CN109517055A - 识别hla-a1-或hla-cw7-限制的mage的t细胞受体 - Google Patents
识别hla-a1-或hla-cw7-限制的mage的t细胞受体 Download PDFInfo
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- CN109517055A CN109517055A CN201811170958.XA CN201811170958A CN109517055A CN 109517055 A CN109517055 A CN 109517055A CN 201811170958 A CN201811170958 A CN 201811170958A CN 109517055 A CN109517055 A CN 109517055A
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Abstract
本发明提供分离的或纯化的T细胞受体(TCR),其具有对a)在HLA‑A1情况下的黑色素瘤抗原家族A(MAGE A)‑3或b)HLA‑Cw7情况下的MAGE‑A12的抗原特异性。本发明进一步提供相关多肽和蛋白,以及相关核酸,重组表达载体,宿主细胞,和细胞群。由本发明进一步提供的是抗体,或其抗原结合部分,和与本发明的TCR有关的药物组合物。由本发明进一步提供检测在宿主中癌症的存在的方法和在宿主中治疗或预防癌症的方法。
Description
本申请是国际申请号PCT/US2012/054623,国际申请日2012年9月11日,中国申请号201280055972.X,发明名称为“识别HLA-A1-或HLA-CW7-限制的MAGE的T细胞受体”的专利申请的分案申请。
本发明由美国国立卫生研究院国家癌症研究所在项目号ZIABC010984的政府支持下完成。政府享有本发明的一些权利。
对相关申请的交叉引用
本申请要求于2011年9月15日申请的美国专利申请号61/535,086的优先权,其通过参考以其整体引入。
电子提交的材料的通过参考引入
在此以其整体通过参考引入的是与此同时提交的计算机可读的核苷酸/氨基酸序列表,识别为如下:日期为2012年8月22日,名为″710922ST25.TXT,″的一个52,162字节ASCII(文本)文件。
发明背景
过继性细胞治疗(ACT)包括转移反应性T细胞到患者内,包括转移肿瘤-反应性T细胞到癌症患者内。使用靶向人白细胞抗原(HLA)-A2限制的T细胞表位的T细胞的过继性细胞治疗在一些患者中引起肿瘤的消退方面已是成功的。然而,缺少HLA-A2表达的患者不能用靶向HLA-A2限制的T细胞表位的T细胞治疗。此种限制产生对过继性细胞治疗的普遍应用产生障碍。因此,存在对改善的用于治疗癌症的免疫组合物和方法的需求。
发明的简单概要
本发明提供分离的或纯化的T细胞受体(TCR),其具有对a)HLA-A1情况下的黑色素瘤抗原家族A(MAGE A)-3或b)HLA-Cw7情况下的MAGE-A12的抗原特异性。本发明进一步提供相关的多肽和蛋白,以及相关的核酸,重组表达载体,宿主细胞,和细胞群。由本发明进一步提供的是抗体,或其抗原结合部分,和与本发明的TCR相关的药物组合物。
由本发明进一步提供检测宿主中癌症的存在的方法和治疗或预防宿主中癌症的方法。所述检测宿主中癌症的存在的本发明的方法包含(i)将包含癌症细胞的样品与在此描述的发明的TCR,多肽,蛋白,核酸,重组表达载体,宿主细胞,宿主细胞群,或抗体,或其抗原结合部分的任一个接触,从而形成复合物,和(ii)检测所述复合物,其中所述复合物的检出表征所述宿主中癌症的存在。
所述治疗或预防宿主中癌症的本发明的方法包含以治疗或预防宿主中癌症的有效量向所述宿主施用在此描述的所述TCR,多肽,或蛋白的任一个,任何包含编码在此描述的所述TCR,多肽,蛋白的任一个的核苷酸序列核酸或重组表达载体,或任何包含编码在此描述的所述TCR,多肽,或蛋白的任一个的重组载体的宿主细胞或宿主细胞群。
附图的一些视图的简述
图1A为显示响应与不同肿瘤细胞系共培养的未转导的(UT)细胞(黑色线条)或转导有抗MAGE-A3TCR A10(SEQ ID NO:46)(无阴影线条)或抗MAGE-A3TCR 13-18(SEQ ID NO:48)(灰色线条)的细胞的干扰素(IFN)-γ分泌(pg/ml)的线条图。
图1B为显示响应与HLA-A1+/MAGE-A3+新鲜肿瘤FrTu 2767(黑色线条),FrTu 3178(灰色线条),FrTu 2823(无阴影线条)或FrTu 3068(对角线线条)或HLA-A*0201+/MART-1+新鲜肿瘤FrTu 2851(水平线线条)或FrTu3242(竖直线线条)共培养的UT细胞或转导有抗MAGE-A3TCR A10(SEQ ID NO:46)或抗MART-1TCR DMF5的细胞的IFN-γ分泌(pg/ml)的线条图。方格线条表示不与肿瘤细胞共培养的细胞。
图2A和2B为显示响应与不同肿瘤细胞系共培养的,源自转导有编码截短的人低亲和力神经生长因子受体(NGFR)的对照构建体(黑色线条),抗MAGE-A12TCR 502(SEQ ID NO:47)(无阴影线条),或抗MAGE-A12TCR FM8(SEQ ID NO:49)(灰色线条)的第一(图2A)和第二(图2B)供体的细胞的IFN-γ分泌(pg/ml)的线条图。
图3A说明表达HLA-A1(线条的无阴影部分),HLA-A2(线条的灰色部分),和/或HLA-Cw7(线条的黑色部分)的正常高加索人群体的累积百分数的线条图。
图3B和3C说明将预计表达HLA-A2和NY-ESO-1(线条的对角线部分);HLA-A1和MAGE-A3(线条的无阴影部分);HLA-A2,MAGE-A3,和MAGE-A12(线条的灰色部分);和/或HLA-Cw7和MAGE-A12(线条的黑色部分)的人黑色素瘤(图3B)和滑膜细胞肉瘤(图3C)患者群体的累积百分数的线条图。
图4为显示响应与由源自MAGE-A12(VRIGHLYIL;SEQ ID NO:4),MAGE-A2(VPISHLYIL;SEQ ID NO:50),MAGE-A3(DPIGHLYIF;SEQ ID NO:51),MAGE-A6(DPIGHVYIF;SEQ ID NO:52),或对照肽(EDGCPAAEK;SEQ ID NO:53)的肽刺激的HLA-Cw*0701和HLA-Cw*0702靶细胞共培养的转导有NGFR(黑色线条),抗MAGE-A12TCR 502(SEQ ID NO:47)(无阴影线条),或抗MAGE-A12TCR FM8(SEQ ID NO:49)(灰色线条)的细胞的IFN-γ分泌(pg/ml)的线条图。
图5A-5D显示在指定的效应物对靶(E:T)的比率下,由未转导的(闭合圆形)或转导有抗MAGE-A12TCR 502(SEQ ID NO:47)抗MAGE-A12TCR FM8(SEQ ID NO:49)(菱形),抗MAGE-A3TCR A10(SEQ ID NO:46)(正方形),抗MAGE-A3TCR 13-18(SEQ ID NO:48)(▲),或抗MAGE-A3TCR 112-120(开放圆形)的PBMC导致的397mel(A),624mel(B),2984mel(C),和2661RCC(D)细胞的溶解百分数的线状图。提供源自两个独立实验中的一个的代表性结果。
图6A为显示响应与不同肿瘤细胞系共培养的未转导的(对照)细胞(条纹线条)或转导有抗MAGE-A3TCR A10(SEQ ID NO:46)(阴影线条)或抗MAGE-A3TCR 13-18(SEQ ID NO:48)(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。提供源自三个独立的评估转导有这些TCR的T细胞的响应的实验中的两个的代表性结果。
图6B为显示对转导有抗MAGE-A3TCR A10(SEQ ID NO:46),抗MAGE-A3TCR 13-18(SEQ ID NO:48),抗MAGE-A12TCR 502(SEQ ID NO:47),或抗MAGE-A12TCR FM8(SEQ ID NO:49)的细胞测量的载体DNA的估计的相对拷贝的线条图。
图6C为显示响应与同不同浓度的MAGE-A3168-176肽孵育的靶细胞的共培养转导有抗MAGE-A3TCR A10(SEQ ID NO:46)(圆形)或抗MAGE-A3TCR 13-18(SEQ ID NO:48)(正方形)的细胞分泌的IFN-γ的量的线状图。
图6D为显示响应与不同肿瘤细胞系共培养的转导有抗MAGE-A12TCR 502(SEQ IDNO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(方格线条)的细胞的的IFN-γ分泌(pg/ml)的线条图。提供源自三个独立的评估转导有这些TCR的T细胞的响应的实验中的两个的代表性结果。
图6E为显示由响应与同不同浓度的MAGE-A12:170-178肽孵育的靶细胞的共培养转导有抗MAGE-A12TCR 502(SEQ ID NO:47)(圆形)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(正方形)的细胞分泌的IFN-γ的量的线状图。
图6F为显示响应与不同肿瘤细胞系共培养的未转导的(对照)(条纹线条)或转导有抗MAGE-A12TCR 502(SEQ ID NO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。提供源自三个独立的评估转导有这些TCR的T细胞的响应的实验中的两个的代表性结果。
图7A为显示响应与不同新鲜未培养的肿瘤共培养的未转导的细胞(对照)(条纹线条)或转导有抗MAGE-A3TCR A10(SEQ ID NO:46)(阴影线条)或抗MAGE-A3TCR 13-18(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。提供源自三个独立的评估转导有这些TCR的T细胞的响应的实验中的一个的代表性结果.
图7B为显示响应与不同新鲜未培养肿瘤共培养的未转导的细胞(对照)(条纹线条)或转导有抗MAGE-A12TCR 502(SEQ ID NO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQID NO:49)(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。提供源自三个独立的评估转导有这些TCR的T细胞的响应的实验中的一个的代表性结果。
图8A为显示与用HLA-A*01加上MAGE-A3,A1,A2,A4,A6,A9,A10或A12之一转染的靶细胞共培养过夜的未转导的细胞(对照)(条纹线条)或转导有抗MAGE-A3TCR A10(SEQ IDNO:46)(阴影线条)或抗MAGE-A3TCR 13-18(方格线条)细胞的IFN-γ分泌(pg/ml)的线条图。
图8B为显示与用HLA-C*07:02加上MAGE-A3,A1,A2,A4,A6,A9,A10或A12之一转染的靶细胞共培养过夜的未转导的细胞(对照)(条纹线条)或转导有抗MAGE-A12TCR 502(SEQID NO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。
图8C为显示与用HLA-C*07:01加上MAGE-A3,A1,A2,A4,A6,A9,A10或A12之一转染的靶细胞共培养过夜的未转导的细胞(对照)(条纹线条)或转导有抗MAGE-A12TCR 502(SEQID NO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(方格线条)的细胞的IFN-γ分泌(pg/ml)的线条图。
图9A和9B为显示与不同肿瘤靶共培养的为未转导的(对照)(条纹线条)或转导有抗MAGE-A3TCR A10(SEQ ID NO:46)(阴影线条)或抗MAGE-A3TCR 13-18(方格线条)的CD8+(图9A)或CD4+细胞(图9B)的IFN-γ分泌的线条图。提供源自两个独立实验中的一个的代表性结果。
图9C为显示与不同肿瘤靶共培养的为未转导的(对照)(条纹线条)或转导有抗MAGE-A12TCR 502(SEQ ID NO:47)(阴影线条)或抗MAGE-A12TCR FM8(SEQ ID NO:49)(方格线条)的CD8+细胞的IFN-γ分泌的线条图。提供源自两个独立实验中的一个的代表性结果。
发明详述
本发明的一个实施方案提供T细胞受体(TCR),所述TCR具有对a)HLA-A1情况下的黑色素瘤抗原家族A(MAGE A)-3(还称为MAGE-3)或b)HLA-Cw7情况下的MAGE-A12(还称为MAGE-12)的抗原特异性。
MAGE-A3和MAGE-A12是12种同源蛋白的MAGE-A家族成员,所述家族还包括MAGE-A1,MAGE-A2,MAGE-A4,MAGE-A5,MAGE-A6,MAGE-A7,MAGE-A8,MAGE-A9,MAGE-A10,和MAGE-A11。所述MAGE-A蛋白是癌睾丸抗原(CTA),所述CTA仅表达在肿瘤细胞和睾丸和胎盘的无MHC表达生殖细胞中。MAGE-A蛋白表达在多种人癌症中,所述人癌症包括,但不限于,黑色素瘤,乳腺癌,白血病,甲状腺癌,胃癌,胰腺癌,肝癌(举例来说,肝细胞癌),肺癌(举例来说,非小细胞肺癌),卵巢癌,多发性骨髓瘤,食道癌,肾癌,头部癌症(举例来说,鳞状细胞癌),颈部癌症(举例来说,鳞状细胞癌),前列腺癌,和泌尿道上皮癌。
