求項15-18任一所述的嵌合抗原受體或編碼該嵌合抗原受體的核酸或請求項22-24任一所述的嵌合抗原受體修飾的免疫細胞的用途,用於製備治療表現IL-13RA2的腫瘤的藥物。
- 如請求項28所述的用途,其特徵在於,所述的表現IL-13RA2的腫瘤為腦癌、胰腺癌、卵巢癌、腎癌、膀胱癌、胰腺癌、胃癌、腸癌、頭頸癌、甲狀腺癌、前列腺癌、卡波氏肉瘤。
- 如請求項29所述的用途,其特徵在於,所述的腦癌選自星形細胞瘤、腦膜瘤、少突神經膠質瘤、神經膠質瘤。
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JP2010190572A (ja) | 2007-06-01 | 2010-09-02 | Sapporo Medical Univ | IL13Ra2に対する抗体およびこれを含む診断・治療薬 |
ES2614284T3 (es) * | 2007-11-30 | 2017-05-30 | Glaxo Group Limited | Construcciones de unión a antígenos |
CN101440130B (zh) * | 2008-11-21 | 2011-07-27 | 中国人民解放军第四军医大学 | 一种抗人IL-13Rα2单克隆抗体的重链和轻链的可变区 |
PE20141790A1 (es) * | 2011-11-17 | 2014-11-27 | Pfizer | Peptidos citotoxicos y conjugados de anticuerpo-farmaco de los mismos |
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WO2016123143A1 (en) * | 2015-01-26 | 2016-08-04 | The University Of Chicago | CAR T-CELLS RECOGNIZING CANCER-SPECIFIC IL 13Rα2 |
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2018
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US20160039938A1 (en) | 2013-03-15 | 2016-02-11 | Wake Forest University Health Sciences | Antibodies against human and canine il-13ra2 |
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NZ756954A (en) | 2022-07-01 |
US11530270B2 (en) | 2022-12-20 |
BR112019017008A2 (pt) | 2020-04-14 |
JP7064663B2 (ja) | 2022-05-11 |
RU2756623C2 (ru) | 2021-10-04 |
BR112019017008A8 (pt) | 2022-06-28 |
US20190359723A1 (en) | 2019-11-28 |
CL2019002323A1 (es) | 2019-12-06 |
EP3594241A4 (en) | 2020-12-30 |
RU2019128921A (ru) | 2021-03-17 |
CL2021003422A1 (es) | 2022-09-30 |
AU2018221110B2 (en) | 2021-04-08 |
JP2020508657A (ja) | 2020-03-26 |
IL268687A (en) | 2019-10-31 |
CN108456250A (zh) | 2018-08-28 |
KR20190127740A (ko) | 2019-11-13 |
AU2018221110A1 (en) | 2019-09-26 |
RU2019128921A3 (zh) | 2021-03-17 |
TW201835106A (zh) | 2018-10-01 |
SG11201907528TA (en) | 2019-09-27 |
CA3053592A1 (en) | 2018-08-23 |
AU2018221110B9 (en) | 2021-04-22 |
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