本发明的TCR提供很多优点,包括当用于过继性细胞转移时。例如,通过靶向a)HLA-A1情况下提呈的MAGE-A3或b)HLA-Cw7情况下提呈的MAGE-A12,发明的TCR有可能治疗患者,其不能使用靶向其它HLA分子(举例来说,HLA-A2)情况下提呈的MAGE抗原的TCR治疗。因为HLA-A1和HLA-Cw7是高度常见等位基因,发明的TCR有利地大大扩展了可以被治疗的患者群体。此外,不受特别的理论限制,人们相信因为MAGE-A3和/或MAGE-A12由多种癌症类型的细胞表达,发明的TCR有利地提供破坏多种类型的癌症的细胞的能力并且,因此,治疗或预防多种类型的癌症。此外,不受特别的理论限制,人们相信因为所述MAGE-A蛋白是癌睾丸抗原,其仅表达在肿瘤细胞和睾丸和胎盘的无MHC表达的生殖细胞中,发明的TCR有利地靶向癌症细胞的破坏,同时最小化或消除对正常,非癌细胞的破坏,从而例如,通过最小化或消除,减少毒性。
如在此使用的短语″抗原特异性″意为所述TCR可以以高亲和力特异结合和免疫识别MAGE-A3或MAGE-A12。例如,如果当分别与分别用低浓度的MAGE-A3肽或MAGE-A12肽(举例来说,约0.05ng/ml到约5ng/ml,0.05ng/ml,0.1ng/ml,0.5ng/ml,1ng/ml,或5ng/ml)刺激的抗原-阴性的HLA-A1+靶细胞或HLA-Cw7+靶细胞共培养时,表达所述TCR的T细胞分泌至少约200pg/ml或更多(举例来说,200pg/ml或更多,300pg/ml或更多,400pg/ml或更多,500pg/ml或更多,600pg/ml或更多,700pg/ml或更多,1000pg/ml或更多,5,000pg/ml或更多,7,000pg/ml或更多,10,000pg/ml或更多)的IFN-γ,TCR可以被认为是具有对MAGE-A3或MAGE-A12的“抗原特异性”。备选地或此外,如果当与用低浓度的MAGE-A3肽或MAGE-A12肽分别刺激的抗原-阴性的HLA-A1+靶细胞或HLA-Cw7+靶细胞分别共培养时,表达所述TCR的T细胞分泌至少如未转导的PBL背景水平的IFN-γ的两倍IFN-γ量,TCR可以被认为是具有对MAGE-A3或MAGE-A12的“抗原特异性”。当与用较高浓度的MAGE-A3肽或MAGE-A12肽分别刺激的抗原-阴性的HLA-A1+靶细胞或HLA-Cw7+靶细胞共培养时,发明的TCR也可以分泌IFN-γ。
本发明的一个实施方案提供具有对于任何MAGE-A3蛋白,多肽或肽的抗原特异性的TCR。发明的TCR可以具有对于MAGE-A3蛋白的抗原特异性,所述MAGE-A3蛋白包含SEQ IDNO:1,由SEQ ID NO:1组成,或主要由SEQ ID NO:1组成。在本发明的一个优选的实施方案中,所述TCR具有对MAGE-A3168-176肽的抗原特异性,所述肽包含EVDPIGHLY(SEQ ID NO:2),由EVDPIGHLY(SEQ ID NO:2)组成,或主要由EVDPIGHLY(SEQ ID NO:2)组成。
发明的TCR可以以人白细胞抗原(HLA)-A1-依赖的方式识别MAGE-A3。由如在此使用的″HLA-A1-依赖的方式″意为所述TCR在结合于HLA-A1分子的情况下的MAGE-A3癌症抗原时诱导免疫反应。发明的TCR可以识别由HLA-A1分子呈递的MAGE-A3并可以结合除MAGE-A3外的HLA-A1分子。典型的HLA-A1分子,在其情况下发明的TCR识别MAGE-A3,包括由HLA-A*0101,HLA-A*0102,和/或HLA-A*0103等位基因编码的那些。
本发明的一个实施方案提供具有对任何MAGE-A12蛋白,多肽或肽的抗原特异性的TCR。发明的TCR可以具有对MAGE-A12蛋白的抗原特异性,所述MAGE-A12蛋白包含SEQ IDNO:3,由SEQ ID NO:3组成,或主要由SEQ ID NO:3组成。在本发明的一个优选的实施方案中,所述TCR具有对MAGE-A12170-178肽的抗原特异性,所述肽包含VRIGHLYIL(SEQ ID NO:4),由VRIGHLYIL(SEQ ID NO:4)组成,或主要由VRIGHLYIL(SEQ ID NO:4)组成。
发明的TCR可以以HLA-Cw7-依赖的方式识别MAGE-A12。由如在此使用的″HLA-Cw7-依赖的方式″意为所述TCR在结合于HLA-Cw7分子情况下的MAGE-A12癌症抗原时诱导免疫反应。发明的TCR可以识别由HLA-Cw7分子呈递的MAGE-A12并可以结合除MAGE-A12之外的HLA-Cw7分子。典型的HLA-Cw7分子,在其情况下发明的TCR识别MAGE-A12,包括由HLA-Cw*0701和/或HLA-Cw*0702等位基因编码的那些。
本发明提供包含两条多肽(即,多肽链)的TCR,所述多肽如TCR的α链,TCR的β链,TCR的γ链,TCR的δ链,或其组合。TCR的此种多肽链在本领域已知。发明的TCR的所述多肽可以包含任何氨基酸序列,条件是所述TCR具有对a)HLA-A1情况下的MAGE-A3或b)HLA-Cw7情况下的MAGE-A12的抗原特异性。
在本发明的一个实施方案中,所述TCR包含两条多肽链,其中每个包含可变区,所述可变区包含TCR的互补决定区(CDR)1,CDR2,和CDR3。在本发明的一个实施方案中,所述TCR具有对MAGE-A3168-176的抗原特异性并且包含第一多肽链,所述第一多肽链包含CDR1(包含SEQ ID NO:5或16(α链的CDR1)的氨基酸序列),CDR2(包含SEQ ID NO:6或17(α链的CDR2)的氨基酸序列,和CDR3(包含SEQ ID NO:7或18(α链的CDR3)的氨基酸序列,和第二多肽链,所述第二多肽链包含CDR1(包含SEQ ID NO:8或19(β链的CDR1)的氨基酸序列),CDR2(包含SEQ ID NO:9或20(β链的CDR2)的氨基酸序列),和CDR3(包含SEQ ID NO:10或21(β链的CDR3)的氨基酸序列)。在本发明的另一个实施方案中,所述TCR具有对MAGE-A12170-178的抗原特异性,并且包含第一多肽链,所述第一多肽链包含CDR1(包含SEQ ID NO:26或36(α链的CDR1)的氨基酸序列),CDR2(包含SEQ ID NO:27或37(α链的CDR2)的氨基酸序列),和CDR3(包含SEQ ID NO:28或38(α链的CDR3)的氨基酸序列),和第二多肽链,所述第二多肽链包含CDR1(包含SEQ ID NO:29或39(β链的CDR1)的氨基酸序列),CDR2(包含SEQ ID NO:30或40(β链的CDR2)的氨基酸序列),和CDR3(包含SEQ ID NO:31或41(β链的CDR3)的氨基酸序列)。在这点上,发明的TCR可以包含选自由SEQ ID NO:5-7,8-10,16-18,19-21,26-28,29-31,36-38,和39-41的任一个或更多组成的组的任一个或更多的氨基酸序列。优选地,所述TCR包含SEQ ID NO:5-10,16-21,26-31,或36-41的氨基酸序列。更优选地,所述TCR包含SEQID NO:5-10或26-31的氨基酸序列。
备选地或此外,所述TCR可以包含包含以上列出的CDR的TCR的可变区的氨基酸序列。在这点上,所述具有对MAGE-A3168-176的抗原特异性的TCR可以包含SEQ ID NO:11或22(α链的可变区)或12或23(β链的可变区),SEQ ID NO:11和12二者或SEQ ID NO:22和23二者的氨基酸序列。在本发明的另一个实施方案中,所述TCR具有对MAGE-A12170-178的抗原特异性并且包含SEQ ID NO:32或42(α链的可变区)或33或43(β链可变区),SEQ ID NO:32和33二者,或SEQ ID NO:42和43二者的氨基酸序列。优选地,发明的TCR包含SEQ ID NO:11和12二者或SEQ ID NO:32和33二者的氨基酸序列。
备选地或此外,所述TCR可以包含TCR的α链和TCR的β链。发明的TCR的α链和β链的每个可以独立地包含任何氨基酸序列。优选地,所述α链包含如以上列出的α链的可变区。在这点上,发明的具有对MAGE-A3168-176的抗原特异性的TCR可以包含SEQ ID NO:13或24的氨基酸序列并且发明的具有对MAGE-A12170-178的抗原特异性的TCR可以包含SEQ ID NO:34或44的氨基酸序列。发明的此种类型的TCR可以与任何TCR的β链配对。优选地,发明的TCR的β链包含如以上列出的β链的可变区。在这点上,发明的具有对MAGE-A3168-176的抗原特异性的TCR可以包含SEQ ID NO:14或25的氨基酸序列并且发明的具有对MAGE-A12170-178的抗原特异性的TCR可以包含SEQ ID NO:35或45的氨基酸序列。发明的TCR,因此,可以包含SEQ ID NO:13,14,24,25,34,35,44,或45,SEQ ID NO:13和14二者,SEQ ID NO:24和25二者,SEQ ID NO:34和35二者,或SEQ ID NO:44和45二者的氨基酸序列。优选地,发明的TCR包含SEQ ID NO:13和14二者或SEQ ID NO:34和35二者的氨基酸序列。
本发明还提供的是包含在此描述的任何所述TCR的功能部分的多肽。如在此使用的术语″多肽″包括寡肽并且指由一个或更多肽键连接的氨基酸单链。
至于发明的多肽,所述功能部分可以是包含所述TCR的连续的氨基酸的任何部分,其是TCR的部分,条件是所述功能部分特异结合MAGE-A3或MAGE-A12。当关于TCR时所使用的术语″功能部分″指本发明的所述TCR的任何部分或片段,所述部分或片段保留所述TCR的生物学活性,其是TCR的部分,(母体TCR)。功能部分包括,例如,保留特异结合MAGE-A3(举例来说,以HLA-A1-依赖的方式)或MAGE-A12(举例来说,以HLA-Cw7-依赖的方式)的能力,或以如母体TCR类似的程度,同样的程度,或更高的程度检测,治疗,或预防癌症的那些TCR的部分。关于所述母体TCR,所述功能部分可以包含,例如,所述母体TCR的约10%,25%,30%,50%,68%,80%,90%,95%,或更多。
功能部分可以在所述部分的氨基或羧基末端,或在二者末端包含另外的氨基酸,所述另外的氨基酸在所述母体TCR的氨基酸序列中未发现。理想地,所述另外的氨基酸不干扰所述功能部分的生物学功能,举例来说,特异结合于MAGE-A3或MAGE-A12;和/或具有检测癌症,治疗或预防癌症的功能,等。更理想地,当与所述母体TCR的生物学活性比较时,所述另外的氨基酸增强生物学活性。
所述多肽可以包含本发明所述TCR的α和β链之一或二者的功能部分,如包含本发明的TCR的α链和/或β链的可变区的CDR1,CDR2,和CDR3的一个或更多的功能部分。在这点上,所述多肽可以包含包含SEQ ID NO:5,16,26,或36(α链的CDR1),6,17,27,或37(α链的CDR2),7,18,28,或38(α链的CDR3),8,19,29,或39(β链的CDR1),9,20,30,或40(β链的CDR2),10,21,31,或41(β链的CDR3),或其组合的氨基酸序列的功能部分。优选地,发明的多肽包含包含SEQ ID NO:5-7;8-10;16-18;19-21;26-28;29-31;36-38;39-41;SEQ ID NO:5-10中全体;SEQ ID NO:16-21中全体;SEQ ID NO:26-31中全体;或SEQ ID NO:36-41中全体的功能部分。更优选地,所述多肽包含包含SEQ ID NO:5-10中全体或SEQ ID NO:26-31中全体的氨基酸序列的功能部分。
备选地或此外,发明的多肽可以包含,例如,包含以上列出的CDR区的组合发明的TCR的可变区。在这点上,所述多肽可以包含SEQ ID NO:11,22,32,或42(α链的可变区),SEQID NO:12,23,33,或43(β链的可变区),SEQ ID NO:11和12二者,SEQ ID NO:22和23,SEQ IDNO:32和33二者,或SEQ ID NO:42和43二者的氨基酸序列。优选地,所述多肽包含SEQ IDNO:11和12二者或SEQ ID NO:32和33二者的氨基酸序列。
备选地或此外,发明的多肽可以包含在此描述的所述TCR的一个的α或β链的全长。在这点上,发明的多肽可以包含SEQ ID NO:13,14,24,25,34,35,44,或45的氨基酸序列。备选地,本发明的所述多肽可以包含在此描述的所述TCR的α和β链。例如,发明的多肽可以包含SEQ ID NO:13和14二者;SEQ ID NO:24和25二者;SEQ ID NO:34和35二者;或SEQ ID NO:44和45二者的氨基酸序列。优选地,所述多肽包含SEQ ID NO:13和14二者或SEQ ID NO:34和35二者的氨基酸序列。
本发明进一步提供包含在此描述的所述多肽的至少一个的蛋白。由″蛋白″意为包含一个或更多多肽链的分子。
在一个实施方案中,本发明的所述蛋白可以包含包含SEQ ID NO:5-7;SEQ ID NO:16-18;SEQ ID NO:26-28;或SEQ ID NO:36-38的氨基酸序列的第一多肽链和包含SEQ IDNO:8-10;SEQ ID NO:19-21;SEQ ID NO:29-31;或SEQ ID NO:39-41氨基酸序列第二多肽链。备选地或此外,本发明的所述蛋白可以包含包含SEQ ID NO:11,22,32,或42的氨基酸序列的第一多肽链和包含SEQ ID NO:12,23,33,或43的氨基酸序列的第二多肽链。本发明的所述蛋白可以,例如,包含包含SEQ ID NO:13,24,34,或44的氨基酸序列的第一多肽链和包含SEQ ID NO:14,25,35,或45的氨基酸序列的第二多肽链。在这种情况下,本发明的所述蛋白可以是TCR。备选地,如果,例如,所述蛋白包含包含SEQ ID NO:13,24,34,或44和SEQ IDNO:14,25,35,或45的单一多肽链,或如果所述蛋白的第一和/或第二多肽链进一步包含其它氨基酸序列,举例来说,编码免疫球蛋白或其部分的氨基酸序列,那么发明的蛋白可以是融合蛋白。在这点上,本发明还提供融合蛋白,所述融合蛋白包含与至少一种其它多肽一起的在此描述的发明的多肽的至少一种。其它多肽可以作为融合蛋白的分离的多肽存在,或可以作为与在此描述的发明的多肽的一种在框中(一前一后地)表达的多肽存在。其它多肽可以编码任何肽或蛋白分子,或其部分,包括,但不限于免疫球蛋白,CD3,CD4,CD8,MHC分子,CD1分子,举例来说,CDla,CD1b,CD1c,CD1d,等。
所述融合蛋白可以包含发明的多肽的一个或更多拷贝和/或其它多肽的一个或更多拷贝。例如,所述融合蛋白可以包含发明的多肽和/或所述其它多肽的1,2,3,4,5,或更多个拷贝。制备融合蛋白的合适方法在本领域中已知,并且包括,例如,重组方法。参见,例如,Choi等,Mol.Biotechnol.31:193-202(2005)。
在本发明的一些实施方案中,本发明的所述TCR,多肽,和蛋白可以表达为包含连接所述α链和所述β链的接头肽单个蛋白。在这点上,包含SEQ ID NO:13,24,34,或44和SEQID NO:14,25,35,或45的本发明的所述TCR,多肽,和蛋白可以进一步包含包含SEQ ID NO:15或54的接头肽。所述接头肽可以有利地促进重组TCR,多肽,和/或蛋白在宿主细胞中的表达。当由宿主细胞表达包括所述接头肽的构建体时,所述接头肽可以切除,产生分离的α和β链。
本发明的蛋白可以是包含在此描述的发明的多肽的至少一种的重组抗体。如在此使用的,″重组抗体″指包含本发明的所述多肽和抗体的多肽链或其部分的至少一种的重组(举例来说,遗传改造的)蛋白。抗体的所述多肽或其部分可以是重链,轻链,重或轻链的可变或恒定区,单链可变片段(scFv),或抗体的Fc,Fab,或F(ab)2′片段,等。抗体的所述多肽链或其部分,可以作为重组抗体的分离的多肽存在。备选地,抗体的所述多肽链,或其部分,可以作为与本发明的所述多肽在框中(一前一后地)表达的多肽存在。抗体的所述多肽,或其部分,可以是任何抗体的多肽或任何抗体片段,包括任何在此描述的抗体和抗体片段。
包括在本发明范围内的是在此描述的发明的TCR,多肽,和蛋白的功能变体。如在此使用的术语″功能变体″指与母体TCR,多肽,或蛋白具有基本上或显著的序列同一性或相似性的TCR,多肽,或蛋白,所述功能变体保留所述TCR,多肽,或蛋白的生物学活性,其是所述TCR,多肽,或蛋白的变体。功能变体包括,例如,在此描述的所述TCR,多肽,或蛋白(所述母体TCR,多肽,或蛋白)的那些变体,所述变体保留特异结合MAGE-A3或MAGE-A12的能力,所述母体TCR对所述MAGE-A3或MAGE-A12具有抗原特异性或母体多肽或蛋白特异以如所述母体TCR,多肽,或蛋白相似的程度,相同的程度,或更高的程度结合于所述MAGE-A3或MAGE-A12。关于所述母体TCR,多肽,或蛋白,所述功能变体可以,例如,是与所述母体TCR,多肽,或蛋白在氨基酸序列方面至少约30%,50%,75%,80%,90%,95%,96%,97%,98%,99%或更多相同。
所述功能变体可以,例如,包含具有至少一种保守氨基酸取代的所述母体TCR,多肽,或蛋白的氨基酸序列。保守氨基酸取代是本领域已知的,并且包括氨基酸取代,其中一个具有一定的物理和/或化学性质的氨基酸以另一个具有相同化学或物理性质的氨基酸交换。例如,所述保守氨基酸取代可以是酸性氨基酸代替另一个酸性氨基酸(举例来说,Asp或Glu),带有非极性侧链的氨基酸代替另一个带有非极性侧链的氨基酸(举例来说,Ala,Gly,Val,Ile,Leu,Met,Phe,Pro,Trp,Val,等),碱性氨基酸代替另一个碱性氨基酸(Lys,Arg,等),带有极性侧链的氨基酸代替另一个带有极性侧链的氨基酸(Asn,Cys,Gln,Ser,Thr,Tyr,等),等。
备选地或此外,所述功能变体可以包含具有至少一个非保守氨基酸取代的所述母体TCR,多肽,或蛋白的氨基酸序列。在该情况下,优选非保守氨基酸取代不干扰或抑制所述功能变体的生物学活性。优选地,所述非保守氨基酸取代增强所述功能变体的生物学活性,这样以至于当与所述母体TCR,多肽,或蛋白比较时,所述功能变体的生物学活性增加。
所述TCR,多肽,或蛋白可以基本由在此描述的一个或多个特定氨基酸序列组成,这样以至于所述功能变体的其它组分,举例来说,其它氨基酸,不本质改变所述功能变体的生物学活性。在这点上,发明的TCR,多肽,或蛋白可以,例如,基本上由SEQ ID NO:13,14,24,25,34,35,44,或45,SEQ ID NO:13和14二者,SEQ ID NO:24和25二者,SEQ ID NO:34和35二者,或SEQ ID NO:44和45二者的氨基酸序列组成。同样,例如,发明的TCR,多肽,或蛋白可以基本上由SEQ ID NO:11,12,22,23,32,33,42,或43,SEQ ID NO:11和12二者,SEQ IDNO:22和23二者,SEQ ID NO:32和33二者,或SEQ ID NO:42和43二者氨基酸序列组成。此外,发明的TCR,多肽,或蛋白可以基本上由SEQ ID NO:5,16,26,或36(α链的CDR1),SEQ ID NO:6,17,27,或37(α链的CDR2),SEQ ID NO:7,18,28,或38(α链的CDR3),SEQ ID NO:8,19,29,或39(β链的CDR1),SEQ ID NO:9,20,30,或40(β链的CDR2),SEQ ID NO:10,21,31,或41(β链的CDR3),或任何其组合,举例来说,SEQ ID NO:5-7;8-10;5-10;16-18;19-21;16-21;26-28;29-31;26-31;36-38;39-41;或36-41的氨基酸序列组成。
本发明的所述TCR,多肽,蛋白(包括功能部分和功能变体)可以是任何长度,即,可以包含任何数量的氨基酸,条件是所述TCR,多肽,或蛋白(或其功能部分或功能变体)保留其生物学活性,举例来说,特异结合MAGE-A3或MAGE-A12;检测宿主中癌症;或治疗或预防宿主中癌症的能力,等。例如,所述多肽可以使在约50到约5000氨基酸长度,如50,70,75,100,125,150,175,200,300,400,500,600,700,800,900,1000或更多氨基酸长度范围内。在这点上,本发明的所述多肽还包括寡肽。
本发明的所述TCR,多肽,和蛋白(包括功能部分和功能变体)可以包含合成的氨基酸替代一个或更多天然存在的氨基酸。此种合成的氨基酸是本领域已知的,并且包括,例如,氨基环己烷羧酸,正亮氨酸,α-氨基n-癸酸,高丝氨酸,S-乙酰氨甲基-半胱氨酸,反式-3-和反式-4-羟脯氨酸,4-氨基苯丙氨酸,4-硝基苯丙氨酸,4-氯代苯丙氨酸,4-羧基苯丙氨酸,β-苯基丝氨酸β-羟基苯丙氨酸,苯基甘氨酸,α-萘基丙氨酸,环己基丙氨酸,环己基甘氨酸,二氢吲哚-2-羧酸,1,2,3,4-四氢异喹啉-3-羧酸,氨基丙二酸,氨基丙二酸单酰胺,N’-苯甲基-N’-甲基-赖氨酸,N’,N’-二苄基-赖氨酸,6-羟基赖氨酸,鸟氨酸,α-氨基环戊烷羧酸,α-氨基环己烷羧酸,α-氨基环庚烷羧酸,α-(2-氨基-2-降莰烷)-羧酸,α,γ-二氨基丁酸,α,β-二氨基丙酸,高苯丙氨酸,和α-叔丁基甘氨酸。
本发明的所述TCR,多肽,和蛋白(包括功能部分和功能变体)可以是通过,举例来说,二硫桥键,或转变为酸式加成盐和/或任选的二聚化或多聚化,或偶联而被糖基化的,酰胺化的,羧化的,磷酸化的,酯化的,N-酰化的,环化的。
当本发明的所述TCR,多肽,和蛋白(包括功能部分和功能变体)是以盐的形式时,优选地,所述多肽是以药学可接受的盐的形式。合适的药学可接受的酸式加成盐包括源自无机酸,如盐酸的,氢溴酸的,磷酸的,偏磷酸的,硝酸的,和硫酸,和有机酸,如酒石酸的,醋酸的,柠檬酸的,苹果酸的,乳酸的,富马酸的,苯甲酸的,乙醇酸的,葡糖酸的,琥珀酸的和芳基磺酸,例如,p-甲苯磺酸的那些。
本发明的所述TCR,多肽,和/或蛋白(包括其功能部分和功能变体)可以通过本领域已知的方法获得。从头合成多肽和蛋白的合适的方法在参考文献中描述,如Chan等,FmocSolid Phase Peptide Synthesis,Oxford University Press,Oxford,United Kingdom,2005;Peptide and Protein Drug Analysis,编辑Reid,R.,Marcel Dekker,Inc.,2000;Epitope Mapping,编辑Westwood等,Oxford University Press,Oxford,United Kingdom,2000;和美国专利号5,449,752。并且,多肽和蛋白可以使用在此描述的核酸使用标准重组方法重组生产。参见,例如,Sambrook等,Molecular Cloning:A Laboratory Manual,第三次编辑,Cold Spring Harbor Press,Cold Spring Harbor,NY 2001;和Ausubel等,Current Protocols in Molecular Biology,Greene Publishing Associates and JohnWiley&Sons,NY,1994。进一步的,本发明的所述TCR,多肽,和蛋白中的一些(包括其功能部分和功能变体)可以从来源如植物,细菌,昆虫,哺乳动物,举例来说,大鼠,人,等分离和/或纯化。分离和纯化的方法是本领域公知的。备选地,在此描述的所述TCR,多肽,和/或蛋白(包括其功能部分和功能变体)可以通过公司,如Synpep(Dublin,CA),PeptideTechnologies Corp.(Gaithersburg,MD),和Multiple Peptide Systems(San Diego,CA)商业合成。在这方面,发明的TCR,多肽,和蛋白可以是合成的,重组的,分离的,和/或纯化的。
包括在本发明的范围内的是偶联物,举例来说,生物偶联物,包含任何发明的TCR,多肽,或蛋白(包括其任何所述功能部分或变体),核酸,重组表达载体,宿主细胞,宿主细胞群,或抗体,或其抗原结合部分。通常偶联物,和合成偶联物的方法,是本领域已知的(参见,例如,Hudecz,F.,Method Mol.Biol.298:209-223(2005)和Kirin等,Inorg Chem.44(15):5405-5415(2005))。
由如在此使用的″核酸″包括″多核苷酸,″″寡核苷酸,″和″核酸分子,″并且通常意为DNA或RNA的聚合物,所述DNA或RNA可以是单链的或双链的,合成的或从天然来源获得的(举例来说,分离的和/或纯化的),其可以包含天然的,非天然的或改变的核苷酸,并且其可以包含天然的,非天然的或改变的核苷酸间连接,如氨基磷酸酯连接或硫代磷酸酯连接替代在未修饰的寡核苷酸之间建立的磷酸二酯。通常优选所述核酸不包含任何插入,缺失,倒位和/或取代。然而,如在此讨论的,在一些情况下,对于核酸其可以是合适的以包含一个或更多插入,缺失,倒位和/或取代。
优选地,本发明的核酸是重组的。如在此使用的,术语″重组″指(i)在活细胞外通过连接天然的或合成的核酸片段与可以在活细胞中复制的核酸分子来构建的分子,或(ii)由描述于以上(i)中的那些复制产生的分子。为了在此的目的,所述复制可以是体外复制或体内复制。
所述核酸可以基于化学合成和/或酶连接反应使用本领域已知的工艺构建。参见,例如,Sambrook等,在前,和Ausubel等,在前。例如,核酸可以使用天然存在的核苷酸或设计以增加分子的生物稳定性或以增加杂交时形成的双链的物理稳定性的不同修饰的核苷酸(举例来说,硫代磷酸酯衍生物和吖啶代核苷酸)来化学合成。可以用于产生核酸的修饰的核苷酸的例子包括,但不限于,5-氟尿嘧啶,5-溴尿嘧啶,5-氯尿嘧啶,5-碘尿嘧啶,次黄嘌呤,黄嘌呤,4-乙酰胞嘧啶,5-(羧基羟甲基)尿嘧啶,5-羧甲基氨甲基-2-硫尿嘧啶,5-羧甲基氨甲基尿嘧啶,二氢尿嘧啶,β-D-半乳糖基queosine,肌苷,N6-异戊烯基腺嘌呤,1-甲基鸟嘌呤,1-甲基肌苷,2,2-二甲基鸟嘌呤,2-甲基腺嘌呤,2-甲基鸟嘌呤,3-甲基胞嘧啶,5-甲基胞嘧啶,N6-替代腺嘌呤,7-甲基鸟嘌呤,5-甲基氨甲基尿嘧啶,5-甲氧基氨甲基-2-硫尿嘧啶,β-D-甘露糖基queosine,5′-甲氧基羧甲基尿嘧啶,5-甲氧基尿嘧啶,2-甲基硫代-N6-异戊烯基腺嘌呤,尿嘧啶-5-羟乙酸(v),wybutoxosine,假尿嘧啶,queosine,2-硫胞嘧啶,5-甲基-2-硫尿嘧啶,2-硫尿嘧啶,4-硫尿嘧啶,5-甲基尿嘧啶,尿嘧啶-5-羟乙酸甲基酯,3-(3-氨基-3-N-2-羧基丙基)尿嘧啶,和2,6-二氨基嘌呤.备选地,本发明的一种或更多核酸可以从公司购买,如Macromolecular Resources(Forr Collins,CO)和Synthegen(Houston,TX).
所述核酸可以包含编码在此描述的任何所述TCR,多肽,或蛋白,或其功能部分或功能变体的任何核苷酸序列。例如,所述核酸可以包含核苷酸序列SEQ ID NO:46-49的任何一个或更多,由核苷酸序列SEQ ID NO:46-49的任何一个或更多组成,或基本上由核苷酸序列SEQ ID NO:46-49的任何一个或更多组成。
本发明还提供包含与在此描述的任何所述核酸的核苷酸序列互补的核苷酸序列或与在此描述的任何所述核酸的核苷酸序列在严格条件下杂交的核苷酸序列的核酸。
所述在严格条件下杂交的核苷酸序列优选在高度严格条件下杂交。由“高度严格条件”意为所述核苷酸序列以强于非特异杂交的可检测的量特异杂交于靶序列(在此描述的任何所述核酸的核苷酸序列)。高度严格条件包括将多核苷酸与正好互补序列区分,或将仅包含一些分散的错配的序列与偶尔具有一些匹配核苷酸序列的小的区域(举例来说,3-10个碱基)的随机序列区分的条件。此种小的互补区域比14-17或更多碱基的全长互补更易于融入,且高度严格条件使它们易于区别。相对地,高度严格条件将包括,例如,低盐和/或高温条件,如在约50-70℃的温度下,由约0.02-0.1M NaCl或相当的量提供的。即便有,此种高度严格条件允许所述核苷酸序列和模板或靶链之间很小的错配,并且尤其适于检测任何发明的TCR的表达。通常理解所述条件可以通过加入增加的甲酰胺的量使变得更严格。
本发明还提供包含与在此描述的任何所述核酸为至少约70%或更多,举例来说,约80%,约90%,约91%,约92%,约93%,约94%,约95%,约96%,约97%,约98%,或约99%相同的核苷酸序列的核酸。
本发明的所述核酸可以整合入重组表达载体。在这点上,本发明提供包含本发明的任何所述核酸的重组表达载体。为了在此的目的,术语″重组表达载体″意为遗传修饰的寡核苷酸或多核苷酸构建体,当包含编码所述mRNA,蛋白,多肽,或肽,和载体的核苷酸序列的构建体在足以使得所述mRNA,蛋白,多肽,或肽在细胞中表达的条件下与所述细胞接触时,其允许通过宿主细胞表达mRNA,蛋白,多肽,或肽。本发明的载体总体上不是天然存在的。然而,载体的部分可以是天然存在的。发明的重组表达载体可以包含任何类型的核苷酸,包括,但不限于DNA和RNA,其可以是单链的或双链的,合成的或部分获自天然来源且,其可以包含天然的,非天然的或改变的核苷酸。所述重组表达载体可以包含天然存在的,非天然存在的核苷酸间连接,或两种类型的连接。优选地,所述非天然存在的或改变的核苷酸或核苷酸间连接不妨碍载体的转录或复制。
本发明的重组表达载体可以是任何合适的重组表达载体,并可以用于转化或转染任何合适的宿主。合适的载体包括为增殖和扩增或为表达或二者设计的那些,如质粒和病毒。所述载体可以选自由以下组成的组:pUC系列(Fermentas Life Sciences),pBluescript系列(Stratagene,LaJolla,CA),pET系列(Novagen,Madison,WI),pGEX系列(Pharmacia Biotech,Uppsala,Sweden),和pEX系列(Clontech,Palo Alto,CA)。也可以使用噬菌体载体,如λGT10,λGT11,λZapII(Stratagene),λEMBL4,和λNM1149。植物表达载体的例子包括pBI01,pBI101.2,pBI101.3,pBI121和pBIN19(Clontech)。动物表达载体的例子包括pEUK-Cl,pMAM和pMAMneo(Clontech)。优选地,所述重组表达载体是病毒载体,举例来说,逆转录病毒载体。
本发明的重组表达载体可以使用描述于例如,Sambrook等,在前,和Ausubel等,在前中的标准重组DNA技术制备。可以制备环形或线形表达载体的构建体以包含在原核或真核宿主细胞中行使功能的复制系统。复制系统可以源自,举例来说,ColEl,2μ质粒,λ,SV40,牛乳头瘤病毒等。
理想地,所述重组表达载体包含调控序列,如转录和翻译起始和终止密码子,所述调控序列是宿主类型(举例来说,细菌,真菌,植物,或动物)特异的,酌情并考虑载体是否是基于DNA或RNA将所述载体整合入所述宿主中。
所述重组表达载体可以包括允许用于筛选转化或转染的宿主的一种或更多标志物基因。标志物基因包括生物杀灭剂抗性,举例来说,对抗生素,重金属的抗性,等,在营养缺陷型宿主中补充以提供原养型等。用于发明的表达载体的合适的标志物基因包括,例如,新霉素/G418抗性基因,潮霉素抗性基因,组胺醇抗性基因,四环素抗性基因,和氨苄青霉素抗性基因。
所述重组表达载体可以包含天然或非天然启动子,所述启动子可操作连接于编码所述TCR,多肽,或蛋白(包括其功能部分和功能变体)的核苷酸序列,或与编码所述TCR,多肽,或蛋白核苷酸序列互补或杂交的核苷酸序列。启动子的选择,举例来说,强,弱,可诱导,组织特异的和发育特异的,在技术人员的普通技术内。类似的,核苷酸序列与启动子的组合也在技术人员的技术内。所述启动子可以是非病毒启动子或病毒启动子,举例来说,巨细胞病毒(CMV)启动子,SV40启动子,RSV启动子,和发现于鼠干细胞病毒的长末端重复中的启动子。
发明的重组表达载体可以为瞬时表达,稳定表达之一,或二者设计。同样,所述重组表达载体可以为构成型表达或诱导型表达制备。进一步的,所述重组表达载体可以制备以包括自杀基因。
如在此使用的,术语″自杀基因″指引起表达所述自杀基因的细胞死亡的基因。所述自杀基因可以是使表达该基因的细胞具有对试剂(举例来说,药物)的敏感性,并当细胞与所述试剂接触或暴露于所述试剂时导致细胞死亡的基因。自杀基因是本领域已知的(参见,例如,Suicide Gene Therapy:Methods and Reviews,Springer,Caroline J.(CancerResearch UK Centre for Cancer Therapeutics at the Institute of CancerResearch,Sutton,Surrey,UK),Humana Press,2004)并且包括,例如,单纯疱疹病毒(HSV)胸苷激酶(TK)基因,胞嘧啶脱氨酶,嘌呤核苷磷酸化酶,和硝基还原酶。
本发明的另一个实施方案进一步提供包含任何在此描述的重组表达载体的宿主细胞。如在此使用的,术语″宿主细胞″指可以包含发明的重组表达载体的任何类型的细胞。所述宿主细胞可以是真核细胞,举例来说,植物,动物,真菌,或藻类,或可以是原核细胞,举例来说,细菌或原生动物。所述宿主细胞可以是培养的细胞或原代细胞,即,直接分离自生物体,举例来说,人。所述宿主细胞可以是粘着细胞或悬浮细胞,即,在悬浮液中生长的细胞。合适的宿主细胞是本领域已知的并且包括,例如,DH5α大肠杆菌细胞,中国仓鼠卵巢细胞,猴VERO细胞,COS细胞,HEK293细胞等。为了扩增或复制所述重组表达载体,所述宿主细胞优选地为原核细胞,举例来说,DH5α细胞。为了生产重组TCR,多肽,或蛋白,所述宿主细胞优选地为哺乳动物细胞。最优选地,所述宿主细胞为人细胞。同时宿主细胞可以是任何细胞类型的,可以源自任何类型的组织,并且可以是任何发育阶段的,宿主细胞优选地为外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。更优选地,所述宿主细胞为T细胞。
为了在此的目的,所述T细胞可以是任何T细胞,如培养的T细胞,举例来说,原代T细胞,或源自培养的T细胞系的T细胞,举例来说,Jurkat,SupT1,等,或获自哺乳动物的T细胞。如果获自哺乳动物,所述T细胞可以获自许多来源,包括但不限于血液,骨髓,淋巴结,胸腺,或其它组织或液体。T细胞还可以是富集的或纯化的。优选地,所述T细胞是人T细胞。更优选地,所述T细胞是分离自人的T细胞。所述T细胞可以是任何类型的T细胞且可以为任何发育阶段的,包括但不限于,CD4+/CD8+双阳性T细胞,CD4+辅助T细胞,举例来说,Th1和Th2细胞,CD8+T细胞(举例来说,细胞毒性T细胞),肿瘤侵润淋巴细胞(TIL),记忆T细胞(举例来说,中央记忆T细胞和效应记忆T细胞),天然T细胞等。优选地,所述T细胞为CD8+T细胞或CD4+T细胞。
由本发明还提供的是包含至少一个在此描述的宿主细胞的细胞群。所述细胞群可以是包含除了至少一个其它细胞(举例来说,不包含任何重组表达载体的宿主细胞(举例来说,T细胞),或除了T细胞之外的细胞,举例来说,B细胞,巨噬细胞,中性粒细胞,红细胞,肝细胞,内皮细胞,上皮细胞,肌肉细胞,脑细胞,等)之外的包含任何描述的重组表达载体的所述宿主细胞的异质群体。备选地,所述细胞群可以是基本上同质群体,其中,所述群体主要包含包含所述重组表达载体的宿主细胞(举例来说,基本由其组成)。所述群体还可以是克隆细胞群,其中所述群体的所有细胞是单个包含重组表达载体的宿主细胞的克隆,这样以至于所述群体的所有细胞包含所述重组表达载体。在本发明的一个实施方案中,所述细胞群是包含包含如在此描述的重组表达载体的宿主细胞的克隆群体。
本发明进一步提供抗体,或其抗原结合部分,其特异结合任何在此描述的所述TCR的功能部分。优选地,所述功能部分特异结合所述癌症抗原,举例来说,所述功能部分包含氨基酸序列SEQ ID NO:5,16,26,或36(α链的CDR1),6,17,27,或37(α链的CDR2),7,18,28,或38(α链的CDR3),8,19,29,或39(β链的CDR1),9,20,30,或40(β链的CDR2),10,21,31,或41(β链的CDR3),SEQ ID NO:11,22,32,或42(α链的可变区),SEQ ID NO:12,23,33,或43(β链的可变区),或其组合,举例来说,5-7;8-10;5-10;16-18,19-21;16-21;26-28;29-31;26-31;36-38;39-41;或36-41。更优选地,所述功能部分包含SEQ ID NO:5-10或SEQ ID NO:26-31的氨基酸序列。在一个优选的实施方案中,所述抗体,或其抗原结合部分,结合由所有6个CDR(α链的CDR1-3和β链的CDR1-3)组成的表位。所述抗体可以是本领域已知的任何类型的免疫球蛋白。例如,所述抗体可以是任何同种型的,举例来说,IgA,IgD,IgE,IgG,IgM,等。所述抗体可以是单克隆的或多克隆的。所述抗体可以是天然存在的抗体,举例来说,分离和/或纯化自哺乳动物(举例来说,小鼠,兔,山羊,马,鸡,仓鼠,人,等)的抗体。备选地,所述抗体可以是遗传改造的抗体,举例来说,人源化抗体或嵌合抗体。所述抗体可以是以单体的或多聚体的形式。同样,所述抗体可以对发明的TCR的所述功能部分具有任何水平的亲和力(affinity)或亲和力(avidity)。理想地,所述抗体是对发明的TCR的所述功能部分特异的,这样以至于与其它肽或蛋白存在最小的交叉反应。
检测抗体结合发明的TCR的任何功能部分的能力的方法是本领域已知的并且包括任何抗体-抗原结合测定法,如,例如,放射性免疫测定(RIA),ELISA,蛋白质印迹,免疫沉淀,和竞争抑制测定(参见,举例来说,Janeway等,在下文,和美国专利申请公开号2002/0197266A1)。
制备抗体的合适的方法是本领域已知的。例如,标准的杂交瘤方法描述于,举例来说,和Milstein,Eur.J.Immunol.,5,511-519(1976),Harlow和Lane(eds.),Antibodies:A Laboratory Manual,CSH Press(1988),和C.A.Janeway等(eds.),Immunobiology,第五次编辑,Garland Publishing,New York,NY(2001))。备选地,其它方法,如EBV-杂交瘤方法(Haskard和Archer,J.Immunol.Methods,74(2),361-67(1984),和Roder等,Methods Enzymol.,121,140-67(1986)),和噬菌体载体表达系统(参见,举例来说,Huse等,Science,246,1275-81(1989))是本领域已知的。进一步地,在非人动物中生产抗体的方法描述于,举例来说,美国专利5,545,806,5,569,825,和5,714,352,和美国专利申请公开号2002/0197266A1。
噬菌体展示此外可以用于产生本发明的抗体。在这点上,编码抗体的抗原-结合可变(V)结构域的噬菌体文库可以使用标准的分子生物学和重组DNA技术(参见,举例来说,Sambrook等(eds.),Molecular Cloning,A Laboratory Manual,第三版,Cold SpringHarbor Laboratory Press,New York(2001))产生。选择特异结合于需要的抗原的编码具有需要的特异性的可变区的噬菌体,并且重组完全或部分抗体为包含选择的可变结构域。编码重组抗体的核酸序列引入合适的细胞系,如用于杂交瘤生产的骨髓瘤细胞,这样以至于具有单克隆抗体的特征的抗体由所述细胞分泌的(参见,举例来说,Janeway等,在前,Huse等,在前,和美国专利6,265,150)。
抗体可以由转基因小鼠生产,所述转基因小鼠对特定重和轻链免疫球蛋白基因是转基因的。此种方法是本领域已知的并描述于,例如美国专利5,545,806和5,569,825,和Janeway等,在前。
用于产生人源化抗体的方法是本领域公知的并详细描述于,例如,Janeway等,在前,美国专利5,225,539,5,585,089和5,693,761,欧洲专利号0239400 B1,和英国专利号2188638。人源化的抗体还可以使用描述于例如,美国专利5,639,641和Pedersen等,J.Mol.Biol.,235,959-973(1994)中的抗体表面重建技术产生。
本发明还提供任何在此描述的抗体的抗原结合部分。所述抗原结合部分可以是具有至少一个抗原结合位点(如Fab,F(ab’)2,dsFv,sFv,二体(diabodies),和三体(triabodies))的任何部分。
单链可变区片段(sFv)抗体片段可以使用常规重组DNA工艺技术产生(参见,举例来说,Janeway等,在前),所述sFv由包含通过合成的肽连接于轻抗体链的V结构域的抗体重链的可变(V)结构域的截短的Fab片段组成。类似的,二硫键稳定的可变区片段(dsFv)可以通过重组DNA技术制备(参见,举例来说,Reiter等,Protein Engineering,7,697-704(1994))。然而,本发明的抗体片段不限于这些典型类型的抗体片段。
并且,所述抗体,或其抗原结合部分,可以修饰以包含可检测标签,如,例如,放射性同位素,荧光团(举例来说,异硫氰酸荧光素(FITC),藻红蛋白(PE)),酶(举例来说,碱性磷酸酶,辣根过氧化物酶),和元素颗粒(举例来说,金颗粒)。
发明的TCR,多肽,蛋白,(包括其功能部分和功能变体),核酸,重组表达载体,宿主细胞(包括其群体),和抗体(包括其抗原结合部分),可以是分离的和/或纯化的。如在此使用的术语″分离的″意为已从其天然环境中移除。如在此使用的术语″纯化的″意为已在纯度方面增加,其中″纯度″是相对的术语,并不必然理解为绝对的纯度。例如,所述纯度可以是至少约50%,可以是大于60%,70%,80%,90%,95%,或可以是100%。
发明的TCR,多肽,蛋白(包括其功能部分和变体),核酸,重组表达载体,宿主细胞(包括其群体),和抗体(包括其抗原结合部分),其全体在下文中共同指为″发明的TCR材料″,可以配制为组合物,如药物组合物.在这点上,本发明提供包含任何所述TCR,多肽,蛋白,功能部分,功能变体,核酸,表达载体,宿主细胞(包括其群体),和抗体(包括其抗原结合部分),和药学可接受的载体的药物组合物。包含任何发明的TCR材料的发明的药物组合物可以包含多于一种发明的TCR材料,举例来说,多肽和核酸,或两种或更多不同的TCR。备选地,所述药物组合物可以包含与其它药学活性试剂或药物组合的发明的TCR材料,所述其它其它药学活性试剂或药物如化学疗法试剂,举例来说,天门冬氨酰酶,白消胺,卡波铂,顺铂,正定霉素,阿霉素,氟尿嘧啶,吉西他宾,羟基脲,氨甲喋呤,紫杉醇,利妥昔单抗,长春碱,长春新碱,等。
优选地,所述载体是药学可接受的载体。至于药物组合物,所述载体可以是任何那些方便使用且仅由化学-物理的考虑(如溶解性和缺少与活性化合物的反应性)和由给药方式限制的载体。在此描述的所述药学可接受的载体,例如,载体(vehicles),佐剂,赋形剂,和稀释剂是本领域技术人员公知的且对于公众容易获得。优选所述药学可接受的载体为化学插入活性试剂的载体和在使用条件下不具有有害副作用或毒性的载体。
载体的选择将部分由特定的发明的TCR材料和由用于施用发明的TCR材料的特定的方法决定。因此,存在多种本发明的药物组合物的合适的制剂。以下用于口服,气溶胶,肠胃外,皮下,静脉内,肌肉内,动脉内,鞘内和腹膜间的制剂是典型的且决不限制。可以使用多于一种途径以施用发明的TCR材料,在一些实例中,特定的途径可以比其它途径提供更直接和更有效的反应。
局部制剂对于本领域技术人员是公知的。此种制剂在本发明的范围内尤其适于施用于皮肤。
适于口腔给药的制剂可以由以下组成,(a)液体溶液,所述液体溶液如溶于稀释剂的有效量的发明的TCR材料,所述稀释剂如水,盐水,或橙汁;(b)胶囊剂,袋剂,片剂,糖锭(lozenges),和锭剂(troches),每个包含以固体或料粒形式的预定量的活性成分;(c)粉末;(d)在合适液体中的悬液;和(e)合适的乳状液。液体制剂可以包括稀释剂,如水和酒精,例如,乙醇,苯甲醇,和聚乙烯醇,加入或不加入药学可接受的表面活性剂。胶囊剂形式可以是普通的硬或软壳凝胶型,其包含,例如,表面活性剂,润滑剂,和惰性填料,如乳糖,蔗糖,磷酸钙,和玉米淀粉。片剂形式可以包括乳糖,蔗糖,甘露糖,玉米淀粉,马铃薯淀粉,海藻酸,微晶纤维素,阿拉伯胶,明胶,瓜尔胶,胶体二氧化硅,交联羧甲基纤维素钠,滑石,硬脂酸镁,硬脂酸钙,硬脂酸锌,硬脂酸和其它赋形剂,着色剂,稀释剂,缓冲剂,崩解剂,湿润剂,防腐剂,调味剂和其它药学可容的赋性剂的一种或更多。糖锭(Lozenge)形式可以在香料中包含发明的TCR材料,所述香料通常为蔗糖,和阿拉伯胶或黄芪胶,且锭剂(pastilles)在惰性基质中包含发明的TCR材料,所述惰性基质如明胶和甘油,或蔗糖和阿拉伯胶,乳状液,胶和包含作为本领域已知的此种赋形剂外的类似物。
发明的TCR材料,单独或与其他合适的组分组合,可以制备为气溶胶制剂以通过吸入给药。这些气溶胶制剂可以置于加压可接受的推进器中,如二氯二氟甲烷,丙烷,氮等。其还可以配制为用于常压制备的药物,如在喷雾器(nebulizer)或喷雾器(atomizer)中。此种喷雾制剂还用于用于喷射粘液。
适于肠胃外给药的制剂包括水性的或非水性的等渗无菌注射溶液,其可以包含抗氧化剂,缓冲剂,抑菌剂,和使制剂与目标受体的血液等渗的溶质,和可以包括悬浮剂,增溶剂,增稠剂,稳定剂和防腐剂的水性的和非水性的无菌悬液。发明的TCR材料可以以药学载体中的生理学可接受的稀释剂施用,所述稀释剂如无菌液体或液体的混合物,包括水,盐水,含水葡萄糖,和相关的糖溶液,酒精,如乙醇或十六烷基醇,乙二醇,如丙二醇或聚乙烯醇,二甲基亚砜,甘油,缩酮如2,2-二甲基-1,3-二氧戊烷-4-甲醇,醚,聚(乙烯醇)400,油,脂肪酸,脂肪酸酯或甘油脂,或加或不加药学可接受的表面活性剂的乙酰化脂肪酸甘油脂,所述表面活性剂,如脂肪酸盐或去污剂,悬浮剂,如果胶,卡波姆,甲基纤维素,羟丙基甲基纤维素,或羧甲基纤维素,或乳化剂和其它药学佐剂。
可以用在肠胃外制剂中的油包括石油,动物、植物、或合成的油。油特别的例子包括花生,大豆,芝麻,棉籽,玉米,橄榄,石蜡油和矿物油。用于用在肠胃外制剂中的合适的脂肪酸包括油酸,硬脂酸和异硬脂酸。油酸乙酯和豆蔻酸异丙酯是合适的脂肪酸酯的实例。
供在肠胃外制剂中使用的合适的脂肪酸盐包括脂肪碱金属,铵,和三乙醇铵盐,且合适的去污剂包括(a)阳离子去污剂如,例如,二甲基二烃基卤化铵,和卤代烷基吡啶,(b)阴离子去污剂如,例如,烷基、芳基、和烯磺酸盐,烷基、烯、醚、和单酸甘油脂硫酸盐,和磺基丁二酸酯,(c)非离子去污剂如,例如,氧化脂肪胺,脂肪酸链烷醇酰胺,和聚氧乙烯聚丙烯共聚物,(d)两性去污剂如,例如,烷基-β-氨基丙酸酯,和2-烷基-咪唑啉季铵盐,和(e)其混合物。
典型地,肠胃外制剂以发明的TCR材料在溶液中的重量计将包含从约0.5%到约25%,或更多。可以使用防腐剂和缓冲剂。为了最小化或消除在注射位点的刺激,此种组合物可以包含一种或更多非离子型表面活性剂,所述表面活性剂具有亲油亲酯平衡(HLB)为从约12到约17。在此种制剂中表面活性剂的质量以重量计典型地在约5%到约15%范围内。合适的表面活性剂包括聚乙二醇脱水山梨糖醇脂肪酸酯,如脱水山梨糖醇单油酸酯和通过环氧丙烷与丙二醇的缩合形成的环氧乙烷与疏水性基质的高分子量加合物。所述肠胃外制剂可以以单位剂量或多剂量密封的容器(如安瓿和小瓶)提供,并且可以储藏在冷冻干燥(冻干)的条件,所述条件仅需要在使用前直接加入无菌液体赋形剂,例如,用于注射的水。可以从之前描述种类的无菌粉末,料粒和片剂制备临时的注射溶液和悬液。
可注射制剂与本发明一致。对用于可注射组合物的有效药学载体的需求是本领域普通技术人员公知的(参见,举例来说,Pharmaceutics and Pharmacy Practice,J.B.Lippincott Company,Philadelphia,PA,Banker and Chalmers,eds.,第238-250页(1982),和ASHP Handbook on Injectable Drugs,Toissel,第四版,第622-630页(1986))。优选地,当施用细胞,举例来说,T细胞时,所述细胞通过注射施用。
本领域技术人员将理解,除了以上描述的药物组合物之外,本发明的发明的TCR材料可以配置为包含复合物,如环糊精包含复合物,或脂质体。
为了本发明,施用的发明的TCR材料的量或剂量应当是足以产生效果的,举例来说,在受试者或动物中在合适的时间范围内的治疗或预防反应。例如,发明的TCR材料的剂量应当足以结合癌症抗原,或在从给药时间开始从约2小时或更长,举例来说,12到24或更多小时的时期内检测,治疗或预防癌症。在一些实施方案中,所述时期可以甚至更长。剂量将由特定的发明的TCR材料的功效和动物(举例来说,人)的状况,以及被治疗动物(举例来说,人)的体重决定。
很多用于确定给药剂量的测定法是本领域已知的。为了本发明,可以使用测定法确定施用于哺乳动物的起始剂量,所述测定法包含在向一组哺乳动物(其中每个给予不同剂量的T细胞)中的哺乳动物施用给定剂量的此种T细胞时,比较靶细胞溶解的程度或由表达发明的TCR,多肽,或蛋白的T细胞分泌IFN-γ的程度。当施用一定剂量时,靶细胞溶解和/或分泌IFN-γ的程度可以由在本领域中已知的方法测试。
发明的TCR材料的剂量还将由任何可能伴随施用特定的发明的TCR材料的有害的副作用的存在,性质和程度决定。典型地,主治医生将考虑多种因素(如年龄,体重,基本健康状况,饮食,性别,施用的发明的TCR材料,给药途径和被治疗病状的严重度)决定用于治疗个体患者的发明的TCR材料的剂量。例如且不意在限制本发明,发明的TCR材料的剂量可以为约0.001到约1000mg/kg被治疗受试者的体重/天或更多,从约0.01到约10mg/kg体重/天或更多,或约0.01mg到约1mg/kg体重/天或更多。在一个实施方案中,其中发明的TCR材料为细胞群,施用的细胞的数量可以改变,举例来说,从约1x106到约1x1011细胞或更多。
本领域普通技术人员将容易理解,本发明的发明的TCR材料可以以许多方式修饰,这样以至于通过修饰增加发明的TCR材料的治疗或预防功效。例如,发明的TCR材料可以直接或间接通过桥偶联于靶向部分。偶联化合物(举例来说,发明的TCR材料对靶向部分)的实施是本领域已知的。参见,例如,Wadwa等,J.Drug Targeting 3:111(1995)和美国专利5,087,616。如在此使用的术语″靶向部分″,指特异识别和结合细胞表面受体,以至于所述靶向部分引导发明的TCR材料向表面表达受体的细胞群递送的任何分子或试剂。靶向部分包括,但不限于,结合细胞表面受体(举例来说,上皮生长因子受体(EGFR),T细胞受体(TCR),B细胞受体(BCR),CD28,血小板源性生长因子受体(PDGF),烟碱乙酰胆碱受体(nAChR),等)的抗体,或其片段,肽,激素,生长因子,细胞因子,和任何其它天然或非天然的配体。如在此使用的术语″桥″,指连接发明的TCR材料到靶向部分的任何试剂或分子。本领域普通技术人员公认发明的TCR材料上的对发明的TCR材料的功能是不必需的位点,是用于附加桥和/或靶向部分理想的位点,条件是桥和/或靶向部分附于发明的TCR材料时,不影响发明的TCR材料的功能,即,结合MAGE-A3或MAGE-A12;或检测,治疗,或预防癌症的能力。
备选地,发明的TCR材料可以修饰为储藏形式,这样以至于发明的TCR材料释放于其所施用的体内的方式相对于体内的时间和位置是可控的(参见,例如,美国专利4,450,150)。发明的TCR材料的储藏形式可以是,例如,包含本发明的TCR材料和多孔的或非多孔的材料(例如聚合物)的可植入组合物,其中本发明的TCR材料由材料形成胶囊或分散于整个材料和/或非多孔材料的降解物。储存物随后移植于身体内需要的部位,且本发明的TCR材料以预定的速率从所述移植物中释放。
预期发明的药物组合物,TCR,多肽,蛋白,核酸,重组表达载体,宿主细胞,或细胞群可以用于治疗或预防癌症方法中。不受特别的理论限制,相信发明的TCR特异结合于MAGE-A3,MAGE-A12,这样以至于所述TCR(或相关的发明的多肽或蛋白)当由细胞表达时能够介导针对表达MAGE-A3或MAGE-A12的靶细胞的免疫反应。在这点上,本发明提供在宿主中治疗或预防癌症的方法,包含以在宿主中的治疗或预防癌症的有效量向宿主施用在此描述的任何的药物组合物,TCR,多肽,或蛋白,包含编码在此描述的任何所述TCR,多肽,蛋白的核苷酸序列的任何核酸或重组表达载体,或包含编码在此描述的任何所述TCR,多肽,或蛋白的重组载体的任何宿主细胞或细胞群。
如在此使用的术语″治疗,″和″预防″以及从其衍生的词不一定意为100%或完全的治疗或预防。反而,存在变化的治疗或预防程度,所述程度为本领域普通技术人员公认具有潜在的好处或治疗效果。在这方面,发明的方法可以提供宿主中癌症的任何水平的治疗或预防的量。此外,由发明的方法提供的治疗或预防可以包括疾病(例如,治疗或预防的癌症)的一个或更多病状或症状的治疗或预防。并且,为了在此的目的,“预防”可以包括延迟疾病或其症状或病状的开始。
还提供的是在宿主中检测癌症的存在的方法。所述方法包含(i)包含癌症细胞的样品与在此描述的任何发明的TCR,多肽,蛋白,核酸,重组表达载体,宿主细胞,细胞群,或抗体或其抗原结合部分接触,从而形成复合物,并检测所述复合物,其中复合物的检出指征宿主中癌症的存在。
关于宿主中发明的检测癌症的方法,癌症细胞的样品可以是包含完整细胞,其溶胞产物,或全细胞溶胞产物的部分(例如,核的或细胞质部分,全部蛋白部分,或核酸部分)的样品。
为了发明的检测方法,所述接触可以发生在相对于宿主的体外或体内。优选的,所述接触是体外的。
此外,复合物检测可以通过在本领域中已知的很多方式发生。例如,在此描述的本发明的TCR,多肽,蛋白,核酸,重组表达载体,宿主细胞,细胞群,或抗体或其抗原结合部分可以用可检测标签标记,所述标签如,例如,放射性同位素,荧光团(例如,异硫氰酸荧光素(FITC),藻红蛋白(PE)),酶(例如,碱性磷酸酶,辣根过氧化物酶),和元素颗粒(例如,金颗粒)。
为了发明的方法,其中施用宿主细胞或细胞群体,所述细胞可以是与宿主异源或自体同源的细胞。优选地,所述细胞与宿主自体同源。
至于发明的方法,所述癌症可以是任何癌症,包括肉瘤(举例来说,滑膜肉瘤,骨源性肉瘤,子宫平滑肌肉瘤,和腺泡状横纹肌肉瘤),淋巴瘤(举例来说,霍奇金淋巴瘤和非霍奇金淋巴瘤),肝细胞癌,神经胶质瘤,头部癌症(举例来说,鳞状细胞癌),颈部癌症(举例来说,鳞状细胞癌),急性淋巴癌,白血病(举例来说,急性髓细胞样白血病和慢性淋巴细胞白血病),骨癌,脑癌,乳腺癌,肛门、肛门管或肛门直肠的癌症,眼部的癌症,肝内胆管的癌症,关节的癌症,颈部、胆囊或胸膜的癌症,鼻、鼻腔或中耳的癌症,口腔的癌症,阴户的癌症,慢性髓样癌,结肠癌(举例来说,结肠恶性肿瘤),食道癌,宫颈癌,胃癌,胃与肠的类癌瘤,下咽癌,喉癌,肝癌(举例来说,肝细胞癌),肺癌(举例来说,非小细胞肺癌),恶性间皮瘤,黑色素瘤,多发性骨髓瘤,鼻咽癌,卵巢癌,胰腺癌,腹膜癌,网膜和肠系膜癌,咽癌,前列腺癌,直肠癌,肾癌(举例来说,肾细胞癌),小肠癌,软组织癌,胃癌,睾丸癌,甲状腺癌,和泌尿道上皮癌(举例来说,输尿管癌症和膀胱癌)的任一种。
发明的方法中宿主指代的可以是任何宿主。优选地,宿主是哺乳动物。如在此使用的,术语″哺乳动物″指任何哺乳动物,包括,但不限于,但不限于,啮齿目的哺乳动物,例如小鼠和仓鼠,和兔形目的哺乳动物,例如兔。优选的,所述哺乳动物源自食肉目,包括猫科的(猫)和犬科的(狗)。更优选的,所述哺乳动物源自偶蹄目,包括牛科的(母牛)和猪科的(猪)或奇蹄目的,包括马科的(马)。最优选的,所述哺乳动物是灵长类的,Ceboids,或Simoids(猴)或类人目的(人和猿)。特别优选的哺乳动物为人。
以下实施例进一步说明本发明,但当然不应理解为以任何方式限制其范围。
实施例1
该实施例表明源自T细胞克隆的TCR基因的克隆和TCR构建体的产生。
最初,四个T细胞克隆鉴别为识别在显性I类(class I)等位基因HLA-A*01和C*07情况下的MAGE-A基因家族的表位。约30%的黑色素瘤患者群体表达HLA-A*01,且多于95%的HLA-A*01+个体表达HLA-A*0101亚型,同时多于50%黑色素瘤的患者表达两种显性HLA-C*07亚型,C*07:01和C*07:02的一种。
表达的TCR α和β链分离自两个克隆,A10和13-18,其识别在HLA-A*01情况下的蛋白MAGE-A3的168-176残基(MAGE-A3:168-176)。此外,识别对应于MAGE-A12蛋白的170-178残基(MAGE-A12:170-178)的肽的HLA-C*07限制的TCR分离自克隆502和FM8。
编码功能性TCR的α和β链分离自两个MAGE-A12反应性,HLA-C*07反应性T细胞克隆,PHIN LB831-501D/19,表示为“502”(Heidecker等,J.Immunol.,164:6041-6045(2000))和“FM8”(Panelli等,J.Immunol.,164:4382-4392(2000)),以及两个MAGE-A3反应性,HLA-A*01限制的T细胞克隆,LAU147CTL1或810/A10,表示为“A10”(Parmentier等,Nat.Immunol.,11:449-454(2010))和NW1000AVP-1 13-18,表示为“13-18”。简要地,使用SMART RACE cDNA扩增试剂盒(Clontech,Mountain View,CA)使用oligo-dT反转录分离自T细胞克隆的总RNA为cDNA。由所述T细胞克隆表达的所述TCR α和β链通过进行5’-RACE反应鉴定,所述5’-RACE反应使用互补于所述TCR α链恒定区的引物5’-CACTGTTGCTCTTGAAGTCC-3’(SEQ ID NO:55)和互补于所述TCR β链恒定区的5’-CAGGCAGTAT CTGGAGTCATTGAG-3’(SEQ ID NO:56)与源自SMART RNA合成试剂盒的接头引物组合。测序5’-RACE产物之后,全长的基因产物使用设计以扩增合适的全长TCR α和β链的特定的引物扩增。A10TCR表达AV12-1/BV24-1,13-18表达AV12-3/BV15,502TCR表达AV13-1/BV25-1,且FM8表达AV38-2/BV4-3。
编码对四个T细胞克隆的每个的配对的α和β链的转录本插入MSGV1逆转录病毒表达载体。
实施例2
该实施例表明表达抗MAGE-A3TCR-A10(SEQ ID NO:13和14)和抗MAGE-A3TCR 13-18(SEQ ID NO:24和25)的细胞响应HLA-A1+/MAGE-A3+细胞的反应性。
评估抗CD3刺激的转导有TCR-A10(SEQ ID NO:46)和TCR 13-18(SEQ ID NO:48)的T细胞识别一组表达MAGE-A3的HLA-A*01+黑色素瘤细胞系的能力。未转导的(UT)和转导的细胞与不同肿瘤细胞系共培养过夜(表1A,1B和图6A),并测量干扰素-γ(IFN-γ)(pg/ml)。
表1A
表1B
肿瘤 | HLA-A*01 | MAGE-A3 |
2984mel | + | + |
397mel | + | + |
2630mel | + | + |
2556mel | + | + |
526mel | - | + |
624mel | - | + |
2359mel | - | + |
2661RCC | + | - |
结果显示评估的八种HLA-A*01+/MAGE-A3+黑色素瘤细胞系中的六种从TCR A10比从TCR 13-18-转导的T细胞刺激更高的IFN-γ释放水平(图1A)。在TCR-转导的T细胞与两株表达相对低水平的MAGE-A3,A375mel和537mel的HLA-A1+黑色素瘤细胞系共培养之后,释放较低水平IFN-γ,而TCR A10-转导的T细胞响应这些靶细胞比TCR 13-18转导的T细胞释放更高水平的IFN-γ。这些反应由HLA-A1限制,因为缺乏HLA-A1表达的1300mel,未能刺激从TCR A10和TCR 13-18-转导的细胞中IFN-γ释放,然而通过用HLA-A*01转染亲本1300mel细胞系产生的细胞系(指定为1300-A1)刺激从TCR A10和TCR 13-18转导的T细胞中的IFN-γ释放。缺乏MAGE-A3表达的HLA-A*01+肾癌细胞系,2661RCC,未能刺激从TCR A10和TCR 13-18转导的T细胞中显著的IFN-γ释放。这些结果表明当与MAGE-A3+/HLA-A1+靶细胞共培养时,表达TCRA10的细胞比表达TCR-13-18的细胞释放更高水平的IFN-γ。这些结果还表明TCR A10和TCR-13-18在MAGE-A3+/HLA-A1+靶细胞存在的情况下是刺激的。
用转导的PBMC进行的共培养测定的结果表明TCRA10-转导的T细胞响应HLA-A*01+/MAGE-A3+肿瘤细胞系397mel,2984mel,和2556mel,产生高水平的IFN-γ。细胞因子水平介于产生自TCR 13-18转导的T细胞的那些的五倍到十倍之间(图6A)。MAGE-A3+但HLA-A*01阴性的细胞系562,624和2359mel,以及MAGE-A3阴性但HLA-A*01+的肾癌细胞系2661RCC未能刺激从TCR A10或13-18转导的T细胞之一中的显著的细胞因子的水平(图6A)。
使用定量PCR测定评估所述TCR的转导水平,所述定量PCR测定使用基因组DNA与设计以特异检测MSGV1逆转录病毒LTR但不是人内源性逆转录病毒序列的正向(SEQ ID NO:58)和反向(SEQ ID NO:59)引物和探针(SEQ ID NO:60)进行。扩增产物的水平标准化于PBMC的正对照样品,所述PBMC转导有针对NY-ESO-1∶157-165表位的TCR,所述表位通过用NY-ESO-1四聚物染色估计为包含约80%转导的T细胞。
在转导有A10或13-18TCR的T细胞的活性方面的差异似乎不是由于用两种TCR转导的频率方面的不同,因为它们似乎是相当的(图6B)。此外,转导有A10TCR的T细胞识别与最小浓度为0.5nM的MAGE-A3168-176肽孵育的靶细胞,所述浓度比用于由转导有13-18TCR的细胞识别所需要的浓度低10倍(图6C),表明A10TCR具有比13-18TCR更高的功能性亲和力。
评估新鲜的,未培养的肿瘤细胞刺激转导有TCR A10(SEQ ID NO:46)或DMF5(针对HLA-A*0201/MART-1:27-35T细胞表位的TCR)之一的T细胞的能力。未转导的(UT)和转导的细胞与不同的新鲜肿瘤共培养,并测量IFN-γ(pg/ml)。
结果表明TCR A10转导的T细胞识别四株测试的HLA-A*01+/MAGE-A3+新鲜肿瘤(FrTu 2767,FrTu 3178,FrTu 2823和FrTu 3068)中的四株,且DMF5-转导的T细胞识别测试的HLA-A*0201+/MART-1+新鲜肿瘤细胞(FrTu 2851和FrTu 3242)二者(图1B)。所述TCR A10转导的T细胞未能识别HLA-A*0201+新鲜肿瘤,而DMF5转导的T细胞未能识别HLA-A*01+新鲜肿瘤,表明由TCR A10导致的IFN-γ分泌是HLA-A1+/MAGE-A3+-特异的反应。
转导有TCR A10和13-18的T细胞识别六株MAGE-A3+和HLA-A*01+新鲜肿瘤(FrTu),FrTu 3178,2767,2823,2830和3068中的五株,但不识别或者FrTu 2685(缺乏MAGE-A3表达的HLA-A*01+新鲜肿瘤)或者三株缺乏HLA-A*01表达的MAGE-A3+新鲜肿瘤,FrTu 2181,3242和2803(图7A;表1C)。
表1C
新鲜肿瘤 | HLA-A*01 | MAGE-A3 |
3178 | + | + |
2767 | + | + |
2823 | + | + |
2830 | + | + |
3068 | + | + |
2268 | + | + |
2685 | + | - |
2181 | - | + |
3242 | - | + |
2803 | - | + |
实施例3
该实施例表明表达抗MAGE-A12TCR 502(SEQ ID NO:34和35)或抗MAGE-A12TCRFM8(SEQ ID NO:44和45)的细胞响应与HLA-Cw*07+/MAGE-A12+细胞的共培养的反应性。
分离自两个患者PBMC样品的抗CD3刺激的CD8+T细胞用编码截短的人低亲和力神经生长因子受体(NGFR)的对照构建体转导,评估TCR502(SEQ ID NO:47),或TCR FM8(SEQID NO:49)识别一组表达MAGE-A12的Cw*07+黑色素瘤细胞系的能力。
MAGE-A12基因产物的表达通过Q-PCR评估,所述Q-PCR使用两条设计以特异扩增MAGE-A12基因产物而不是MAGE-A基因家族的其它成员的引物(SEQ ID NO:61和62)以及MAGE-A12特异的探针(SEQ ID NO:63)。使用质粒对照作为用以评估拷贝数的标准和使用甘油醛3-磷酸脱氢酶(GAPDH)以标准化来确定抗原表达。表达大于1,000拷贝的MAGE-A12每106拷贝的GAPDH的肿瘤细胞系和新鲜肿瘤表示为对于MAGE-A12表达是阳性。
转导的细胞与不同肿瘤细胞系(表2A;图6D和6F)共培养过夜,并测量IFN-γ(pg/m1)。
表2A
刺激物 | HLA-C等位基因 | MAGE-A12 |
1910mel | 0701,0303 | + |
586mel | 0701 | + |
2359mel | 0701,16 | + |
F002mel | 0701,1203 | + |
1300mel | 0702 | + |
624mel | 0702,0802 | + |
SK23mel | 0701,0702 | + |
1909mel | 0701,0702 | + |
1011mel | 0702 | - |
397mel | 0701 | + |
526mel | - | + |
2556mel | - | + |
2984mel | - | + |
2630mel | 0701 | - |
结果表明转导有TCR 502的T细胞识别测试的八株表达HLA-Cw*0701或0702之一的MAGE-A12+黑色素瘤细胞系中的八株,然而仅转导有TCR FM8的T细胞识别表达HLA-Cw*0702的黑色素瘤细胞系(图2A和2B;还参见图6F)。此外,当与TCR FM8转导的T细胞比较时,TCR502转导的T细胞响应HLA-Cw*0702+靶SK23mel,1300mel和624mel释放更高水平的IFN-γ(Figs.6D和6F)。1011mel细胞(其表达HLA-Cw*0702但缺乏MAGE-A12的表达)不刺激从转导有TCR 502或TCR FM8的细胞中的显著的细胞因子释放。转导有编码NGFR的对照构建体的T细胞未能显著响应于测试的靶的任一个。这些结果表明当与MAGE-A12+/HLA-Cw7靶细胞共培养时,表达TCR的502细胞比表达TCR FM8的细胞释放更高水平的IFN-γ,并且TCR 502识别HLA-Cw0701或HLA-Cw0702之一情况下的MAGE-A12。这些结果还表明在存在MAGE-A12+细胞的情况下,TCRA502和TCR FM8被刺激。
所述TCR 502转导的T细胞识别HLA-C*0702+,MAGE-A12+肿瘤624mel以及两株HLA-C*07:01+,MAGE-A12+肿瘤,397和2359mel,然而FM8转导的T细胞识别HLA-C*07:02+肿瘤细胞系624mel但未能识别397和2359mel(图6D)。转导的T细胞群体中没有一个识别526,2556,或2984mel(缺乏HLA-C*07表达的MAGE-A3+黑色素瘤细胞系),或2630mel(缺乏MAGE-A12表达的HLA-C*07:01+肿瘤细胞系)(图6D)。这些差异似乎不是由于两个TCR的转导频率方面的差异(如在实施例2中描述的测量),其在转导有任一TCR的细胞中是相似的(图6B)。此外,转导有502TCR的细胞识别与最低浓度为2.5nM MAGE-A12:170-178孵育的靶细胞,所述浓度是对于由转导有FM8TCR的细胞的识别所需要的浓度低100倍的浓度(图6E),指示502TCR比FM8TCR具有更高的功能性亲和力。
随后评估转导有MAGE-A12反应性TCR的T细胞对新鲜,未培养的肿瘤细胞的酶消化的反应。转导有TCR 502的T细胞识别四种表达HLA-C*0701的MAGE-A12+新鲜肿瘤中的一种,FrTu 3068,且TCR 502以及FM8转导的T细胞识别两种表达HLA-C*07:02的MAGE-A12+肿瘤中的一种,FrTu 2181(图7B;表2B)。TCR转导的T细胞群体中没有一种识别HLA-C*07:01-和07:02-新鲜肿瘤2767或2823,或缺乏MAGE-A12表达的MAGE-A12-肿瘤2685,3242和2803。
表2B
实施例4
该实施例表明可以使用发明的TCR治疗的群体。
约28%的患者群体表达HLA-A*01,和约54%的患者群体表达HLA-Cw*07。由约27%和约31%的患者群体分别表达HLA-Cw*07,Cw*0701和Cw*0702中的两种优势亚型。图3A说明预期为通过使用由HLA-A1,HLA-A2,和/或HLA-Cw7限制的TCR可治疗的群体的累积百分数(基于在普通高加索人群体中这些等位基因的百分数)。
因为约30%的患者表达高水平的MAGE-A3和MAGE-A12,发明的TCR的使用将让显著更高百分率的患者适合于基于TCR过继性免疫疗法。图3B和3C说明预期是使用TCR可治疗的人黑色素瘤(图3B)和滑膜细胞肉瘤(图3C)患者群体的累积百分数,所述TCR识别HLA-A2情况下的NY-ESO-1;HLA-A1情况下的MAGE-A3;HLA-A2情况下的MAGE-A3和MAGE-A12;和/或HLA-Cw7情况下的MAGE-A12。
实施例5
该实施例表明表达TCR 502或TCR FM8的细胞响应与用源自MAGE家族的不同蛋白的肽刺激的表达HLA-Cw*0701或HLA-Cw*0702的靶细胞的共培养的反应性。
转导有NGFR,TCR 502(SEQ ID NO:47),或TCR FM8(SEQ ID NO:49)的细胞与表达HLA-Cw*0701或HLA-Cw*0702的细胞共培养。测量IFN-γ(pg/ml)分泌。
结果表明当用MAGE-A12(VRIGHLYIL;SEQ ID NO:4)刺激时,转导有TCR 502的细胞识别表达HLA-Cw*0701或HLA-Cw*0702细胞,并且当用MAGE-A12(VRIGHLYIL;SEQ ID NO:4)刺激时,转导有TCR FM8的细胞识别表达HLA-Cw*0702的细胞(图4)。转导有NGFR的细胞不显示显著的反应性。
实施例6
该实施例表明抗MAGE-A3和抗MAGE-A12TCR的特异性。
在用抗CD3抗体刺激后,源自单个供体的PMBC用未转导的或转导有抗MAGE-A12TCR502(SEQ ID NO:47),抗MAGE-A12TCR FM8(SEQ ID NO:49),抗MAGE-A3TCR A10(SEQ ID NO:46),抗MAGE-A3TCR 13-18(SEQ ID NO:48),或抗MAGE-A3TCR 112-120的PBMC转导。在刺激后十三天,在标准的4小时51Cr释放测试中,转导的T细胞与列于表3中的肿瘤靶孵育。
表3
MAGE-A3 | MAGE-A12 | HLA-A | HLA-C | |
397mel | + | + | 01/02 | 0401/0701 |
624mel | + | + | 02/03 | 0702/0802 |
2984mel | + | + | 01/02 | 06 |
2661RCC | - | - | 01/02 | 07 |
如在图5(A)-5(D)中显示的,抗MAGE-A12TCR 502特异溶解表达的MAGE-A12和HLA-Cw7的肿瘤细胞且不溶解缺乏MAGE-A12或HLA-Cw7表达的肿瘤细胞。抗MAGE-A3TCR A10特异溶解表达MAGE-A3和HLA-A1的肿瘤细胞且不溶解缺乏MAGE-A3或HLA-A1表达的肿瘤细胞。
实施例7
该实施例表明抗MAGE-A3和抗MAGE-A12TCR的特异性。
猴肾细胞系COS-7用HLA-A*01,C*07:01或C*07:02之一加上MAGE-A3,A1,A2,A4,A6,A9,A10或A12之一瞬时转染过夜。次日加入T细胞,或者转导有TCR A10,13-18或着未转导的对照细胞或者TCR 502,FM8或者未转导的对照细胞,并在过夜共培养之后通过ELISA评估可溶IFN-γ的释放。
转导有MAGE-A3-反应性TCR A10的T细胞识别转染有MAGE-A3的HLA-A1+靶细胞,但未能识别转染有MAGE-A1,A2,A4,A6,A9,A10或A12构建体的靶标(图8A),所述构建体编码与MAGE-A3:170-178表位介于1-3个位点之间不同的肽。转导有TCR 502或FM8之一的T细胞识别转染有MAGE-A12的HLA-C*07:02+靶标但不识别MAGE-A3,A1,A2,A4,A6,A9,A10(图8B),而转导有TCR 502而不是FM8的T细胞识别转染有MAGE-A12的HLA-C*07:01+靶标,而不识别测试的另外的MAGE-A家族成员(图8C)。
实施例8
该实施例表明转导的T细胞的反应性。
纯化的CD8+和CD4+T细胞通过使用CD8和CD4T淋巴细胞富集试剂盒(Becton/Dickinson,Franklin Lakes,N.J.)阴性筛选,继之以使用CD8和CD4磁珠(Becton/Dickinson)的阳性筛选分离。通过荧光激活细胞筛选术(FACS)分析评估分离的CD8+和CD4+细胞,以分别包含小于1%的污染CD4+和CD8+T细胞。
随后评价转导有TCR的分离的CD8+和CD4+T细胞群体对肿瘤细胞靶标的反应。高度纯化的转导有TCR A10的包含少于1%污染CD8+T细胞的CD4+T细胞响应稳定转染有HLA-A*01的MAGE-A3+肿瘤细胞系397mel以及MAGE-A3+肿瘤细胞系1300Almel,释放低但显著水平的IFN-γ(表4A;图9B)。转导有TCR A10的CD8+T细胞响应397mel或1300-Al mel释放干扰素-γ(表4A;图9A)。转导有TCR 502或TCR FM8的CD8+T细胞响应624mel释放干扰素-γ,且TCR 502响应397mel释放干扰素-γ(图9C和表4B)。
表4A
表4B
细胞系 | HLA-C*07 | MAGE-A12 |
397mel | 01 | + |
624mel | 02 | + |
2359mel | 01 | + |
526mel | - | + |
2661RCC | - | - |
在此引用的所有参考文献,包括出版物,专利申请,和专利,像每个参考文献单独和特异地指出以作为参考引入一样,以相同的程度作为参考引入,且在此以其整体列出。
在描述本发明的上下文中(尤其在以下的权利要求的上下文中),术语“一个(种)(a)”和“一个(种)(an)”和“所述(the)”和“至少一种(个)”和类似的指示物的使用将理解为覆盖单数和复数二者,除非在此另有陈述或与上下文明显抵触。术语“至少一个(种)”继之以一系列一个或更多项(例如,“A和B中的至少一个”)将理解为意味着选自列出的项(A或B)的一项或列出的项(A和B)的两个或更多的组合,除非在此另有陈述或与上下文明显抵触。术语“包含(comprising),”“具有(having),”“包括(including),”和“包含(containing)”将理解为开放的术语(即,意为“包括,但不限于,”),除非另有说明。在此,值的范围的叙述仅意在用作单独指在范围内的每个分离的值的简写方法,除非在此另有陈述,且每个分离的值像其在此单独陈述一样引入说明书。所有在此描述的方法可以以任何合适的顺序进行,除非在此另有陈述或与上下文明显抵触。在此提供的任何或所有实施例,或典型术语(例如,“例如(such as)”)的使用,仅意在更好阐明本发明且不造成对本发明范围的限制,除非另有要求。说明书中没有术语应该理解为指示任何非要求的作为对本发明的实践必要的成分。
本发明优选的实施方案在此描述,包括对于发明人来说用于实现本发明的最好的方式。在阅读上文描述时,那些优选的实施方案的改变可以成为对于本领域技术人员来讲显而易见的。发明人预期熟练技术人员酌情使用此种改变,且发明人意在除了如在此详细描述之外,使本发明付诸实践。因此,本发明包括在如由适用的法律允许的附于此的权利要求中陈述的主题的所有改变和相等物。此外,以上描述的成分的以其所有可能的改变形式的任何组合由本发明包括,除非在此另有陈述或与上下文明显抵触。
Claims (12)
1.一种分离的或纯化的T细胞受体(TCR),其具有对a)在HLA-A1情况下的黑色素瘤抗原家族A(MAGE A)-3或b)在HLA-Cw7情况下的MAGE-A12的抗原特异性。
2.如权利要求1所述的分离的或纯化的TCR,其具有对a)包含EVDPIGHLY(SEQ ID NO:2)的MAGE-A3表位或b)包含VRIGHLYIL(SEQ ID NO:4)的MAGE-A12表位的抗原特异性。
3.一种分离的或纯化的多肽,其包含如权利要求1至2中任一项所述的TCR的功能部分,其中所述功能部分包含SEQ ID NO:5-10、16-21、26-31或36-41的氨基酸序列。
4.一种分离的或纯化的蛋白,其包含如权利要求6所述的至少一个所述多肽。
5.如权利要求4所述的分离的或纯化的蛋白,其包含:
第一多肽链,包含SEQ ID NO:5-7、16-18、26-28或36-38的氨基酸序列;和
第二多肽链,包含SEQ ID NO:8-10、19-21、29-31或39-41的氨基酸序列。
6.如权利要求4所述的蛋白,其中所述蛋白是融合蛋白或重组抗体。
7.一种分离的或纯化的核酸,其包含编码权利要求1-2中任一项所述的TCR的核苷酸序列。
8.一种重组表达载体,其包含如权利要求7所述的核酸。
9.一种分离的宿主细胞,其包含如权利要求8所述的重组表达载体。
10.一种药物组合物,其包含如权利要求1至2中任一项所述的TCR和药学上可接受的载体。
11.权利要求1至2中任一项所述的TCR在制备用于检测宿主中癌症存在的检测剂的用途,其中通过使包含癌症细胞的样品与TCR接触形成的复合物的检测表明宿主中癌症的存在。
12.权利要求1至2中任一项所述的TCR在制备用于治疗或预防宿主中的癌症的药物中的用途。
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Families Citing this family (110)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3065947C (en) | 2005-10-18 | 2023-03-07 | National Jewish Health | Conditionally immortalized long-term stem cells and methods of making and using such cells |
US8986702B2 (en) | 2008-05-16 | 2015-03-24 | Taiga Biotechnologies, Inc. | Antibodies and processes for preparing the same |
ES2681478T3 (es) | 2008-08-28 | 2018-09-13 | Taiga Biotechnologies, Inc. | Moduladores de MYC, métodos de uso de los mismos y métodos para identificar agentes que modulan MYC |
CA2848209C (en) | 2011-09-15 | 2021-06-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell receptors recognizing hla-a1- or hla-cw7-restricted mage |
CA3133302A1 (en) | 2012-07-20 | 2014-01-23 | Taiga Biotechnologies, Inc. | Enhanced reconstitution and autoreconstitution of the hematopoietic compartment comprising a myc polypeptide |
KR102480188B1 (ko) | 2012-09-14 | 2022-12-21 | 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 | Mhc ii형 제한된 mage-a3을 인식하는 t 세포 수용체 |
US10272115B2 (en) | 2013-03-11 | 2019-04-30 | Taiga Biotechnologies, Inc. | Production and use of red blood cells |
WO2015077717A1 (en) | 2013-11-25 | 2015-05-28 | The Broad Institute Inc. | Compositions and methods for diagnosing, evaluating and treating cancer by means of the dna methylation status |
WO2015085147A1 (en) | 2013-12-05 | 2015-06-11 | The Broad Institute Inc. | Polymorphic gene typing and somatic change detection using sequencing data |
CA2934073A1 (en) | 2013-12-20 | 2015-06-25 | The Broad Institute, Inc. | Combination therapy with neoantigen vaccine |
AU2014407539B2 (en) * | 2014-10-02 | 2020-10-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of isolating T cell receptors having antigenic specificity for a cancer-specific mutation |
JP6599450B2 (ja) | 2014-10-02 | 2019-10-30 | アメリカ合衆国 | がん特異的突然変異に対し抗原特異性を有するt細胞を単離する方法 |
GB201417803D0 (en) * | 2014-10-08 | 2014-11-19 | Adaptimmune Ltd | T cell receptors |
EP3212774A4 (en) * | 2014-10-31 | 2018-04-11 | Baylor College of Medicine | Survivin specific t-cell receptor targeting tumor but not t cells |
EP3757211A1 (en) | 2014-12-19 | 2020-12-30 | The Broad Institute, Inc. | Methods for profiling the t-cell-receptor repertoire |
EP3234193B1 (en) | 2014-12-19 | 2020-07-15 | Massachusetts Institute of Technology | Molecular biomarkers for cancer immunotherapy |
EP3289082A4 (en) * | 2015-04-27 | 2018-09-12 | AbVitro LLC | Methods of sequencing, determining, pairing, and validating therapeutic agents and disease specific antigens |
RU2020132040A (ru) | 2015-05-20 | 2020-10-12 | Те Брод Инститьют Инк. | Общие неоантигены |
WO2016205749A1 (en) | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Novel crispr enzymes and systems |
SG10201913868XA (en) | 2015-09-15 | 2020-03-30 | The United States Of America As Represented By The Secretary | T cell receptors recognizing hla-cw8 restricted mutated kras |
CN114195882A (zh) * | 2015-10-01 | 2022-03-18 | 圣拉斐尔医院有限公司 | Tcr及其用途 |
US20190255107A1 (en) | 2015-10-09 | 2019-08-22 | The Brigham And Women's Hospital, Inc. | Modulation of novel immune checkpoint targets |
WO2017070042A1 (en) | 2015-10-20 | 2017-04-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of producing t cell populations using akt inhibitors |
EP3368689B1 (en) | 2015-10-28 | 2020-06-17 | The Broad Institute, Inc. | Composition for modulating immune responses by use of immune cell gene signature |
WO2017075465A1 (en) | 2015-10-28 | 2017-05-04 | The Broad Institute Inc. | Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3 |
WO2017075451A1 (en) | 2015-10-28 | 2017-05-04 | The Broad Institute Inc. | Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1 |
US11001622B2 (en) | 2015-11-19 | 2021-05-11 | The Brigham And Women's Hospital, Inc. | Method of treating autoimmune disease with lymphocyte antigen CD5-like (CD5L) protein |
WO2017139199A1 (en) | 2016-02-10 | 2017-08-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inducible arginase |
HUE059159T2 (hu) | 2016-04-08 | 2022-10-28 | Immunocore Ltd | T-sejt-receptorok |
WO2017184590A1 (en) | 2016-04-18 | 2017-10-26 | The Broad Institute Inc. | Improved hla epitope prediction |
WO2017189254A1 (en) * | 2016-04-26 | 2017-11-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-kk-lc-1 t cell receptors |
MA45491A (fr) * | 2016-06-27 | 2019-05-01 | Juno Therapeutics Inc | Épitopes à restriction cmh-e, molécules de liaison et procédés et utilisations associés |
LT3494133T (lt) | 2016-08-02 | 2022-12-12 | The U.S.A. As Represented By The Secretary, Department Of Health And Human Services | Anti-kras-g12d t ląstelės receptoriai |
US11630103B2 (en) | 2016-08-17 | 2023-04-18 | The Broad Institute, Inc. | Product and methods useful for modulating and evaluating immune responses |
WO2018049025A2 (en) | 2016-09-07 | 2018-03-15 | The Broad Institute Inc. | Compositions and methods for evaluating and modulating immune responses |
US20200016202A1 (en) | 2016-10-07 | 2020-01-16 | The Brigham And Women's Hospital, Inc. | Modulation of novel immune checkpoint targets |
WO2018097951A1 (en) | 2016-11-22 | 2018-05-31 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-mage-a3/a6 antibodies |
EP4242298A2 (en) | 2016-12-02 | 2023-09-13 | Taiga Biotechnologies, Inc. | Nanoparticle formulations |
PL3551221T3 (pl) | 2016-12-08 | 2022-02-28 | Immatics Biotechnologies Gmbh | Nowe receptory komórek t i immunoterapia z ich zastosowaniem |
DE102016123847B3 (de) | 2016-12-08 | 2018-04-05 | Immatics Biotechnologies Gmbh | Neue T-Zellrezeptoren und deren Verwendung in Immuntherapie |
WO2018140391A1 (en) | 2017-01-24 | 2018-08-02 | The Broad Institute, Inc. | Compositions and methods for detecting a mutant variant of a polynucleotide |
US11649288B2 (en) | 2017-02-07 | 2023-05-16 | Seattle Children's Hospital | Phospholipid ether (PLE) CAR T cell tumor targeting (CTCT) agents |
ES2965475T3 (es) | 2017-02-12 | 2024-04-15 | Biontech Us Inc | Métodos y composiciones basados en HLA y usos de los mismos |
WO2018160622A1 (en) | 2017-02-28 | 2018-09-07 | Endocyte, Inc. | Compositions and methods for car t cell therapy |
WO2018183908A1 (en) | 2017-03-31 | 2018-10-04 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating ovarian tumors |
EP3606518A4 (en) | 2017-04-01 | 2021-04-07 | The Broad Institute, Inc. | METHODS AND COMPOSITIONS FOR DETECTION AND MODULATION OF IMMUNOTHERAPY RESISTANCE GENE SIGNATURE IN CANCER |
EP3610266A4 (en) | 2017-04-12 | 2021-04-21 | Massachusetts Eye and Ear Infirmary | TUMOR SIGNATURE OF METASTASIS, COMPOSITIONS OF SUBSTANCES AND USES THEREOF |
MX2019012398A (es) | 2017-04-18 | 2020-09-25 | Broad Inst Inc | Composiciones para detectar secreciones y metodos de uso. |
WO2018232195A1 (en) | 2017-06-14 | 2018-12-20 | The Broad Institute, Inc. | Compositions and methods targeting complement component 3 for inhibiting tumor growth |
DK3490584T3 (da) | 2017-08-03 | 2022-01-31 | Taiga Biotechnologies Inc | Fremgangsmåder og sammensætninger til behandlingen af melanom |
US10149898B2 (en) | 2017-08-03 | 2018-12-11 | Taiga Biotechnologies, Inc. | Methods and compositions for the treatment of melanoma |
AU2018318303A1 (en) * | 2017-08-18 | 2020-04-09 | Gritstone Bio, Inc. | Antigen-binding proteins targeting shared antigens |
CN111511388A (zh) | 2017-09-21 | 2020-08-07 | 博德研究所 | 用于靶向核酸编辑的系统、方法和组合物 |
WO2019075055A1 (en) | 2017-10-11 | 2019-04-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | METHODS FOR PRODUCING T-CELL POPULATIONS USING P38 MAPK INHIBITORS |
WO2019084055A1 (en) | 2017-10-23 | 2019-05-02 | Massachusetts Institute Of Technology | CLASSIFICATION OF GENETIC VARIATION FROM UNICELLULAR TRANSCRIPTOMS |
EP3710039A4 (en) | 2017-11-13 | 2021-08-04 | The Broad Institute, Inc. | METHODS AND COMPOSITIONS FOR CANCER TREATMENT BY TARGETING THE CLEC2D-KLRB1 PATH |
WO2019126186A1 (en) | 2017-12-18 | 2019-06-27 | Neon Therapeutics, Inc. | Neoantigens and uses thereof |
US11311576B2 (en) | 2018-01-22 | 2022-04-26 | Seattle Children's Hospital | Methods of use for CAR T cells |
AU2019218785A1 (en) | 2018-02-09 | 2020-09-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tethered interleukin-15 and interleukin-21 |
US20210363215A1 (en) * | 2018-04-19 | 2021-11-25 | Board Of Regents, The University Of Texas System | T cell receptors with mage-b2 specificity and uses thereof |
AU2019260656A1 (en) | 2018-04-24 | 2020-12-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of producing T cell populations using hydroxycitric acid and/or a salt thereof |
US11957695B2 (en) | 2018-04-26 | 2024-04-16 | The Broad Institute, Inc. | Methods and compositions targeting glucocorticoid signaling for modulating immune responses |
WO2019232542A2 (en) | 2018-06-01 | 2019-12-05 | Massachusetts Institute Of Technology | Methods and compositions for detecting and modulating microenvironment gene signatures from the csf of metastasis patients |
WO2020041387A1 (en) | 2018-08-20 | 2020-02-27 | The Brigham And Women's Hospital, Inc. | Degradation domain modifications for spatio-temporal control of rna-guided nucleases |
WO2020041384A1 (en) | 2018-08-20 | 2020-02-27 | The Broad Institute, Inc. | 3-phenyl-2-cyano-azetidine derivatives, inhibitors of rna-guided nuclease activity |
WO2020068304A2 (en) | 2018-08-20 | 2020-04-02 | The Broad Institute, Inc. | Inhibitors of rna-guided nuclease target binding and uses thereof |
WO2020072700A1 (en) | 2018-10-02 | 2020-04-09 | Dana-Farber Cancer Institute, Inc. | Hla single allele lines |
US20210379057A1 (en) | 2018-10-16 | 2021-12-09 | Massachusetts Institute Of Technology | Nutlin-3a for use in treating a mycobacterium tuberculosis infection |
US20220170097A1 (en) | 2018-10-29 | 2022-06-02 | The Broad Institute, Inc. | Car t cell transcriptional atlas |
GB201819540D0 (en) * | 2018-11-30 | 2019-01-16 | Adaptimmune Ltd | T cell modification |
US20220062394A1 (en) | 2018-12-17 | 2022-03-03 | The Broad Institute, Inc. | Methods for identifying neoantigens |
MX2021007556A (es) | 2018-12-21 | 2021-09-10 | Biontech Us Inc | Método y sistemas de predicción de epítopos específicos de hla de clase ii y caracterización de células t cd4+. |
US11739156B2 (en) | 2019-01-06 | 2023-08-29 | The Broad Institute, Inc. Massachusetts Institute of Technology | Methods and compositions for overcoming immunosuppression |
CA3126611A1 (en) * | 2019-01-17 | 2020-07-23 | Immunocore Limited | Formulations of soluble t cell receptor(tcr) and single chain fragment variable (scfv) bispecific proteins |
US20220154282A1 (en) | 2019-03-12 | 2022-05-19 | The Broad Institute, Inc. | Detection means, compositions and methods for modulating synovial sarcoma cells |
EP3942023A1 (en) | 2019-03-18 | 2022-01-26 | The Broad Institute, Inc. | Compositions and methods for modulating metabolic regulators of t cell pathogenicity |
US20220235340A1 (en) | 2019-05-20 | 2022-07-28 | The Broad Institute, Inc. | Novel crispr-cas systems and uses thereof |
WO2020243371A1 (en) | 2019-05-28 | 2020-12-03 | Massachusetts Institute Of Technology | Methods and compositions for modulating immune responses |
CA3142513A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
US11642409B2 (en) | 2019-06-26 | 2023-05-09 | Massachusetts Insttute of Technology | Immunomodulatory fusion protein-metal hydroxide complexes and methods thereof |
US20220282333A1 (en) | 2019-08-13 | 2022-09-08 | The General Hospital Corporation | Methods for predicting outcomes of checkpoint inhibition and treatment thereof |
WO2021041922A1 (en) | 2019-08-30 | 2021-03-04 | The Broad Institute, Inc. | Crispr-associated mu transposase systems |
WO2021061648A1 (en) | 2019-09-23 | 2021-04-01 | Massachusetts Institute Of Technology | Methods and compositions for stimulation of endogenous t cell responses |
US11793787B2 (en) | 2019-10-07 | 2023-10-24 | The Broad Institute, Inc. | Methods and compositions for enhancing anti-tumor immunity by targeting steroidogenesis |
US11844800B2 (en) | 2019-10-30 | 2023-12-19 | Massachusetts Institute Of Technology | Methods and compositions for predicting and preventing relapse of acute lymphoblastic leukemia |
US11865168B2 (en) | 2019-12-30 | 2024-01-09 | Massachusetts Institute Of Technology | Compositions and methods for treating bacterial infections |
BR112022014623A2 (pt) | 2020-02-14 | 2022-09-13 | Jounce Therapeutics Inc | Anticorpos e proteínas de fusão que se ligam a ccr8 e usos dos mesmos |
IL296242A (en) | 2020-03-10 | 2022-11-01 | Massachusetts Inst Technology | Methods for producing engineered memory-like nk cells and preparations containing them |
JP2020143057A (ja) * | 2020-04-01 | 2020-09-10 | アメリカ合衆国 | がん特異的突然変異に対し抗原特異性を有するt細胞受容体を単離する方法 |
WO2021221783A1 (en) | 2020-05-01 | 2021-11-04 | Massachusetts Institute Of Technology | Methods for identifying chimeric antigen receptor-targeting ligands and uses thereof |
WO2021221782A1 (en) | 2020-05-01 | 2021-11-04 | Massachusetts Institute Of Technology | Chimeric antigen receptor-targeting ligands and uses thereof |
CN111693702A (zh) * | 2020-07-11 | 2020-09-22 | 成都益安博生物技术有限公司 | 一种黑色素瘤的外周血tcr标志物及其检测试剂盒和应用 |
EP4211228A1 (en) | 2020-09-08 | 2023-07-19 | The United States of America, as represented by the Secretary, Department of Health and Human Services | T cell phenotypes associated with response to adoptive cell therapy |
JP2023542208A (ja) * | 2020-09-24 | 2023-10-05 | メディジーン イミュノテラピーズ ゲーエムベーハー | Mage-a3特異的t細胞受容体およびその使用 |
TWI815194B (zh) | 2020-10-22 | 2023-09-11 | 美商基利科學股份有限公司 | 介白素2-Fc融合蛋白及使用方法 |
EP4243937A2 (en) | 2020-11-13 | 2023-09-20 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Enhanced antigen reactivity of immune cells expressing a mutant non-signaling cd3 zeta chain |
US20240150711A1 (en) | 2021-03-01 | 2024-05-09 | Dana-Farber Cancer Institute, Inc. | Personalized redirection and reprogramming of t cells for precise targeting of tumors |
TW202313094A (zh) | 2021-05-18 | 2023-04-01 | 美商基利科學股份有限公司 | 使用FLT3L—Fc融合蛋白之方法 |
WO2023076983A1 (en) | 2021-10-28 | 2023-05-04 | Gilead Sciences, Inc. | Pyridizin-3(2h)-one derivatives |
AU2022376954A1 (en) | 2021-10-29 | 2024-05-02 | Gilead Sciences, Inc. | Cd73 compounds |
WO2023122581A2 (en) | 2021-12-22 | 2023-06-29 | Gilead Sciences, Inc. | Ikaros zinc finger family degraders and uses thereof |
US20230242508A1 (en) | 2021-12-22 | 2023-08-03 | Gilead Sciences, Inc. | Ikaros zinc finger family degraders and uses thereof |
WO2023130040A2 (en) | 2021-12-31 | 2023-07-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell therapy with vaccination as a combination immunotherapy against cancer |
TW202340168A (zh) | 2022-01-28 | 2023-10-16 | 美商基利科學股份有限公司 | Parp7抑制劑 |
TW202346277A (zh) | 2022-03-17 | 2023-12-01 | 美商基利科學股份有限公司 | Ikaros鋅指家族降解劑及其用途 |
TW202400138A (zh) | 2022-04-21 | 2024-01-01 | 美商基利科學股份有限公司 | Kras g12d調節化合物 |
US20240116928A1 (en) | 2022-07-01 | 2024-04-11 | Gilead Sciences, Inc. | Cd73 compounds |
WO2024015743A1 (en) * | 2022-07-11 | 2024-01-18 | Board Of Regents, The University Of Texas System | Peptides and engineered t cell receptors targeting vcy antigen and methods of use |
WO2024077256A1 (en) | 2022-10-07 | 2024-04-11 | The General Hospital Corporation | Methods and compositions for high-throughput discovery ofpeptide-mhc targeting binding proteins |
CN117946247A (zh) * | 2023-02-23 | 2024-04-30 | 暨南大学 | 一种识别mage-a3抗原短肽的t细胞受体及其应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1402782A (zh) * | 1999-10-19 | 2003-03-12 | 路德维哥癌症研究院 | Mage-a12抗原肽及其应用 |
US20110104129A1 (en) * | 2006-02-24 | 2011-05-05 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | T cell receptors and related materials and methods of use |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4450150A (en) | 1973-05-17 | 1984-05-22 | Arthur D. Little, Inc. | Biodegradable, implantable drug delivery depots, and method for preparing and using the same |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
IN165717B (zh) | 1986-08-07 | 1989-12-23 | Battelle Memorial Institute | |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
CA2072356A1 (en) | 1989-12-29 | 1991-06-30 | James L. Urban | Diagnosis and treatment of diseases |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
ES2108048T3 (es) | 1990-08-29 | 1997-12-16 | Genpharm Int | Produccion y utilizacion de animales inferiores transgenicos capaces de producir anticuerpos heterologos. |
JP3266311B2 (ja) | 1991-05-02 | 2002-03-18 | 生化学工業株式会社 | 新規ポリペプチドおよびこれを用いる抗hiv剤 |
US5662907A (en) | 1992-08-07 | 1997-09-02 | Cytel Corporation | Induction of anti-tumor cytotoxic T lymphocytes in humans using synthetic peptide epitopes |
EP0658113B1 (en) * | 1992-08-31 | 2004-10-20 | Ludwig Institute For Cancer Research | Isolated nonapeptide derived from mage-3 gene and presented by hla-a1, and uses thereof |
US5405940A (en) * | 1992-08-31 | 1995-04-11 | Ludwig Institute For Cancer Research | Isolated nonapeptides derived from MAGE genes and uses thereof |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
EP0668350B2 (en) | 1994-02-16 | 2008-12-03 | The Government of the United States of America, as represented by the Secretary, Department of Health and Human Services | Melanoma associated antigenic polypeptide, epitopes thereof and vaccines against melanoma |
US6265150B1 (en) | 1995-06-07 | 2001-07-24 | Becton Dickinson & Company | Phage antibodies |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
DE19625191A1 (de) | 1996-06-24 | 1998-01-02 | Boehringer Mannheim Gmbh | Nierenkarzinom-spezifische T-Zellen |
IL127142A0 (en) * | 1998-11-19 | 1999-09-22 | Yeda Res & Dev | Immune cells having predefined biological specificity |
US6897288B1 (en) | 1999-10-19 | 2005-05-24 | Ludwig Institute For Cancer Research | Mage-A12 antigenic peptides and uses thereof |
WO2001058479A1 (en) | 2000-02-08 | 2001-08-16 | The Penn State Research Foundation | Immunotherapy using interleukin 13 receptor subunit alpha 2 |
AU2001253029A1 (en) * | 2000-03-30 | 2001-10-15 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | T-cell epitope of mage-12 and related nucleic acids, vectors, cells, compositions and methods of inducing an immune response to cancer |
WO2005019258A2 (en) | 2003-08-11 | 2005-03-03 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
ES2672895T3 (es) * | 2005-08-05 | 2018-06-18 | Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt Gmbh | Generación de células T específicas de antígeno |
US8003770B2 (en) * | 2005-09-13 | 2011-08-23 | Mie University | T-cell receptor and nucleic acid encoding the receptor |
JP5292550B2 (ja) * | 2007-03-23 | 2013-09-18 | 静岡県 | T細胞レセプターβ鎖遺伝子及びα鎖遺伝子 |
WO2008133772A1 (en) * | 2007-04-26 | 2008-11-06 | Ludwig Institute For Cancer Research | Method for modulating activity of t lymphocytes |
EP3031916B1 (en) | 2007-06-11 | 2017-06-07 | Takara Bio Inc. | Method for expression of specific gene |
GB0720118D0 (en) | 2007-10-15 | 2007-11-28 | Achour Adnane | Modified mhc class 1 binding peptides |
WO2010075417A1 (en) * | 2008-12-23 | 2010-07-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Survivin specific t cell receptor for treating cancer |
WO2010088160A1 (en) * | 2009-01-28 | 2010-08-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell receptors and related materials and methods of use |
GB0908613D0 (en) * | 2009-05-20 | 2009-06-24 | Immunocore Ltd | T Cell Reseptors |
US8956828B2 (en) | 2009-11-10 | 2015-02-17 | Sangamo Biosciences, Inc. | Targeted disruption of T cell receptor genes using engineered zinc finger protein nucleases |
CA2805320A1 (en) * | 2010-07-28 | 2012-02-02 | Immunocore Ltd | T cell receptors |
EP2601521B1 (en) * | 2010-08-06 | 2018-05-02 | Ludwig-Maximilians-Universität München | Identification of t cell target antigens |
WO2012054825A1 (en) * | 2010-10-22 | 2012-04-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-mage-a3 t cell receptors and related materials and methods of use |
CA2848209C (en) | 2011-09-15 | 2021-06-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell receptors recognizing hla-a1- or hla-cw7-restricted mage |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1402782A (zh) * | 1999-10-19 | 2003-03-12 | 路德维哥癌症研究院 | Mage-a12抗原肽及其应用 |
US20110104129A1 (en) * | 2006-02-24 | 2011-05-05 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | T cell receptors and related materials and methods of use |
Non-Patent Citations (8)
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